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ACTIVE-W: Warfarin superior to combination

Issue: December 2005

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DALLAS — Treatment with an oral anticoagulant was found superior to treatment with clopidogrel and aspirin in patients with atrial fibrillation and one risk factor for stroke.

“Oral anticoagulation is the most effective antithrombotic therapy for use in anticoagulation. To achieve benefit it must be used properly,” Stuart Connolly, MD, director of the division of cardiology at McMaster University, said at the AHA Scientific Sessions 2005.

Connolly presented the results of ACTIVE-W — Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events. ACTIVE-W examined whether combination treatment with clopidogrel (Plavix, Bristol-Myers Squibb) and aspirin would be superior to oral anticoagulation with warfarin.

Warfarin has been shown to reduce the risk of stroke and vascular events, but it is often difficult to use and is poorly tolerated in patients, Connolly said. Researchers hypothesized that a combination of clopidogrel and aspirin would be a noninferior alternative.

ACTIVE-W enrolled 6,706 patients from 522 centers in 31 countries. About a third of patients were older than 75, 17% had LVEF <45%, 81% had hypertension and 15% had a prior stroke. Seventy-seven percent of patients had received prior oral anticoagulation therapy.

Patients were randomized to oral anticoagulation or to an active treatment group of clopidogrel at 75 mg daily and aspirin at 75 mg to 100 mg daily. INR was monitored monthly, with the target range of 2.0 to 3.0. Connolly said that the target range was achieved in about 64% of patients.

The primary outcome was stroke, non-CNS embolism, MI or vascular death. The safety outcome was major bleeding.

Although ACTIVE-W was designed as a noninferiority trial, the Data and Safety Monitoring Board stopped the trial early due to the clear evidence of superiority of warfarin. ACTIVE-W is one of three trials in the ACTIVE trial program of patients with AF who are at risk of stroke.

The event rate for the active treatment group was 5.64% per year compared to 3.93% per year in the control group (RR=1.45). This effect was primarily driven by an increase in stroke (RR=1.75) and non-CNS embolism (RR=5.13) in patients treated with the combination of clopidogrel and aspirin. There were no significant differences in the rate of MI, vascular death or total mortality. Connolly reported that the largest benefit in the primary endpoint was in patients on oral anticoagulant therapy at study entry and in patients at sites where 65% of INR was in the target range.

The clinical event and bleeding rates were higher at sites where the INR was not in the target range. “For patients not achieving good INR control, oral anticoagulation may offer little benefit over clopidogrel plus aspirin,” Connolly said.

For more information:

• Connolly SJ. The atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE-W)—non inferiority trial versus oral anticoagulation. Presented at the American Heart Association Scientific Sessions 2005. Nov. 13-16, 2005. Dallas.