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Frequently Asked Questions

Is clopidogrel plus aspirin an effective treatment in patients with atrial fibrillation?

Atrial fibrillation (AF) has a significant impact on the risk of stroke. In particular, the presence of AF is associated with a higher stroke risk that increases with age.1 Due to the increased risk, the prevention of stroke in patients with AF remains an important component of patient care. It is well known that antithrombotic therapy, such as oral anticoagulants and antiplatelet agents, reduces the risk of stroke by preventing thromboembolism. Adjusted-dose warfarin therapy reduces the risk of stroke by 64%; while aspirin is associated with a 22% risk reduction.2 In 2006, the results from the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) study showed that oral anticoagulation was more effective than clopidogrel plus aspirin in the prevention of vascular events in patients with AF at a high-risk for stroke.3 Currently, guidelines recommend the use of oral anticoagulation (warfarin) for the prevention of stroke in high-risk patients with AF or aspirin for patients who are at a low risk of stroke or with contraindications to anticoagulant therapy.1,4 However, warfarin is associated with an increased risk of bleeding. In addition, some patients may not be candidates for warfarin therapy due to drug interactions, inadequate international normalized ratio (INR) monitoring, and refusal of therapy.5 The recently published ACTIVE A trial was conducted to compare clopidogrel plus aspirin to aspirin alone for reducing the risk of vascular events in patients with AF who cannot take warfarin therapy.

ACTIVE A trial
Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE) consisted of 3 separate trials, ACTIVE W, ACTIVE A, and ACTIVE I; all studies evaluated the role of antiplatelet or antihypertensive therapies in patients with AF.5 Patients who met the following criteria were eligible for enrollment into either ACTIVE A or ACTIVE W: AF at enrollment or at least 2 episodes of intermittent AF in the past 6 months with at least 1 of the following risk factors for stroke: (age ≥75 years; receiving treatment for systemic hypertension; previous stroke, transient ischemic attack, or non-central nervous system embolism; left ventricular ejection fraction <45%; peripheral vascular disease; or 55 to 74 years of age with diabetes mellitus or coronary heart disease). Patients who required warfarin or clopidogrel or had risk factors for hemorrhage were excluded from the ACTIVE A trial.

The ACTIVE A trial included 7554 patients with AF who were not candidates for warfarin.5 In this randomized, double-blind trial, patients received either clopidogrel 75 mg (n=3772) or matching placebo (n=3782) once daily, both treatment groups also received aspirin 75 to 100 mg/day. Enrolled patients were assessed for the primary endpoint, occurrence of any vascular event (i.e., stroke, non-central nervous system embolism, myocardial infarction, or vascular-related death). Secondary outcomes included stroke, major hemorrhage, and individual and composite components of the primary outcome.

Results were analyzed according to the intention-to-treat population.5 The median follow-up period was 3.6 years. In the clopidogrel treatment group, 832 patients had a major vascular event (6.8% per year); whereas, a major vascular event occurred in 924 patients in the aspirin alone group (7.6% per year; relative risk [RR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; p=0.01). There were fewer episodes of stroke in the clopidogrel group (n=296) compared to the aspirin alone group (n=408; 2.4% per year versus 3.3 % per year). This resulted in a significant reduction in the risk of stroke in the combination therapy group compared to the aspirin alone group (RR, 0.72; 95% CI, 0.62 to 0.83; p<0.001). With regard to hemorrhage, extracranial hemorrhage was more common than intracranial hemorrhage. Major bleeding occurred more frequently in patients receiving clopidogrel plus aspirin (n=251) compared to patients receiving aspirin monotherapy (n=162; 2.0% per year versus 1.3% per year). This resulted in a statistically significant difference in major bleeding episodes between the 2 groups (RR, 1.57; 95% CI, 1.29 to 1.92; p<0.001). There was no statistically significant difference in other secondary outcomes (myocardial infarction, non-central nervous system embolism, and death) between the 2 groups (p=0.08, p=0.84, p=69, respectively). Based on these results, the authors concluded that clopidogrel plus aspirin reduced the risk of vascular events and increased the risk of major hemorrhage in high-risk patients with AF who were not candidates for warfarin.

Clinical guidelines
There are 2 sets of guidelines that provide recommendation for antithrombotic therapy in patients with AF. One guideline is developed by the American College of Cardiology, American Heart Association, and European Society of Cardiology, and the other guideline is from the American College of Chest Physicians.1,4 Both guidelines have similar recommendations that are summarized in Table 1 below.

Table 1. Guidelines for antithrombotic therapy in patients with AF.1,4
Risk category Recommendation
No risk factors OR Contraindication to warfarin therapy   Aspirin 75 to 325 mg daily
  1 risk factor   Aspirin 75 to 325 mg daily OR Warfarin (INR 2.0 to 3.0, target 2.5)
Prior ischemic stroke, TIA, or embolism OR More than 1 risk factor   Warfarin (INR 2.0 to 3.0, target 2.5)
INR=international normalized ration; TIA=transient ischemic attack.
Risk factors: age >75, history of hypertension, diabetes mellitus, moderate to severe impaired left ventricular dysfunction or heart failure.

Conclusion
The prevention of thrombosis is critical in patients with AF due to an increased risk of stroke. Clinical evidence has shown antithrombotic therapy to be effective in the prevention of stroke in this patient group. In patients with risk factors for stroke, warfarin is the preferred agent as it is associated with a greater stroke risk reduction and has been proven to be superior to other therapy. In patients with contraindications to warfarin or those who have no risk factors, aspirin is recommended. In the ACTIVE A study, clopidogrel plus aspirin therapy was associated with a greater reduction in the risk of stroke and an increase in the risk of bleeding when compared to aspirin alone. As a result, clopidogrel plus aspirin may be an alternative to warfarin in patients with AF no risk factors or those with contraindications to warfarin. Similar to warfarin, patients treated with clopidogrel plus aspirin should be closely monitored for risks of bleeding.

References

  1. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):700-752.
  2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-867.
  3. ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903-1912.
  4. Singer DE, Albers GW, Dalen JE. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(Suppl 6):546S-592S.
  5. ACTIVE Writing Group of the ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066-2078.