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

May 16, 2009
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Author/Summarized by Author:
Anthony A. Bavry, MD,MPH,FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Sanofi-Aventis and Bristol-Myers Squibb
Date Presented:
01/01/2009
Date Published:
01/01/2009
Date Updated:
05/16/2009
Original Posted Date:
05/16/2009
References

Description:

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.

Hypothesis:

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

Exclusions:

  • 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.

Interpretation:

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.

References:

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.

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


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