Dr Sonia Anand (McMaster University, Hamilton, ON) told the audience that the bleeding complications of the combination "neutralized any benefit." Those taking warfarin plus aspirin had a significantly higher rate of life-threatening bleeds than those taking aspirin alone. "Oral anticoagulation added to antiplatelet therapy does not lower the risk of cardiovascular events in patients with PAD," she concluded.

Discussant Dr Freek WA Verheught (Heartcenter, University Medical Center St Radboud, Nijmegen, the Netherlands) said there are two possible reasons for the negative findings—bad luck, or the low baseline risk of the PAD patients. The explanation is most likely the low risk, he added, noting, "This combination cannot be advised in PAD."

Anand explained that the role of oral anticoagulants with antiplatelet agents in coronary artery disease "seems promising" but the issue has not been sufficiently investigated in PAD patients.

In the WAVE study, conducted in 80 centers in seven countries, approximately 2000 PAD patients were randomized to aspirin alone or aspirin plus warfarin. Both groups had therapy titrated to reach INR levels of 1.8 to 3.5.

There were two coprimary end points: cardiovascular death, MI, and stroke; and cardiovascular death, MI, stroke, and severe ischemia in the coronary or peripheral arteries. There were also two safety end points—life-threatening bleeding and moderate bleeding.

Neither of the efficacy end points showed any significant benefit in favor of the two-drug regimen. And the combination significantly increased the risk of moderate and life-threatening bleeds—including a 15-fold risk of hemorrhagic stroke among those taking both drugs compared with those receiving aspirin alone (HR 15.2; p<0.001).

Verheught said that other studies have shown that oral anticoagulation alone, aspirin plus clopidogrel, or clopidogrel alone do not seem to be viable alternatives for PAD, either.

"We need more studies with better antithrombotics in PAD, such as aspirin given with oral thrombin blockers or with oral factor Xa inhibitors," he concluded.