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Canadian Stroke Best Practice

Recommendations: Secondary Prevention
of Stroke Update 2020
David J. Gladstone, M. Patrice Lindsay, James Douketis, Eric E. Smith ,
Dar Dowlatshahi, Theodore Wein , Aline Bourgoin, Jafna Cox, John B. Falconer,
Brett R. Graham, Marilyn Labrie, Lena McDonald, Jennifer Mandzia, Daniel Ngui,
Paul Pageau, Amanda Rodgerson, William Semchuk, Tammy Tebbutt,
Carmen Tuchak, Stephen van Gaal , Karina Villaluna, Norine Foley,
Shelagh Coutts, Anita Mountain, Gord Gubitz, Jacob A Udell, Rebecca McGuff,
Manraj K.S. Heran, Pascale Lavoie, Alexandre Y. Poppe ; on behalf of the
Canadian Stroke Best Practice Recommendations Advisory Committee, in
collaboration with the Canadian Stroke Consortium*

Abstract 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.

*Manraj K.S. Heran and Pascale Lavoie have been added as authors; their information has been added to the author affiliations, “Conflicts of Interest,” and “Statement of Authorship”
sections. Additionally, the supplementary material has been updated with new files. A corrigendum detailing these changes has also been published (doi: 10.1017/cjn.2022.57).
From the Division of Neurology, Department of Medicine, and Regional Stroke Centre, Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre and Sunnybrook Research
Institute, Toronto, Canada (DJG); Heart and Stroke Foundation of Canada, Toronto, Canada (MPL, RMG); Department of Medicine, McMaster University, Hamilton, Canada (JD);
University of Calgary, Cumming School of Medicine, Department of Clinical Neurosciences, Calgary, Canada (EES, SC); University of Ottawa, Department of Neurology, Ottawa,
Canada (DD); Stroke Prevention Clinic, McGill University Health Centre, Montreal, Canada (TW); Stroke Prevention Clinic, Champlain Regional Stroke Network, Ottawa, Canada (AB);
Departments of Medicine and of Community Health and Epidemiology, Dalhousie University, Halifax, Canada (JC); Division of Neurology, Faculty of Medicine, University of British
Columbia, Kelowna, Canada (JBF); Faculty of Medicine, Department of Neurology, University of Saskatchewan, Saskatoon, Canada (BRG); Faculty of Medicine (Neurology), Laval
University, Quebec City, Canada (ML); Heart Health Clinic, St. Martha’s Regional Hospital, Antigonish, Canada (LMD); Department of Clinical Neurological Sciences, Western
University, London, Canada (JM); Dept of Family Medicine, University of British Columbia, Vancouver, Canada (DN); The Ottawa Hospital, Department of Emergency Medicine,
Ottawa, Canada (PP); Provincial Rehabilitation Unit, Queen Elizabeth Hospital, Charlottetown, Canada (AR); College of Pharmacy, University of Saskatchewan, Regina, Canada (WS);
District Stroke Centre, Waterloo Wellington, Kitchener, Canada (TT); Division of Physical Medicine and Rehabilitation, University of Alberta, Edmonton, Canada (CT); Division of
Neurology, Faculty of Medicine, University of British Columbia, Vancouver, Canada (SvG); Vancouver Stroke Program, Vancouver, Canada (KV); WorkHORSE Consulting Inc.,
London, Canada (NF); Queen Elizabeth II Health Sciences Centre, Nova Scotia Rehabilitation Centre Site, Halifax, Canada (AM); Queen Elizabeth II Health Sciences Centre, Stroke
Program, Halifax, Canada (GG); Division of Cardiology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Canada (JAU); Department of Surgery, Laval
University; Hôpital de l'Enfant-Jésus, Quebec City, Canada (PL); Division of Neuroradiology, University of British Columbia, Vancouver, Canada (MKSH); and Department of
Neurosciences, Centre hospitalier de l’Université de Montréal (CHUM), Montréal, Canada (AYP)
RECEIVED APRIL 5, 2021. FINAL REVISIONS SUBMITTED MAY 14, 2021. DATE OF ACCEPTANCE MAY 15, 2021.
Correspondence to: Dr. M. Patrice Lindsay, RN, PhD, FWSO, Senior Editor, Canadian Stroke Best Practice Recommendations, Director, Health Systems Change, Heart and Stroke
Foundation, Toronto, Canada. Email: [email protected]

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RÉSUMÉ : La mise à jour 2020 des Recommandations canadiennes pour les pratiques optimales de soins de l’AVC, relatives à la prévention
secondaire. La mise à jour 2020 des Recommandations canadiennes pour les pratiques optimales de soins de l’AVC, relatives à la prévention secondaire
de ce type de trouble comprend des recommandations fondées sur les dernières données probantes ainsi que des avis d’experts courants, émis à l’intention
des cliniciens pratiquant dans divers milieux de soins. Les lignes de conduite présentées dans ces recommandations visent la prévention de futurs accidents
vasculaires cérébraux (AVC) ischémiques, et ce, par la reconnaissance et la prise en charge de facteurs de risque vasculaire modifiables. L’équipe de
travail s’est ainsi penchée sur le triage, les examens de diagnostic, le mode de vie, le vapotage, l’hypertension, l’hyperlipidémie, le diabète, la fibrillation
auriculaire et autres troubles cardiaques, les traitements antiplaquettaire et anticoagulant ainsi que l’atteinte des artères carotides et vertébrales. La mise à
jour des lignes directrices de 2017 contient plusieurs recommandations nouvelles ou révisées. Celles relatives au triage et à l’évaluation initiale des
accidents ischémiques transitoires (AIT) aigus et des petits AVC ont été simplifiées, et certains aspects du bilan étiologique des AVC, révisés. La mise à
jour des recommandations relatives au traitement fondées sur de nouvelles données probantes touche la bithérapie antiplaquettaire pour les AIT et les petits
AVC; l’anticoagulothérapie pour la fibrillation auriculaire; les AVC emboliques de cause indéterminée; l’abaissement du taux de LDL; l’hypertriglycér-
idémie; le traitement du diabète; et la prise en charge de la persistance du foramen ovale. À cela s’ajoute une nouvelle section qui offre des conseils
pratiques sur l’arrêt temporaire du traitement antithrombotique en vue d’une intervention chirurgicale. Il est également question des AVC ischémiques
associés au cancer. Dans une autre section portant sur la prestation virtuelle des services de prévention secondaire de l’AVC, on fait ressortir un
changement de paradigme dans la prestation des soins, changement qui s’est imposé plus que jamais avec la pandémie. Les auteurs ont aussi traité des
différences de traitement en lien avec le sexe lorsque c’était pertinent. Enfin se greffent aux nouvelles recommandations des ressources didactiques, par
exemple de la documentation sur la mise en œuvre visant à faciliter la transposition des données probantes en des mesures de pratique et de performance
afin de rendre possible la surveillance de l’application et de l’efficacité des recommandations.

Keywords: Stroke, Transient ischemic attack, Guidelines, Secondary prevention, Risk assessment, Management
doi:10.1017/cjn.2021.127 Can J Neurol Sci. 2022; 49: 315–337

INTRODUCTION methodology can be found on our Canadian Stroke Best Practices

Optimizing stroke prevention is a major public health priority. website at www.strokebestpractices.ca. A broad interdisciplinary
Stroke remains a leading cause of adult neurological disability group of experts was convened and participated in reviewing,
(both physical and cognitive), dementia, and death globally. The drafting, and revising all recommendation statements, and a panel
seventh update of the Canadian Stroke Best Practice Recom- of people with lived experience participated in a parallel review
mendations (CSBPR) Secondary Prevention of Stroke guidelines process.6 Evidence levels were assigned based on the quality of
includes a summary of current evidence-based recommendations available evidence and expert opinion. These guidelines have
for healthcare professionals. They focus on reducing the risk of undergone extensive internal and objective external review and
recurrent stroke following an index ischemic stroke or transient consensus was achieved for all content. For additional methodol-
ischemic attack (TIA) and are applicable to patients managed ogy and information on these recommendations, including ratio-
across a variety of care settings. They emphasize a coordinated nale, system implications, performance measures, knowledge
and organized approach to assessment and aggressive risk factor translation and implementation tools, and an extended summary
management. The core elements of integrated and effective of the evidence, please visit https://www.strokebestpractices.ca/
secondary stroke prevention services are included in the supple- recommendations/secondary-prevention-of-stroke.
mental material, Appendix Four. Patient management aims to
identify treatable risk factors, apply evidence-based treatment SECONDARY PREVENTION OF STROKE RECOMMENDATIONS
interventions to minimize risk, provide patient education and Section 1: Triage and Initial Diagnostic Evaluation of
shared decision-making, and encourage patient adherence and Transient Ischemic Attack and Non-Disabling Stroke
persistence with treatment recommendations.
These recommendations have been developed in collaboration An acute TIA or minor stroke is a medical emergency. Initial
with the Canadian Stroke Consortium. We collaborate with the management aims to establish an accurate diagnosis, determine
Canadian Cardiovascular Society, Thrombosis Canada, Diabetes the likely etiology, and institute secondary prevention therapy as
Canada, and Hypertension Canada to ensure alignment of recom- quickly as possible. Patients with acute TIA or minor stroke are at
mendations wherever possible. Those guidelines should be con- risk of recurrent stroke both in the short-term (particularly within
sulted for additional detail and information beyond the scope of the first week)7 and long-term.8 Our triage recommendations
the CSBPR. The Canadian Stroke Best Practice Recommenda- have been simplified to focus on patients presenting within the
tions (CSBPR) Secondary Prevention of Stroke 2020 Seventh first 48 h of a suspected new acute TIA or stroke as they are at
Edition module supersedes all recommendations contained in the highest risk of early recurrent stroke. For such patients, immedi-
CSBPR Secondary Prevention of Stroke 2017 Sixth Edition ate assessment is recommended, with imaging of both brain (head
module. 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
GUIDELINE DEVELOPMENT METHODOLOGY An embolic stroke or TIA can be the first manifestation of
The CSBPR development and update process follows a previously unrecognized atrial fibrillation. We recommend a
rigorous framework1,2 and addresses all criteria defined within tiered approach to searching for atrial fibrillation in patients with
the AGREE trust model.3 The methodology for development and a new acute embolic ischemic stroke or TIA.10 The goal of
updates to the CSBPR has previously published4,5 and detailed post-stroke electrocardiogram (ECG) monitoring is to detect

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high-burden atrial fibrillation for which anticoagulation would ii. Urgent brain imaging (CT or MRI) with concurrent
likely be beneficial. However, ECG monitoring often reveals neurovascular imaging (e.g., CT angiography [CTA])
brief subclinical paroxysmal atrial fibrillation, and it remains should be completed as soon as possible and before dis-
unclear what amount of device-detected atrial fibrillation war- charge from the emergency department [Evidence Level B].
rants anticoagulation. Trials underway are evaluating this ques- iii. Patients presenting after 48 h from the onset of an acute
tion. The effect of post-stroke prolonged ECG monitoring on stroke or TIA event should receive a comprehensive
hard clinical outcomes (i.e., recurrent stroke) remains to be clinical evaluation and investigations as soon as possible
determined and is the subject of ongoing research (FIND-AF2 by a healthcare professional with stroke expertise
trial, NCT04371055). [Evidence Level B].
Echocardiography can be a valuable tool in the etiological
assessment and risk stratification of patients with stroke and TIA. Section 1.1 Clinical Considerations:
However, it can be overutilized and we recommend responsible
use of this resource. Thus, the recommendations emphasize that 1. Referral to a healthcare professional with expertise in
echocardiography is not required for all stroke patients but should stroke care should be considered for patients with a
be considered for those with an embolic ischemic stroke or suspected uncommon cause of stroke, including for
TIA of undetermined source (ESUS) or when a cardioembolic young stroke patients (e.g., <45 years);15 family history
etiology or paradoxical embolism is suspected. of young-onset stroke; suspected cerebral vasculitis or
We have recommended against extensive thrombophilia testing other intracranial vasculopathy; or suspected hereditary
for hereditary hypercoagulable disorders in the routine investiga- or acquired thrombophilia.
tion of adults with arterial ischemic stroke events. Such testing is 2. Patients presenting with symptoms of vertebrobasilar
often overused in practice and should be limited to selected patients ischemia may present with fluctuating brainstem/cerebel-
such as those with unexplained cerebral venous thrombosis or lar type symptoms (e.g., diplopia, dysarthria, dysphagia,
patent foramen ovale-related (PFO) paradoxical embolism. non-positional vertigo, ataxia; rarely as isolated symp-
An important lesson of the COVID-19 pandemic has been toms) over a longer time course (i.e., more than 48 h) and
how essential remote or virtual contact with patients and families can be mistaken for stroke mimics; however, they also
is to providing safe and timely care for stroke patients. In require urgent assessment, neurovascular imaging and
particular, care for patients living in rural or remote communities management as these types of strokes can have a high
or patients for whom mobility and transport to clinic or hospital morbidity. Consultation with a healthcare professional
are prohibitive, can be improved via virtual care. Home blood with expertise in stroke care is strongly encouraged.
pressure monitoring is encouraged in accordance with Hyperten- 3. Setting: In some regions, urgent/rapid TIA clinics are
sion Canada guidelines.11 Home delivery of ECG patch monitors available that have rapid access to diagnostic services,
that can be self-applied by patients is a welcome option in regions and they may be considered as appropriate referral
where it is available. Virtual care interventions can be effective options for TIA and minor stroke patients where avail-
for blood pressure lowering, improvements in diet, increased able and accessible.
physical activity, drug adherence, and satisfaction with access to
care,12 reduced HgbA1c, smoking cessation,13 and reduced risk 1.2 Brain and Vascular Imaging
of cardiovascular events.14
i. Brain imaging (CT or MRI) and non-invasive vascular
imaging (CTA or MR Angiogram [MRA] from aortic
arch to vertex) should be completed as soon as possible
Section 1 Recommendations 2020 following acute stroke or TIA [Evidence Level B].
1.0 Patients with acute stroke or transient ischemic attack a. CTA of head and neck (from aortic arch to vertex),
(TIA) who present to an ambulatory setting (such as primary which can be performed at the time of initial brain CT,
care) or a hospital should undergo clinical evaluation by a is recommended as an ideal way to assess both the
healthcare professional with expertise in stroke care to deter- extracranial and intracranial circulation [Evidence
mine risk for recurrent stroke and initiate appropriate and Level B]. Note: Some facilities may not have CTA
timely investigations and management strategies. readily available; the timing and type of vascular
imaging will need to be based on available resources
1.1 HIGH Risk for Recurrent Stroke (Symptom onset and local practice protocols.
within last 48 h) b. Neurovascular imaging is recommended to identify
patients with significant symptomatic extracranial
i. Individuals presenting within 48 h of symptoms consistent carotid artery stenosis (i.e., 50%–99% stenosis),
with a new acute stroke or TIA event (especially transient which should trigger an urgent referral for potential
focal motor or speech symptoms, or persistent stroke carotid revascularization [Evidence Level A].
symptoms) are at the highest risk for recurrent stroke c. CTA is the first-line vascular imaging test for stroke/
and should be immediately sent to an emergency department TIA patients. MRA and carotid ultrasound (for extra-
(refer to Clinical Consideration 1.1.3) with capacity for cranial vascular imaging) are reasonable alternatives
stroke care (including onsite brain imaging, and ideally to CTA as first-line tests for assessment of carotid
access to acute stroke treatments) [Evidence Level B]. vessels if CTA is not possible, and selection should be

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based on availability and patient characteristics [Evi- hematology or thrombosis expertise [Evidence
dence Level C]. Level C].

Section 1.2 Clinical Considerations: 1.4 Cardiac Studies

1.4A Detection of Atrial Fibrillation
1. Brain MRI is superior to a head CT scan in terms of
diagnostic sensitivity for identifying small ischemic i. Patients with suspected ischemic stroke or TIA should
lesions in patients presenting clinically with a TIA or have a 12-lead ECG to assess for atrial fibrillation,
minor stroke event and can provide additional informa- concurrent myocardial infarction, or structural heart dis-
tion for guiding diagnosis, prognosis, and treatment ease (e.g., left ventricular hypertrophy) as potential causes
decision-making. Decisions regarding MRI scanning or risk factors of stroke [Evidence Level B].
should be based on MRI access, availability, and timing ii. For patients being investigated for an acute embolic
of appointments. For maximal diagnostic yield, MRI ischemic stroke or TIA, ECG monitoring for 24 h or
should be completed as soon as possible after the symp- more is recommended as part of the initial stroke work-up
tomatic event, ideally within 7 d of symptom onset. MRI to detect paroxysmal atrial fibrillation in patients who
is particularly useful in lower risk patients with transient would be potential candidates for anticoagulant therapy
symptoms in whom the presence of ischemia would [Evidence Level A].
change their management. iii. For patients being investigated for an embolic ischemic
2. Common scenarios where urgent brain MRI can be stroke or TIA of undetermined source whose initial short-
valuable include: term ECG monitoring does not reveal atrial fibrillation
a. Normal CT head despite symptoms persisting >24 h but a cardioembolic mechanism is suspected, continuous
(if diffusion-weighted imaging [DWI]-MRI is negative, ECG monitoring for at least 2 weeks is recommended to
cerebral ischemia is unlikely). improve detection of paroxysmal atrial fibrillation in se-
b. Suspected brainstem or cerebellar ischemia (CT head lected patients aged ≥55 years who are not already receiv-
is insensitive for detecting strokes in the posterior ing anticoagulant therapy but who would be potential
fossa due to bone artifact). candidates for anticoagulant therapy [Evidence Level A].
c. Focal transient symptoms that are clinically atypical iv. (New for 2020): For patients aged >65 years with
for ischemia. ischemic stroke or TIA, pulse palpation or heart auscul-
tation or ECG rhythm strip is recommended to screen for
1.3 Blood Work undiagnosed atrial fibrillation [Evidence Level B].

i. The following laboratory investigations should be rou- 1.4B Echocardiography

tinely considered for patients with a TIA or minor ische-
mic stroke as part of the initial evaluation: i. Echocardiography should be considered for patients with
a. Initial bloodwork: hematology (complete blood an embolic ischemic stroke or TIA of undetermined
count), electrolytes, coagulation (aPTT, INR), renal source or when a cardioembolic etiology or paradoxical
function (creatinine, estimated glomerular filtration embolism is suspected [Evidence Level C]. Routine
rate), random glucose, ALT [Evidence Level C]. echocardiography is not required for all stroke patients.
Refer to Appendix Two for full list of recommended [Evidence Level C].
lab tests. ii. (New for 2020): For patients aged 60 years or younger
b. Additional laboratory tests may be completed during who are being investigated for an embolic ischemic
patient encounter or as an outpatient, including a lipid stroke or TIA of undetermined source, echocardiography
profile (fasting or non-fasting); and screening for with saline bubble study is recommended for detection of
diabetes with either a glycated hemoglobin (HbA1c), a possible PFO if it may change patient management (i.e.,
fasting glucose or 75 g oral glucose tolerance test in patients who would be potential candidates for PFO
[Evidence Level C]. closure or anticoagulant therapy if a PFO were detected)
c. (New for 2020): If giant cell arteritis is suspected [Evidence Level B].
(e.g., retinal ischemia or headache), erythrocyte sedi- a. Contrast-enhanced (agitated saline) transesophageal
mentation rate (ESR) and C-reactive protein (CRP) echocardiography or transcranial Doppler has greater
should be measured [Evidence Level C]. sensitivity than transthoracic echocardiography for
ii. (New for 2020): Extensive thrombophilia testing for detection of right-to-left cardiac and extra-cardiac
hereditary hypercoagulable disorders is not recom- shunts [Evidence Level B].
mended for routine investigation of a patient with arterial
ischemic stroke and should be limited to selected situa- 1.5 Functional Assessment:
tions (e.g., but not limited to, unexplained cerebral
venous thrombosis; PFO-related paradoxical embolism) i. Patients with stroke should be assessed for neurological
[Evidence Level C]. impairments and functional limitations (e.g., cognitive
a. If a hypercoagulable state is suspected, consider evaluation, screening for depression, screening for dys-
consultation with a healthcare professional with phagia, screening of fitness to drive, need for potential

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rehabilitation therapy, and assistance with activities of education or reliable resources on proper use. Mechan-
daily living) [Evidence Level B]. isms should be in place for follow-up and management of
ii. Patients found to have neurological impairments and BP for patients using home BP devices, by either primary
functional limitations should be considered for referral care providers or Stroke Prevention Services (SPS).
to the appropriate rehabilitation specialist for in-depth 10. For timely investigations, consider use of prolonged
assessment and management [Evidence Level B]. cardiac monitors, if available, that can be sent to patient’s
homes and self-applied, then returned by mail.
1.6 Virtual Care for Secondary Stroke Prevention (New 11. Data collection and quality improvement mechanisms
2020) should be in place to monitor efficiency, effectiveness,
and quality of virtual care encounters.
i. Secondary stroke prevention services should establish
processes and technology to increase and ensure access
to services through virtual care delivery mechanisms for
patients who do not require in-person visits, and espe- Section 2: Lifestyle Behaviors and Risk Factor Management
cially patients living in rural and remote settings without A healthy lifestyle, which includes a Mediterranean or Dietary
local access to healthcare professionals with stroke ex- Approaches to Stop Hypertension (DASH) diet, exercise, weight
pertise [Evidence Level C]. control, reduction, and avoidance of alcohol and tobacco, reduces
a. Clinicians should follow established/validated criteria the risk of an initial stroke and the risk of a subsequent stroke for
to determine the best modality for each patient at each patients with a prior history of stroke. Although individually,
encounter based on the purpose and goals for each these habits can reduce the risk of stroke, their impact is greater
visit [Evidence Level C]. when combined. Even greater impacts can be achieved with
b. Shared decision-making should also take into account population level interventions for physical activity include invest-
patient values, preferences, health goals, medical ments in health promoting infrastructure (e.g., sidewalks, walking
complexity, social determinants of health, and health paths, bike lanes). At the core of these of interventions is a focus
needs [Evidence Level C]. on making the healthy choice the easy choice.

Section 1.6 Clinical Considerations:

1. Consulting sites and individual clinicians should have

triage protocols and local intake criteria in place to ensure Section 2 Recommendations 2020
patients referred for their services are seen in a timely 2.1 Risk Factor Assessment:
manner, especially high-risk patients as described in
section 1.1 of this module. i. Persons at risk of stroke and patients who have had a
2. The use of virtual care for stroke prevention should stroke or TIA should be assessed for vascular disease risk
include decision tools to identify patients who require factors, lifestyle management issues (diet, sodium intake,
in-person visits and those who can reasonably be managed exercise, weight, alcohol intake, smoking), as well as use
through virtual care, and a scheduling mechanism for of oral contraceptives or hormone replacement therapy
virtual visits that support a collaborative team approach [Evidence Level B].
to care where appropriate and feasible. ii. Persons at risk of stroke or TIA and their family members
3. A contingency plan should be established to have should receive individualized information and counsel-
patients seen in person in a timely way should the need ling about possible strategies to modify their lifestyle and
arise following a virtual care encounter. vascular risk factors [Evidence Level B].
4. Virtual care-enabled evaluations of patients for second- iii. Referrals to appropriate specialists should be made to
ary stroke prevention should be modeled on the topics support and manage specific vascular risk factors and
defined in the post-stroke checklist and core elements of lifestyle behaviors and choices where required [Evi-
stroke prevention care. dence Level B].
5. Validated approaches to virtual neurological exams
should be followed. 2.2 Healthy Balanced Diet
6. Barriers to access, equity, and utilization should be
considered and work-around solutions implemented. i. Counsel and educate individuals with TIA or stroke to
7. Ensure processes in place for booking follow-up tests, follow a healthy eating pattern and balanced diet [Evi-
referrals, and other consultations following a virtual care dence Level B] or refer to a registered dietitian where
visit. available [Evidence Level C].
8. Ensure appropriate documentation and communication ii. Counsel and educate individuals with TIA or stroke to
to other team members who may also be involved in care follow a Mediterranean-type or Dietary Approach to Stop
remotely. Hypertension (DASH) diet, which is high in vegetables,
9. Encourage patients and their families to acquire home fruit, whole grains, fish, nuts and olive oil and low in red
blood pressure monitors where appropriate and provide meat [Evidence Level B].

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iii. Counselling may include: work toward increased activity goals as tolerated [Evi-
a. consuming a variety of natural, whole, and minimally dence Level B].
processed foods at each meal [Evidence Level B]. ii. Most individuals post-stroke who are medically stable
b. consuming fewer highly processed foods, which in- should start a regular exercise program [Evidence
clude refined foods, confectionaries, sugary drinks, Level B].
processed meats and meat alternatives, and pre-pre- iii. Counsel and educate individuals with TIA or stroke to
pared foods [Evidence Level B]. participate in aerobic exercise 4 to 7 d per week, to
c. consuming a diet high in vegetables and fruit; encourage accumulate at least 150 min per week in episodes of
patients to choose fresh or frozen unsweetened fruit, or 10 min or more, in addition to routine activities of daily
fruit canned in water without added sugars and low in living [Evidence Level B].
sodium; fresh or frozen vegetables without added iv. Initiation of aerobic training should be considered after a
sauces, or canned vegetables with no added salt [Evi- stroke or TIA once the patient is medically stable. To
dence Level B]. ensure continuity of appropriate interventions, patients
d. consuming lower fat and lower sugar dairy products should be reassessed at transition points along the con-
and unsweetened fortified soy beverages [Evidence tinuum of care based on changing neuromotor and car-
Level B]. diopulmonary capacities to participate in aerobic training
e. shift to consuming more protein from plant-based [Evidence Level B].
sources (legumes, nuts, and seeds) and other protein
options which are lower in saturated fats such as fish, Section 2.4 Clinical considerations
poultry, and lean meats [Evidence Level B].
f. consuming high fiber choices such as whole grains, 1. Aerobic exercise intensity should be individualized.
beans, and legumes instead of processed or refined grains Factors to consider include functional limitation, co-
such as white bread and pasta [Evidence Level B]. existing medical problems such as cardiac disease, need
g. consuming water as the drink of choice for hydration. for an exercise stress test with electrocardiogram, and
Sugary drinks (such as energy drinks, fruit drinks, planned exercise intensity (i.e., light, moderate, or
juice, soft drinks, and flavored coffees) add calories vigorous).
and have little to no nutritional value and should be 2. Screening and supervision of adults with comorbid
discouraged [Evidence Level A]. disease such as cardiac disease which places them at
h. consuming foods low in sodium [Evidence Level B]. higher risk of medical complications should be
considered.
Section 2.2 Clinical Consideration 3. Supervision by a healthcare professional (such as a
physiotherapist) at exercise initiation should be consid-
1. Counsel and educate individuals regarding healthy eating ered in individuals with stroke at risk of falls or injury.
patterns that focus on whole, natural, minimally pro-
cessed foods, instead of specific nutrients such as dietary 2.5 Weight Management
cholesterol.
i. Counsel and educate individuals with TIA or stroke to
2.3 Sodium Intake achieve and maintain a waist circumference of <88 cm
for women and <102 cm for men*, or a body mass
i. To prevent hypertension and to reduce blood pressure in index (BMI) of 18.5–24.9 kg/m2 [Evidence Level B].
patients with hypertension, counsel and educate indivi- (*Note: these numbers are reflective of current research
duals with TIA or stroke to reduce sodium intake to a goal based mostly on Caucasian patients. Refer to Reference
of no more than 2000 mg (5 g table salt or 87 mmol list for waist circumference values for other ethnic
sodium, equal to less than one teaspoon) per day [Evi- groups.)
dence Level A]. ii. Counsel and educate individuals with TIA or stroke who
are overweight to set healthy weight loss goals and
Section 2.3 Clinical Consideration develop individualized plans to achieve goals [Evidence
Level B].
i. Achieving a sodium intake of <2000 mg may be very iii. A multi-pronged approach should be used to support
difficult for the general population and average daily sustainable weight loss or weight gain that includes
intake among people in Canada is 2760 mg. Encourage counselling and education, increased physical activity,
a gradual decrease in foods that are high in sodium and behavioral interventions [Evidence Level B].
which will allow taste buds and behavior to adapt
appropriately. Section 2.5 Clinical Consideration

2.4 Physical Activity 1. When discussing weight, consider completion of a com-

prehensive history that explores root causes of weight
i. Counsel and educate individuals with TIA or stroke to gain and avoids stigma and judgment.
reduce sedentary behaviors and sedentary time, and to

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2.6 Alcohol Consumption v. A combination of pharmacotherapy and behavioral ther-

apy should be considered in all smoking cessation pro-
i. Counsel and educate individuals with TIA or stroke to grams and interventions [Evidence Level A].
avoid heavy alcohol use as excessive alcohol intake vi. The three classes of pharmacological agents that should
increases the risk of hypertension, ischemic stroke and be considered as first-line therapy for smoking cessation
intracerebral hemorrhage. [Evidence Level B]. are nicotine replacement therapy, varenicline, and bupro-
ii. Counsel and educate individuals with TIA or stroke to pion [Evidence Level A].
follow Canada’s Low-Risk Alcohol Drinking Guidelines a. The choice of appropriate pharmacotherapy should
(2018): for women, no more than 10 drinks per week, take into account the patient’s medical stability, clini-
with no more than 2 drinks per day most days, and no cal needs, other medical factors, patient preferences,
more than 3 drinks on any single occasion; for men, no and patient’s ability to afford the therapy in those
more than 15 drinks per week, with no more than 3 drinks cases in which it is not covered under a provincial
per day most days, and no more than 4 drinks on any drug formulary [Evidence Level C].
single occasion [Evidence Level B]. b. The initiation of pharmacotherapy for smoking cessa-
Note: one standard drink is considered to be approxi- tion should begin as soon as possible and supported
mately 44 mL (1.5 oz) of 80 proof (40%) spirits, 355 mL while in hospital for index stroke-related event
(12 oz) of 5% beer or 148 mL (5 oz) of 12% wine. [Evidence Level C]. Earlier initiation of smoking cessa-
tion discussions may be beneficial [Evidence Level C].
vii. For stroke patients in hospital who are current smokers,
2.7 Recreational Drug Use protocols should be in place to manage nicotine with-
drawal during hospitalization [Evidence Level B].
i. Individuals with stroke and known recreational drug use viii. Interdisciplinary team members should counsel
that may increase the risk of stroke (such as cocaine, patients, family members, and caregivers about the
amphetamines) should be counseled to discontinue use harmful effects of exposure to environmental (second
[Evidence Level C]; and should be provided with appro- hand) smoke [Evidence Level B].
priate support and referrals to services and resources for ix. A referral to virtual smoking cessation services, smoking
drug addiction and rehabilitation [Evidence Level B]. cessation programs, supportive resources, and clinics
ii. For cannabis, that may be prescribed for medical indica- should be considered depending on regional availability
tions, counsel patients regarding any potential increased to optimize the success of smoking cessation [Evidence
risk of stroke to support informed decision-making re- Level B]
garding the use of these agents [Evidence Level B]. x. People who are not ready to quit should be offered a
motivational intervention to help enhance their readiness
Section 2.7 Clinical Consideration to quit [Evidence Level B].

1. At present, there has been some association of smoking Section 2.8 Clinical Considerations
cannabis products with possible increased stroke and Use of E-Cigarettes
cardiovascular events. However, there is a lack of
high-quality evidence to provide clear guidance. Individ- 1. Although some individuals may find vape products
ual patient factors should be considered. helpful in smoking cessation, the evidence base around
their population-based effectiveness is not clear.
2.8 Smoking Cessation 2. There is some evidence that shows people who use
Note, the term “Smoking” in these recommendations vaping as a mechanism to quit cigarettes may continue
refers to tobacco and other inhaled substances. to vape even after cessation of cigarette use, in contrast to
use of nicotine replacement therapy which has not been
i. In all healthcare settings along the stroke continuum found to be continued in an ongoing basis.16
(inpatient, ambulatory, and community), patient smoking 3. Emerging evidence indicates an association between
status should be identified, assessed, and documented vaping and elevated blood pressure; the strength of the
[Evidence Level A]. association is not clear at this time.
ii. Provide unambiguous, non-judgmental, and patient-spe- 4. The most common pattern of use in Canada is dual
cific advice regarding the importance of cessation to all use of both vape and combustible tobacco products
smokers [Evidence Level B] and others who reside with and therefore smoking cessation strategies should
the patient. include consideration for both methods of nicotine
iii. Offer assistance with the initiation of a smoking cessa- consumption.
tion attempt – either directly or through referral to 5. Education and counselling should be provided regarding
appropriate resources [Evidence Level A]. the risks versus benefits of e-cigarettes in people with
iv. A stepwise approach that starts with reduction in smok- stroke, including in younger age groups who have expe-
ing and progresses to full cessation is a valid approach rienced stroke.
[Evidence Level B].

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2.9 Pregnancy, Oral Contraceptives, and Hormone 2.11 Emerging Risk Factors
Replacement Therapy Influenza infection, vaccination, and stroke risk
i. Influenza vaccination is recommended as it has been
i. Discussions of pregnancy and implications for stroke
shown to be associated with a decreased risk of stroke
recurrence should be included as a routine part of post-
or cardiovascular events, particularly in patients with pre-
stroke management for all female stroke survivors of
existing cardiovascular risk factors [Evidence Level B].
reproductive age [Evidence Level C].
ii. Contraception should be addressed based upon the
Air pollution and stroke risk
patients’ fertility and pregnancy plans as well as the
stroke mechanism and type [Evidence Level C]. i. Counsel individuals regarding long-term exposure to air
iii. In cases of ischemic stroke, systemic estrogen-contain- pollutants, particularly avoiding or minimizing exposure
ing contraceptives or hormone replacement therapy to particulate matter ≤2.5 μm in diameter, which may be
that can increase the risk of thrombosis should be associated with an increased risk of stroke and cardiovas-
carefully considered and, in most cases, should be cular disease [Evidence Level B].
avoided due to an increased risk of stroke [Evidence
Level B].
iv. Management alternatives, including progesterone-only
oral contraceptives, progesterone-only or non-hormonal Section 3: Blood Pressure and Stroke Prevention
intrauterine devices, or barrier contraception can be
Hypertension is the major modifiable risk factor for stroke. In
considered in consultation with a provider experienced
Canada, systolic hypertension is estimated to account for about
with contraceptive methods [Evidence Level C].
45% of the total stroke burden.18 Although the optimal target
v. Estrogen-containing oral contraceptives or hormone
blood pressure to prevent a first or recurrent stroke has not been
replacement therapy should be discouraged or
formally established, the current treatment recommendation to
discontinued in female patients with TIA or ischemic
attain a blood pressure of consistently lower than 140/90 mm Hg
stroke [Evidence Level B]. Management alterna-
for people who have had an ischemic stroke or TIA, can help to
tives should be considered in these patients [Evidence
reduce recurrent events. Using the results from a subset of 13
Level C].
randomized controlled trials (RCTs) that included persons with a
vi. (New for 2020) Contraceptive management alternatives
previous history of stroke, Law et al.19 reported that blood
to estrogen containing hormonal contraceptives should
pressure treatment resulting in a reduction of 10 mm Hg systolic
be considered for women with a history of migraine with
and 5 mm Hg diastolic was associated with a 34% reduced risk of
aura [Evidence Level C], especially if they are also
recurrent stroke (RR = 0.66, 95% CI 0.56–0.79). In the RE-
current tobacco smokers [Evidence Level B].17
SPECT trial,20 persons with a history of stroke within the
vii. Hypertensive Disorders of Pregnancy: Discussion
previous 30 d to three years who were randomized to a standard
on the use and dose of acetylsalicylic acid (ASA) to
treatment group with a target of <140/90 mm Hg or an intensive
reduce the risk of a hypertensive disorder of pregnan-
treatment group with a target of <120/80 mm Hg, did not have a
cy (HDP) should be individualized based upon a
significantly reduced risk of recurrent stroke (HR = 0.73, 95% CI
woman’s risk of HDP (i.e., women with a prior
0.49–1.11, p = 0.15); however, when these results were incorpo-
ischemic stroke, prior HDP or other risk factors) and
rated into an updated meta-analysis, the risk was reduced signifi-
in consultation with obstetrical care providers [Evi-
cantly with intensive therapy. The number needed to treat to
dence Level C]. Refer to CSBPR Stroke during Preg-
prevent one recurrent stroke was 67, with an absolute risk
nancy recommendations for additional information.
reduction of 1.5%.
viii. Invitro Fertilization: For women who have had a
cerebral event and are considering invitro fertiliza-
tion, provide counselling and education about risks
of fertility therapy including the potential risk of
hyperstimulation, and monitor for complications Section 3 Recommendations 2020
assuming all other stroke in the young management 3.0 Blood pressure should be assessed and managed in all
plans followed and optimized [Evidence Level C]. persons with stroke or TIA [Evidence Level A].

2.10 Adherence to individual prevention plans 3.1 Blood pressure assessment

i. At each healthcare encounter, discuss and document i. All persons at risk of recurrent stroke should have their
patient adherence to their prescribed secondary preven- blood pressure measured routinely [Evidence Level A],
tion treatment plans (pharmacotherapy and lifestyle no less than once annually and more frequently based on
changes), explore and address non-adherence, and pro- individual clinical circumstances [Evidence Level C].
vide counselling and engage in joint goal setting to ii. Proper standardized techniques should be followed for
encourage adherence and persistence with treatment initial and subsequent blood pressure measurement includ-
[Evidence Level C]. ing office, home, and community testing [Evidence Level
B] as outlined by the Hypertension Canada Guidelines.

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iii. Patients found to have an automated office measured viii. The use of an ACE inhibitor combined with an angio-
resting elevated blood pressure (systolic greater than tensin II receptor blockers (ARB) is not recommended
135 mm Hg and/or diastolic greater than 85 mm Hg) [Evidence Level B].*
should undergo thorough assessment for the diagnosis of ix. Patients who are not started on antihypertensive therapy in
hypertension [Evidence Level C]. acute care should have arrangements made for follow-up
a. During an office visit for assessment of hypertension with primary care or stroke prevention service for ongoing
consider taking the average of three blood pressure evaluation and management [Evidence Level C]. Note:
measurements conducted in accordance with the Blood pressure management is the responsibility of all
current Hypertension Canada Guidelines [Evidence healthcare team members, and initially stroke patients
Level C]. Refer to Hypertension Canada Algorithm may require frequent monitoring (e.g., monthly) until they
for Diagnosis of Hypertension, including Home Blood achieve target blood pressure levels and optimal therapy
Pressure Monitoring Targets. has been established.
iv. Patients with refractory hypertension should have com- Notes: *For recommendations on specific agents and
prehensive investigations for secondary causes of hyper- sequence of agents in blood pressure management for
tension [Evidence Level B]. the secondary prevention of ischemic stroke, refer to
v. Patients with hypertension or at risk for hypertension the current Hypertension Canada treatment guide-
(in pre-hypertension state or other risk factors) should lines11
receive aggressive risk factor modification, lifestyle
counselling, and lifestyle modification interventions Section 3 Clinical Considerations
[Evidence Level B].
1. (New for 2020) For patients with a non-revascularized
3.2 Blood pressure management
critical intracranial or extracranial arterial stenosis
who are experiencing neurological symptoms attribut-
i. Strong consideration should be given to the initiation of ed to hemodynamic (low flow) cerebral or retinal
antihypertensive therapy after the acute phase of a stroke ischemia (e.g., orthostatic TIAs), it is reasonable to
or TIA [Evidence Level A]. aim for higher than usual blood pressure targets (i.e.,
ii. For patients who have had an ischemic stroke or TIA, permissive hypertension), and avoidance of hypoten-
blood pressure lowering treatment is recommended to sion, for prevention of hemodynamic stroke; if such
achieve a target of consistently lower than 140/90 mm Hg patients are asymptomatic, then usual blood pressure
[Evidence Level B]; this includes individuals with chron- targets should be followed in the post-acute phase of
ic kidney disease. stroke.
iii. For patients who have had a small subcortical stroke
(i.e., lacunar stroke), aggressive blood pressure lower-
ing treatment is reasonable to achieve a systolic target of
consistently lower than 130 mm Hg [Evidence Level B]. Section 4: Lipid Management
iv. In patients with intracerebral hemorrhage, blood
pressure should be aggressively monitored, treated, and New evidence supports more aggressive lipid management for
controlled [Evidence Level A] to sustain a target blood secondary stroke prevention. The recommended target low-den-
pressure consistently lower than 130/80 mm Hg [Evi- sity lipoprotein (LDL) cholesterol level has been lowered to
dence Level B]. Refer to Canadian Stroke Best Practice <1.8 mmol/L, from previously recommended targets of LDL <
Recommendations: Management of Intracerebral Hem- 2.0 mmol/L or 50% LDL reduction. If this target cannot be
orrhage module. achieved with maximum tolerated statin therapy, ezetimibe or a
v. In patients with stroke and diabetes, blood pressure PCSK9 inhibitor may be added for ischemic stroke patients with
lowering treatment is recommended for the prevention of atherosclerotic disease. Clinicians are reminded that lipid lower-
first or recurrent stroke to attain a target systolic blood ing therapies are not recommended for secondary prevention of
pressure consistently lower than 130 mm Hg [Evi- intracerebral hemorrhage, or for patients with cardioembolic
dence Level C] and a target diastolic blood pressure ischemic stroke (e.g., atrial fibrillation) in the absence of athero-
consistently lower than 80 mm Hg [Evidence Level A]. sclerotic disease.
vi. Randomized controlled trials have not defined the opti- The Treat Stroke to Target trial studied 2860 patients with
mal time to initiate blood pressure lowering therapy after atherosclerotic disease who had an ischemic stroke within the
an acute stroke or TIA. Blood pressure lowering treat- previous 3 months or a TIA within the previous 15 d. Treatment to
ment should be initiated or modified before discharge an LDL cholesterol target <1.8 mmol/L, as compared to a target
from hospital [Evidence Level B]. of 2.3–2.8 mmol/L, was associated with a lower risk of major
vii. Treatment with an angiotensin-converting enzyme cardiovascular events over a median of 3.5 years (8.5% vs.
(ACE) inhibitor and thiazide/thiazide-like diuretic com- 10.9%, HR = 0.78, 95% CI 0.61–0.98; p = 0.04).21 About a
bination is recommended [Evidence Level A]. Long- third of patients in this study required the addition of ezetimibe
acting diuretics may be considered over short-acting to their high-dose statin to achieve the more aggressive LDL
[Evidence Level B].* target.

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 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES

Treatment of hypertriglyceridemia with icosapent ethyl 2 g 4.3 Statin Intolerance (New 2020)
bid may be considered for patients with ischemic stroke who have
established atherosclerotic cardiovascular disease, or diabetes i. For patients with an intolerance to statins (including
plus additional vascular risk factors, and elevated serum trigly- persistent myalgias, persistent significant liver enzyme
cerides (≥1.5 mmol/L) despite statin therapy. abnormalities or rarely, myopathy or rhabdomyolysis),
the indication for statin therapy should be confirmed and
in general, systematic evaluation of the contribution of
statins to the patient’s symptoms should be considered
Section 4 Recommendations 2020 (including temporary statin cessation with observation of
4.0 Individuals who have had an ischemic stroke or TIA symptoms, dose-adjustment, use of alternate agents)
should have their serum lipid levels assessed and optimally [Evidence Level C]
managed [Evidence level A].

4.1 Lipid Assessment

Section 5: Diabetes Management in Stroke
i. Lipid levels, including total cholesterol, triglycerides, In Canada, almost 2.5 million people have type 1 or 2
low-density lipoprotein [LDL] cholesterol, and high-den- diabetes.23 Diabetes is known to increase the risk of ischemic
sity lipoprotein [HDL] cholesterol, should be measured in stroke by 227%.24Although tighter glycemic control along with
patients presenting with ischemic stroke or TIA [Evi- other risk factor reduction strategies, can collectively help to
dence Level B]. Refer to Appendix Two for more infor- reduce stroke risk, on its own, aggressive glycemic control does
mation on laboratory tests. not reduce stroke risk.25,26 However, trials of newer antihyper-
glycemic agents, including SGLT-2 and GLP-1 receptor agonists,
4.2 Lipid Management have demonstrated benefit for major cardiovascular outcomes,
including stroke.27–31
i. Individuals with ischemic stroke or TIA should be man-
aged with aggressive lifestyle changes to lower lipid
levels, including dietary modification and exercise, as
part of a comprehensive approach to lower risk of recur- Section 5 Recommendations 2020
rent stroke and other vascular events unless contraindi- 5.0 Patients with diabetes who have had an ischemic stroke or
cated [Evidence Level B]. TIA should have their diabetes assessed and optimally man-
ii. Statin pharmacotherapy should be prescribed for second- aged [Evidence Level A].
ary prevention of stroke in individuals who have had a
non-cardioembolic ischemic stroke or TIA, [Evidence 5.1 Diabetes Screening and Assessment
Level A].
a. A target LDL cholesterol level of <1.8 mmol/L is i. Patients with ischemic stroke or TIA should be screened
recommended [Evidence Level B]. for diabetes with either a fasting plasma glucose, or 2-h
iii. Statin therapy should not be initiated for secondary pre- plasma glucose, or glycated hemoglobin (A1C), or 75 g
vention of intracerebral hemorrhage [Evidence Level C].22 oral glucose tolerance test in either an inpatient or outpa-
iv. Add-on therapies for LDL-Lowering (New 2020): tient setting [Evidence Level C].
a. For individuals with ischemic stroke and atheroscle- ii. For patients with diabetes and either ischemic stroke or
rotic cardiovascular disease with an LDL > 1.8 mmol/ TIA, glycated hemoglobin (A1C) should be considered as
L in spite of maximal tolerated statin therapy, ezeti- part of a comprehensive stroke assessment [Evidence
mibe may be considered for additional LDL lowering Level B].
[Evidence Level B].
b. For individuals with concomitant atherosclerotic 5.2 Diabetes Management
cardiovascular disease in which target LDL level is
not achievable, consider referral to a health profes- i. Glycemic targets should be individualized to achieve:
sional with expertise in metabolic and lipid manage- a. In general, A1C values should be targeted to ≤7.0% in
ment, or stroke expertise for consideration of adding patients with either type 1 or type 2 diabetes (and
PCSK9 inhibitor [Evidence Level A]. stroke or TIA), as this target provides strong benefits
v. Add-on therapies for hypertriglyceridemia (New for the prevention of microvascular complications
2020) For ischemic stroke patients with established [Evidence Level A].
atherosclerotic cardiovascular disease or diabetes plus b. To achieve a target of A1C ≤7.0%, most patients with
additional vascular risk factors, who have elevated serum type 1 or type 2 diabetes should aim for a fasting
triglyceride levels (≥1.5 mmol/L) despite statin therapy, plasma glucose or pre-prandial plasma glucose target
icosapent ethyl 2 g bid may be considered to decrease the of 4.0–7.0 mmol/L [Evidence Level B].
risk of vascular events [Evidence Level B]. c. The 2-h postprandial plasma glucose target is 5.0–
10.0 mmol/L [Evidence Level B].

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d. If A1C targets cannot be achieved with a postprandial The defining features of ESUS are an acute brain infarct
target of 5.0–10.0 mmol/L, further postprandial blood visualized on neuroimaging (not a subcortical lacune <1.5 cm);
glucose lowering, to 5.0–8.0 mmol/L, should be con- absence of proximal atherosclerotic vessel stenosis >50%; no
sidered [Evidence Level C]. atrial fibrillation or other major risk cardioembolic source; and no
ii. (New 2020) In patients with stroke and type 2 diabetes in other likely cause for the stroke.43 Patients with ESUS have an
whom glycemic targets are not achieved with standard average annual stroke recurrence risk of approximately 5%. Two
oral antihyperglycemic medications, an antihyperglyce- trials published since the last edition investigated whether
mic agent with demonstrated benefit on major cardiovas- patients with ESUS would benefit more from anticoagulation
cular outcomes (e.g., SGLT-2 inhibitors or GLP-1 recep- than aspirin. Neither trial showed found a significant reduction in
tor agonists) should be considered [Evidence Level B]. recurrent stroke risk and therefore anticoagulation is not recom-
mended for patients with ESUS.44,60 The lack of an overall
Section 5.2 Clinical Consideration (New 2020): benefit of anticoagulation likely reflects that ESUS comprises
a heterogeneous group of many etiologies, with atherosclerotic or
1. The Pioglitazone after Ischemic Stroke or TIA trial32 other mechanisms likely predominating over occult atrial fibril-
suggested that while there is a benefit of pioglitazone for lation in the patients enrolled in these trials. The ARCADIA trial
stroke prevention in patients with positive insulin resis- (NCT03192215) is testing apixaban versus aspirin in a subset of
tance, it is offset by the increased risk of fractures and ESUS patients who have markers of atrial myopathy.
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 in- Section 6 Recommendations 2020
farction (MI)/hospitalization for heart failure, and pro- 6.1 Acute Antiplatelet Therapy
gression to diabetes. The decision to use this agent could
be considered based on the specific risk profile for each i. All patients with acute ischemic stroke or TIA not already
patient. on an antiplatelet agent should be treated with at least
160 mg of acetylsalicylic acid immediately as a one-time
loading dose after brain imaging has excluded intracranial
hemorrhage [Evidence Level A].
Section 6.0: Antiplatelet Therapy for Individuals with ii. For patients with dysphagia, acetylsalicylic acid (80 mg
Ischemic Stroke or TIA daily) or clopidogrel (75 mg daily) may be administered
by enteral tube or acetylsalicylic acid by rectal supposi-
Short-term administration of dual antiplatelet therapy with tory (325 mg daily) [Evidence Level A]. Note: acetylsa-
aspirin and clopidogrel is recommended for secondary stroke licylic acid should only be administered orally once
prevention, starting within 24 h for eligible patients with acute dysphagia screening has been performed and indicates
non-hemorrhagic high-risk TIA or minor ischemic stroke based absence of potential dysphagia.
on the POINT,33 CHANCE,34 and FASTER35 trials. The optimal iii. Antiplatelet therapy should be started as soon as possible
duration of dual antiplatelet therapy has been clarified by addi- after brain imaging has excluded hemorrhage, within
tional analyses36,37 with net benefit of dual antiplatelet therapy 24 h of symptom onset (ideally within 12 h) [Evidence
over aspirin alone likely confined to the first 21 d post-TIA/stroke Level B].
(maximal within the first 10 d). Compared with aspirin, the short- iv. For patients receiving intravenous thrombolysis therapy,
term dual antiplatelet therapy protocol prevents 20 more strokes avoid antiplatelet therapy within the first 24 h; antiplate-
(and causes two major bleeds) for every 1000 patients treated. let therapy could then be initiated after brain imaging has
Pharmacogenetic testing can identify patients with clopidogrel excluded secondary hemorrhage [Evidence Level B].
resistance, however, its clinical implications for stroke prevention v. For TIA or minor ischemic stroke patients who are being
practice are unclear at this time.38–40 discharged from the emergency department, antiplatelet
Another short-term dual antiplatelet treatment option is the therapy should be started prior to discharge [Evidence
combination of daily low-dose aspirin and ticagrelor, a P2Y12 Level C].
antagonist most often used in coronary artery disease. The
Acute Stroke or Transient Ischemic Attack Treated With Tica- 6.2 Antiplatelet Therapy for Secondary Stroke Prevention
grelor and ASA for Prevention of Stroke and Death (THALES)
trial tested a 30-d course of the aspirin–ticagrelor combination i. For patients with ischemic stroke or TIA, antiplatelet
starting within 24 h of a high-risk TIA or minor ischemic therapy is recommended for long-term secondary stroke
stroke.41 Ticagrelor was administered as a 180 mg loading dose prevention to reduce the risk of recurrent stroke and other
followed by 90 mg twice daily, along with aspirin 75–100 mg vascular events unless there is an indication for anticoag-
daily. This combination reduced the risk of recurrent stroke or ulant therapy [Evidence Level A].
death compared with aspirin alone, although the risk of severe ii. Antiplatelet therapy should be started as soon as possible
bleeding, intracranial bleeding, and fatal bleeding was higher in after brain imaging has excluded hemorrhage, within
the ticagrelor–aspirin group. Maximum benefit was observed in 24 h of symptom onset (ideally within 12 h) [Evidence
patients with ipsilateral large vessel atherosclerotic disease.42 Level B].

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 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES

iii. For long-term secondary stroke prevention, either acet- Section 6.2 Clinical Considerations
ylsalicylic acid (80–325 mg daily), or clopidogrel (75 mg
daily), or combined acetylsalicylic acid and extended- 1. For patients who experience a stroke while receiving one
release dipyridamole (25mg/200 mg BID), are all appro- antiplatelet agent, stroke etiology should be reassessed
priate treatment options and selection depends on patient and addressed, and all other vascular risk factors aggres-
factors or clinical circumstances [Evidence Level A] sively managed. Either continuing the current agent or
switching to a different antiplatelet agent are reasonable
6.2.1 Short-Term Dual Antiplatelet Therapy for Second- options. At the present time, evidence is lacking to make
ary Stroke Prevention more specific recommendations.
2. (New for 2020): Pharmacogenetic testing can identify
iv. For patients with an acute high-risk TIA or minor patients with clopidogrel resistance, however, its clinical
ischemic stroke of non-cardioembolic origin (NIHSS implications for stroke prevention treatment are unclear at
0–3), who are not at high bleeding risk, dual antiplatelet this time.
therapy is recommended with clopidogrel 75 mg daily 3. (New for 2020): For carefully selected patients with coro-
plus acetylsalicylic acid 81 mg daily for a duration of nary artery disease or peripheral vascular disease meeting
21 d after the event, followed by antiplatelet monother- the eligibility criteria of the COMPASS trial, including a
apy thereafter (acetylsalicylic acid or clopidogrel alone) low-estimated bleeding risk and no history of lacunar stroke
[Evidence Level A]. or hemorrhagic stroke, the combination of rivaroxaban
v. (Revised for 2020): Dual antiplatelet therapy for longer 2.5 mg BID plus daily low-dose acetylsalicylic acid is a
than the first 21 d following a TIA or minor stroke is not reasonable treatment option. It should not be used within
recommended unless there is a specific indication (e.g., the first month after a stroke event.
arterial stent; symptomatic intracranial artery stenosis), due
to an increased risk of bleeding without clear benefit beyond
21 d [Evidence Level B]. Patients should be counseled that Section 7: Anticoagulant Therapy for Atrial Fibrillation
dual antiplatelet therapy with acetylsalicylic acid and clo-
pidogrel should continue for only 21 d, followed by anti- Oral anticoagulant therapy is strongly recommended for
platelet monotherapy to be continued indefinitely. secondary stroke prevention in patients with atrial fibrillation.
vi. A single loading dose of clopidogrel (either 300 mg Anticoagulation for AF has been associated with a 66% relative
(CHANCE trial) or 600 mg (POINT trial)) and acetylsa- risk reduction of recurrent stroke, with an absolute risk reduc-
licylic acid (160–325 mg) should be administered at the tion of 7.3%.45 Direct oral anticoagulants (DOACs) are gener-
start of treatment [Evidence Level A]. ally preferred over warfarin for most patients with non-valvular
vii. (New for 2020): Another reasonable short-term dual atrial fibrillation (non-valvular is now defined as atrial fibrilla-
antiplatelet treatment option is the combination of daily tion without moderate–severe mitral stenosis or mechanical
low-dose acetylsalicylic acid plus ticagrelor (180 mg heart valves).46 A recent trial supports the use of rivaroxaban
loading dose, followed by 90 mg bid) for 30 d [Evidence over warfarin for patients with atrial fibrillation and a biopros-
Level B]. thetic mitral valve.47
viii. (New for 2020): For patients with a recent stroke or TIA Clinicians are reminded to avoid inappropriate underdosing of
due to symptomatic intracranial atherosclerotic stenosis DOACs, a practice that is associated with increased stroke risk.
of 70%–99%, and a low estimated bleeding risk, the For patients with atrial fibrillation and chronic stable coronary
SAMMPRIS protocol should be considered, which artery disease (or >1-year post-percutaneous coronary interven-
includes dual antiplatelet therapy (acetylsalicylic acid tion [PCI] or coronary artery bypass graft [CABG]), the addition
and clopidogrel) for the first 3 months, typically fol- of an antiplatelet agent to chronic DOAC therapy is not recom-
lowed by antiplatelet monotherapy thereafter, in addi- mended as it increases bleeding risk without providing additional
tion to intensive lipid-lowering therapy with high-dose benefit in reducing ischemic events (cardiac or cerebral). The
statin, blood pressure treatment, and structured lifestyle Atrial Fibrillation and Ischemic Events With Rivaroxaban in
modification addressing smoking cessation, exercise and Patients With Stable Coronary Artery Disease Study (AFIRE)
diet [Evidence Level B]. trial showed that rivaroxaban alone was as effective as the
combination of rivaroxaban and aspirin in this patient population,
6.2.2 Specific Clinical Situations with a lower incidence of bleeding.48

ix. (New for 2020): For patients with an embolic stroke of

undetermined source, and no known atrial fibrillation,
anticoagulant therapy is not currently recommended Section 7 Recommendations
over low-dose acetylsalicylic acid for secondary stroke 7.1 Detection of Atrial Fibrillation following Stroke
prevention [Evidence Level A]. Additional trials are
ongoing to investigate this issue. i. Patients with suspected ischemic stroke or TIA should
have a 12-lead ECG to assess for atrial fibrillation,

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myocardial infarction, or structural heart disease (e.g., left is recommended unless also contraindicated [Evidence
ventricular hypertrophy) as potential causes or risk factors Level A].
of stroke [Evidence Level B]. a. For patients at high risk of bleeding, dual antiplatelet
ii. For patients being investigated for an acute embolic therapy is not recommended in preference to antic-
ischemic stroke or TIA, ECG monitoring for 24 h or oagulation as the risks of bleeding are comparable,
more is recommended as part of the initial stroke work- and dual antiplatelet therapy is less effective for stroke
up to detect paroxysmal atrial fibrillation in patients who prevention [Evidence Level B].
would be potential candidates for anticoagulant therapy iv. For ischemic stroke or TIA in patients with atrial fibril-
[Evidence Level A]. lation who cannot receive long-term oral anticoagulant
iii. For patients being investigated for an embolic ischemic therapy, a left atrial appendage occlusion procedure may
stroke or TIA of undetermined source whose initial short- be considered [Evidence Level B].
term ECG monitoring does not reveal atrial fibrillation v. For patients with a mechanical heart valve, warfarin is
but a cardioembolic mechanism is suspected, prolonged recommended for stroke prevention with careful INR
ECG monitoring for at least 2 weeks is recommended to monitoring; direct oral anticoagulants (DOACs) are con-
improve detection of paroxysmal atrial fibrillation in traindicated [Evidence Level B]. Note, patients with
selected patients aged ≥55 years who are not already bioprosthetic heart valves do not routinely require
receiving anticoagulant therapy but would be potential long-term anticoagulation.
anticoagulant candidates [Evidence Level A]. vi. (New for 2020): For patients with atrial fibrillation who
iv. (New for 2020): For patients aged >65 years with experience ischemic stroke or TIA in spite of anticoag-
ischemic stroke or TIA, routine pulse palpation is ulant therapy, we recommend the following: (1) identify
recommended to screen for undiagnosed atrial fibrilla- and address medication non-adherence; (2) ensure cor-
tion [Evidence Level C]. rect DOAC dosing or warfarin INR control; (3) avoid
DOACs drug–drug interactions; (4) investigate for and
7.2 Secondary Stroke Prevention in Patients with Atrial treat other potential stroke etiologies; and (5) promote
Fibrillation general vascular risk factor modification [Evidence
Level C].
i. Patients with ischemic stroke or TIA and atrial fibrillation
should receive oral anticoagulant therapy for secondary Section 7.2 Clinical Considerations Revised for 2020
stroke prevention [Evidence Level A].
a. (New for 2020): For patients with an ischemic stroke Timing of Initiation of Oral Anticoagulant Therapy
or TIA and atrial fibrillation, oral anticoagulant therapy following Acute Stroke:
is strongly recommended [Evidence Level A]. It is
recommended over acetylsalicylic acid [Evidence 1. The optimal timing to start anticoagulant therapy after
Level A] and dual antiplatelet therapy [Evidence an ischemic stroke has not yet been well defined by
level B]. clinical trial evidence and should be based on individual
b. For most patients requiring anticoagulants for non- benefit/risk assessment taking into account the clinical
valvular atrial fibrillation, a direct oral anticoagulant circumstances, stroke severity, infarct size, imaging
(DOAC) such as apixaban, dabigatran, edoxaban, or appearances, risk of hemorrhagic transformation, age,
rivaroxaban should be prescribed in preference over comorbidities, and estimated stroke recurrence risk.
warfarin [Evidence Level A]. 2. There is a lack of randomized evidence to guide specific
c. For patients already receiving warfarin with good timing. According to expert consensus, a general ap-
International Normalized Ratio (INR) control (range proach to the target timing of initiation of DOAC therapy
2.0–3.0, with time in therapeutic range (TTR) of post-stroke is as follows:
>70%) and without adverse effects, continuing war- a. For patients with a brief TIA and no visible infarct or
farin, rather than switching to a DOAC, is a reason- hemorrhage on imaging, anticoagulation may be
able anticoagulant option [Evidence Level B]. started within the first 24 h post-TIA.
Patient preferences should be considered in deci- b. For patients with a minor clinical stroke/small non-
sion-making [Evidence Level C]. hemorrhagic infarct on imaging, anticoagulation may
d. When selecting an oral anticoagulant, patient specific be started 3 d post-stroke.
criteria should be considered [Evidence Level C]. c. For patients with a moderate clinical stroke/moderate-
ii. For patients with acute ischemic stroke and atrial fibrillation sized infarct on imaging (without hemorrhage on CT),
who are being started on warfarin, routine use of bridging anticoagulation may be started 6–7 d post-stroke.
with heparin is not recommended [Evidence Level B]. d. For patients with a severe clinical stroke/large-sized
a. Bridging with antiplatelet therapy (e.g., low-dose infarct on imaging (without hemorrhage on CT),
acetylsalicylic acid) is suggested until the patient is anticoagulation may be started 12–14 d post-stroke.
anticoagulated within therapeutic range [Evidence 3. If anticoagulation is delayed beyond 24 h, it is recom-
Level C]. mended to obtain repeat brain imaging for reassessment
iii. For patients with ischemic stroke or TIA and atrial prior to initiation of anticoagulation to exclude the
fibrillation who are unable to take oral anticoagulant presence of asymptomatic hemorrhagic transformation
therapy (DOAC or warfarin), acetylsalicylic acid alone of the index infarct.

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4. It is reasonable to delay the initiation of anticoagulation antiplatelet therapy is not recommended due to increased
for more than 2 weeks post-stroke if in the judgement of bleeding risk unless there is a specific medical indication
the clinician the risk of intracranial bleeding is felt to be for antiplatelet therapy (e.g., recent vascular stent; cer-
high, for example, for some patients with large infarcts tain mechanical heart valves) [Evidence Level B].
and those with hemorrhagic transformation. v. (New for 2020): For patients with atrial fibrillation and
chronic stable coronary artery disease (and >1-year post-
Stroke while on DOAC Therapy PCI or CABG), the addition of an antiplatelet agent to
DOAC therapy is not recommended as it increases
1. (New for 2020): For patients with atrial fibrillation who bleeding risk without providing any significant benefit
experience ischemic stroke or TIA despite anticoagulant in reducing ischemic events (cardiac or cerebral) [Evi-
therapy, either continuing the current agent or switching dence Level B].
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 antico- Section 8: Perioperative Management of Anticoagulant and
agulant therapy is not recommended because of increased Antiplatelet Therapy (New for 2020)
bleeding risk without clear evidence of benefit and potential
This edition features a new section on perioperative antithrom-
for harm unless there is a specific medical indication.
botic management – a commonly encountered issue in the stroke
7.3 Enhancing anticoagulant therapy effectiveness in population and one in which practice variations abound. Our
practice and minimizing bleeding complications. recommendations are aligned with Thrombosis Canada.49 For stroke
or TIA patients who require temporary interruption of chronic
i. Medication adherence should be continually assessed and antiplatelet or anticoagulant therapy for an upcoming elective
reinforced for patients on all oral anticoagulants at each surgery, decisions regarding the duration of therapy interruption
follow-up visit [Evidence Level B]. depend on the agent and the estimated bleeding risk associated with
a. Patients who are prescribed a DOAC should be the surgery or procedure. The goal is to minimize the risk of
reassessed at intervals and educated regarding the ischemic stroke while simultaneously minimizing the risk of clini-
short half-life of this class of drugs, the importance cally important (major) bleeding. Patients should avoid unnecessary
of daily medication adherence and the dangers of or prolonged interruptions of their antithrombotic therapy. Clinicians
missed doses or prolonged interruptions of therapy should communicate clear instructions to patients regarding their
[Evidence Level C]. perioperative management plan before an elective procedure.
b. For patients with atrial fibrillation taking warfarin, Because DOACs have a rapid offset (average half-life of
careful dosing and consistent INR monitoring is approximately 12 h) and a rapid onset of action, the duration of
recommended to minimize adverse events; warfarin DOAC interruption can be kept short to minimize the risk of
efficacy is dependent on maintaining therapeutic INR ischemic stroke. This approach of standardized DOAC interruption
control and declines significantly when the INR falls and resumption appeared safe in the Perioperative Anticoagulation
below 2.0 [Evidence Level A]. Use for Surgery Evaluation (PAUSE) study of 3007 DOAC-
c. Patients and family members should be provided treated patients; the 30-d post-operative rates of arterial thrombo-
education, resources, and ongoing monitoring embolism and major bleeding were <1% and <2%, respectively.50
regarding atrial fibrillation and adherence to en- For patients undergoing a minimal-bleed-risk procedure, antic-
hance compliance and address potential barriers in oagulants can generally be continued without interruption, with
a timely way to facilitate self-management [Evi- some caveats; for DOACs, it is reasonable to omit the morning
dence Level C]. DOAC dose before the procedure to reduce bleeding risk.
ii. (New for 2020): For patients prescribed DOAC therapy, Descriptions of type of surgery or procedure and bleeding
avoid inappropriate underdosing as it is associated with risk category:
increased stroke risk [Evidence Level C].
iii. For patients prescribed DOACs, creatinine clearance • A high-bleed-risk surgery or procedure includes major
should be routinely monitored at least once annually, and abdominal surgery (e.g., cancer resection), major thoracic
when there is a change in health status [Evidence Level C]. surgery, major orthopedic surgery, and any cardiac,
a. Dose adjustments or a change in selected agent may spinal, or intracranial surgery. Any patient having neur-
be required based on changes in renal function if axial anesthesia is classified as high-bleed-risk because of
detected [Evidence Level C]. the risk for spinal epidural hematomas which could cause
b. More frequent monitoring of renal function (every 6 limb paralysis.
months or more frequently) may be considered for • A low-to-moderate-bleed-risk surgery or procedure
patients with renal impairment or a dehydrating illness includes most surgeries that are <1-h duration and proce-
for medication adjustment if required, particularly for dures that do not involve neuraxial anesthesia.
patients receiving dabigatran [Evidence Level C]. • A minimal-bleed-risk surgery or procedure includes tooth
iv. For patients taking chronic oral anticoagulant therapy extractions, root canal, skin biopsies, cataract surgery, and
for non-valvular atrial fibrillation, the addition of selected colonoscopies, for which anticoagulants can be

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continued without interruption. Permanent pacemaker and • Heparin bridging is recommended for selected patients
internal cardiac defibrillator implantation, as well as cardiac with a mitral valve prosthesis and for high-risk patients
catheterization, also can be done without stopping with an aortic valve prosthesis (e.g., with additional
anticoagulants. risk factors for stroke) [Evidence Level B].
• If bridging is used pre-operatively, it is recommended
to forego post-operative bridging in selected patients,
Section 8 Recommendations 2020 especially those undergoing high-bleed-risk proce-
dures [Evidence Level B].
i. Patients with atrial fibrillation or a mechanical heart v. For patients receiving acetylsalicylic acid for stroke
valve who are receiving oral anticoagulant therapy and prevention who require an elective or urgent (within
require a procedure associated with a minimal risk of 7 d) carotid endarterectomy (CEA) or coronary artery
bleeding (e.g., tooth extraction, skin biopsy, cataract bypass surgery, acetylsalicylic acid should be continued
removal, cardiac pacemaker) should not have anticoa- without interruption [Evidence Level B].
gulation interrupted around the time of the procedure vi. For patients who are receiving dual antiplatelet therapy
[Evidence Level B]. with acetylsalicylic acid and a P2Y12 inhibitor (e.g.,
ii. For patients with atrial fibrillation receiving a DOAC clopidogrel, ticagrelor) for secondary stroke prevention
for stroke prevention who require temporary DOAC who require urgent CEA (within 7 d), acetylsalicylic acid
interruption for an elective surgery or procedure, and a P2Y12 inhibitor should be continued periopera-
the following approach is recommended [Evidence tively [Evidence Level C].
Level B]: vii. For patients undergoing other types of surgery, continu-
a. For a low-to-moderate-bleed-risk surgery or proce- ing acetylsalicylic acid could be considered before a
dure, stop the DOAC the day before the procedure and low/moderate-bleed-risk surgery or procedure. Interrupt-
the day of the procedure (i.e., skip 2 d total), and ing acetylsalicylic acid before a high-bleed-risk surgery
restart the day after the procedure. or procedure could be considered for 7–10 d [Evidence
b. For a high-bleed-risk surgery or procedure, stop the Level C].
DOAC 2 d before the procedure, the day of the
procedure, and one day after the procedure (i.e., skip Section 8 Clinical Considerations
4 d total). Perioperative management of patients undergoing a mini-
Note: An exception involves patients on dabigatran with mal-bleed-risk procedure
impaired renal function (CrCl <50 mL/min) in whom an
additional 1–2 d of interruption is suggested before 1. For patients undergoing minor procedures that are con-
surgery or procedure. Refer to clinical considerations sidered minimal-bleed-risk (refer to definition above), it
for additional information. is not routinely necessary to stop anticoagulants. How-
iii. For patients with atrial fibrillation receiving warfarin ever, there are some caveats to the management of such
for stroke prevention who require temporary warfarin patients:
interruption for an elective surgery or procedure: a. Any of the minimal-bleed-risk procedures could be
a. For patients at low-to-moderate stroke risk (e.g., considered as having a higher bleed risk warranting
CHADS2 score 0–4), warfarin should be stopped anticoagulant interruption (e.g., tooth extraction in a
for 5 d pre-procedure, and resumed within 24 h patient with poor dentition or cataract surgery with
post-procedure, without heparin bridging [Evidence retrobulbar anesthesia) based on individual patient
Level A]. circumstances.
b. For patients at high-stroke risk (e.g., CHADS2 score b. In patients receiving a DOAC who are undergoing a
5–6 or prior perioperative stroke), heparin bridging is minimal bleed-risk procedure, it is prudent to omit the
suggested during warfarin interruption, typically with morning DOAC dose just before the procedure be-
twice-daily subcutaneous injections of low-molecu- cause the peak anticoagulant effect, occurring 1–3 h
lar-weight heparin for 3 d before and 3 d after the after intake, may coincide with the timing of the
surgery or procedure [Evidence Level B]. If bridging procedure and may increase the risk for bleeding.
is used pre-operatively, it is recommended to forego c. For pacemaker or ICD implantation, patients can
post-operative bridging in selected patients, especially continue warfarin, but the INR should be <3.0 at the
those undergoing high-bleed-risk procedures [Evi- time of the procedure.
dence Level B]. d. For coronary angiography, continuing anticoagulants
iv. For patients with a mechanical heart valve who are if a femoral artery approach is used may not be
receiving warfarin for stroke prevention and require advisable as such patients are at increased risk for
temporary warfarin interruption for elective surgery or developing a hematoma or false aneurysm.
procedure, stopping warfarin 5 d pre-procedure is e. For colonoscopy, anticoagulation can be continued in
recommended and should be resumed within 24 h selected patients in which the likelihood of polypect-
post-procedure [Evidence Level A]. omy or multiple biopsies is low.

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 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES

f. For dental procedures, oral tranexamic acid mouth- myocardial infarction, restenosis or TIA. The trial was terminated
wash can be used before and 2–3 times daily after the early due to low recruitment. In this same trial, there were no
procedure to reduce bleeding since such oral bleeding, significant differences in the same outcomes for the comparison of
although not clinically important, may cause distress best medical management versus carotid-artery angioplasty.
to patients.

Perioperative management of patients undergoing a mod-

erate-to-high-risk procedure Section 9 Recommendations 2020
9.1 Symptomatic Carotid Artery Stenosis
1. Patients having a high-bleed-risk surgery or procedure
9.1.1 Imaging
only need to be off DOACs for 2 d before the procedure,
corresponding to a 60–68-h interval between the last
i. If revascularization is being considered for carotid steno-
DOAC dose and the time of surgery, which means there
sis based only on carotid ultrasound, then CTA or contrast
is little to no residual anticoagulant effect at surgery
enhanced MRA is recommended to confirm the degree of
given the 12–15-h half-life of DOACs.
stenosis and guide surgical decision-making, as well as to
2. Patients having a low/moderate-bleed-risk surgery or
assess for tandem disease [Evidence Level C].
procedure only need to be off DOACs for 1 d before the
a. Conversely, carotid ultrasound may be required after
procedure, corresponding to a 36–42-h interval between
initial diagnosis of carotid stenosis using CTA or
the last dose and the surgery.
contrast-enhanced MRA if heavily calcified plaque
3. For all patients, no DOAC should be taken on the day of
or other features make quantification of stenosis less
surgery/procedure.
reliable [Evidence Level C].
4. The exception to this approach is patients on dabigatran
with impaired renal function (creatinine clearance
9.1.2 Indications for carotid revascularization
<50 mL/minute). Because dabigatran is cleared primarily
by the kidneys, a longer interruption interval is needed i. Patients with a symptomatic event attributed to an ipsi-
(4 d before a high-bleed-risk surgery: 2 d before a low/ lateral 50%–99% carotid artery stenosis should be evaluat-
moderate-bleed-risk surgery). ed without delay for potential carotid revascularization by a
5. Post-operative resumption of DOACs should wait at least health professional with stroke expertise [Evidence Level B].
24 h after a low/moderate-bleed-risk surgery or procedure a. In men with 50%–99% and women with 70%–99%
and 48–72 h after a high-bleed-risk surgery or procedure. symptomatic carotid artery stenosis, CEA is recom-
6. There are caveats to post-operative DOAC management: mended and should be performed as soon as possible
First, the 48–72-h resumption interval can be extended if following the qualifying event [Evidence Level A].
there is greater than expected post-operative bleeding, b. In women with 50 to 69 percent symptomatic carotid
which is important because the full anticoagulant effect stenosis, CEA may be considered in those at highest
of DOAC is almost immediate after oral intake. Second, risk of stroke recurrence and upon consideration of
in patients who are unable to take medications by mouth other patient factors [Evidence Level B].
and who are at high risk for venous thromboembolism,
low-dose low molecular weight heparin (LMWH) can be 9.1.3 Procedures
given for the initial 1–3 post-operative days
i. Carotid revascularization (CEA or Carotid artery stenting
[CAS]) should be performed by a proceduralist/centre
Section 9: Management of Extracranial Carotid Disease and that routinely audits their performance results, espe-
Intracranial Atherosclerosis cially perioperative stroke, and death rates [Evidence
Carotid endarterectomy (CEA) has been shown to prevent Level B].
stroke recurrence in patients who have sustained a minor stroke or a. For CEA, the randomized trials upon which these
TIA with ipsilateral high-grade carotid stenosis. For those with recommendations are based (benefits accrued for
50%–99% stenosis, the number of persons needed to undergo patients undergoing surgery within 6 months of symp-
surgery to prevent one ipsilateral stroke in five years was toms) involved combined perioperative stroke and
estimated to be 9 for men versus 36 for women. Women with death rates of 6%–7% [Evidence Level A].
symptomatic disease had significantly higher odds of 30-d mor- b. For CAS, the randomized trial upon which these
tality following CEA compared with men. (adjusted OR = 1.4, recommendations are based involved combined peri-
95% CI 1.02–1.94).51 procedural stroke and death rates of 5% [Evidence
The use of CEA for asymptomatic carotid artery disease is Level B].
controversial. One-year results from the recent SPACE-2 trial,52 ii. CEA is generally more appropriate than CAS for patients
indicated there were no significant differences between groups (CEA over age 70 years who are otherwise fit for surgery as current
vs. best medical management) in the occurrences of any stroke after evidence indicates stenting carries a higher peri-procedural
day 30, up to one-year, ipsilateral stroke, disabling stroke, any death, risk of stroke and death in older patients [Evidence Level A].

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iii. Carotid stenting may be considered for patients who are antiplatelet therapy, smoking cessation, and lifestyle
not operative candidates for technical, anatomic, or changes) [Evidence Level B].
medical reasons [Evidence Level A]. ii. CEA may be considered for highly selected patients
with 60%–99% carotid stenosis who are asymptomatic
9.1.4 Timing or were remotely symptomatic (i.e., greater than six
months prior to presentation) [Evidence Level A].
i. In clinically stable patients (men and women), CEA a. The benefit of CEA for women with 60%–99%
should be performed as early as possible following a asymptomatic carotid artery stenosis is not clear and
qualifying event [Evidence Level B] and ideally within should only be considered in highly selected patients
14 d [Evidence Level A]. [Evidence Level B] in consultation with a health
ii. In men with 50%–69% stenosis, the benefit of CEA is professional with stroke expertise.
greatest when performed within 14 d of the qualifying b. Patients should be evaluated to determine eligibility
event [Evidence Level A] and is attenuated when per- for CEA, such as a life expectancy of more than five
formed beyond 14 d of the qualifying event (Refer to years, and an acceptable risk of surgical complications
Appendix Three below for summary of recurrent stroke [Evidence Level A].
risk at various time points). c. In carefully selected patients, CEA should be performed
by a surgeon who routinely audits their performance
Section 9.1 Clinical Considerations results and demonstrates a less than 3% risk of
peri-operative morbidity and mortality [Evidence
1. Most data regarding optimal timing of carotid revascu- Level B].
larization for symptomatic carotid stenosis are derived d. Important improvements in best medical therapy
from studies of CEA and not CAS. However, it may be (control of blood pressure, lipids, diabetes, and smok-
reasonable to consider that similar recommendations ing) since the major trials of endarterectomy for
regarding timing also apply to CAS. asymptomatic stenosis possibly make their results
2. In exceptional situations, if local system barriers preclude less applicable to contemporary management practise
timely access to CEA while CAS is more rapidly accessi- (Evidence Level C).
ble, this latter revascularization procedure may be consid- iii. Carotid stenting may be considered in patients with
ered in patients otherwise considered eligible for CAS. 60%–99% asymptomatic carotid stenosis who are not
However, every effort must be made to enable local operative candidates for technical, anatomic, or medical
systems of care to ensure timely access to CEA. reasons provided there is a less than 3% risk of peri-
3. It may be reasonable to consider delaying CEA beyond procedural morbidity and mortality [Evidence Level A].
48 h of the qualifying event as surgery before this time
may be associated with a higher risk of perioperative Section 9.2 Clinical Considerations:
complications, particularly when the qualifying event
was a stroke and not a TIA. 1. Although their impact on clinical decision-making re-
4. For patients with moderate or severe stroke due to garding revascularization of asymptomatic patients is
symptomatic carotid stenosis, the benefit of carotid uncertain, several factors may confer a higher risk of
revascularization is uncertain and should be considered stroke in patients with asymptomatic stenosis, including:
on an individual basis, as such patients were excluded a. Progression of stenosis over time.
from trials of CEA and CAS. b. Ipsilateral covert brain infarcts on imaging.
5. In acute stroke patients with tandem lesions (cervical carotid c. Ipsilateral intracranial embolization detected on tran-
stenosis or occlusion and ipsilateral intracranial large vessel scranial Doppler.
occlusion) who have undergone endovascular thrombectomy d. Plaque morphology on non-invasive imaging (e.g.,
(EVT) but in whom no acute CAS has been performed volume, echolucency, intraplaque hemorrhage).
during the EVT procedure, subsequent carotid revasculari-
zation by CAS and CEA should be considered if the patient 9.3 Symptomatic Vertebral Artery Stenosis
otherwise remains a candidate for either procedure (as
determined by residual degree of carotid stenosis, stroke i. (New for 2020): For patients with symptomatic vertebral
severity, patient recovery, infarct size, reperfusion and bleed- artery stenosis (extracranial or intracranial), medical ther-
ing risk, and other factors). apy is recommended over stenting for secondary stroke
prevention [Evidence Level B].
9.2 Asymptomatic and Remotely Symptomatic Carotid
Artery Stenosis 9.4 Symptomatic Intracranial Artery Stenosis

i. Individuals with asymptomatic carotid artery stenosis i. For patients with a recent ischemic stroke or TIA due to
should receive aggressive medical management of risk symptomatic intracranial artery stenosis of 70%–99%,
factors as defined throughout the Secondary Prevention of medical therapy is recommended over stenting for sec-
Stroke Module (e.g., blood pressure, diabetes, cholesterol, ondary stroke prevention [Evidence Level B].

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Note: The SAMMPRIS protocol consisted of 3 months of Section 9.5 Clinical Considerations
dual antiplatelet therapy with acetylsalicylic acid and
clopidogrel (excluding high-bleeding risk patients), and 1. There is an insufficient evidence at this time to make a
is typically followed by antiplatelet monotherapy there- recommendation regarding the use of DOACs in patients
after, plus intensive lipid-lowering therapy with high- with arterial dissections [Evidence Level C].
dose statin, blood pressure treatment, and structured
lifestyle modification addressing smoking cessation, exer-
cise, and diet.
ii. In patients who have been managed with maximal Section 10: Other Cardiac Issues in Individuals with Stroke
medical therapy in the presence of intracranial stenosis
Since the last edition, a new randomized trial53 and additional
and experience a recurrent stroke, there is lack of evi-
meta-analyses and other reports further support PFO closure for
dence to guide management decisions; intracranial an-
secondary stroke prevention in selected patients.54–56 Given that
gioplasty (with or without stenting) may be reasonable in
TIA can be difficult to differentiate from mimics and the fact that
carefully selected patients [Evidence Level C].
only one of the PFO trials enrolled patients with TIA as an index
event, clinicians should be cautious when contemplating PFO
9.5 Cervicocephalic Artery Dissection
closure for TIA unless there is a high certainty of ischemia;
accordingly, these 2021 recommendations no longer indicate TIA
i. (New for 2020): For patients with ischemic stroke or TIA as an unqualified indication for closure. There is now moderate-
that is preceded by head/neck trauma, cervical spine strength evidence that PFO closure may be targeted to patient
mechanical trigger event, or prominent head/neck pain, groups with higher risk echocardiographic features.
a diagnosis of carotid or vertebral artery dissection should For patients with heart failure and without atrial fibrillation,
be suspected [Evidence Level C]. the COMMANDER-HF trial,57 which compared rivaroxaban to
ii. For patients with ischemic stroke or TIA in whom a standard care, found no significant difference in the frequency of
carotid or vertebral artery dissection is suspected, CTA the primary outcome (a composite of death from any cause, MI,
or MRA of the head and neck (or catheter angiogram) is or stroke) between groups. The risks of the individual compo-
recommended as the diagnostic neurovascular imaging nents of the primary outcome did not differ between groups with
test rather than ultrasound [Evidence Level C]. the exception of the risk of stroke, which was reduced signifi-
Note: CTA or MRA are the preferred non-invasive cantly with rivaroxaban (1.08 vs. 1.63 events/100-person years;
diagnostic imaging tests for patients with a suspected HR = 0.66, 95% CI 0.47–0.95). In the Warfarin versus Aspirin in
cervicocephalic artery dissection, as neck ultrasound Reduced Cardiac Ejection Fraction (WARCEF) trial,58 which
does not fully visualize the vertebral arteries and can compared the effectiveness of anticoagulation compared with
miss distal carotid artery dissections originating above antiplatelet therapy for stroke prevention in patients with heart
the angle of the jaw. failure in sinus rhythm, warfarin was associated with a signifi-
iii. Antithrombotic therapy for stroke prevention is recom- cantly reduced risk of ischemic stroke (HR = 0.52, 95% CI
mended for individuals with a diagnosis of an acute or 0.33–0.82, p = 0.005); however, the risks of major and minor
recent extracranial carotid or vertebral artery dissection hemorrhages were significantly increased.59
[Evidence Level B].
a. (New for 2020): There is an uncertainty about the
comparative efficacy of antiplatelet therapy versus
anticoagulation with heparin or warfarin; either treat- Section 10 Recommendations
ment is considered reasonable based on current evi- 10.1 Patent Foramen Ovale (PFO)
dence [Evidence Level B]; decisions should be based
on individual risk/benefit analysis taking into consid- i. Patients with a recent ischemic stroke suspected to be
eration the imaging features of the dissection (pres- related to a PFO should have an evaluation by healthcare
ence and degree of stenosis, intraluminal thrombus, professionals with stroke and cardiovascular expertise
vessel occlusion, pseudoaneurysm), brain imaging, [Evidence Level C].
patient characteristics, and estimated bleeding risk ii. For carefully selected patients with a recent ischemic
[Evidence Level C]. stroke attributed to a PFO, PFO device closure plus long-
b. The optimal duration of antithrombotic therapy post- term antiplatelet therapy is recommended over long-term
dissection is uncertain; decisions may be based on antithrombotic therapy alone provided all the following
individual clinical factors and imaging appearances criteria are met [Evidence Level A]:
on follow-up vascular imaging [Evidence Level C]. a. Age 18–60 years.
iv. There is a lack of evidence regarding the safety and b. The diagnosis of the index stroke event is confirmed
efficacy of anticoagulation for intracranial arterial dis- by imaging as a non-lacunar embolic ischemic stroke.
sections and treatment decisions should be individualized c. The patient has been evaluated by a neurologist or
[Evidence Level C]. healthcare professional with stroke expertise, and the
PFO is felt to be the most likely cause for the index

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stroke event following a thorough etiological evaluation Section 11: Cancer-Associated Ischemic Stroke
that has excluded alternate likely etiologies.
iii. (New for 2020): It is reasonable to recommend against A diagnosis of cancer can increase the risk of stroke in the
PFO closure for patients who have none of the following months or years following the diagnosis, particularly among
higher-risk anatomical features on echocardiography: (a) persons with lung cancer or with more advanced cancers.60,61
atrial septal aneurysm; (b) large right-to-left shunt (e.g., Thrombosis is a common complication of malignancy and
>20 microbubbles); and (c) large diameter PFO (e.g., represents a frequent cause of death in cancer patients with
≥2 mm) [Evidence Level B]. a history of stroke.
iv. For patients requiring long-term anticoagulation for other
reasons, the benefit of PFO closure is uncertain, and
treatment decisions should be based on individual patient Section 11 Recommendations
characteristics and risk versus benefit profile [Evidence 11.1 Cancer-Associated Ischemic Stroke
Level C].
v. For patients with a recent ischemic stroke attributed to a i. Patients with active malignancy who experience an arte-
PFO who do not undergo PFO closure and are aged 60 rial ischemic stroke or TIA should undergo a standard
years or younger, either antiplatelet or anticoagulant etiological work-up for their stroke, including vascular
therapy is recommended for secondary stroke prevention, imaging and cardiac rhythm monitoring [Evidence Level
unless there is a separate evidence-based indication for C]. Refer to Section 1 on Stroke Investigations for addi-
chronic anticoagulant therapy [Evidence Level B]. tional information.
ii. Stroke mechanisms associated with malignancy may be
Section 10.1 Clinical Considerations considered when determining etiological investigations,
including non-bacterial (marantic) endocarditis, hyperco-
1. Warfarin can reduce recurrent stroke; however, this agulability, paradoxical embolism due to venous throm-
benefit may be outweighed by the increased risk of major bosis, tumor-related vascular compression, and stroke
hemorrhage. related to anti-cancer treatments [Evidence Level C].
2. The role of DOACs is unknown in this population. iii. In patients with active malignancy and arterial ischemic
stroke or TIA in whom a cancer-associated hypercoagu-
10.2 Aortic Arch Atheroma: lable state may have contributed to the stroke, antic-
oagulation could be considered over antiplatelet therapy
i. Aortic arch atheroma should be managed according to the [Evidence Level C].
stroke prevention recommendations included in all rele- a. When anticoagulation is used, low-molecular weight
vant sections of the Secondary Prevention of Stroke heparin therapy is preferred [Evidence Level C]. The
Module [Evidence Level C]. role of DOACs is unknown but under study and may
ii. In the Aortic Arch Related Cerebral Hazard (ARCH) trial, be reasonable after consideration of patient prefer-
no significant difference was found in individuals treated ence.
with dual antiplatelet therapy (acetylsalicylic acid plus
clopidogrel) as compared with warfarin; the effectiveness Section 11 Clinical considerations
of anticoagulant therapy compared with antiplatelet therapy
in this context is uncertain and the choice should be 1. Management decisions for these patients should be made
individualized [Evidence Level B]. in collaboration with a health professional with expertise
in Hematology, Oncology or Thrombosis, and should
10.3 Heart Failure, Decreased Left Ventricular Ejection take into account the type of underlying cancer, the risk
Fraction, Cardiac Thrombus of bleeding, the extent of neoplastic disease, the patient’s
overall prognosis and expressed goals of care.
i. For patients with ischemic stroke or TIA who are in sinus 2. In patients with active malignancy and arterial ischemic
rhythm and have a left atrial or left ventricular thrombus stroke or TIA with a concurrent venous thromboembo-
demonstrated by echocardiography or other imaging lism (deep vein thrombosis [DVT] or pulmonary
modality, anticoagulant therapy is recommended for embolism [PE]) in whom the stroke is presumed to be
greater than 3 months [Evidence Level C]. due to a paradoxical embolus, anticoagulation for sec-
ii. For patients with ischemic stroke or TIA who are in sinus ondary prevention should follow guidelines for the man-
rhythm and have severe left ventricular dysfunction agement of DVT and PE in cancer patients which
(ejection fraction ≤35%) without evidence of left atrial includes LMWH and selected DOACs (Refer to
or left ventricular thrombus, the net benefit of anticoagu- www.thrombosiscanada.ca).
lant therapy (with either vitamin K antagonists or
DOACs) compared with antiplatelet therapy is uncertain,
and the choice of management strategies should be CHALLENGES AND FUTURE DIRECTIONS
individualized [Evidence Level B].
Advances in stroke prevention, driven by high-quality clinical
studies, continue to inform each new edition of these guidelines.

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 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES

However, we are still far from adequately addressing, at a global Margie Burns, Elena Adela Cora, Roxanne Cournoyer, Laurent
level, the 10 modifiable risk factors that account for 90% of the Derex, Paul Dorian, Charles Duffy, Eric Ehrensperger, Yuriy
population attributable risk of stroke.62 The largest impact on Flomin, Kirsten George-Phillips, Sarah Grant, Milan Gupta,
stroke prevention globally will likely be achieved by continued Rahul Jain, Shirin Jalani, Glen Jickling, Hooman Kamel, Hong
large-scale efforts to address hypertension, diabetes, diet, exer- Kao, Puneet Kapur, Lisa Keon, Lisa Korec, Catherine Legault,
cise, smoking, in addition to atrial fibrillation at both policy and Gerald MacDonald, GB John Mancini, Michael MacDonald,
individual levels. Kaylee Murphy, Kelvin Kuan Huei Ng, Darlene Peacock, Andre
A key tenet of secondary stroke prevention remains the Roussin, Joanna D Schaafsma, Peter Senior, Aleksander Tkach,
importance of identifying the most likely stroke etiology and Sean Virani, Elissa Weinberg, Heather Williams, and Janice
tailoring therapy accordingly. Although the completed ESUS Williams. We thank the Canadian Stroke Best Practices and
trials found no overall benefit of anticoagulation, further research Quality Advisory Committee members, including Eric Smith
aims to identify whether specific subgroups may benefit. Dual (Co-Chair), Anita Mountain (Co-Chair), Leanne Casaubon, Gord
pathway inhibition is a promising strategy.63 Newer anticoagu- Gubitz, Dar Dowlatshahi, Dylan Blacquiere, Louise Clement,
lants targeting factor XI represent promising future treatments for Thalia Field, Farrell Leibovitch, Christine Papoushek, Jeffrey
stroke prevention. Studies are ongoing (NCT02604667) and Habert, Barbara Campbell, Joyce Fung, Michael Hill, Tim
others are needed to better define when and how occult cancer Hillier, Thomas Jeerakathil, Eddy Lang, Pascale Lavoie, Beth
should be investigated in cryptogenic stroke patients, and if Linkewich, Colleen O’Connell, Melanie Penn, Jai Shankar,
found, what antithrombotic regimen best protects these patients Debbie Timpson, Theodore Wein, and Katie White. We acknowl-
from recurrent arterial strokes.64 edge and thank Norine Foley and the evidence analysis team at
Immediate challenges to optimal secondary stroke prevention workHORSE; Laurie Charest of Heart & Stroke for her coordi-
would therefore include the need to develop, grow, and maintain nation of the Canadian Stroke Best Practice Recommendations
systems for virtual delivery of care to patients through telemedi- (CSBPR) teams and processes; Andrea deJong, Francine Forget
cine.65,66 The SARS-CoV2 virus represents a well-documented Marin, and the Heart & Stroke internal teams who contributed to
challenge to acute stroke care67 but its impact on the risk of stroke the development of these recommendations and publication:
recurrence, either directly among patients having been infected Communications, Translation, Knowledge Translation, Engage-
with the virus, or on other patients who have suffered collateral ment, Health Policy, and Digital Solutions. Heart & Stroke is
damage from diminished access to stroke care, will be important especially grateful to the members of the Community Consulta-
to now study. tion and Review Panel who reviewed all sections of this module,
A challenge that concerns research in all fields of medicine – shared their personal experiences and insights on what did or
including stroke68 – is the need to ensure adequate sex and gender would have made their journey optimal. The members of the
representation in therapeutic trials to ensure generalizability of Secondary Prevention of Stroke Community Consultation and
results to both men and women. This edition is the first of our Review Panel (CCRP) included: Cheryl Beattie, Jennifer Bogart,
guidelines to start incorporating a sex and gender descriptive Dan Dobbin, Glen Hilton, Judy Hilton, Allan Morrison, and
analysis into the literature review for each recommendation, and additional volunteers who reviewed all sections and provided
future editions will strive to include gender and sex-based input and developed patient infographic resources.
recommendations where appropriate.
FUNDING
SUMMARY
The development of the CSBPR is funded in its entirety by
The 2020 update of the Canadian Stroke Best Practice Heart & Stroke. No funds for the development of these guidelines
Secondary Prevention of Stroke Recommendations provide a come from commercial interests, including pharmaceutical and
common set of guiding principles for important aspects of device companies. All members of the recommendation writing
secondary stroke prevention, emphasizing that individuals who groups, and external reviewers are volunteers and do not receive
have experienced a stroke or TIA require access expert preven- any remuneration for participation in guideline development,
tion care in a timely way. In Canada, coordinated systems have updates, and reviews. All participants complete a conflict of
evolved over time, growing the number of stroke prevention interest declaration prior to participation.
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 inequi- CONFLICTS OF INTEREST
ties in access to care.
The following authors have identified actual or potential
conflicts of interest which have been mitigated through the design
ACKNOWLEDGEMENTS of a multidisciplinary writing group model and additional mea-
Heart &Stroke gratefully acknowledges the Secondary Pre- sures by the advisory committee as required. David J. Gladstone
vention of Stroke writing group leaders and members all of whom received a Mid-Career Investigator Award from the Heart and
have volunteered their time and expertise to the update of these Stroke Foundation, a peer-reviewed provincial operating grant
recommendations. Members of the Canadian Stroke Consortium from Ontario Genomics; all funds paid to his institution to
were involved in all aspects of the development of these recom- support the project (no personal fees); Independent Medical
mendations. These recommendations (in whole or specific parts) Safety Monitor for the NINDS-sponsored ARCADIA trial
underwent external review by: Jason Andrade, Rohit Bhatia, (uncompensated), and local site PI for the NASPAF-ICH and

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 LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES

ENRICH-AF trials (with all site fees paid to his institution; no honorarium for leadership of a multicenter RCT from Boehringer
personal fees); served as PI of the SCREEN-AF trial (uncom- Ingelheim; grant to Women’s College Hospital for clinical
pensated); operating grant from the Canadian Stroke Prevention research study from Janssen; grant to Women’s College Hospital
Intervention Network (C-SPIN), a peer-reviewed Canadian Insti- to be a site in a multicenter RCT and honorarium for steering
tutes of Health Research [CIHR]) national network grant; Adju- committee membership in cohort study by Novartis; grant to
dication Committee SAFE-HD trial (uncompensated); and is the Women’s College Hospital for site participation in a multicenter
Site Investigator for NAVIGATE ESUS trial and NASPAF-ICH RCT and honorarium for national co-PI role in multicenter RCT
trial (all site fees paid to my institution); co-leader of NAVI- for Sanofi; grants to his institutions for clinical trial participation
GATE ESUS atrial myopathy/atrial fibrillation working group from Boehringer Ingelheim, Novartis, Sanofi; grant from Bayer.
(uncompensated). Alexandre Y. Poppe is Site PI and Site Stephen van Gaal is a site investigator who enrolls patients for
co-investigator for ESCAPE-NA1 (NoNo), NAVIGATE-ESUS Portola, Bayer; advisory board member for Servier (edoxaban);
(Bayer), RESPECT-ESUS (Boehringer-Ingelheim), POINT support for conference attendance from Bayer (rivaroxaban);
(NIH); DSMB for FLOW; Canadian Stroke Trials for Optimized Canadian Stroke Consortium committee member. Karina Villa-
Results (CaSTOR) networking grant; Chair, Canadian Stroke luna is a Clinical Research Coordinator participating in research
Consortium National Stroke Fellowship Program; receives sup- for NoNO Inc, Portola and BMS. Eric E. Smith participates in
port for fellowship program from Servier; and research grant consulting for clinical trials in cerebral amyloid angiopathy,
support from Stryker. Jafna Cox is a Medical Consultant vascular cognitive impairment, and preventing atrial fibrilla-
(received payment) for Bayer, HLS Therapeutics, Novartis; tion-related stroke with Bayer, Biogen, Javelin; Royalties from
Lecture Series (received payment) with Bayer; holds an Investi- UpToDate for chapter on diagnosing vascular dementia; and is
gator-initiated grant from Bayer; and participating in a Phase II Study site for Biogen study on adacanumab for Alzheimer’s
study of a Factor XI inhibitor, funded by Bayer. James Douketis disease. Dar Dowlatshahi holds a Heart & Stroke Foundation of
is an Advisory Board Consultant for BMS Pfizer, Servier, Canada Research Grant and Salary Award; a Patent for CARL for
Leo Pharma, Sanofi, Bayer; holds a grant/Honorarium from detection of contrast extravasation; and is involved in several
Thrombosis Canada (non-profit); participation in PAUSE trial. funded clinical trials; member, Canadian Stroke Consortium
Monies received as personal fees from Janssen, Pfizer, Bayer, board of directors. Theodore Wein is a consultant for Servier,
Bristol Myers Squibb, Sanofi, Servier Canada, Portola are de- Allergan Inc, Ipsen Inc; a speaker for Servier; receives research
posited in hospital-based (St. Joseph’s Healthcare Hamilton) and funding from Allergan and Servier; and is PI on a Servier funded
university-based (McMaster University) research accounts and/or study. Shelagh Coutts holds a current CIHR grant. Gord Gubitz is
charitable foundations. Brett R. Graham holds a Canadian Stroke an Advisory Board member for Bayer, BI, Pfizer; Member,
Consortium Catalytic Research Capacity Generation Grant; is site DSMB CATIS-ICAD trial; Member, Steering Committee. HSF
PI University of British Columbia, University of Calgary - Canada Stroke Best Practices; Co-Chair, World Stroke Organiza-
SECRET and TOPSECRET; site sub-I for TEMPO-2 an tion Education Committee; Atlantic Canada Together Enhancing
ESCAPE NA1. Honorarium received from Servier Canada (to Acute Stroke Treatment (ACTEAST): Improving Access and
give a talk on anticoagulation in afib to family physicians. Efficiency of Treatment. Co-Investigator. Canadian Institutes of
Marilyn Labrie is an advisory board member for Teva Canada Health Research (CIHR) Project Grant; Optimization and Valida-
– Fremanezumab 2020–08–23. Jennifer Mandzia is an advisory tion of a Novel Emergency Department Point-of-Care MRI. Nova
board with Bayer; and is clinical trial Site PI for several studies. Scotia Health Research Foundation. Research Nova Scotia Trust,
Daniel Ngui is a member of the Advisory Board for Amgen, Industry collaborator; the effects of prism adaptation training on
Astra Zeneca, BMS, BI, Lilly, Novonordisk; moderating and visual attention and functional activities in stroke patients with
speaking engagements for Amgen, Astra Zeneca, BMS, BI, Lilly, neglect. Nova Scotia Health Research Foundation – Establishment
Novonordisk; EMR grants and audits for Amgen, Astra Zeneca, Grant. Paul Pageau is a past board member, Canadian Association
BI, Novartis; holds research grants from Simple Trial, Amgen of Emergency Physicians. Pascale Lavoie holds investments in
20170191 trial, IHE eCare CV Risk, CHRC EMR Registry Johnson and Johnson/United health group. The following authors
Trials: AF OAC, Advantage CV, and Advantage OP-Phase 4 have no conflicts of interest to declare: M. Patrice Lindsay, Anita
and EMR audits; Health Choices First Video Education shares; Mountain, Aline Bourgoin, John B. Falconer, Norine Foley,
Investments in communications companies including CHRC, Manraj K.S. Heran, Lena McDonald, Rebecca McGuff, Amanda
CCRN, MD Briefcase, Medplan, Liv Agency, Four Health; board Rodgerson, Tammy Tebbutt, and Carmen Tuchak.
membership on CCS Lipid guideline Panel, CCS A. fib guideline
second panel, SPH Hospital CME Committee, BC Guidelines,
UBC CPD CME “This changed my practice,” Alliance for Best STATEMENT OF AUTHORSHIP
Practices in Health Education. William Semchuk is an Advisory David J Gladstone (First author) and Alexandre Y. Poppe
Board Member for BMS Pfizer; Speaker Honorarium from BMS, (Senior Author) are co-chairs of the Secondary Prevention of
Pfizer, Astra Zeneca, Sanofi, Servier, Bayer, BI. Jacob A Udell is Stroke expert writing group and lead authors contributing to all
an advisory board member for Boehringer Ingelheim, Novartis, aspects of the development, evidence and data analysis, writing,
Sanofi; Secondary analysis of banked biospecimens from a editing, and final approval of this manuscript; M. Patrice Lindsay is
completed RCT for Janssen; Consultant on clinical research corresponding author, senior editor of the Canadian Stroke Best
development, (no involvement in marketing) with Boehringer Practice Recommendations (CSBPR) and of this manuscript,
Ingelheim, Janssen, Sanofi, Amgen, Merck, Novartis; received involved in all aspects of scientific literature review, writing group
grant to University Health Network for clinical trial from Astra- deliberations, external review process, manuscript preparation, and
Zeneca; grant to University Health Network for clinical trial and a writer of supplementary documentation. Aline Bourgoin, Jafna

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 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES

Cox, James Douketis, John B. Falconer, Brett R. Graham, Marilyn diagnosis, risk assessment, and treatment of hypertension in
Labrie, Lena McDonald, Jennifer Mandzia, Daniel Ngui, Paul adults and children. Can J Cardiol. 2020;36:596–624. DOI: 10.
1016/j.cjca.2020.02.086.
Pageau, Amanda Rodgerson, William Semchuk, Tammy Tebbutt, 12. Salisbury C, O’Cathain A, Thomas C, et al. Telehealth for patients at
Carmen Tuchak, Jacob Udell, Stephen van Gaal, Karina Villaluna, high risk of cardiovascular disease: pragmatic randomised con-
Manraj K.S. Heran, and Pascale Lavoie are all members of trolled trial. BMJ. 2016;353:i2647. DOI: 10.1136/bmj.i2647.
Secondary Prevention of Stroke expert writing group and contrib- 13. Liu S, Feng W, Chhatbar PY, Liu Y, Ji X, Ovbiagele B. Mobile
health as a viable strategy to enhance stroke risk factor control: a
uted by reviewing, analyzing and discussing the evidence and systematic review and meta-analysis. J Neurol Sci.
collectively finalizing the wording of all included recommenda- 2017;378:140–5. DOI: 10.1016/j.jns.2017.04.050.
tions. Norine Foley conducted the evidence searches and complet- 14. Widmer RJ, Collins NM, Collins CS, West CP, Lerman LO, Lerman
ed the evidence tables and evidence summaries supporting this A. Digital health interventions for the prevention of cardiovascu-
guideline update and contributed to writing of this manuscript. Dar lar disease: a systematic review and meta-analysis. Mayo Clin
Proc. 2015;90:469–80. DOI: 10.1016/j.mayocp.2014.12.026.
Dowlatshahi, Theodore Wein, Eric E. Smith, Anita Mountain, and 15. Kapoor A, Lindsay MP, Yu AYX, et al. Call 911: lower ambulance
Gord Gubitz are senior leaders of the stroke best practices advisory utilization among young adults, especially women, with stroke.
committee and provided inputs throughout development of the Can J Neurol Sci. 2020;47:764–9. DOI: 10.1017/cjn.2020.119.
recommendations, and participated in development, preparation, 16. Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-
cigarettes versus nicotine-replacement therapy. N Engl J Med.
and editing of this manuscript. Shelagh Coutts led a subgroup 2019;380:629–37. DOI: 10.1056/NEJMoa1808779.
focused on updates to section one recommendations for triage. 17. McClester M, Mounsey A, Mackler L. Clinical inquiry: do oral
Rebecca McGuff provided inputs to this manuscript and is respon- contraceptives carry a significant risk of stroke for women with
sible for development of knowledge translation resources. migraines? J Fam Pract. 2013;62:662–3.
18. Feigin VL, Roth GA, Naghavi M, et al. Global burden of stroke and
risk factors in 188 countries, during 1990–2013: a systematic
SUPPLEMENTARY MATERIAL analysis for the Global Burden of Disease Study 2013. Lancet
Neurol. 2016;15:913–24. DOI: 10.1016/s1474-4422(16)30073-4.
To view supplementary material for this article, please visit 19. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering
https://doi.org/10.1017/cjn.2021.127. drugs in the prevention of cardiovascular disease: meta-analysis
of 147 randomised trials in the context of expectations from
prospective epidemiological studies. BMJ. 2009;338:b1665.
REFERENCES DOI: 10.1136/bmj.b1665.
1. Graham ID, Harrison MB, Brouwers M, Davies BL, Dunn S. 20. Kitagawa K, Yamamoto Y, Arima H, et al. Effect of standard vs
Facilitating the use of evidence in practice: evaluating and intensive blood pressure control on the risk of recurrent stroke: a
adapting clinical practice guidelines for local use by health care randomized clinical trial and meta-analysis. JAMA Neurol.
organizations. JOGNN. 2002;31:599–611. 2019;76:1309–18. DOI: 10.1001/jamaneurol.2019.2167.
2. Vernooij RW, Alonso-Coello P, Brouwers M, Martinez Garcia L. 21. Amarenco P, Kim JS, Labreuche J, et al. A Comparison of two LDL
Reporting items for updated clinical guidelines: checklist for the cholesterol targets after ischemic stroke. N Engl J Med.
reporting of updated guidelines (CheckUp). PLoS Med. 2017;14: 2020;382:9–19. DOI: 10.1056/NEJMoa1910355.
e1002207. DOI: 10.1371/journal.pmed.1002207. 22. Shoamanesh A, Patrice Lindsay M, Castellucci LA, et al. Canadian
3. Brouwers MC, Kho ME, Browman GP, et al. AGREE II: advancing stroke best practice recommendations: management of spontaneous
guideline development, reporting and evaluation in health care. intracerebral hemorrhage, 7th edition update 2020. Int J Stroke.
CMAJ. 2010;182:E839–842. DOI: 10.1503/cmaj.090449. 2020:1747493020968424. DOI: 10.1177/1747493020968424.
4. Coutts SB, Wein TH, Lindsay MP, et al. Canadian stroke best 23. Global Burden of Disease Results Tool. Available at: http://
practice recommendations: secondary prevention of stroke guide- ghdx.healthdata.org/gbd-results-tool; accessed November 15,
lines, update 2014. Int J Stroke. 2015;10:282–91. DOI: 10.1111/ 2020.
ijs.12439. 24. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood
5. Wein T, Lindsay MP, Cote R, et al. Canadian stroke best practice glucose concentration, and risk of vascular disease: a collabora-
recommendations: secondary prevention of stroke, sixth edition tive meta-analysis of 102 prospective studies. Lancet.
practice guidelines, update 2017. Int J Stroke. 2018;13:420–43. 2010;375:2215–22. DOI: 10.1016/s0140-6736(10)60484-9.
DOI: 10.1177/1747493017743062. 25. Group AtCCRiDS. Effects of intensive glucose lowering in type 2
6. Lindsay MP, Gierman N, Harris JE, et al. People with lived diabetes. N Engl J Med. 2008;2008:2545–59.
experience at the centre of Canadian stroke best practice recom- 26. Duckworth W, Abraira C, Moritz T, et al. Glucose control and
mendations: a model for guideline developers. J Patient Exp. vascular complications in veterans with type 2 diabetes. N Engl J
2020;7:951–56. DOI: 10.1177/2374373520956538. Med. 2009;360:129–39.
7. Rothwell PM, Giles MF, Chandratheva A, et al. Effect of urgent 27. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal
treatment of transient ischaemic attack and minor stroke on early outcomes in type 2 diabetes and nephropathy. N Engl J Med.
recurrent stroke (EXPRESS study): a prospective population- 2019;380:2295–306. DOI: 10.1056/NEJMoa1811744.
based sequential comparison. Lancet. 2007;370:1432–42. DOI: 28. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular out-
10.1016/s0140-6736(07)61448-2. comes with ertugliflozin in type 2 diabetes. N Engl J Med.
8. Lioutas VA, Ivan CS, Himali JJ, et al. Incidence of transient 2020;383:1425–1435. DOI: 10.1056/NEJMoa2004967.
ischemic attack and association with long-term risk of stroke. 29. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and
Jama. 2021;325:373–81. DOI: 10.1001/jama.2020.25071. cardiovascular outcomes in type 2 diabetes (REWIND): a double-
9. Kamal N, Hill MD, Blacquiere DP, et al. Rapid assessment and blind, randomised placebo-controlled trial. Lancet.
treatment of transient ischemic attacks and minor stroke in 2019;394:121–30. DOI: 10.1016/s0140-6736(19)31149-3.
Canadian emergency departments: time for a paradigm shift. 30. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and
Stroke. 2015;46:2987–90. DOI: 10.1161/strokeaha.115.010454. cardiovascular outcomes in patients with type 2 diabetes. N Engl J
10. Schnabel RB, Haeusler KG, Healey JS, et al. Searching for atrial Med. 2019;381:841–51. DOI: 10.1056/NEJMoa1901118.
fibrillation poststroke: a white paper of the AF-SCREEN Inter- 31. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin
national Collaboration. Circulation. 2019;140:1834–50. DOI: 10. vs placebo on major cardiovascular events in adults with type 2
1161/circulationaha.119.040267. diabetes and high cardiovascular and renal risk: The CARME-
11. Rabi DM, McBrien KA, Sapir-Pichhadze R, et al. Hypertension LINA Randomized Clinical Trial. Jama. 2019;321:69–79. DOI:
Canada’s 2020 comprehensive guidelines for the prevention, 10.1001/jama.2018.18269.

336
https://doi.org/10.1017/cjn.2021.127 Published online by Cambridge University Press
 LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES

32. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after oral anticoagulant. JAMA Intern Med. 2019;179:1469–78. DOI:
ischemic stroke or transient ischemic attack. N Engl J Med. 10.1001/jamainternmed.2019.2431.
2016;374:1321–31. DOI: 10.1056/NEJMoa1506930. 51. Dansey KD, Pothof AB, Zettervall SL, et al. Clinical impact of sex
33. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in on carotid revascularization. J Vasc Surg. 2020;71:1587–
acute ischemic stroke and high-risk TIA. N Engl J Med. 94.e1582. DOI: 10.1016/j.jvs.2019.07.088.
2018;379:215–25. DOI: 10.1056/NEJMoa1800410. 52. Reiff T, Eckstein HH, Mansmann U, et al. Angioplasty in asymp-
34. Wong KS, Wang Y, Leng X, et al. Early dual versus mono tomatic carotid artery stenosis vs. endarterectomy compared to
antiplatelet therapy for acute non-cardioembolic ischemic stroke best medical treatment: one-year interim results of SPACE-2. Int J
or transient ischemic attack: an updated systematic review and Stroke. 2019;15:1747493019833017. DOI: 10.1177/17474930
meta-analysis. Circulation. 2013;128:1656–66. DOI: 10.1161/ 19833017.
circulationaha.113.003187. 53. Lee PH, Song JK, Kim JS, et al. Cryptogenic stroke and high-risk
35. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, patent foramen ovale: the DEFENSE-PFO trial. J Am Coll
Buchan AM. Fast assessment of stroke and transient ischaemic Cardiol. 2018;71:2335–42. DOI: 10.1016/j.jacc.2018.02.046.
attack to prevent early recurrence (FASTER): a randomised 54. Saver JL, Mattle HP, Thaler D. Patent foramen ovale closure
controlled pilot trial. Lancet Neurol. 2007;6:961–9. DOI: 10. versus medical therapy for cryptogenic ischemic stroke: a topi-
1016/s1474-4422(07)70250-8. cal review. Stroke. 2018;49:1541–8. DOI: 10.1161/strokeaha.
36. Pan Y, Elm JJ, Li H, et al. Outcomes associated with clopidogrel- 117.018153.
aspirin use in minor stroke or transient ischemic attack: A pooled 55. Mas JL, Derex L, Guérin P, et al. Transcatheter closure of patent
analysis of clopidogrel in high-risk patients with acute non- foramen ovale to prevent stroke recurrence in patients with
disabling cerebrovascular events (CHANCE) and platelet-orient- otherwise unexplained ischaemic stroke: expert consensus of the
ed inhibition in new TIA and minor ischemic stroke (POINT) French Neurovascular Society and the French Society of Cardi-
trials. JAMA Neurol. 2019;76:1466–73. DOI: 10.1001/ ology. Arch Cardiovasc Dis. 2019;112:532–42. DOI: 10.1016/j.
jamaneurol.2019.2531. acvd.2019.06.002.
37. Hao Q, Tampi M, O’Donnell M, Foroutan F, Siemieniuk RA, 56. Turc G, Calvet D, Guerin P, Sroussi M, Chatellier G, Mas JL.
Guyatt G. Clopidogrel plus aspirin versus aspirin alone for acute Closure, anticoagulation, or antiplatelet therapy for cryptogenic
minor ischaemic stroke or high risk transient ischaemic attack: stroke with patent foramen ovale: systematic review of random-
systematic review and meta-analysis. BMJ. 2018;363:k5108. ized trials, sequential meta-analysis, and new insights from the
DOI: 10.1136/bmj.k5108. CLOSE study. J Am Heart Assoc. 2018;7:e008356. DOI: 10.
38. Pereira NL, Farkouh ME, So D, et al. Effect of genotype-guided oral 1161/jaha.117.008356.
P2Y12 inhibitor selection vs conventional clopidogrel therapy on 57. Zannad F, Anker SD, Byra WM, et al. Rivaroxaban in patients with
ischemic outcomes after percutaneous coronary intervention: the heart failure, sinus rhythm, and coronary disease. N Engl J Med.
TAILOR-PCI randomized clinical trial. Jama. 2020;324:761–71. 2018;379:1332–42. DOI: 10.1056/NEJMoa1808848.
DOI: 10.1001/jama.2020.12443. 58. Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin
39. Wang Y, Zhao X, Lin J, et al. Association Between CYP2C19 Loss-of- in patients with heart failure and sinus rhythm. N Engl J Med.
Function Allele Status and Efficacy of Clopidogrel for Risk Reduc- 2012;366:1859–69. DOI: 10.1056/NEJMoa1202299.
tion Among Patients With Minor Stroke or Transient Ischemic 59. Homma S, Thompson JL, Sanford AR, et al. Benefit of warfarin
Attack. Jama. 2016;316:70–8. DOI: 10.1001/jama.2016.8662. compared with aspirin in patients with heart failure in sinus
40. Meschia JF, Walton RL, Farrugia LP, et al. Efficacy of clopidogrel for rhythm: a subgroup analysis of WARCEF, a randomized con-
prevention of stroke based on CYP2C19 allele status in the POINT trolled trial. Circ Heart Fail. 2013;6:988–97. DOI: 10.1161/
trial. Stroke. 2020;51:2058–65. DOI: 10.1161/strokeaha.119.028713. circheartfailure.113.000372.
41. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and aspirin 60. Navi BB, Reiner AS, Kamel H, et al. Risk of arterial thromboem-
or aspirin alone in acute ischemic stroke or TIA. N Engl J Med. bolism in patients with cancer. J Am Coll Cardiol. 2017;70:926–
2020;383:207–17. DOI: 10.1056/NEJMoa1916870. 38. DOI: 10.1016/j.jacc.2017.06.047.
42. Amarenco P, Denison H, Evans SR, et al. Ticagrelor added to 61. Jang HS, Choi J, Shin J, et al. The long-term effect of cancer on
aspirin in acute nonsevere ischemic stroke or transient ischemic incident stroke: a nationwide population-based cohort study in
attack of atherosclerotic origin. Stroke. 2020;51:3504–13. DOI: Korea. Front Neurol. 2019;10:52. DOI: 10.3389/fneur.2019.
10.1161/strokeaha.120.032239. 00052.
43. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undeter- 62. O’Donnell MJ, Chin SL, Rangarajan S, et al. Global and regional
mined source: the case for a new clinical construct. Lancet effects of potentially modifiable risk factors associated with acute
Neurol. 2014;13:429–38. DOI: 10.1016/s1474-4422(13)70310-7. stroke in 32 countries (INTERSTROKE): a case-control study.
44. Diener HC, Sacco RL, Easton JD, et al. Dabigatran for prevention of Lancet. 2016;388:761–75. DOI: 10.1016/s0140-6736(16)30506-2.
stroke after embolic stroke of undetermined source. N Engl J 63. Sharma M, Hart RG, Connolly SJ, et al. Stroke outcomes in the
Med. 2019;380:1906–17. DOI: 10.1056/NEJMoa1813959. cardiovascular outcomes for people using anticoagulation strate-
45. Secondary prevention in non-rheumatic atrial fibrillation after tran- gies (COMPASS) trial. Circulation. 2019;139:1134–45. DOI: 10.
sient ischaemic attack or minor stroke. EAFT (European Atrial 1161/circulationaha.118.035864.
Fibrillation Trial) study group. Lancet. 1993;342:1255–62. 64. Rioux B, Touma L, Nehme A, Gore G, Keezer MR, Gioia LC.
46. Andrade JG, Aguilar M, Atzema C, et al. The 2020 Canadian Frequency and predictors of occult cancer in ischemic stroke: a
cardiovascular society/Canadian heart rhythm society compre- systematic review and meta-analysis. Int J Stroke. 2021;16:12–9.
hensive guidelines for the management of atrial fibrillation. Can J DOI: 10.1177/1747493020971104.
Cardiol. 2020;36:1847–1948. DOI: 10.1016/j.cjca.2020.09.001. 65. Smith EE, Mountain A, Hill MD, et al. Canadian stroke best practice
47. Guimarães HP, Lopes RD, de Barros ESPGM, et al. Rivaroxaban in guidance during the COVID-19 pandemic. Can J Neurol Sci.
patients with atrial fibrillation and a bioprosthetic mitral valve. N 2020;47:474–8. DOI: 10.1017/cjn.2020.74.
Engl J Med. 2020;383:2117–26. DOI: 10.1056/NEJMo 66. Iodice F, Romoli M, Giometto B, et al. Stroke and digital technolo-
a2029603. gy: a wake-up call from COVID-19 pandemic. Neurol Sci.
48. Yasuda S, Kaikita K, Akao M, et al. Antithrombotic therapy for 2021;42:805–9. DOI: 10.1007/s10072-020-04993-3.
atrial fibrillation with stable coronary disease. N Engl J Med. 67. Nogueira R, Abdalkader M, Qureshi MM, et al. EXPRESS: global
2019;381:1103–13. DOI: 10.1056/NEJMoa1904143. impact of the COVID-19 pandemic on stroke hospitalizations
49. Thrombosis Canada. NOACs DOACs: Perioperative Management and mechanical thrombectomy volumes. Int J Stroke. 2021:
(May 2020). Available at: https://thrombosiscanada.ca/wp- 1747493021991652. DOI: 10.1177/1747493021991652.
uploads/uploads/2021/01/22.-NOACs-DOACs-Perioperative-Ma 68. O’Neill ZR, Deptuck HM, Quong L, et al. Who says “no” to
nagement-17May2020.pdf; accessed December 15, 2020. participating in stroke clinical trials and why: an observational
50. Douketis JD, Spyropoulos AC, Duncan J, et al. Perioperative study from the Vancouver stroke program. Trials. 2019;20:313.
management of patients with atrial fibrillation receiving a direct DOI: 10.1186/s13063-019-3434-0.

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