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Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events - ACTIVE W
Description:
The goal of the trial was to evaluate treatment with clopidogrel and aspirin compared with oral anticoagulant therapy among patients with atrial fibrillation and at least one risk factor for stroke.
Hypothesis:
Treatment with clopidogrel and aspirin will be noninferior compared with oral anticoagulant therapy among patients with atrial fibrillation.
Study Design
Study Design:
Patients Screened: 7,455
Patients Enrolled: 6,706
Mean Follow Up: Median 1.28 years
Mean Patient Age: Mean age 70 years
Female: 33
Patient Populations:
Documented atrial fibrillation with ≥1 risk factor, including age ≥75 years, hypertension, prior stroke or TIA, LVEF <45%, peripheral artery disease, or age 55-75 with coronary artery disease or diabetes
Exclusions:
Contraindication for clopidogrel or oral anticoagulant, documented peptic ulcer disease in prior 6 months, previous intracerebral hemorrhage, significant thrombocytopenia, or mitral stenosis
Primary Endpoints:
Efficacy: Composite of stroke, non-CNS systemic embolism, MI, or vascular death, evaluated for noninferiority with an upper bound of 1.186
Safety: Major bleeding
Drug/Procedures Used:
Patients who were eligible for oral anticoagulant therapy were randomized to either clopidogrel (75 mg/d) and aspirin (75-100 mg/d) (n = 3,335) or oral anticoagulant therapy with warfarin (n = 3,371). International normalized ratio (INR) was monitored monthly and the target range was 2.0-3.0. ACTIVE W is part of the ACTIVE trial program, consisting of three trials in patients with atrial fibrillation at risk for stroke.
Principal Findings:
Baseline characteristics were well balanced, with prior stroke or transient ischemic attack (TIA) in 15%, left ventricular ejection fraction (LVEF) <45% in 17% of patients, and an average CHADS risk score of 2.0. Prior oral anticoagulation therapy was used in 77% of patients. Target INR range of 2.0-3.0 was achieved in 64% of patients.
The trial was discontinued early at the recommendation of the data safety monitoring board due to evidence of superiority on the primary endpoint with oral anticoagulant therapy over clopidogrel plus aspirin (3.90% per year vs. 5.60% per year; relative risk [RR], 1.44; p = 0.0003). Among the individual components of the composite, the oral anticoagulant therapy group had lower rates of stroke (1.4% per year vs. 2.4% per year, p = 0.001) and non-CNS embolism (0.10% per year vs. 0.43% per year, p = 0.005), with no significant difference in myocardial infarction (MI) (0.55% per year vs. 0.86% per year, p = 0.09) or vascular death (2.52% per year vs. 2.87% per year, p = 0.34). There was also no difference in total mortality (3.8% per year in both groups). In subgroup analysis, the largest benefit in the primary endpoint was observed in patients who were on oral anticoagulant therapy at study entry (RR, 1.50; p = 0.0005).
Interpretation:
Among patients with atrial fibrillation and at least one risk factor for stroke, treatment with oral anticoagulant therapy was associated with a reduction in the composite of stroke, non-CNS systemic embolism, MI, or vascular death compared with treatment with clopidogrel and aspirin. The trial was discontinued early due to overwhelming efficacy for oral anticoagulant therapy.
Oral anticoagulant therapy is the current standard of care for the treatment of atrial fibrillation. While efficacious, oral anticoagulant therapy can be difficult to use and requires monitoring of INR on a regular basis. Newer therapies have been evaluated with varied success as an alternative to standard warfarin therapy, including the oral direct thrombin inhibitor ximelagatran and, in the present trial, clopidogrel in addition to aspirin.
The present study highlights the need for maintaining proper INR ranges, as noted by the higher clinical event and bleeding rates in sites where INR was not in range in at least 65% of cases. The majority of the patients in the present trial were already on oral anticoagulation therapy (77%). It is possible that patients naive to oral anticoagulation therapy may have different results in response to clopidogrel and aspirin, although the present trial was not powered to evaluate such a difference.
References:
ACTIVE Writing Group. 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;367:1903–12.
Presented by Dr. Stuart J. Connolly at the American Heart Association Scientific Sessions, Dallas, Texas, November 2005.
Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Warfarin, Clinical Trials Data Monitoring Committees, Peripheral Arterial Disease, Ticlopidine, Risk Factors, Azetidines, Benzylamines, Stroke Volume, Embolism, Hypertension, Diabetes Mellitus
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