The 2020 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for the Secondary Prevention of Stroke includes current evidence-based recommendations and expert opinions intended for use by clinicians across a broad range of settings. They provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations address triage, diagnostic testing, lifestyle behaviors, vaping, hypertension, hyperlipidemia, diabetes, atrial fibrillation, other cardiac conditions, antiplatelet and anticoagulant therapies, and carotid and vertebral artery disease. This update of the previous 2017 guideline contains several new or revised recommendations. Recommendations regarding triage and initial assessment of acute transient ischemic attack (TIA) and minor stroke have been simplified, and selected aspects of the etiological stroke workup are revised. Updated treatment recommendations based on new evidence have been made for dual antiplatelet therapy for TIA and minor stroke; anticoagulant therapy for atrial fibrillation; embolic strokes of undetermined source; low-density lipoprotein lowering; hypertriglyceridemia; diabetes treatment; and patent foramen ovale management. A new section has been added to provide practical guidance regarding temporary interruption of antithrombotic therapy for surgical procedures. Cancer-associated ischemic stroke is addressed. A section on virtual care delivery of secondary stroke prevention services in included to highlight a shifting paradigm of care delivery made more urgent by the global pandemic. In addition, where appropriate, sex differences as they pertain to treatments have been addressed. The CSBPR include supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.# INTRODUCTION
Optimizing stroke prevention is a major public health priority. Stroke remains a leading cause of adult neurological disability (both physical and cognitive), dementia, and death globally. The seventh update of the Canadian Stroke Best Practice Recommendations (CSBPR) Secondary Prevention of Stroke guidelines includes a summary of current evidence-based recommendations for healthcare professionals. They focus on reducing the risk of recurrent stroke following an index ischemic stroke or transient ischemic attack (TIA) and are applicable to patients managed across a variety of care settings. They emphasize a coordinated and organized approach to assessment and aggressive risk factor management. The core elements of integrated and effective secondary stroke prevention services are included in the supplemental material, Appendix Four. Patient management aims to identify treatable risk factors, apply evidence-based treatment interventions to minimize risk, provide patient education and shared decision-making, and encourage patient adherence and persistence with treatment recommendations.
These recommendations have been developed in collaboration with the Canadian Stroke Consortium. We collaborate with the Canadian Cardiovascular Society, Thrombosis Canada, Diabetes Canada, and Hypertension Canada to ensure alignment of recommendations wherever possible. Those guidelines should be consulted for additional detail and information beyond the scope of the CSBPR. The Canadian Stroke Best Practice Recommendations (CSBPR) Secondary Prevention of Stroke 2020 Seventh Edition module supersedes all recommendations contained in the CSBPR Secondary Prevention of Stroke 2017 Sixth Edition module.

# GUIDELINE DEVELOPMENT METHODOLOGY
The CSBPR development and update process follows a rigorous framework 1,2 and addresses all criteria defined within the AGREE trust model. 3 The methodology for development and updates to the CSBPR has previously published 4,5 and detailed methodology can be found on our Canadian Stroke Best Practices website at www.strokebestpractices.ca. A broad interdisciplinary group of experts was convened and participated in reviewing, drafting, and revising all recommendation statements, and a panel of people with lived experience participated in a parallel review process. 6 Evidence levels were assigned based on the quality of available evidence and expert opinion. These guidelines have undergone extensive internal and objective external review and consensus was achieved for all content. For additional methodology and information on these recommendations, including rationale, system implications, performance measures, knowledge translation and implementation tools, and an extended summary of the evidence, please visit / recommendations/secondary-prevention-of-stroke.

# SECONDARY PREVENTION OF STROKE RECOMMENDATIONS Section 1: Triage and Initial Diagnostic Evaluation of Transient Ischemic Attack and Non-Disabling Stroke
An acute TIA or minor stroke is a medical emergency. Initial management aims to establish an accurate diagnosis, determine the likely etiology, and institute secondary prevention therapy as quickly as possible. Patients with acute TIA or minor stroke are at risk of recurrent stroke both in the short-term (particularly within the first week) 7 and long-term. 8 Our triage recommendations have been simplified to focus on patients presenting within the first 48 h of a suspected new acute TIA or stroke as they are at highest risk of early recurrent stroke. For such patients, immediate assessment is recommended, with imaging of both brain (head computerized tomography  or magnetic resonance imaging ) and vessels (ideally with a CT angiogram from aortic arch to vertex) on an urgent basis. 9 An embolic stroke or TIA can be the first manifestation of previously unrecognized atrial fibrillation. We recommend a tiered approach to searching for atrial fibrillation in patients with a new acute embolic ischemic stroke or TIA. 10 The goal of post-stroke electrocardiogram (ECG) monitoring is to detect high-burden atrial fibrillation for which anticoagulation would likely be beneficial. However, ECG monitoring often reveals brief subclinical paroxysmal atrial fibrillation, and it remains unclear what amount of device-detected atrial fibrillation warrants anticoagulation. Trials underway are evaluating this question. The effect of post-stroke prolonged ECG monitoring on hard clinical outcomes (i.e., recurrent stroke) remains to be determined and is the subject of ongoing research (FIND-AF2 trial, NCT04371055).
Echocardiography can be a valuable tool in the etiological assessment and risk stratification of patients with stroke and TIA. However, it can be overutilized and we recommend responsible use of this resource. Thus, the recommendations emphasize that echocardiography is not required for all stroke patients but should be considered for those with an embolic ischemic stroke or TIA of undetermined source (ESUS) or when a cardioembolic etiology or paradoxical embolism is suspected.
We have recommended against extensive thrombophilia testing for hereditary hypercoagulable disorders in the routine investigation of adults with arterial ischemic stroke events. Such testing is often overused in practice and should be limited to selected patients such as those with unexplained cerebral venous thrombosis or patent foramen ovale-related (PFO) paradoxical embolism.
An important lesson of the COVID-19 pandemic has been how essential remote or virtual contact with patients and families is to providing safe and timely care for stroke patients. In particular, care for patients living in rural or remote communities or patients for whom mobility and transport to clinic or hospital are prohibitive, can be improved via virtual care. Home blood pressure monitoring is encouraged in accordance with Hypertension Canada guidelines. 11 Home delivery of ECG patch monitors that can be self-applied by patients is a welcome option in regions where it is available. Virtual care interventions can be effective for blood pressure lowering, improvements in diet, increased physical activity, drug adherence, and satisfaction with access to care, 12 reduced HgbA1c, smoking cessation, 13 and reduced risk of cardiovascular events. 14 Section 1 Recommendations 2020 1.0 Patients with acute stroke or transient ischemic attack (TIA) who present to an ambulatory setting (such as primary care) or a hospital should undergo clinical evaluation by a healthcare professional with expertise in stroke care to determine risk for recurrent stroke and initiate appropriate and timely investigations and management strategies. 1. Referral to a healthcare professional with expertise in stroke care should be considered for patients with a suspected uncommon cause of stroke, including for young stroke patients (e.g., <45 years); 15 

# Section 2: Lifestyle Behaviors and Risk Factor Management
A healthy lifestyle, which includes a Mediterranean or Dietary Approaches to Stop Hypertension (DASH) diet, exercise, weight control, reduction, and avoidance of alcohol and tobacco, reduces the risk of an initial stroke and the risk of a subsequent stroke for patients with a prior history of stroke. Although individually, these habits can reduce the risk of stroke, their impact is greater when combined. Even greater impacts can be achieved with population level interventions for physical activity include investments in health promoting infrastructure (e.g., sidewalks, walking paths, bike lanes). At the core of these of interventions is a focus on making the healthy choice the easy choice. 

# Section 2.8 Clinical Considerations
Use of E-Cigarettes 1. Although some individuals may find vape products helpful in smoking cessation, the evidence base around their population-based effectiveness is not clear. 2. There is some evidence that shows people who use vaping as a mechanism to quit cigarettes may continue to vape even after cessation of cigarette use, in contrast to use of nicotine replacement therapy which has not been found to be continued in an ongoing basis. 16 

# Emerging evidence indicates an association between
vaping and elevated blood pressure; the strength of the association is not clear at this time. 4. The most common pattern of use in Canada is dual use of both vape and combustible tobacco products and therefore smoking cessation strategies should include consideration for both methods of nicotine consumption. 5. Education and counselling should be provided regarding the risks versus benefits of e-cigarettes in people with stroke, including in younger age groups who have experienced stroke. Hypertension is the major modifiable risk factor for stroke. In Canada, systolic hypertension is estimated to account for about 45% of the total stroke burden. 18 Although the optimal target blood pressure to prevent a first or recurrent stroke has not been formally established, the current treatment recommendation to attain a blood pressure of consistently lower than 140/90 mm Hg for people who have had an ischemic stroke or TIA, can help to reduce recurrent events. Using the results from a subset of 13 randomized controlled trials (RCTs) that included persons with a previous history of stroke, Law et al. 19 reported that blood pressure treatment resulting in a reduction of 10 mm Hg systolic and 5 mm Hg diastolic was associated with a 34% reduced risk of recurrent stroke (RR = 0.66, 95% CI 0.56-0.79). In the RE-SPECT trial, 20 persons with a history of stroke within the previous 30 d to three years who were randomized to a standard treatment group with a target of <140/90 mm Hg or an intensive treatment group with a target of <120/80 mm Hg, did not have a significantly reduced risk of recurrent stroke (HR = 0.73, 95% CI 0.49-1.11, p = 0.15); however, when these results were incorporated into an updated meta-analysis, the risk was reduced significantly with intensive therapy. The number needed to treat to prevent one recurrent stroke was 67, with an absolute risk reduction of 1.5%. Section 3 Clinical Considerations 1. (New for 2020) For patients with a non-revascularized critical intracranial or extracranial arterial stenosis who are experiencing neurological symptoms attributed to hemodynamic (low flow) cerebral or retinal ischemia (e.g., orthostatic TIAs), it is reasonable to aim for higher than usual blood pressure targets (i.e., permissive hypertension), and avoidance of hypotension, for prevention of hemodynamic stroke; if such patients are asymptomatic, then usual blood pressure targets should be followed in the post-acute phase of stroke.

# Section 4: Lipid Management
New evidence supports more aggressive lipid management for secondary stroke prevention. The recommended target low-density lipoprotein (LDL) cholesterol level has been lowered to <1.8 mmol/L, from previously recommended targets of LDL < 2.0 mmol/L or 50% LDL reduction. If this target cannot be achieved with maximum tolerated statin therapy, ezetimibe or a PCSK9 inhibitor may be added for ischemic stroke patients with atherosclerotic disease. Clinicians are reminded that lipid lowering therapies are not recommended for secondary prevention of intracerebral hemorrhage, or for patients with cardioembolic ischemic stroke (e.g., atrial fibrillation) in the absence of atherosclerotic disease.
The Treat Stroke to Target trial studied 2860 patients with atherosclerotic disease who had an ischemic stroke within the previous 3 months or a TIA within the previous 15 d. Treatment to an LDL cholesterol target <1.8 mmol/L, as compared to a target of 2.3-2.8 mmol/L, was associated with a lower risk of major cardiovascular events over a median of 3.5 years (8.5% vs. 10.9%, HR = 0.78, 95% CI 0.61-0.98; p = 0.04). 21 About a third of patients in this study required the addition of ezetimibe to their high-dose statin to achieve the more aggressive LDL target.
Treatment of hypertriglyceridemia with icosapent ethyl 2 g bid may be considered for patients with ischemic stroke who have established atherosclerotic cardiovascular disease, or diabetes plus additional vascular risk factors, and elevated serum triglycerides (1.5 mmol/L) despite statin therapy. In Canada, almost 2.5 million people have type 1 or 2 diabetes. 23 Diabetes is known to increase the risk of ischemic stroke by 227%. 24 Although tighter glycemic control along with other risk factor reduction strategies, can collectively help to reduce stroke risk, on its own, aggressive glycemic control does not reduce stroke risk. 25,26 However, trials of newer antihyperglycemic agents, including SGLT-2 and GLP-1 receptor agonists, have demonstrated benefit for major cardiovascular outcomes, including stroke.   1. The Pioglitazone after Ischemic Stroke or TIA trial 32 suggested that while there is a benefit of pioglitazone for stroke prevention in patients with positive insulin resistance, it is offset by the increased risk of fractures and bladder cancer. A post-hoc analysis of patients in the trial with prediabetes and good drug adherence suggested a benefit of pioglitazone over placebo with regards to stroke, acute coronary syndrome, stroke/myocardial infarction (MI)/hospitalization for heart failure, and progression to diabetes. The decision to use this agent could be considered based on the specific risk profile for each patient.
Section 6.0: Antiplatelet Therapy for Individuals with Ischemic Stroke or TIA Short-term administration of dual antiplatelet therapy with aspirin and clopidogrel is recommended for secondary stroke prevention, starting within 24 h for eligible patients with acute non-hemorrhagic high-risk TIA or minor ischemic stroke based on the POINT, 33 CHANCE, 34 and FASTER 35 trials. The optimal duration of dual antiplatelet therapy has been clarified by additional analyses 36,37 with net benefit of dual antiplatelet therapy over aspirin alone likely confined to the first 21 d post-TIA/stroke (maximal within the first 10 d). Compared with aspirin, the shortterm dual antiplatelet therapy protocol prevents 20 more strokes (and causes two major bleeds) for every 1000 patients treated. Pharmacogenetic testing can identify patients with clopidogrel resistance, however, its clinical implications for stroke prevention practice are unclear at this time.  Another short-term dual antiplatelet treatment option is the combination of daily low-dose aspirin and ticagrelor, a P2Y12 antagonist most often used in coronary artery disease. The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial tested a 30-d course of the aspirin-ticagrelor combination starting within 24 h of a high-risk TIA or minor ischemic stroke. 41 Ticagrelor was administered as a 180 mg loading dose followed by 90 mg twice daily, along with aspirin 75-100 mg daily. This combination reduced the risk of recurrent stroke or death compared with aspirin alone, although the risk of severe bleeding, intracranial bleeding, and fatal bleeding was higher in the ticagrelor-aspirin group. Maximum benefit was observed in patients with ipsilateral large vessel atherosclerotic disease. 42 The defining features of ESUS are an acute brain infarct visualized on neuroimaging (not a subcortical lacune 50%; no atrial fibrillation or other major risk cardioembolic source; and no other likely cause for the stroke. 43 Patients with ESUS have an average annual stroke recurrence risk of approximately 5%. Two trials published since the last edition investigated whether patients with ESUS would benefit more from anticoagulation than aspirin. Neither trial showed found a significant reduction in recurrent stroke risk and therefore anticoagulation is not recommended for patients with ESUS. 44,60 The lack of an overall benefit of anticoagulation likely reflects that ESUS comprises a heterogeneous group of many etiologies, with atherosclerotic or other mechanisms likely predominating over occult atrial fibrillation in the patients enrolled in these trials. The ARCADIA trial (NCT03192215) is testing apixaban versus aspirin in a subset of ESUS patients who have markers of atrial myopathy. 

# Section 7: Anticoagulant Therapy for Atrial Fibrillation
Oral anticoagulant therapy is strongly recommended for secondary stroke prevention in patients with atrial fibrillation. Anticoagulation for AF has been associated with a 66% relative risk reduction of recurrent stroke, with an absolute risk reduction of 7.3%. 45 Direct oral anticoagulants (DOACs) are generally preferred over warfarin for most patients with non-valvular atrial fibrillation (non-valvular is now defined as atrial fibrillation without moderate-severe mitral stenosis or mechanical heart valves). 46 A recent trial supports the use of rivaroxaban over warfarin for patients with atrial fibrillation and a bioprosthetic mitral valve. 47 Clinicians are reminded to avoid inappropriate underdosing of DOACs, a practice that is associated with increased stroke risk. For patients with atrial fibrillation and chronic stable coronary artery disease (or >1-year post-percutaneous coronary intervention  or coronary artery bypass graft ), the addition of an antiplatelet agent to chronic DOAC therapy is not recommended as it increases bleeding risk without providing additional benefit in reducing ischemic events (cardiac or cerebral). The Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE) trial showed that rivaroxaban alone was as effective as the combination of rivaroxaban and aspirin in this patient population, with a lower incidence of bleeding. 48 1. The optimal timing to start anticoagulant therapy after an ischemic stroke has not yet been well defined by clinical trial evidence and should be based on individual benefit/risk assessment taking into account the clinical circumstances, stroke severity, infarct size, imaging appearances, risk of hemorrhagic transformation, age, comorbidities, and estimated stroke recurrence risk. 2. There is a lack of randomized evidence to guide specific timing. According to expert consensus, a general approach to the target timing of initiation of DOAC therapy post-stroke is as follows: a. For patients with a brief TIA and no visible infarct or hemorrhage on imaging, anticoagulation may be started within the first 24 h post-TIA. b. For patients with a minor clinical stroke/small nonhemorrhagic infarct on imaging, anticoagulation may be started 3 d post-stroke. c. For patients with a moderate clinical stroke/moderatesized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 6-7 d post-stroke. d. For patients with a severe clinical stroke/large-sized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 12-14 d post-stroke. 3. If anticoagulation is delayed beyond 24 h, it is recommended to obtain repeat brain imaging for reassessment prior to initiation of anticoagulation to exclude the presence of asymptomatic hemorrhagic transformation of the index infarct.
- It is reasonable to delay the initiation of anticoagulation for more than 2 weeks post-stroke if in the judgement of the clinician the risk of intracranial bleeding is felt to be high, for example, for some patients with large infarcts and those with hemorrhagic transformation.
Stroke while on DOAC Therapy 1. (New for 2020): For patients with atrial fibrillation who experience ischemic stroke or TIA despite anticoagulant therapy, either continuing the current agent or switching to a different anticoagulant agent are reasonable options. At the present time, evidence is lacking to make more specific recommendations. 2. The routine addition of acetylsalicylic acid to chronic anticoagulant therapy is not recommended because of increased bleeding risk without clear evidence of benefit and potential for harm unless there is a specific medical indication. months or more frequently) may be considered for patients with renal impairment or a dehydrating illness for medication adjustment if required, particularly for patients receiving dabigatran . iv. For patients taking chronic oral anticoagulant therapy for non-valvular atrial fibrillation, the addition of antiplatelet therapy is not recommended due to increased bleeding risk unless there is a specific medical indication for antiplatelet therapy (e.g., recent vascular stent; certain mechanical heart valves) . v. (New for 2020): For patients with atrial fibrillation and chronic stable coronary artery disease (and >1-year post-PCI or CABG), the addition of an antiplatelet agent to DOAC therapy is not recommended as it increases bleeding risk without providing any significant benefit in reducing ischemic events (cardiac or cerebral) .
Section 8: Perioperative Management of Anticoagulant and Antiplatelet Therapy (New for 2020)
This edition features a new section on perioperative antithrombotic managementa commonly encountered issue in the stroke population and one in which practice variations abound. Our recommendations are aligned with Thrombosis Canada. 49 For stroke or TIA patients who require temporary interruption of chronic antiplatelet or anticoagulant therapy for an upcoming elective surgery, decisions regarding the duration of therapy interruption depend on the agent and the estimated bleeding risk associated with the surgery or procedure. The goal is to minimize the risk of ischemic stroke while simultaneously minimizing the risk of clinically important (major) bleeding. Patients should avoid unnecessary or prolonged interruptions of their antithrombotic therapy. Clinicians should communicate clear instructions to patients regarding their perioperative management plan before an elective procedure.
Because DOACs have a rapid offset (average half-life of approximately 12 h) and a rapid onset of action, the duration of DOAC interruption can be kept short to minimize the risk of ischemic stroke. This approach of standardized DOAC interruption and resumption appeared safe in the Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study of 3007 DOACtreated patients; the 30-d post-operative rates of arterial thromboembolism and major bleeding were <1% and <2%, respectively. 50 For patients undergoing a minimal-bleed-risk procedure, anticoagulants can generally be continued without interruption, with some caveats; for DOACs, it is reasonable to omit the morning DOAC dose before the procedure to reduce bleeding risk.

# Descriptions of type of surgery or procedure and bleeding risk category:
- A high-bleed-risk surgery or procedure includes major abdominal surgery (e.g., cancer resection), major thoracic surgery, major orthopedic surgery, and any cardiac, spinal, or intracranial surgery. Any patient having neuraxial anesthesia is classified as high-bleed-risk because of the risk for spinal epidural hematomas which could cause limb paralysis.
- A low-to-moderate-bleed-risk surgery or procedure includes most surgeries that are <1-h duration and procedures that do not involve neuraxial anesthesia.
- A minimal-bleed-risk surgery or procedure includes tooth extractions, root canal, skin biopsies, cataract surgery, and selected colonoscopies, for which anticoagulants can be continued without interruption. Permanent pacemaker and internal cardiac defibrillator implantation, as well as cardiac catheterization, also can be done without stopping anticoagulants.

# Section 8 Recommendations 2020
i. Patients with atrial fibrillation or a mechanical heart valve who are receiving oral anticoagulant therapy and require a procedure associated with a minimal risk of bleeding (e.g., tooth extraction, skin biopsy, cataract removal, cardiac pacemaker) should not have anticoagulation interrupted around the time of the procedure . ii. For patients with atrial fibrillation receiving a DOAC for stroke prevention who require temporary DOAC interruption for an elective surgery or procedure, the following approach is recommended : a. For a low-to-moderate-bleed-risk surgery or procedure, stop the DOAC the day before the procedure and the day of the procedure (i.e., skip 2 d total), and restart the day after the procedure. b. For a high-bleed-risk surgery or procedure, stop the DOAC 2 d before the procedure, the day of the procedure, and one day after the procedure (i.e., skip 4 d total). Note: An exception involves patients on dabigatran with impaired renal function (CrCl <50 mL/min) in whom an additional 1-2 d of interruption is suggested before surgery or procedure. Refer to clinical considerations for additional information. iii. For patients with atrial fibrillation receiving warfarin for stroke prevention who require temporary warfarin interruption for an elective surgery or procedure: a. For patients at low-to-moderate stroke risk (e.g., CHADS2 score 0-4), warfarin should be stopped for 5 d pre-procedure, and resumed within 24 h post-procedure, without heparin bridging . 

# Section 8 Clinical Considerations
Perioperative management of patients undergoing a minimal-bleed-risk procedure 1. For patients undergoing minor procedures that are considered minimal-bleed-risk (refer to definition above), it is not routinely necessary to stop anticoagulants. However, there are some caveats to the management of such patients: a. Any of the minimal-bleed-risk procedures could be considered as having a higher bleed risk warranting anticoagulant interruption (e.g., tooth extraction in a patient with poor dentition or cataract surgery with retrobulbar anesthesia) based on individual patient circumstances. b. In patients receiving a DOAC who are undergoing a minimal bleed-risk procedure, it is prudent to omit the morning DOAC dose just before the procedure because the peak anticoagulant effect, occurring 1-3 h after intake, may coincide with the timing of the procedure and may increase the risk for bleeding. c. For pacemaker or ICD implantation, patients can continue warfarin, but the INR should be <3.0 at the time of the procedure. d. For coronary angiography, continuing anticoagulants if a femoral artery approach is used may not be advisable as such patients are at increased risk for developing a hematoma or false aneurysm. e. For colonoscopy, anticoagulation can be continued in selected patients in which the likelihood of polypectomy or multiple biopsies is low.
f. For dental procedures, oral tranexamic acid mouthwash can be used before and 2-3 times daily after the procedure to reduce bleeding since such oral bleeding, although not clinically important, may cause distress to patients. Carotid endarterectomy (CEA) has been shown to prevent stroke recurrence in patients who have sustained a minor stroke or TIA with ipsilateral high-grade carotid stenosis. For those with 50%-99% stenosis, the number of persons needed to undergo surgery to prevent one ipsilateral stroke in five years was estimated to be 9 for men versus 36 for women. Women with symptomatic disease had significantly higher odds of 30-d mortality following CEA compared with men. (adjusted OR = 1.4, 95% CI 1.02-1.94). 51 The use of CEA for asymptomatic carotid artery disease is controversial. One-year results from the recent SPACE-2 trial, 52 indicated there were no significant differences between groups (CEA vs. best medical management) in the occurrences of any stroke after day 30, up to one-year, ipsilateral stroke, disabling stroke, any death, myocardial infarction, restenosis or TIA. The trial was terminated early due to low recruitment. In this same trial, there were no significant differences in the same outcomes for the comparison of best medical management versus carotid-artery angioplasty.  53 and additional meta-analyses and other reports further support PFO closure for secondary stroke prevention in selected patients.  Given that TIA can be difficult to differentiate from mimics and the fact that only one of the PFO trials enrolled patients with TIA as an index event, clinicians should be cautious when contemplating PFO closure for TIA unless there is a high certainty of ischemia; accordingly, these 2021 recommendations no longer indicate TIA as an unqualified indication for closure. There is now moderatestrength evidence that PFO closure may be targeted to patient groups with higher risk echocardiographic features.
For patients with heart failure and without atrial fibrillation, the COMMANDER-HF trial, 57 which compared rivaroxaban to standard care, found no significant difference in the frequency of the primary outcome (a composite of death from any cause, MI, or stroke) between groups. The risks of the individual components of the primary outcome did not differ between groups with the exception of the risk of stroke, which was reduced significantly with rivaroxaban (1.08 vs. 1.63 events/100-person years; HR = 0.66, 95% CI 0.47-0.95). In the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, 58 which compared the effectiveness of anticoagulation compared with antiplatelet therapy for stroke prevention in patients with heart failure in sinus rhythm, warfarin was associated with a significantly reduced risk of ischemic stroke (HR = 0.52, 95% CI 0.33-0.82, p = 0.005); however, the risks of major and minor hemorrhages were significantly increased. 59 A diagnosis of cancer can increase the risk of stroke in the months or years following the diagnosis, particularly among persons with lung cancer or with more advanced cancers. 60,61 Thrombosis is a common complication of malignancy and represents a frequent cause of death in cancer patients with a history of stroke. 

# CHALLENGES AND FUTURE DIRECTIONS
Advances in stroke prevention, driven by high-quality clinical studies, continue to inform each new edition of these guidelines.
However, we are still far from adequately addressing, at a global level, the 10 modifiable risk factors that account for 90% of the population attributable risk of stroke. 62 The largest impact on stroke prevention globally will likely be achieved by continued large-scale efforts to address hypertension, diabetes, diet, exercise, smoking, in addition to atrial fibrillation at both policy and individual levels.
A key tenet of secondary stroke prevention remains the importance of identifying the most likely stroke etiology and tailoring therapy accordingly. Although the completed ESUS trials found no overall benefit of anticoagulation, further research aims to identify whether specific subgroups may benefit. Dual pathway inhibition is a promising strategy. 63 Newer anticoagulants targeting factor XI represent promising future treatments for stroke prevention. Studies are ongoing (NCT02604667) and others are needed to better define when and how occult cancer should be investigated in cryptogenic stroke patients, and if found, what antithrombotic regimen best protects these patients from recurrent arterial strokes. 64 Immediate challenges to optimal secondary stroke prevention would therefore include the need to develop, grow, and maintain systems for virtual delivery of care to patients through telemedicine. 65,66 The SARS-CoV2 virus represents a well-documented challenge to acute stroke care 67 but its impact on the risk of stroke recurrence, either directly among patients having been infected with the virus, or on other patients who have suffered collateral damage from diminished access to stroke care, will be important to now study.
A challenge that concerns research in all fields of medicineincluding stroke 68 is the need to ensure adequate sex and gender representation in therapeutic trials to ensure generalizability of results to both men and women. This edition is the first of our guidelines to start incorporating a sex and gender descriptive analysis into the literature review for each recommendation, and future editions will strive to include gender and sex-based recommendations where appropriate.

# SUMMARY
The 2020 update of the Canadian Stroke Best Practice Secondary Prevention of Stroke Recommendations provide a common set of guiding principles for important aspects of secondary stroke prevention, emphasizing that individuals who have experienced a stroke or TIA require access expert prevention care in a timely way. In Canada, coordinated systems have evolved over time, growing the number of stroke prevention services and protocols to increase access in many under-serviced areas. In the age of Covid-19, there are new opportunities to provide prevention interventions remotely to narrow the inequities in access to care.