Effect of Clopidogrel Added to Aspirin in Patients With Atrial Fibrillation - ACTIVE A


The goal of the trial was to evaluate treatment with aspirin and clopidogrel compared with aspirin and placebo among patients with atrial fibrillation and increased risk for stroke.


Aspirin and clopidogrel would be more effective at reducing major adverse events.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patients Enrolled: 7,554
Mean Follow Up: Median 3.6 years
Mean Patient Age: 71 years
Female: 41%

Patient Populations:

  • Patients with atrial fibrillation at enrollment or at least two episodes of atrial fibrillation in the last 6 months, plus:
  • One of the following risk factors for stroke:
    • Age greater than 75 years,
    • Hypertension,
    • Prior stroke, transient ischemic attack, or noncentral nervous system systemic embolism,
    • Left ventricular ejection fraction
    • Peripheral arterial disease
    • Age 55-74 years with diabetes or coronary artery disease


  • Patients who were deemed to require warfarin or clopidogrel
  • Any of the following:
    • Peptic ulcer disease within the last 6 months
    • Intracerebral hemorrhage
    • Thrombocytopenia
    • Alcohol abuse

Primary Endpoints:

  • Stroke,
  • Myocardial infarction,
  • Noncentral nervous system systemic embolism, or
  • Death from vascular causes

Secondary Endpoints:

  • Individual components of the primary outcome
  • Major bleeding
  • Minor bleeding

Drug/Procedures Used:

Patients with atrial fibrillation were randomized to aspirin and clopidogrel (n = 3,772) versus aspirin and placebo (n = 3,782). Patients who underwent cardioversion were treated with open-label warfarin for 4 weeks before and after cardioversion.

Principal Findings:

Overall, 7,554 patients were randomized. The mean age was 71 years, 41% were women, the mean CHADS2 score was 2.0, 64% had permanent atrial fibrillation, and 54% had duration of atrial fibrillation longer than 2 years. Reasons for enrollment were increased risk for bleeding in 24%, physician’s judgment that warfarin was not appropriate in 50%, and patient preference not to take warfarin in 26%. The dose of aspirin was 75-100 mg in 96% of patients.

The primary outcome occurred in 6.8% per year in the aspirin and clopidogrel group versus 7.6% in the aspirin and placebo group (p = 0.01). Any stroke was 2.4% versus 3.3% (p < 0.001), hemorrhagic stroke was 0.2% versus 0.2%, myocardial infarction was 0.7% versus 0.9% (p = 0.08), all-cause mortality was 6.4% versus 6.6% (p = 0.69), and major bleeding was 2.0% versus 1.3% (p < 0.001), respectively.


Among patients with atrial fibrillation and increased risk for stroke, aspirin and clopidogrel is superior to aspirin and placebo. The use of dual antiplatelet therapy was associated with a reduction in the primary composite outcome, which was driven by a reduction in stroke. Aspirin and clopidogrel increased major bleeding by an absolute 0.7%.

The companion trial, ACTIVE W, found that warfarin is superior to aspirin and clopidogrel in preventing stroke. Meta-analysis also documented a greater reduction in stroke risk with warfarin compared with aspirin alone. Therefore, warfarin therapy remains the preferred treatment for the prevention of ischemic stroke; however, aspirin and clopidogrel appear to be appropriate for many patients due to factors such as increased risk for bleeding, alcohol abuse, and patient preference/noncompliance/poor understanding.


ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066-78.

Presented by Dr. Stuart Connolly at ACC.09/i2, Orlando, FL, March 2009.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), EP Basic Science, Hypertension

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Warfarin, Electric Countershock, Peripheral Arterial Disease, Ticlopidine, Stroke Volume, Embolism, Patient Preference, Hypertension, Diabetes Mellitus, Hemorrhage

< Back to Listings