• Arrhythmias
• Thrombotic Disorders Clinical Trials

For high-risk atrial fibrillation (AF) patients who are unsuitable for Vitamin K antagonist (eg, warfarin) therapy, dual antiplatelet therapy with clopidogrel and aspirin reduces the risk of major vascular events compared with aspirin alone, according to findings from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE)-A trial (NCT000249873).

Stuart Connolly, MD, McMaster University, Hamilton, ON, Canada, reported findings from ACTIVE-A, which was designed to evaluate the addition of clopidogrel to aspirin in high-risk AF patients who were unsuitable for oral anticoagulation. A vitamin K antagonist, such as warfarin, is the treatment of choice for the prevention of stroke in high-risk patients with AF. However, due to increased bleeding risk, patient preference, or other medical contraindications, fewer than 50% of high-risk patients are suitable candidates for oral anticoagulation therapy.

ACTIVE-A included 7554 patients with documented AF, at least one risk factor for stroke, and no major risk factors for bleeding. All patients were treated with aspirin 75 to 100 mg/day, and were randomly assigned to additional treatment with clopidogrel 75 mg/day (n=3772) or placebo (n=3782). The primary outcome was a composite of major vascular events including stroke, myocardial infarction (MI), non-central nervous system (CNS) systemic embolism, or vascular death.

After a median follow-up of 3.6 years, dual antiplatelet therapy reduced the risk of the primary outcome by 11% compared with aspirin alone, from an annual rate of 7.6% to 6.8% (HR, 0.89; 95% CI, 0.81 to 0.98; p=0.01).

According to an analysis of the components of the primary endpoint, the benefit of clopidogrel was mainly in the reduction of stroke risk from 3.3% per year with aspirin alone to 2.4% per year with clopidogrel and aspirin (HR, 0.72; 95% CI, 0.62 to 0.83; p<0.001). Moreover, the risk reduction was particularly related to the annual risk of non-hemorrhagic stroke in the aspirin alone (3.2%) and clopidogrel plus aspirin (2.1%) groups (RR, 0.68; 95% CI, 0.59 to 0.80; p<0.001). The annual risk of hemorrhagic stroke was 0.2% in both treatment groups (RR, 1.37; 95% CI, 0.79 to 2.37; p=0.27).

There was also a nonsignificant trend toward a reduction in the risk of MI from 0.9% with aspirin alone to 0.7% with dual antiplatelet therapy (HR, 0.78; 95% CI, 0.59 to 1.03; p=0.08). However, there were no differences between treatment groups in the risk of vascular death (4.7% per year in both groups; p=0.97) or non-CNS systemic embolism (0.4% per year in both groups; p=0.84).

Clopidogrel increased the risk of bleeding in patients on long-term aspirin therapy. Compared with patients taking aspirin alone, those taking clopidogrel and aspirin had a higher rate of major bleeding (1.3% vs 2.0% per year; RR, 1.57; 95% CI, 1.29 to 1.92; p<0.001), including severe bleeding (1.0% vs 1.5% per year; p<0.001), with a trend toward increased fatal bleeding (0.2% vs 0.3% per year; p=0.07). The excess risk of major bleeding included both intracranial bleeding (0.2% vs 0.4% per year; p=0.006) and extracranial bleeding (1.1% vs 1.6%; p<0.001).

Overall, adding clopidogrel to aspirin therapy for 3 years in 1000 patients with atrial fibrillation unsuitable for anticoagulation will prevent 28 strokes, including 17 fatal or disabling strokes, and 6 MIs. This strategy will also cause 20 major bleeds, including 3 fatal bleeds, which is an acceptable balance of clinical benefits and hemorrhagic risks, Dr. Connolly concluded.

Findings from the ACTIVE-A trial were simultaneously published online in the New England Journal of Medicine.

• © 2009 MD Conference Express