Patients with peripheral artery disease (PAD), compared with other vascular patients, experience a three-fold excess rate of death from cardiovascular disease, MI, and ischemic stroke. Although antiplatelet therapy reduces cardiovascular events in vascular patients, and combining it with oral anticoagulant agents is promising in coronary artery disease, information about oral anticoagulants and antiplatelet therapy in PAD is limited, stated Sonia Anand, MD, of McMaster University in Hamilton, Ontario, Canada. A study called WAVE (Warfarin Antiplatelet Vascular Evaluation) was conducted:

  • to determine whether moderate-intensity oral anticoagulants (with an International Normalized Ratio [INR] of 2 to 3), in combination with antiplatelet therapy, was superior to antiplatelet therapy alone in preventing cardiovascular death, MI, or stroke, or severe ischemia of the coronary or peripheral arterial circulation.
  • to precisely quantify the risk of bleeding.
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The trial was conducted at 80 centers in seven countries. After a two-week run-in period with antiplatelets and an anticoagulant (warfarin [Coumadin], target INR of 1.8-3.5), 2,161 patients were randomly assigned either to antiplatelet therapy alone or to antiplatelets in combination with an oral anticoagulant. Antiplatelet therapy consisted of aspirin 81-325 mg daily. The co-primary endpoints were (1) combined cardiovascular death, MI, or stroke or (2) cardiovascular death, MI, stroke, or severe ischemia of the coronary or peripheral arterial circulation. The safety endpoints were life-threatening bleeding or moderate bleeding requiring 3 or more units of blood products. Enrolled in WAVE were 2,161 men and women between 35 and 85 years of age (mean age, 64) with at least one or more of the following criteria:

  • intermittent claudication with objective evidence of PAD (ankle brachial index [ABI] of less than 0.9)
  • prior vascular reconstruction (including amputation) or angioplasty of a peripheral artery
  • asymptomatic PAD (other vascular disease plus an ABI of less than 0.9 or asymptomatic carotid stenosis above 50%)

The following patients were excluded from the study:

  • patients with active bleeding or with a high risk of bleeding
  • patients with a clear indication for long-term oral anti-coagulation
  • patients with a clear indication for long-term (more than three months) daily nonsteroidal anti-inflammatory agents
  • patients who had experienced a recent stroke (less than six months earlier) cialis professional

The analysis revealed that adding oral anticoagulation to antiplatelet therapy conferred no advantage but did carry additional bleeding risks. Reporting these results, Dr. Anand said that the first primary endpoint (cardiovascular death, MI, or stroke) occurred in 12.2% of the anticoagulant/antiplatelet group of patients and in 13.3% of the antiplatelet group (P = .49). The second endpoint (severe ischemia) was met by 15.9% of the patients in the anticoagulant/antiplatelet group and in 17.4% of the patients in the antiplatelet group (P = .38). No significant differences were found among the separate components of the combined endpoints. Life-threatening bleeding occurred at a significant rate (P < .001) more often in the anticoagulant/antiplatelet group (4%) than in the antiplatelet group (1.2%). Dr. Anand concluded: “Oral anticoagulants (targeting INR, 2-3), added to anti-platelet therapy, do not lower the rate of cardiovascular events, and [they] increase life-threatening bleeding, compared with antiplatelet therapy alone in patients with PAD.” Freek Verheught, MD, from University Hospital of Nijme-gen in The Netherlands, commented: “More studies with better antithrombotic agents are needed in PAD: comparisons of aspirin alone versus oral factor Xa blockers alone, or comparisons of aspirin alone versus aspirin plus oral factor Xa blockers.”