Adjusted-dose warfarin (INR 2-3) offers large (~65%) reductions in stroke in patients with atrial fibrillation, while aspirin treatment provides smaller benefits (~20% relative risk reduction, mainly affecting nondisabling, noncardioembolic strokes).1 Because of the enhanced clinical antithrombotic effects of the combination of clopidogrel and aspirin in trials of acute coronary syndromes and coronary stents, the Af Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE) investigators compared combination antiplatelet therapy to adjusted-dose warfarin (target INR 2-3) in atrial fibrillation patients with one additional risk factor for stroke (i.e. CHADS2 risk factors, peripheral vascular disease, or coronary artery disease) in ACTIVE-W and to aspirin (75-100 mg daily) alone in atrial fibrillation patients deemed unsuitable for anticoagulation in ACTIVE-A (sponsored by Bristol-Myers Squibb/Sanofi Aventis Pharma).2
The ACTIVE-W trial included 6706 participants (mean age 70 yrs, 67% men, 83% hypertensive, 15% with prior stroke/TIA, and 77% taking warfarin prior to entry) with a median CHADS2 score of 2, followed for an average of 1.3 years. The trial was stopped after interim analysis revealed a 42% relative risk reduction in stroke by warfarin compared with combination antiplatelet therapy.3 (See Table 1.) Serious bleeding was about the same with warfarin and combined antiplatelet therapy, although it differed depending on whether warfarin had been taken prior to study participation (i.e. whether the participant was warfarin-naïve at entry). While adjusted-dose warfarin was again shown to be superior to antiplatelet therapy, ACTIVE W extends this observation to dual antiplatelet therapy with clopidogrel plus aspirin. The relative risk of major bleeding depended on whether warfarin was being used at the time of study entry.
Carefully managed adjusted-dose warfarin is difficult to beat in atrial fibrillation patients, as it appears to prevent almost all of the “extra” strokes caused by this stasis-producing dysrhythmia. Sufficient time spent in the therapeutic range is critical to accrue the benefits of warfarin.8
Further, in a subgroup analysis of participants with atrial fibrillation in the randomized PROGRESS blood pressure trial, modest reduction in blood pressure using perindopril and indapamide resulted in ~25% reduction in stroke and major vascular events.4 Control of blood pressure in atrial fibrillation patients is doubly important, reducing both ischemic strokes and intracerebral bleeding—the most feared complication of antithrombotic therapy in the elderly.
In atrial fibrillation patients deemed unsuitable for warfarin (because of presumed bleeding risk, patient preference, or physician recommendation based on estimated balance of benefit/risk), ACTIVE A compared clopidogrel 75 mg daily plus aspirin (most 75-100mg daily) (double-blind) to aspirin alone in 7554 atrial fibrillation patients entered from 561 centers in 33 countries (10% of participants from North America, 31% from Western Europe/Israel).5 Reasons unsuitable for warfarin were risk factors for bleeding in 23%, patient preference in 26%, and physician recommendation (inability to comply with INR monitoring, falling risk, alcohol habituation) in 50%. Participant features were similar to the warfarin-eligible patients enrolled in ACTIVE W: Mean age ...