Notes: These recommendations are applicable to ischemic stroke and transient ischemic attack. These recommendations focus on atrial fibrillation in the context of secondary prevention of stroke. For information on the primary prevention of stroke in individuals with non-valvular atrial fibrillation (AF), please refer to the current Canadian Cardiovascular Society/Canadian Heart Rhythm Society (CCS/CHRS) Guidelines for the Management of Atrial Fibrillation: Prevention of Stroke and Systemic Thromboembolism in Atrial Fibrillation and Flutter (October 2020).
Non-valvular atrial fibrillation refers to atrial fibrillation in the absence of moderate to severe mitral stenosis or mechanical heart valve (CCS 2020 AF guideline).
DOAC refers to Direct (non-vitamin K) Oral Anticoagulant.
7.1 Detection of Atrial Fibrillation following Stroke
Patients with suspected ischemic stroke or transient ischemic attack should have a 12-lead ECG to assess for atrial fibrillation, myocardial infarction, or structural heart disease (e.g., left ventricular hypertrophy) as potential causes or risk factors of stroke [Evidence Level B].
For patients being investigated for an acute embolic ischemic stroke or transient ischemic attack, ECG monitoring for 24 hours or more is recommended as part of the initial stroke work-up to detect paroxysmal atrial fibrillation in patients who would be potential candidates for anticoagulant therapy [Evidence Level A].
For patients being investigated for an embolic ischemic stroke or transient ischemic attack of undetermined source whose initial short-term ECG monitoring does not reveal atrial fibrillation but a cardioembolic mechanism is suspected, prolonged ECG monitoring for at least 2 weeks is recommended to improve detection of paroxysmal atrial fibrillation in selected patients aged ≥ 55 years who are not already receiving anticoagulant therapy but would be potential anticoagulant candidates [Evidence Level A]. Refer to CSBPR Secondary Prevention of Stroke Module for additional guidance in management of patients with stroke and atrial fibrillation, and the Canadian Cardiovascular Society current recommendations on atrial fibrillation.
(NEW FOR 2020): For patients aged >65 years with ischemic stroke or transient ischemic attack, routine pulse palpation is recommended to screen for undiagnosed atrial fibrillation [Evidence Level C].
7.2 Secondary Stroke Prevention in Patients with Atrial Fibrillation
Patients with ischemic stroke or transient ischemic attack and atrial fibrillation should receive oral anticoagulant therapy for secondary stroke prevention [Evidence Level A]. Refer to Appendix Four for additional information on selection of anticoagulant medications.
(NEW FOR 2020): For patients with an ischemic stroke or transient ischemic attack and atrial fibrillation, oral anticoagulant therapy is strongly recommended [Evidence Level A]. It is recommended over acetylsalicylic acid [Evidence Level A] and dual antiplatelet therapy [Evidence level B].
For most patients requiring anticoagulants for atrial fibrillation, a direct oral anticoagulant (DOAC) such as apixaban, dabigatran, edoxaban, or rivaroxaban should be prescribed in preference over warfarin [Evidence Level A].
For patients already receiving warfarin with good International Normalized Ratio (INR) control (range 2.0 – 3.0, with time in therapeutic range (TTR) of >70%) and without adverse effects, continuing warfarin, rather than switching to a DOAC, is a reasonable anticoagulant option [Evidence Level B]. Patient preferences should be considered in decision-making [Evidence Level C].
When selecting an oral anticoagulant, patient specific criteria should be considered [Evidence Level C]. Refer to Appendix 4 for Selection of Anticoagulant Agents for Management of Atrial Fibrillation after stroke or transient ischemic attack.
For patients with acute ischemic stroke and atrial fibrillation who are being started on warfarin, routine use of bridging with heparin is not recommended [Evidence Level B].
Bridging with antiplatelet therapy (e.g., low-dose acetylsalicylic acid) is suggested until the patient is anticoagulated within therapeutic range [Evidence Level C]. Refer to Secondary Prevention of Stroke Section on Antiplatelet Therapy for Ischemic Stroke and Transient Ischemic Attack for additional information.
For patients with ischemic stroke or transient ischemic attack and atrial fibrillation who are unable to take oral anticoagulant therapy (DOAC or warfarin), acetylsalicylic acid alone is recommended unless also contraindicated [Evidence Level A].
For patients at high risk of bleeding, dual antiplatelet therapy is not recommended in preference to anticoagulation as the risks of bleeding are comparable, and dual antiplatelet therapy is less effective for stroke prevention [Evidence Level B].
For ischemic stroke or transient ischemic attack in patients with non-valvular atrial fibrillation who cannot receive long-term oral anticoagulant therapy, a left atrial appendage occlusion procedure may be considered [Evidence Level B]. Refer to current Canadian Cardiovascular Society guideline for Atrial Fibrillation for additional information.
For patients with a mechanical heart valve, warfarin is recommended for stroke prevention with careful INR monitoring; direct oral anticoagulants (DOACs) are contraindicated [Evidence Level B]. Note, patients with bioprosthetic heart valves do not routinely require long-term anticoagulation. Refer to Thrombosis Canada Clinical Guide for additional information regarding INR targets and concomitant acetylsalicylic acid for different valve types and locations (https://thrombosiscanada.ca/clinicalguides/#)
NEW RECOMMENDATION FOR 2020: For patients with atrial fibrillation who experience ischemic stroke or transient ischemic attack in spite of anticoagulant therapy, we recommend the following: (1) identify and address medication nonadherence; (2) ensure correct DOAC dosing or warfarin INR control; (3) avoid DOACs drug-drug interactions; (4) investigate for and treat other potential stroke etiologies, and (5) promote general vascular risk factor modification [Evidence Level C]. Refer to current Canadian Cardiovascular Society guideline for Atrial Fibrillation secondary prevention of stroke section for additional information.
Section 7.2 Clinical Considerations Revised for 2020
Timing of Initiation of Oral Anticoagulant Therapy following Acute Stroke:
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.
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 poststroke is as follows:
a. For patients with a brief transient ischemic attack and no visible infarct or hemorrhage on imaging, anticoagulation may be started within the first 24 hours post- transient ischemic attack.
b. For patients with a minor clinical stroke/small non-hemorrhagic infarct on imaging, anticoagulation may be started 3 days post-stroke.
c. For patients with a moderate clinical stroke/moderate-sized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 6-7 days 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 days post-stroke.
If anticoagulation is delayed beyond 24 hours, 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, e.g., for some patients with large infarcts and those with hemorrhagic transformation.
Stroke while on DOAC Therapy
(NEW FOR 2020): For patients with atrial fibrillation who experience ischemic stroke or transient ischemic attack 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.
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.
7.3 Enhancing anticoagulant therapy effectiveness in practice and minimizing bleeding complications.
Medication adherence should be continually assessed and reinforced for patients on all oral anticoagulants at each follow-up visit [Evidence Level B].
Patients who are prescribed a DOAC should be reassessed at intervals and educated regarding the short half-life of this class of drugs, the importance of daily medication adherence and the dangers of missed doses or prolonged interruptions of therapy [Evidence Level C].
For patients with atrial fibrillation taking warfarin, careful dosing and consistent INR monitoring is recommended to minimize adverse events; warfarin efficacy is dependent on maintaining therapeutic INR control and declines significantly when the international normalized ratio falls below 2.0 [Evidence Level A].
Patients and family members should be provided education, resources, and ongoing monitoring regarding atrial fibrillation and adherence to enhance compliance and address potential barriers in a timely way to facilitate self-management [Evidence Level C].
New for 2020: For patients prescribed DOAC therapy, avoid inappropriate under-dosing as it is associated with increased stroke risk [Evidence Level C].
For patients prescribed DOACs, creatinine clearance should be routinely monitored at least once annually, and when there is a change in health status [Evidence Level C]. Refer to Appendix Four for Selection of Anticoagulant Agents for Management of Atrial Fibrillation after stroke or transient ischemic attack.
Dose adjustments or a change in selected agent may be required based on changes in renal function if detected [Evidence Level C].
More frequent monitoring of renal function (every 6 months or more frequently) may be considered for patients with renal impairment or a dehydrating illness for medication adjustment if required, particularly for patients receiving dabigatran [Evidence Level C].
For patients taking chronic oral anticoagulant therapy for non-valvular atrial fibrillation, the addition of antiplatelet therapy is not recommended due to increased bleeding risk unless there is a specific medical indication for antiplatelet therapy (e.g., recent vascular stent; certain mechanical heart valves) [Evidence Level B]. Refer to Section 7.2 (iv) for information on mechanical valves.
(New for 2020): For patients with atrial fibrillation and chronic stable coronary artery disease (and >1-year post-PCI or CABG), the addition of an antiplatelet agent to DOAC therapy is not recommended as it increases bleeding risk without providing any significant benefit in reducing ischemic events (cardiac or cerebral) [Evidence Level B]. Refer to current Canadian Cardiovascular Society Atrial Fibrillation guidelines for patients with recent coronary ischemic events.
Refer to current Canadian Cardiovascular Society Atrial Fibrillation guidelines and Thrombosis Canada Clinical Guide for additional information on detection and management of atrial fibrillation.
Refer to Thrombosis Canada clinical guide for peri-operative management of patients on oral anticoagulant therapy at https://thrombosiscanada.ca/clinicalguides
Atrial fibrillation (AF) is a significant risk factor for stroke, and a strong example of the heart brain connection. One in six patients admitted to hospital in Canada with ischemic stroke have atrial fibrillation, and this proportion increases with age. Since AF can be paroxysmal and subclinical, AF may go undetected.
In the general population, people with atrial fibrillation who are not treated with anticoagulant therapy are at a 3 – to – 5 times increased risk of stroke. Most strokes in individuals with atrial fibrillation are potentially preventable with anticoagulant therapy. The number needed to treat (NNT) to prevent one recurrent stroke (i.e., secondary prevention) was 12 with warfarin (compared with placebo) (Hart 2007). The newer class of direct oral anticoagulants (DOAC) have been shown to be as effective as warfarin with decreased bleeding risk. The number needed to treat (NNT) to prevent one recurrent stroke (i.e., secondary prevention) when being treated with DOACs compared to warfarin has been reported at 65 (Park et al, 2019) and to prevent the composite outcome of recurrent stroke or major bleeding the NNT is 48. Detection of atrial fibrillation is a critical step in stroke workups. Searching for atrial fibrillation post-stroke with prolonged ECG monitoring has been found to increase detection rates significantly, thereby enabling treatment aimed at preventing recurrent stroke.
As with all management strategies aimed at reduction in recurrent stroke and transient ischemic attack, compliance by individuals who have had a stroke or transient ischemic attack is an important component of risk reduction and they often require support from their healthcare team and family to be successful. When discussing anticoagulation for atrial fibrillation, people who have experienced stroke emphasized the need for health professionals to understand the magnitude of the heart-brain connection and to explain this link clearly to patients and families. This is especially important for health professionals right from initial contact with someone experiencing a stroke, such as emergency department teams. Following stroke, individuals often experience challenges in managing new medications or maintaining previous prescriptions, and report confusion when different members of their circle of care provide inconsistent guidance with regards to their anticoagulant medication.
- Increased public awareness of atrial fibrillation as a risk factor for stroke.
- Establishment of stroke prevention clinics to improve secondary stroke prevention including management of atrial fibrillation in patients with stroke and transient ischemic attack (effective, consistent prevention with early recognition of risk factors and timely, targeted interventions).
- A process for appropriate outpatient monitoring of patients’ international normalized ratio and follow-up communication with patients taking anticoagulants.
- Optimization of comprehensive strategies at the local, regional and provincial levels to prevent the recurrence of stroke.
- Stroke prevention awareness and education about secondary prevention for primary care practitioners and specialists who manage stroke patients during the acute phase and after discharge from acute care, including content regarding the heart-brain connection and the importance of integrated care that addresses vascular risk factors in a coordinated manner.
- For patients taking warfarin, access to a dedicated anticoagulant management clinic is associated with better patient outcomes compared to routine medical care.
- Universal and equitable access to cost-effective medicines for all people in Canada, regardless of ability to pay or geography, through private and/or public drug coverage plans which can help manage atrial fibrillation.
- Proportion of acute ischemic stroke patients with atrial fibrillation who are treated with anti-coagulant therapy.
- Proportion of eligible stroke and transient ischemic attack patients with atrial fibrillation prescribed anticoagulant therapy on discharge from acute care.
- Proportion of eligible stroke and transient ischemic attack patients with atrial fibrillationprescribed anticoagulant therapy after a visit to a secondary prevention clinic.
- Proportion of atrial fibrillation patients taking anticoagulant therapy at the time of hospital admission for acute ischemic stroke or transient ischemic attack.
- Proportion of atrial fibrillation patients with stroke or transient ischemic attack on antiplatelet therapy and not prescribed anticoagulant therapy.
- Proportion of atrial fibrillation patients with stroke or transient ischemic attack continuing on anticoagulant therapy at 3 months, 6 months, and 1 year following initiation of therapy.
- For atrial fibrillation patients on warfarin, the proportion with an international normalized ratio in the therapeutic range at three months.
- Heart & Stroke: Post-Stroke Checklist
- CSBPR: Secondary Prevention of Stroke: Appendix Four: Oral Anticoagulants for the Prevention of Stroke in Individuals with Atrial Fibrillation
- Canadian Cardiovascular Society: 2020 CCS/CHRS Comprehensive Guidelines for the Management of Atrial Fibrillation
- Canadian Cardiovascular Society Atrial Fibrillation Pocket Guides
- Canadian Cardiovascular Society tools (app, slide decks, pocket guides, e-learning)
- Thrombosis Canada Clinical guides
- Thrombosis Canada Clinical Tools (including Direct Oral Anticoagulant (DOAC) Follow-Up Checklist)
Anticoagulant Therapy for Atrial Fibrillation in Individuals with Ischemic Stroke or Transient Ischemic Attack
Evidence Table and Reference List
Detecting Atrial Fibrillation
Atrial fibrillation (AF) is a common arrhythmia, associated with an increased risk of ischemic stroke. Detecting AF in patients following minor stroke or transient ischemic attack, is important particularly in those with a cryptogenic stroke or embolic stroke of unknown source, since once identified, it can be effectively managed. Typically, this entails a change from an antiplatelet to an anticoagulant. However, AF is under-diagnosed because it is frequently paroxysmal and asymptomatic, and patients do not routinely undergo prolonged screening. AF can be detected using a variety of methods including a12-lead electrocardiogram (ECG), Holter monitoring, event recorders and implantable devices.
Prolonged ECG monitoring using wearable or insertable devices has been shown to be effective for improving the detection of paroxysmal AF (numbers needed to screen range from 8-14), with longer monitoring durations associated with an increased probability of AF detection. A systematic review and meta-analysis (Tsivgoulis et al. 2019) included the results from 2 RCTs (FIND-AF and Crystal AF and 2 observational studies). The outcomes of persons who received prolonged cardiac monitoring (PCM) using implantable cardiac monitoring or ambulatory ECG monitoring, were compared with patients who received conventional (non-PCM) cardiac monitoring. Among persons who received PCM, AF was detected more frequently (RR=2.46; 95% CI, 1.61–3.76), the risk of recurrent stroke and recurrent stroke or transient ischemic attack during follow-up was significantly lower (RR=0.45; 95% CI, 0.21–0.97 and RR=0.49; 95% CI, 0.30–0.81, respectively) and anticoagulation therapy was initiated more frequently (RR=2.07; 95% CI, 1.36–3.17).
In the FIND-AF Randomized trial, Wachter et al. (2016) recruited 398 patients, >60 years admitted with acute ischemic stroke, within 7 days of symptom onset, in sinus rhythm at admission and without a history of AF. Patients were randomized to receive prolonged Holter ECG monitoring for 10 days, starting in the first week post stroke, and repeated at 3 and 6 months or standard care (an average of 73 hours of inpatient telemetry plus an average of 24 hours of Holter monitoring). At both 6 and 12 months, detection of AF was significantly higher in the prolonged monitoring group (13.5% vs. 4.5% and 13.5% vs. 6.1%, respectively). The associated numbers needed to screen were 11 and 13. There were no significant differences between groups in stroke recurrence (2.5 vs. 4.5%, p=0.28) or death (3.0 vs. 4.5%, p=0.45). A UK trial (Higgins et al. 2013) that randomized 100 patients with no history of AF and in sinus rhythm, reported that a strategy of 7-day ECG monitoring in the acute phase post-stroke was superior to standard care for the detection of paroxysmal AF (18% vs. 2%; p<0.05). Significantly more patients who received additional monitoring were started on anticoagulants. Among persons with nonacute stroke, Gladstone et al. (2014), found 30-day ambulatory cardiac event monitor to be superior to repeat 24-hour Holter monitoring in identifying AF in 572 patients aged 52 to 96 years without known AF, who had sustained a cryptogenic ischemic stroke or transient ischemic attack within the previous 6 months. Atrial fibrillation lasting ≥30 seconds was detected more frequently in persons using the cardiac event monitor (16.1% vs. 3.2%, absolute difference, 12.9%; 95% CI 8.0 to 17.6; p<0.001; number needed to screen= 8). The cardiac event monitor was also more likely to identify cases of AF lasting longer than ≥2.5 minutes (9.9% vs. 2.5%, absolute difference, 7.4%, 95% CI, 3.4 to 11.3; p<0.001). By 90 days, oral anticoagulant therapy had been prescribed for more patients in the intervention group (18.6% vs. 11.1%, p=0.01). Three-quarters of AF cases identified in the intervention group were detected within the first 2 weeks of monitoring.
Warfarin is well established as an effective medication for reducing the risk of stroke in patients with AF and atrial flutter and has been evaluated in a variety of adjusted-dose regimens, alone and in combination with ASA, as well as in low intensity and fixed, mini-dose treatment plans. A systematic review & meta-analysis (Hart et al. 2007) included the results of 29 trials involving 28,044 patients who had non-valvular atrial fibrillation. Six of the included trials compared placebo with adjusted-dose warfarin (2,900 participants, 20% with previous stroke or transient ischemic attack). Treatment with adjusted dose warfarin was associated with a 64% reduction in all strokes (ARR= 2.7%/year, NNT=37 for primary prevention; ARR=8.4%/year, NNT=12 for secondary prevention of stroke) and a 67% reduction for ischemic stroke. Mean INRs ranged from 2.0 – 2.6 in primary prevention studies and was 2.9 in the only secondary prevention study included. In trials that compared the effectiveness of warfarin with other antiplatelets, including clopidogrel and dipyridamole, the use of warfarin was associated with a 37% reduction in all strokes (95% CI 23%- 48%). An increased risk of intracranial hemorrhage was found to be associated with the use of adjusted-dose warfarin, although it was very small (absolute risk=0.2%/year).
The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study recruited 973 patients (12.5% with previous stroke or transient ischemic attack aged 75 years or greater from primary care and randomly assigned them to receive adjusted-dose warfarin (INR 2.0 - 3.0) or ASA (75 mg once daily) and followed them for a mean of 2.7 years (Mant et al. 2007). The primary endpoint was fatal or disabling stroke (ischemic or hemorrhagic), other intracranial hemorrhage, or clinically significant systemic embolism. There were fewer primary events among participants assigned to warfarin (21 strokes, 2 other intracranial hemorrhages, and 1 systemic embolus), compared to those assigned to ASA (48 primary events: 44 strokes, 1 other intracranial hemorrhage, and 3 systemic emboli). The corresponding annual risks were 1.8% vs. 3.8%, RRR=52%, 95% CI 20-72%, p=0.003. To prevent one event each year, the number needed to treat was 50. The annual risk of extracranial hemorrhage was 1.4% for patients assigned warfarin and 1.6% for those assigned ASA. A Cochrane review authored by Saxena & Koudstaal (2004) also examined the effectiveness of oral anticoagulants with antiplatelet therapy in individuals with non-rheumatic (non-valvular) AF and history of previous stroke or transient ischemic attack. Two RCTs were included. The European Atrial Fibrillation Trial (EAFT) included 455 patients within three months of transient ischemic attack or minor stroke who were randomly assigned to warfarin (INR 2.5 to 4.0) or ASA (300 mg/day) and followed for a mean of 2.3 years (EAFT 1993). The Studio Italiano Fibrillazione Atriale (SIFA) trial included 916 patients within 15 days of transient ischemic attack or minor stroke who were randomized to open-label warfarin (INR 2.0 to 3.5) or indobufen (a reversible platelet cyclooxygenase inhibitor, 100 or 200 mg twice a day), and followed for one year (Morocutti 1997). Pooled analysis of the 2 trials revealed a significant protective effect in favour of anti-coagulant therapy over antiplatelet therapy for all vascular events (OR=0.67, 95%CI 0.50, 0.91) and for recurrent stroke (OR=0.49, 95% CI 0.33, 0.72). In terms of absolute risk, anticoagulant therapy was associated with a risk of approximately 4% per year in both studies, whereas the risk was 10%/year and 5%/year for individuals assigned to treatment with antiplatelet therapy in the EAFT and SIFA study, respectively. Warfarin use was not associated with significant increases in the risk of intracranial bleeding. Although major extracranial bleeding complications occurred more often in patients on warfarin (OR=5.16, 95% CI 2.08–12.83), the absolute difference was small (2.8% vs. 0.9%/year in EAFT and 0.9% vs. 0%/year in SIFA).
Novel Anticoagulants (versus warfarin)
In response to some of the management challenges associated with warfarin use such as the need for frequent monitoring and food and drug interactions, several new (novel) oral anticoagulants have been developed. Dabigatran, one such agent, is a direct thrombin inhibitor with a serum half-life of 12 to 17 hours, which was evaluated in the landmark Randomized Evaluation of Long-term anticoagulant therapy (RE-LY) trial (Connolly et al. 2009), which included 18,113 patients with AF and at least one other stroke risk factor. Patients were randomly allocated to receive dabigatran (110 mg or 150 mg twice daily) or warfarin (adjusted to an INR of 2.0-3.0) and followed for a median of two years. The primary outcome was a composite of stroke or systemic embolism. Both doses of dabigatran were found to be non-inferior to warfarin therapy in terms of risk for stroke or systemic embolism. In addition, the fixed dose of 150 mg was superior to warfarin therapy for the primary study outcome (RR=0.66, 95% CI 0.53, 0.82, p<0.001). However, when the subgroup of patients with previous transient ischemic attack /stroke were analysed separately, neither the 110 mg dose of dabigatran nor the 150 mg dose was associated with significant reductions in risk for recurrent events when compared with warfarin (p=0.65 and p=0.34, respectively). Compared to warfarin, the risks for major bleeding events, including life-threatening bleeding, intracranial bleeding, and gastrointestinal bleeding, were reduced in the 110 mg group only (RR=0.80, 95% CI 0.69, 0.93, p = 0.003), while the 150 mg dose was associated with increased risk for gastrointestinal bleeding (RR=1.50, 95% CI 1.19, 1.89, p<0.001). During the long-term extension of the RELY-ABLE trial (Connolly et al. 2013), which included 5,851 participants who had been assigned to either of the dabigatran dosing schedules in the original trial, the annual rates of stroke or systemic embolism were 1.46% and 1.6% in the 150 mg and 110 mg dose groups, respectively. The risk of this combined outcome was not significantly different between groups (HR=0.91, 95% CI 0.69-1.20). Similarly, annual rates of ischemic stroke were 1.15% in the 150 mg group and 1.24% in the 110 mg group (HR=0.92, 95% CI 0.67, 1.27), with low incidences of hemorrhagic stroke and myocardial infarction in both groups. There was a significantly increased risk of bleeding events associated with the higher dose of dabigatran (3.74% vs. 2.99%; HR=1.26, 95% CI 1.04-1.53), although gastrointestinal bleeding events were similar in both groups (1.54% and 1.56%/year). Mortality was similar in both dose conditions (3.1% and 3.02% per year).
Three Factor Xa inhibitors, rivaroxaban, apixaban and edoxaban, have been investigated in large clinical trials. The results indicate they reduce the risk of recurrent vascular events, and lead to fewer hemorrhagic complications, compared with warfarin. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF, Patel et al. 2011), 14,264 patients with elevated risk for stroke were randomized to receive fixed-dose rivaroxaban (20 mg daily or 15 mg daily in patients with reduced creatinine clearance) or adjusted-dose warfarin (target INR of 2.0 to 3.0). The median length of treatment was 590 days. Stroke or systemic embolism occurred less frequently in patients who received rivaroxaban (1.7% vs. 2.2% per year; HR= 0.79; 95% CI 0.66- 0.96, p<0.001 for non-inferiority). There were fewer incidences of intracranial hemorrhage in the rivaroxaban group (HR=0.67, 95% CI 0.47, 0.93; p=0.02), although the risk of major bleeding from a gastrointestinal site was increased (3.2% vs. 2.2%, p<0.001).
The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial (Granger et al. 2011) randomized 18,201 patients with AF and at least one other risk factor for stroke to treatment with apixaban (5 mg twice daily) or dose-adjusted warfarin (target INR 2.0-3.0). The primary outcome of stroke or systemic embolism occurred in significantly fewer patients in the apixaban group (212 vs 265; HR= 0.79; 95% CI 0.66- 0.95; p<0.001 for non-inferiority and p=0.01 for superiority). There was no between group difference for ischemic stroke alone (p=0.42); however, treatment with apixaban was associated with a significant reduction in risk for hemorrhagic stroke when compared to warfarin (HR=0.51, 95% CI 0.35-0.75; p<0.001). There was a significant reduction in risks of death from any cause and fatal or disabling stroke associated with apixaban (HR=0.89, 95% CI 0.80- 0.99; p=0.047 and HR=0.71; 95% CI, 0.54-0.94, respectively). Intracranial bleeding occurred more often in individuals assigned to treatment with warfarin (HR=0.42, 95% CI 0.3-0.58; p<0.001). The risk of major bleeding was significantly lower in the apixaban group (HR= 0.69; 95% CI, 0.60- 0.80; p<0.001). Overall, apixaban was found to be superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial (Giugliano et al. 2013) assessed the use of edoxaban versus warfarin in patients with atrial fibrillation. The trial randomized 21,105 patients to receive dose-adjusted warfarin, high-dose edoxaban (60mg), or low-dose edoxaban (30mg). The target INR for the warfarin group was 2.0-3.0 and the median duration of the treatment was 2.5 years. The primary efficacy outcome was the occurrence of stroke or systemic embolic event and the primary safety outcome was the occurrence of major bleeding during treatment. Patients in the high-dose and low-dose edoxaban groups experienced non-inferior rates of stroke and systemic embolic events compared to the patients receiving warfarin (HR 0.79, 97.5% CI 0.63 to 0.99, p<0.001 and HR 1.07, 97.5% CI 0.87 to 1.31, p=0.005). A superiority analysis for the annualized rate of stroke or systemic embolic event found no evidence for the superiority of either high-dose edoxaban (HR 0.87, 97.5% CI 0.73 to 1.04, p=0.08) or low-dose edoxaban (HR 1.13, 97.5% CI 0.96 to 1.34, p=0.10) compared to warfarin. The safety profile of edoxaban was supported by significantly lower annualized rates of bleeding events for both high-dose and low-dose treatment regimens compared to warfarin (HR 0.8, 95% CI 0.71 to 0.91, p<0.001 and HR 0.47, 95% CI, 0.41 to 0.55, p<0.001).
Novel Anticoagulants (versus ASA)
In addition to comparison with warfarin, the potential benefit of NOACs has also been compared with ASA. In the NAVIGATE ESUS trial (Hart et al. 2018), 7,213 patients with an ischemic, non-lacunar stroke of undetermined source were randomized to receive 15 mg rivaroxaban + aspirin placebo or 100 mg of enteric coated aspirin + rivaroxaban placebo. The trial was terminated early due to an excess risk of bleeding among patients in the rivaroxaban group and an absence of benefit. The primary efficacy outcome (ischemic or hemorrhagic stroke or systemic embolism) occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (HR=1.07; 95% CI, 0.87 to 1.33; p=0.52). A similar finding was reported in the RE-SPECT ESUS Trial (Diener et al. 2019). 5,390 patients ≥60 years, with stroke of undetermined source, sustained within the previous 3 months, or with at least one vascular risk factor identified within the previous 6 months, were randomized to receive 150 (or 110 mg depending on age and kidney function) dabigatran twice daily or 100 mg plain aspirin once daily. After a median duration of follow-up of 19 months, neither the risk of recurrent stroke, nor the risk of ischemic stroke was reduced significantly in the dabigatran group (4.1% vs. 6.6% and 4.0% vs. 4.7%, respectively). While the risk of major bleeding was not significantly higher in the dabigatran group (1.7% vs. 1.4% per year, HR= 1.19; 95% CI, 0.85 to 1.66), the risk of clinically relevant nonmajor bleeding was (1.6% vs. 0.9% per year, HR= 1.73, 95% CI 1.17–2.54), as was the risk of major or clinically relevant nonmajor bleeding (3.3% vs. 2.3% per year, HR=1.44, 95% CI 1.12–1.85).
Apixaban has also been compared with ASA in patients with AF. In the Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES, Connolly et al. 2011) trial, 5,599 patients were randomized to receive apixaban 5 mg twice daily or ASA at a dose of 81 to 324 mg daily. The median length of follow-up was 1.1 years. The primary efficacy outcome was the occurrence of stroke (ischemic or hemorrhagic) or systemic embolism. The trial was terminated early given the clear benefit demonstrated in favour of apixaban. There were significantly fewer primary outcome events recorded in the apixaban condition than in the ASA condition (113 vs. 51, HR=0.45, 95% CI 0.32-0.62; p<0.001). For stroke events in particular, there were significantly fewer ischemic events in individuals treated with apixaban (HR=0.37, 95% CI 0.25-0.55; p<0.001), although there were no significant between group differences in hemorrhagic stroke (p=0.45). There was no difference in the incidence of major bleeding events between groups.
Mechanical Heart Valves
Lifelong anticoagulation is usually required for patients with prosthetic heart valve replacement due to the risk of thromboembolic complications; however, questions remain regarding the most appropriate regimens. Current Canadian guidelines recommend target INRs of 2.5-3.0, depending on the location of the replacement valve with a vitamin K antagonist (VKA). Puskas et al. (2014) evaluated whether a less aggressive target for anticoagulation could be as effective. In this study, 425 patients with elevated risk of thromboembolism, including chronic atrial fibrillation or left ventricular ejection fraction<30% were recruited in the Prospective Randomized On-X Valve Anticoagulation Clinical Trial (PROACT). In addition to receiving 81 mg aspirin daily, patients were randomized to a lower-dose warfarin group with a target INR of 1.5-2.0, or to a standard therapy group with a target INR=2.0-3.0 through self-management three months following aortic valve replacement. After a mean duration of just under 4 years, there were significantly fewer major, minor and total bleeding events in the lower-dose warfarin group (10 vs. 25, RR=0.45, 95% CI 0.21-0.94, p=0.032: p 8 vs. 25, RR=0.36, 95% CI 0.16-0.79, p=0.011 and 18 vs. 50, RR=0.40, 95% CI 0.24-0.69, p<0.001, respectively). The risks of hemorrhagic, ischemic stroke and transient ischemic attack were similar between groups (1 vs. 2, RR=0.56, 95% CI 0.001-10.7, p=0.63: 5 vs. 5, RR=1.12, 95% CI 0.32-3.87, p=0.859 and 9 vs. 6, RR=1.68, 95% CI 0.60-4.72. p=0.326, respectively). The potential benefit of dabigatran was examined in the Randomized, Phase II Study to Evaluate the Safety and Pharmokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN). This trial randomized patients to warfarin with a target INR of 2-3, or 2.5-3.5 depending on thromboembolic risk, following aortic and/or mitral valve replacement, or two escalating doses of dabigatran for 12 weeks (Eikelboom et al. 2013). The trial was stopped early due to an excess of thromboembolic and bleeding events in the dabigatran group. Among patients in whom treatment was initiated within 7 days of valve replacement, there were 9 strokes and two TIAs in the dabigatran group and no strokes and two TIAs in the warfarin group, respectively. The addition of antiplatelets to VKA therapy following heart valve replacement was the topic of a Cochrane review (Massel & Little 2013), which included the results from 13 trials. The addition of either aspirin or dipyridamole significantly reduced the risk of thromboembolic events (OR= 0.43, 95% CI 0.32- 0.59, p < 0.00001) and total mortality (OR= 0.57, 95% CI 0.42- 0.78, p = 0.0004); however, the risk of major bleeding was increased significantly (OR=1.58, 95% CI 1.14- 2.18, p= 0.006).
Timing of Resumption of Anticoagulation Following Ischemic Stroke
It is generally agreed that anticoagulation can be resumed within the first two weeks following an ischemic stroke, although the exact timing remains uncertain. The results from several recent studies differ slightly. Yaghi et al. (2020) compared the outcomes of patients who initiated anticoagulation from 0-3 days (n=617), 4-14 days (n=535), or >14 days (n=137) following stroke. Overall, there was no significant difference in the primary composite endpoint (recurrent ischemic stroke, transient ischemic attack, and systemic arterial embolism, and sICH, or major extracranial hemorrhage) within 90 days, between the three groups: 0-3 days (10.3%), 4-14 days (9.7%) and >14 days (10.2%), p=0.933, nor was there a difference in the occurrence of anticoagulation related sICH between the 3 groups: 0-3 days (1.1%), 4-14 days (1.7%), and >14 days (2.9%), p=0.295). Wilson et al. (2019) compared the outcomes of patients with atrial fibrillation who reinitiated oral anticoagulation within 4 days of ischemic stroke or transient ischemic attack (n=358), ≥5 days or in those who did not resume OACs (n=997). After adjusting for all potential confounders, there was no increased risk of the of the composite outcome (transient ischemic attack, stroke, or death within 90 days) in the late OAC group compared with the early group (OR= 1.17, 95% CI 0.48 to 2.84), nor was there an increased risk of ischemic stroke or transient ischemic attack (OR=1.25, 95% CI 0.36 to 4.41). Multivariable sensitivity analyses comparing later (5 to 14 days) and very late OAC (≥15 days or not started at all) to early OAC (0 to 4 days) showed little difference in the odds of the primary composite outcome (OR= 1.19, 95% CI 0.45 to 3.90 and OR= 1.14, 95% CI 0.42 to 3.09, respectively). The RAF-NOAC trial (Paciaroni et al. 2017) included 1,127 patients, with acute ischemic stroke and known or newly diagnosed atrial fibrillation. All patients were initiated on NOACs. The timing of recurrent events including stroke, transient ischemic attack, systemic embolism, and symptomatic and major bleeding was examined in relation to the timing of NOACs. The risk of the primary outcome was not associated with the timing of initiation of NOACs (<3 days; OR=1.00 (ref), days 3-7: OR=1.30, 95% CI 0.54–3.71; days 8-14: OR=1.44, 95% CI, 0.36–3.02; >14 days: OR=0.59, 95% CI 0.15–1.95). 80% of patients received NOACs within the first 15 days following stroke. Results from the Early Recurrence and cerebral bleeding in patients with acute ischemic stroke and Atrial Fibrillation (RAF) study (Paciaroni et al. 2015) also suggest that the optimal window for initiation or resumption of treatment with anticoagulants is between 4-14 days following stroke. Of 1,029 patients admitted with acute ischemic stroke and known or newly diagnosed AF, significantly fewer patients treated with oral anticoagulants had a primary outcome event (composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding at 90 days) compared with patients treated with either LMWHs alone or LMWH followed by oral anticoagulants (7% vs. 16.8% and 12.3%, respectively, p=0.003). Adjusted for age, sex, CHA2DS2-VASc score, lesion size, reperfusion therapy, and NIHSS on admission, patients who had been initiated on treatment with anticoagulants between 4 and 14 days had a significantly reduced risk of the primary outcome and in ischemic events compared with patients who had their treatments initiated before 4 or after 14 days from stroke onset (HR=0.53, 95% CI 0.30–0.93, p=0.025 and HR=0.43, 95% CI 0.19–0.97, p=0.043, respectively).
Left Atrial Appendage (LAA) Devices
In patients with non-valvular AF, embolic stroke can occur through the formation of a thrombus in the left atrium. Several devices are available to exclude blood flow from the LAA, reducing stroke risk. The WATCHMAN device has been evaluated (for non-inferiority) in several large RCTs. In the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT-AF, Holmes et a. 2009), 707 patients with a CHADS2 score of ≥1 were randomized to undergo LAA occlusion with the WATCHMAN device (n=463) or to continuing warfarin therapy (n=244). After a mean duration of follow-up of 18 months, the event rate/100 patient- years for the primary outcome (a composite of the occurrence of stroke, cardiovascular or unexplained death, or systemic embolism), was 3.0 for the intervention group vs. 4.9 for the control group (RR=0.62, 95%, Cr I 0.35 to1.25), which met the threshold for non-inferiority. However, the risk of events related to excessive bleeding was significantly higher in the intervention group (7.4 vs. 4.4/100 patient-years). The Watchman LAA Closure Device in Patients with Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL) study (Holmes et al. 2014) was similar to PROTECT-AF, in terms of treatment contrasts and eligibility criteria. In this trial, which included 407 participants, the mean age was slightly older and the proportion of patients with a CHADS2 score of ≥2 was higher. While the results of this trial failed to demonstrate non-inferiority of the WATCHMAN device compared with warfarin for the reduction of the early primary efficacy endpoint (a composite of ischemic or hemorrhagic stroke, systemic embolism and cardiovascular death), evidence of non-inferiority was reached for the late primary efficacy endpoint (events excluding the first 7 days post procedure). A patient-level meta-analysis (Holmes et al. 2015) including the results from the PREVAIL and PROTECT-AF trials reported the risk of the primary outcome (stroke, systemic embolization and CV death) was not significantly different between groups (2.72 per 100-person years for device and 3.50 for warfarin; HR=0.79, 95% CI 0.53 to 1.2, p=0.22). The risk of hemorrhagic stroke was significantly lower in the device group (HR=0.22; 95% CI 0.08 to 0.61), as was the risk of CV/unexplained death (HR= 0.48,95% CI: 0.28 to 0.8).
Sex and Gender Considerations
Although the prevalence of atrial fibrillation (AF) is known to be higher in men, women may suffer the consequences disproportionately more. A systematic review (Emdin et al. 2016) including 30 studies with 4,371,714 participants found that was associated with a higher risk of all-cause mortality in women (ratio of relative risks for women compared with men 1.12, 95% CI 1.07 to 1.17) and a significantly higher risk of stroke and cardiovascular mortality. While women were less likely to receive oral anticoagulants (OAC) after a recent diagnosis of AF in the PINNACLE study (Thompson et al. 2017), (56.7% vs. 61.3%; P<0.001), there was no evidence of a difference in OAC use in the GARFIELD-AF study (60.9% of men versus 60.8% of women) (Lip et al. 2015). In terms of treatment efficacy, women with AF taking warfarin were at a significantly greater residual risk of stroke and other systemic embolism compared with men, while there were no differences between sexes for treatment with novel oral anticoagulants (Pancholy et al. 2014).
Ko et al (2017) reported that many RCTs were not powered to study sex-specific differences in primary or secondary outcomes, which might contribute to false-negative findings. Their ability to derive sex-specific results is further limited by underrepresentation of women in cardiovascular disease prevention trials. Only 25–30% of the participants in the major trials of warfarin were women. The proportion of women participants has increased in trials of the non-vitamin K antagonist oral anticoagulants (NOACs) to approximately 40%, to reflect more accurately the relative prevalence of AF in women compared with men.