Antiplatelet Alone is Safer for PAD Treatment Than Combo With Anticoagula

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This article originally posted 31 July, 2007 and appeared in Issue 375

In patients with peripheral arterial disease (PAD), guideline-based treatment with an antiplatelet agent is as effective with or without the addition of an anticoagulant. However, combination treatment is more hazardous than monotherapy with an antiplatelet, according to evidence from the Warfarin Antiplatelet Vascular Evaluation (WAVE) trial investigators

PAD is associated with nearly 3-fold increase for major cardiovascular events, Dr. Sonia Anand at from McMaster University in Hamilton, Ontario, and her associates note. Antiplatelet therapy reduces the risk of major cardiovascular events in patients with PAD by about 25%, which suggests that there is room for improvement, and that it is "reasonable to consider" the addition of an anticoagulant to further reduce the risk.

In the New England Journal of Medicine for July 19, the researchers report the results of their randomized, open-label, clinical trial conducted at 80 centers in Canada, Europe, China, and Australia. Among the 2159 patients who enrolled the trial, the mean age was about 64 years. Patients were followed on average for 35 months.

The trialists randomly assigned subjects with PAD to an antiplatelet agent alone (aspirin, ticlopidine, or clopidogrel, n = 1081), or to treatment with an anticoagulant (either warfarin or acenocoumarol, n = 1080) in addition to the antiplatelet. The target International Normalized Ratio (INR) was 2.0 to 3.0.

The incidence of MI, stroke, or death from cardiovascular causes did not differ significantly between groups: 17.4% in the monotherapy group and 15.9% in the combination group.

However, the incidence of fatal bleeding (relative risk, 3.34), life-threatening bleeding (RR 3.34) and moderate bleeding (RR 2.82) were all significantly higher in the combination group than in the monotherapy group, as was hemorrhagic stroke.
Dr. Anand and her co-investigators estimate that for every 1000 patients treated for 3 years with both the antiplatelet therapy and anticoagulant therapy, there would be 24 fewer cardiovascular events, but 28 more episodes of life-threatening bleeding.
In a related editorial, Dr. Emile R. Mohler III, from the University of Pennsylvania School of Medicine in Philadelphia, comments that "further information on the pathobiologic basis for bleeding in patients with peripheral arterial disease is needed to develop successful clinical strategies to prevent bleeding and to devise safer antiplatelet and anticoagulant drugs."

N Engl J Med 2007;357:217-227,293-295.