The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events

Trial Sponsor: Sanofi-Aventis, Bristol-Myers Squibb
Year Presented: 2009
Topic(s): Arrhythmias, Prevention/Vascular
Summary Posted: 3/31/2009

Description
The goal of the trial was to evaluate treatment with the combination of aspirin and clopidogrel compared with aspirin and placebo in patients with atrial fibrillation (AF) at high risk for stroke who are not candidates for warfarin therapy.

Hypothesis
Combination therapy with aspirin and clopidogrel would be more effective in preventing vascular complications in patients with AF at high risk for stroke.

Drugs/Procedures Used
Patients with AF and at least one risk factor for stroke were enrolled. All patients received aspirin 75-100 mg daily, and were randomized to receive either clopidogrel 75 mg daily (n = 3,772) or matching placebo (n = 3,782).

Concomitant Medications
In the clopidogrel and placebo groups: antiarrhythmic agents (22.5%, 23.5%)

Principal Findings
Permanent AF was present in 64% of patients. There was a high incidence of cardiovascular risk factors, including hypertension (85%), prior stroke (13%), prior myocardial infarction (MI) (14%), and heart failure (33%). Aspirin and clopidogrel combination therapy was well tolerated, and reduced the incidence of the primary composite endpoint of stroke, MI, systemic embolus, or vascular death (6.8% vs. 7.6% per year, relative risk [RR] 0.89, 95% confidence interval [CI] 0.81-0.98, p = 0.01). The incidence of stroke was lower with combination therapy (2.4% vs. 3.3% per year, RR 0.72, 95% CI 0.62-0.83, p < 0.001); however, the incidence of major hemorrhage was increased (2.0% vs. 1.3% per year, RR 1.57, 95% CI 1.29-1.92, p < 0.001).

Interpretation
Anticoagulation with warfarin remains the standard of care for patients with AF and at least one risk factor for stroke. The ACTIVE W trial demonstrated that combination therapy with aspirin and clopidogrel was not as effective as warfarin anticoagulation for stroke prevention in patients with AF. Nevertheless, some patients with AF are not candidates for warfarin anticoagulation due to excessive bleeding risk.
The results from the ACTIVE A trial demonstrate that aspirin and clopidogrel combination therapy may reduce the risk of stroke in this important subgroup. However, the benefit of this treatment strategy is somewhat attenuated by the increased risk of major hemorrhage observed with combination therapy.

Conditions
 Arrhythmias
 Arrhythmias / Atrial fibrillation
 Prevention
 Cerebrovascular disease

Therapies
 Antiplatelet agent
 Antiplatelet agent / Aspirin
 Antiplatelet agent / Clopidogrel

Study Design

Placebo controlled. Randomized. Blinded.

Patients Enrolled: 7,554

Mean Follow-Up: 3.6 years

Mean Patient Age: 71 years   Female: 42%

Primary Endpoints

 Composite of stroke, MI, systemic embolus, or vascular death

Secondary Endpoints

 Stroke

 Major bleeding

 The individual components of the primary composite endpoint

 The composite of the primary endpoint + major bleeding

Patient Population

 Documented AF

 At least one of the following risk factors for stroke: age >75 years, hypertension, prior stroke, prior   transient ischemic attack, or prior systemic embolism, left ventricular ejection fraction <45%, peripheral vascular disease, or age 54-74 years and diabetes mellitus or coronary artery disease  Patients unsuitable for vitamin K antagonist therapy

Exclusions:

 Excessive risk of hemorrhage

 Prior intracerebral hemorrhage

 Peptic ulcer disease

 Requirement for oral vitamin K antagonist or clopidogrel therapy

 Significant thrombocytopenia

Ongoing alcohol abuse