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Anticoagulation for Individuals with Stroke and Atrial Fibrillation

5th Edition
2014 UPDATE
December 2014

The Canadian Stroke Best Practice Recommendations for the Secondary Prevention of Stroke, 5th Edition 2014 module is published in the International Journal of Stroke (IJS) (Online Open‑Access available December 2014; Printed Journal scheduled for April 2015).

To access the specific recommendations for Anticoagulation for Individuals with Stroke and Atrial Fibrillation and all other sections of the Secondary Prevention of Stroke module, please click on this URL which will take you to the recommendations online in the IJS:  http://onlinelibrary.wiley.com/doi/10.1111/ijs.12439/full. For the French version of these recommendations, open the appendix at this link : http://onlinelibrary.wiley.com/store/10.1111/ijs.12439/asset/supinfo/ijs12439-sup-0001-si.pdf?v=1&s=b0ed4fff1d7fc435cf4e2a83ccbcbffbdad767de.

All other supporting information, including performance measures, implementation resources, evidence summaries and references, remain available through www.strokebestpractices.ca, and not through the IJS.  Please click on the appropriate sections below for this additional content.

Rationale

Atrial fibrillation is a significant risk factor for stroke, with one in six patients with ischemic stroke found to have atrial fibrillation. Stroke caused by atrial fibrillation is highly preventable if patients are treated with anticoagulants. New classes of drugs are available that have demonstrated benefits over previous standard therapy with warfarin.

 

 

System Implications
  • 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.
  • For patients taking warfarin, access to a dedicated anticoagulant management clinic is associated with better patient outcomes compared to routine medical care.
  • Improved access to pharmaceuticals through private and public drug coverage plans.
Performance Measures
  1. Proportion of acute ischemic stroke patients with atrial fibrillation who are treated with anti-coagulant therapy (core).
  2. Proportion of eligible stroke and transient ischemic attack patients with atrial fibrillation prescribed anticoagulant therapy on discharge from acute care (core).
  3. Proportion of eligible stroke and transient ischemic attack patients with atrial fibrillation prescribed anticoagulant therapy after a visit to a secondary prevention clinic (core).
  4. Proportion of atrial fibrillation patients taking anticoagulant therapy at the time of hospital admission for acute ischemic stroke or transient ischemic attack.
  5. Proportion of atrial fibrillation patients with stroke or transient ischemic attack on antiplatelet therapy and not prescribed anticoagulant therapy.
  6. 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.
  7. For atrial fibrillation patients on warfarin, the proportion with an international normalized ratio in the therapeutic range at three months.

Measurement Notes

  • Performance measure 3: reasons why patients with atrial fibrillation and stroke are not on anticoagulants should be collected and reported. These may include contraindications, compliance issues and physician prescribing patterns, among others. This additional information will help to inform the direction for quality improvement initiatives.
  • If there is documentation of atrial fibrillation, the chart should be reviewed for medications prescribed to the patient at the time of discharge, specifically including warfarin, dabigatran, rivaroxaban, apixaban or heparin.  Performance measures should be stratified to include proportions prescribed each of these medications.
  • Data sources may include discharge summary, history and physical examination, physician’s orders, nurses’ notes from inpatient chart, stroke prevention clinic documents, and primary charts.
  • To measure whether the patient’s International Normalized Ratio was in the therapeutic range, laboratory reports or other reliable documentation are required to verify the International Normalized Ratio levels, and these should be reviewed over a period of time rather than as one single measure.
  • Providing a prescription does not ensure patient adherence with medication administration. Adherence can be determined through patient self-report and through International Normalized Ratio measurements over time.
  • At this time, adherence to the new oral anticoagulants cannot be objectified in the same way as having INR in therapeutic range
Implementation Resources and Knowledge Transfer Tools

Health Care Provider Information

Patient Information

Summary of the Evidence, Evidence Tables and References

Atrial Fibrillation and Stroke Evidence Tables and Reference List

Atrial fibrillation (AF) is a common arrhythmia, which is associated with an increased risk of ischemic stroke. Strokes due to AF are generally more severe than those occurring in patients in sinus rhythm and are associated with higher case-fatality, longer hospitalization, and increased disability (Kimura et al. 2005). The risk of stroke among people with AF can be estimated using prediction instruments such as CHADS2 Index, which include the presence of other risk factors such as congestive heart failure, age, hypertension, age, diabetes and previous stroke. (Gage et al. 2001). Among patients who have sustained a recent stroke or TIA, the risk of subsequent stroke may be 7-10% per year, if no other risk factors are present (The Stroke Risk in Atrial Fibrillation Working Group, 2007, European Atrial Fibrillation Trial Study Group, 1993). Detecting AF following a stroke or TIA is important since once identified, it can be effectively treated. However, AF is under-diagnosed because it is frequently paroxysmal and asymptomatic, and patients do not routinely undergo prolonged screening. The results from two recent RCTs, EMBRACE (Gladstone et al. 2014) and CRYSTAL-AF (Sanna et al. 2014) demonstrated the benefits of enhanced monitoring using insertable or portable devices, compared with repeat 24-hour Holter Monitoring, to detect AF. In both studies, more cases of AF were detected using enhanced monitoring techniques.

Several large clinical trials have examined the efficacy of various antithrombotic drug regimens for patients with AF.

Warfarin has been well established as an effective medication in 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 TIA). 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 antiplatelet including clopidogrel and dipyridamole, the use of warfarin was associated with a 37% reduction in all strokes (95% CI 23%- 48%). An increased risk was reported for intracranial hemorrhage associated with the use of adjusted-dose warfarin, although it was very small (absolute risk=0.2%/year).

The BAFTA trial (the Birmingham Atrial Fibrillation Treatment of the Aged study) recruited 973 patients (12.5% with previous stroke or TIA) 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 (21 strokes, two other intracranial hemorrhages, and one systemic embolus) among participants assigned to warfarin versus 48 primary events (44 strokes, one other intracranial hemorrhage, and three systemic emboli) among those assigned ASA. 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, NNT=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 anti-coagulants with antiplatelet therapy in individuals with non-rheumatic (non-valvular) AF and history of previous stroke or TIA. Two RCTs were included. The European Atrial Fibrillation Trial (EAFT) included 455 patients who were within three months of TIA 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 TIA 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 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 oral anticoagulants have been developed. Dabigatran, one such agent, is a direct thrombin inhibitor with a serum half-life of 12 to 17 hours. The landmark Randomized Evaluation of Long-term anticoagulant therapy, (RE-LY) trial (Connolly et al. 2009), 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 noninferior 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 TIA/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 0.34, respectively). The risks for major bleeding events, including life-threatening bleeding, intracranial bleeding and gastrointestinal bleeding, were reduced (vs. warfarin) 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). When interpreting the results of this trial, it is noteworthy that patients in the warfarin group had a therapeutic INR only about 64% of the time, which is consistent with other clinical trials. To achieve a stroke rate similar to that of the dabigatran 150 mg twice daily group, it is estimated that patients assigned to warfarin in RE-LY needed to have a therapeutic INR 80% of the time, a degree of control unlikely to be achieved in clinical trials or clinical practice (Birman-Deych et al. 2006).

The long-term results of the RE-LY trial have been published recently (Connolly et al. 2013). In this extension of the trial, 5,851 participants who had been assigned to either of the dabigatran dosing schedules in the original trial were able to continue in the RELY-ABLE study if they did not discontinue study medication at trial termination. Participants continued to receive the same dose of dabigatran (still blinded to the dose condition) as they had throughout the original trial. Patients enrolled in the warfarin condition did not continue in the trial. Median duration of follow-up for the patients enrolled in RELY-ABLE was 5.5 years. During the study period, 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). Dyspeptic symptoms were reported in approximately 5% of patients in each group. In subgroup analysis (Diener et al. 2010) examined treatment effects between patients with and without previous history of stroke or TIA. No interactions for any of the outcomes of interest (stroke, ICH, ischemic or unknown stroke, disabling or fatal stroke, MI, vascular death, or death from any cause, were reported.

Three Factor Xa inhibitors, rivaroxaban, apixaban and edoxaban, have been investigated in large clinical trials. In the ROCKET-AF trial (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), while the risk of major bleeding from a gastrointestinal site was increased (3.2% vs. 2.2%, p<0.001). A post hoc analysis from the ROCKET-AF trial demonstrated no significant difference in treatment effectiveness or risk for adverse events between groups of individuals with or without previous stroke or TIA suggesting that rivaroxaban may be considered as a potential alternative to warfarin in secondary prevention of stroke (Hankey et al. 2012).

The 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. In the subgroup analysis of patients with previous stroke or TIA (Easton et al. 2012), the rate of stroke or systemic embolism was similar between groups (2.46 per 100 patient-years of follow-up in the apixaban vs. 3.24 in the warfarin group; HR= 0.76, 95% CI 0.56-1·03, p for interaction=0·71).

Apixaban has also been compared with ASA in patients with AF. 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 randomized 5,599 patients 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 were no differences in the incidence of major bleeding events between groups.

The 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 international normalized ratio (INR) for the warfarin group was 2.0-3.0, and the median duration of the treatment was 2.5 years. Blinding was maintained throughout the study by using sham INR values for the edoxaban group, and giving all patients a placebo tablet in addition to their active medication. 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 noninferior 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).