ACTIVE W Trial

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

In the ACTIVE W trial, dual antiplatelet therapy with aspirin(75-100 mg per day) and clopidogrel (75 mg per day) was found to be statistically inferior to coumadin therapy (target INR 2.0 to 3.0) in the management of patients with atrial fibrillation who had one or more risk factors for stroke. The primary endpoint of ACTIVE W was the first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. The annual risk in the coumadin group was 3.93% per year, and in the Aspirin/Clopidogrel group it was 5.60% per year yielding a relative risk of 1.44 (1.18-1.76; p=0.0003). The efficacy was not as great among patients who were coumadin naive, although the p-value for the interaction was negative. The benefit was confined to those patients at sites whose management style was such that that patients were in the therapeutic range > 65% of the time. There was no excess bleeding among patients treated with coumadin, and in fact there was an excess of minor bleeds among patients treated with ASA and clopidogrel (13.6% / yr vs 11.5% year, p=0.0009).

When examining the data from atrial fibrillation trials, it is critical to evaluate the results in patients who were previously treated with coumadin separate from those patients who were naive to coumadin. Patients previously treated with coumadin are likely to be those patients who best tolerate coumadin and have passed their "bleeding stress test" and have a lower rate of bleeding on coumadin. Those patients who bleed while on coumadin have already been culled out from the population. When the data in ACTIVE W were evaluated including only those patients previously treated with coumadin(again a population to be anticipated to be at low risk of bleeding), the risk of major bleeding was indeed statistically significantly lower among patients previously treated with coumadin (p=0.03) than patients not previously treated.

The majority of the reduction in events was due to a reduction in stroke and non-CNS emolization associated with [[coumadin therapy. The pathophysiology of stroke among patients with atrial fibrillation is thought to be embolization from clot in the left atrium. The data from ACTIVE W suggest that platelet activation and its treatment may not play a pivotal role in the treatment of mural thrombus and embolization in atrial fibrillation. Coumadin was more effective in the reduction of non-disabling stroke rather than disabling stroke. There were more fatal hemorrhagic strokes (which may more often be fatal), and this may explain in part why coumadin was not associated with a reduction in mortality in the study.

While clopidogrel plus aspirin has been found to reduce the risk of recurrent myocardial infarction among patients with presumed plaque rupture and acute coronary syndromes, it is notable in ACTIVE W that the risk of myocardial infarction tended to be higher among patients treated with aspirin plus clopidogrel versus coumadin (0.86% vs 0.55%,p=0.09).

Limitations

This trial does not answer whether ASA plus clopidogrel would be non-inferior to coumadin among patients who are coumadin naive. 77% of the patients were already on coumadin and were already tolerating coumadin. The 23% of patients who were coumadin naive sustained no apparent benefit from coumadin.