Antithrombotic Therapy for Atrial Fibrillation

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.

• 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 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.

1. Proportion of acute ischemic stroke patients with atrial fibrillation who are treated with anti-coagulant therapy unless contraindicated (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 coumadin, warfarin, or heparin.
• Data sources may include discharge summary, history and physical examination, physician’s orders, nurses’ notes from inpatient chart, stroke prevention clinic documents, and primary care 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.

• Thrombosis Interest Group of Canada (available at www.tigc.org)

Atrial fibrillation is a common arrhythmia. The prevalence of atrial fibrillation in the general population increases with age;¹⁵⁷ about 12 percent of people aged over 75 years have atrial fibrillation.¹⁵⁸ The incidence of AF in the general population appears to be increasing over time.¹⁵⁹

Atrial fibrillation is a major risk factor for stroke. The presence of atrial fibrillation increases the risk of stroke approximately five-fold; the relative risk is higher still if there is associated valvular heart disease.¹⁶⁰ Stroke risk also varies according to the presence of other risk factors and can be estimated using a score that takes into account the presence of congestive heart failure, hypertension, age, stroke and systemic embolism.¹⁵⁵

Atrial fibrillation most often causes stroke via embolism of thrombus from the left atrium. Several clinical trials involving many thousands of patients with AF have examined the efficacy of various antithrombotic drug regimens. The majority of the trial evidence concerns prevention of first stroke; the evidence-base for prevention of stroke recurrence in patients with AF is much smaller. Strokes due to atrial fibrillation are generally more severe than those occurring in patients in sinus rhythm. Consequently, atrial fibrillation strokes are associated with higher case-fatality, longer hospitalization, and increased disability.¹⁶¹

To characterize the efficacy and safety of antithrombotic agents for stroke prevention in patients who have atrial fibrillation, conducted a meta-analysis of all randomized trials published between 1966 and March 2007, identified by using the Cochrane Stroke Group search strategy.¹⁶² The analysis included 29 trials involving 28 044 patients who had non-valvular atrial fibrillation (mean age 71 years; mean follow-up 1.5 years). Most trials studied warfarin or aspirin in varying dosages and intensities, but other anticoagulants

(low-molecular-weight heparin, ximelagatran, and dabigatran) and other antiplatelet agents (clopidogrel, dipyridamole, indobufen, and trifusal) were also tested. There were 3003 participants assigned to placebo or control groups in 12 trials. The average stroke rate for these untreated participants was 13 percent per year in trials that were restricted to those who had previous stroke or TIA (secondary prevention trials) and 4.1 percent per year for those in primary prevention trials.

Compared with control, adjusted-dose warfarin (6 trials, 2,900 participants 20 percent of whom had previous stroke or TIA) and antiplatelet agents (8 trials, 4,876 participants 29 percent of whom had previous stroke or TIA) reduced stroke by 64 percent (95% CI 49-74%) and 22 percent (95% CI 6-35%), respectively.¹⁶² Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (relative risk reduction, 39 percent [95% CI 22-52%]) (12 trials, 12,963 participants 23 percent of whom had previous stroke or TIA). Adjusted dose warfarin doubled the risk of intracranial and major extracranial hemorrhage; however, absolute rates of these adverse events were only 0.2 percent per year.

The largest trial comparing adjusted-dose warfarin with antiplatelet therapy was ACTIVE-W (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events), which included 6706 participants.¹⁶³ Anticoagulant therapy was superior to the combination of clopidogrel plus aspirin (relative risk reduction, 40 percent [95% CI 18-56%]). The ACTIVE-A trial,¹⁶⁴ published after the meta-analysis by Hart et al,¹⁶² included 7,554 participants in whom warfarin was unsuitable, randomly allocated them to receive clopidogrel plus aspirin or aspirin alone, and followed them for a median of 3.6 years. The results showed that treating 1000 AF patients for one year with clopidogrel plus aspirin prevented eight major vascular events (including two fatal and three disabling strokes) and caused seven major hemorrhages (one fatal).

Also published after the meta-analysis by Hart et al was the BAFTA trial (the Birmingham Atrial Fibrillation Treatment of the Aged study) which recruited 973 patients (12.5 percent of whom had previous stroke or TIA) aged 75 years or more (mean 81.5 years) from primary care, randomly assigned them to adjusted-dose warfarin (INR 2.0 - 3.0) or aspirin 75 mg once daily, and followed them for a mean of 2.7 years.¹⁶⁵ The primary endpoint was fatal or disabling stroke (ischemic or hemorrhagic), other intracranial hemorrhage, or clinically significant systemic embolism. There were 24 primary events (21 strokes, two other intracranial hemorrhages, and one systemic embolus) among participants assigned warfarin and 48 primary events (44 strokes, one other intracranial hemorrhage, and three systemic emboli) among those assigned aspirin (annual risk 1.8% vs. 3.8%, relative risk reduction 52 percent [95% CI 20-72%], p=0.003; treat 50 patients for one year to prevent one event). The annual risk of extracranial hemorrhage was 1.4 percent for patients assigned warfarin and 1.6 percent for those assigned aspirin.

Two trials in the meta-analysis by Hart et al included only patients who recently had a stroke or TIA. The European Atrial Fibrillation Trial (EAFT) involved 455 patients who were within three months of TIA or minor stroke, randomly assigned them to warfarin (INR 2.5 to 4.0) or aspirin (300 mg/day), and followed them for a mean of 2.3 years.¹⁶⁶ In the Studio Italiano Fibrillazione Atriale (SIFA) trial,916 patients within 15 days of TIA or minor stroke 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.¹⁶⁷ The combined results showed that anticoagulants were significantly more effective than antiplatelet therapy for the prevention of all ischemic vascular events (odds ratio 0.67, 95% CI 0.50–0.91) and for the prevention of stroke recurrence (odds ratio 0.49, 95% CI 0.33–0.72). Warfarin did not significantly increase the frequency of intracranial bleeding.¹⁶⁸ Although major extracranial bleeding complications occurred more often in patients on warfarin (odds ratio 5.16, 95% CI 2.08–12.83), the absolute difference was small (2.8 percent per year versus 0.9 percent per year in EAFT and 0.9 percent per year versus zero percent in SIFA). Heparin anticoagulation confers no net benefit over antiplatelet therapy in patients with AF and recent (within 14 days) acute ischemic stroke.¹⁶⁹

A Danish cohort study investigated the risks of bleeding on monotherapy compared to combined therapy in patients with atrial fibrillation.¹⁷⁰ Records from nation-wide registries were used to identify patients with a first-time hospitalization for AF between 1997 and 2006. A total of 82 854 of 118 606 patients (69.9 percent) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13 573 patients (11.4 percent) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9 percent per patient-year) and triple therapy (15.7 percent per patient- year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end

point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89- 4.76) for warfarin-aspirin-clopidogrel. Triple therapy posed a bleeding risk, which was three times higher than the risk of bleeding for warfarin alone.

In spite of convincing evidence linking AF to stroke, and the benefits of warfarin therapy in reducing this risk, AF patients are often not optimally managed. A recent analysis by Gladstone and colleagues using data from the Registry of the Canadian Stroke Network (RCSN) examined this issue in a cohort of 597 patients presenting to hospital with an ischemic stroke and previously known atrial fibrillation.¹⁷¹ They found that on admission for stroke, only 40 percent of patients were on warfarin, 30 percent on antiplatelet therapy, and 29% were not on any antithrombotics. Of those taking warfarin, three fourths had a subtherapeutic INR (<2.0) at the time of stroke admission. Overall, only 10 percent of patients with acute stroke and previously known atrial fibrillation were therapeutically anticoagulated (INR >2.0) at admission. Among the high-risk subgroup of stroke patients with a history of atrial fibrillation and a previous TIA or ischemic stroke (n=323), only 18 percent were taking warfarin with a therapeutic INR at the time of admission for their recurrent stroke; 39 percent were taking warfarin with a subtherapeutic INR, and 15 percent were on no antithrombotic therapy. These findings are particularly troublesome given that all subjects selected for inclusion in this study were considered high risk for stroke according to published criteria (low and moderate risk patients were not included), were living independently, and were considered ideal candidates for warfarin therapy (patients with known contraindications to warfarin were excluded from the study).

The problems associated with warfarin therapy have stimulated the development of oral agents that produce more predictable anticoagulation and do not require frequent monitoring. Most of the trial evidence concerns dabigatran, an oral thrombin inhibitor that does not have the drug and food interactions of warfarin or the inconvenience of INR monitoring.

The RE-LY (Randomized Evaluation of Long-term anticoagulant therapy) study tested two doses of dabigatran against warfarin in a non-inferiority trial with a prospective, randomized, open-label (warfarin only), blinded-end-point (PROBE) design.¹⁵⁶ Collaborators in 44 countries enrolled 18,1130 patients (mean age 71 years, 64 percent men) who had AF and at least one of: past stroke or TIA (20 percent of participants), left ventricular ejection fraction less than 40 percent, heart failure symptoms within six months (New York Heart Association class II or higher), age 75 years or higher, or 65-74 years of age plus diabetes mellitus, hypertension, or coronary heart disease. Exclusion criteria included severe valvular heart disease (including prosthetic valves), stroke within 14 days or severe stroke within six months, conditions that increase risk for hemorrhage, creatinine clearance less than 30 mL/min, active liver disease, and pregnancy. Participants were randomly allocated to receive dabigatran, 110 mg (n=6015) or 150 mg (n=6076) twice daily, or warfarin adjusted to an INR of 2.0-3.0 (n=6022), and followed for a median of two years (follow-up was 99.9 percent complete). The primary outcome was a composite of stroke or systemic embolism. Other outcomes included major hemorrhage, stroke, and death.

Dabigatran 150 mg twice daily reduced the risk of stroke or systemic embolism more than warfarin or dabigatran 110 mg twice daily. Rates of major hemorrhage were similar for warfarin and dabigatran 150 mg twice daily; dabigatran 110 mg twice daily was associated with lower rates of major hemorrhage than warfarin. Specifically, the rates of the primary outcome were 1.69 percent per year in the warfarin group, as compared with 1.53 percent per year in the group that received 110 mg bid of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11 percent per year in the group that received 150 mg bid of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36 percent per year in the warfarin group, as compared with 2.71 percent per year in the group receiving 110 mg bid of dabigatran (P = 0.003) and 3.11 percent per year in the group receiving 150 mg bid of dabigatran (P = 0.31). The rate of hemorrhagic stroke was 0.38 percent per year in the warfarin group, as compared with 0.12 percent per year with 110 mg bid of dabigatran (P<0.001) and 0.10 percent per year with 150 mg bid of dabigatran (P<0.001). The mortality rate was 4.13 percent per year in the warfarin group, as compared with 3.75 percent per year with 110 mg bid of dabigatran (P = 0.13) and 3.64 percent per year with 150 mg bid of dabigatran (P = 0.051).

The only adverse effect that was significantly more common with dabigatran than with warfarin was dyspepsia. Dyspepsia occurred in 348 patients (5.8 percent) in the warfarin group and in 707 patients (11.8 percent) and 688 patients (11.3 percent) in the 110-mg and 150-mg dabigatran groups, respectively

(p<0.001 for both comparisons). Elevations in the serum aspartate aminotransferase or alanine aminotransferase of more than three times the upper limit of the normal range did not occur more frequently with dabigatran, at either dose, than with warfarin. The rate of myocardial infarction was 0.53% per year with warfarin and was higher with dabigatran: 0.72 percent per year in the 110-mg group (relative risk 1.35; 95% CI 0.98-1.97; p=0.07) and 0.74 percent in the 150-mg group (relative risk 1.38, 95% CI 1.00-1.91; p=0.048). An as yet unpublished trial is testing dabigatran in acute coronary syndromes.

Warfarin patients in the RE-LY trial had a therapeutic INR only about 64 percent of the time.¹⁷¹ This is consistent with other clinical trials and underscores the problems with warfarin therapy.¹⁷² To have a stroke rate similar to that of he dabigatran 150 mg twice daily group, patients assigned to warfarin in RE-LY needed to have a therapeutic INR 80 percent of the time.¹⁷³This degree of control is unlikely to be achieved in clinical trials or clinical practice.¹⁷⁴

Ongoing questions remain about dabigatran.¹⁷⁵These include: a) the potential safety and utility of the lower, 100 mg twice daily, dose in older patients with renal impairment; b) the safety and efficacy of dabigatran in the longer term, beyond the mean follow-up of two years, which is being evaluated in an ongoing follow-up study of RE-LY patients (NCT00808067); c) the implications, if any, of there being no antidote to dabigatran; and d) the cost of dabigatran.