Warfarin Antiplatelet Vascular Evaluation - WAVE


The goal of the trial was to evaluate treatment with moderate levels of oral anticoagulation (OAC) with warfarin in addition to antiplatelet therapy compared with antiplatelet therapy alone among patients with peripheral arterial disease (PAD).

Study Design

Study Design:

Patients Enrolled: 2,161
Mean Follow Up: 42 months
Mean Patient Age: Mean age 64 years
Female: 26

Patient Populations:

PAD, defined as the presence of intermittent claudication, ischemic rest pain of the lower limbs, nonhealing ulcers or focal gangrene, previous limb amputations, arterial bypass surgery or angioplasty of the lower limbs, symptomatic or asymptomatic carotid artery disease, or subclavian artery occlusive disease; age 35-85 years


Active bleeding or deemed to be high risk for bleeding, stroke in the previous 6 months, or renal insufficiency requiring dialysis

Primary Endpoints:

1) CV death, MI, and stroke; and 2) CV death, MI, stroke, and acute limb or coronary ischemia requiring urgent intervention

Secondary Endpoints:

1) Primary endpoints plus admission to hospital for unstable angina with ECG changes; 2) first coprimary plus revascularization of the coronary, carotid, or leg arteries; and 3) mortality, MI, stroke, amputation, or revascularization of the coronary or peripheral arteries

Drug/Procedures Used:

Following a 2-4 week run-in phase in which all patients were treated with OAC plus antiplatelet therapy, patients were randomized in an open-label manner to OAC with warfarin in addition to antiplatelet therapy (n = 1,080) or antiplatelet therapy alone (n = 1,081). In the OAC group, target international normalized ratio [INR] was 2.0 to 3.0.

Concomitant Medications:

Acceptable antiplatelet agents included aspirin (81-325 mg), ticlopidine, or clopidogrel. Dual antiplatelet therapy was not allowed unless patients had acute coronary syndrome or coronary stent placement.

Principal Findings:

The qualifying condition was PAD limbs in 82% and other PAD in 18%. Baseline mean ankle-brachial index was 0.83. Prior coronary artery disease was present in 47% of patients, and a history of stroke in 16%. OAC therapy was discontinued in 319 patients (29.5%) in the OAC group; antiplatelet therapy was discontinued in only 21 patients in the monotherapy arm. Mean achieved INR was 2.2 in the OAC group.

There was no difference between treatment groups in the primary endpoint of cardiovascular (CV) death, myocardial infarction (MI), or stroke (12.2% in the OAC group vs. 13.3% in the antiplatelet alone group, p = 0.48) or in the coprimary endpoint, which also included acute limb or coronary ischemia requiring urgent intervention (15.9% vs. 17.4%, p = 0.37). There was also no difference in the individual components of the composite: CV death 6.1% vs. 6.0%, p = 0.84; MI 5.0% vs. 6.1%, p = 0.28, stroke 3.5% each, p = 0.96; and severe ischemia requiring intervention 5.7% vs. 5.5%, p = 0.76, for OAC group vs. antiplatelet therapy alone group, respectively.

Life-threatening bleeding rates were higher in the OAC group (4.0% vs. 1.2%, relative risk 3.41, p < 0.001), as was moderate bleeding (2.9% vs. 1.0%, p = 0.0018) and the composite of either type of bleeding (6.9% vs. 2.2%, p = 0.0001). Fatal bleeds trended higher in the OAC group (0.9% vs. 0.3%, p = 0.0513).


Among patients with PAD, treatment with OAC therapy with warfarin in addition to antiplatelet therapy was not associated with a difference in CV death, MI, stroke, and ischemia requiring urgent intervention compared with antiplatelet therapy alone.

In addition to a lack of efficacy, OAC with warfarin in addition to antiplatelet therapy was associated with higher rates of both life-threatening and moderate bleeding. OAC therapy has been shown to be beneficial in the setting of post-MI therapy. The commentator suggested that one possible explanation of the lack of efficacy in the present trial is the low baseline risk of the population studied, unlike the post-MI population.


The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral Anticoagulant and Antiplatelet Therapy and Peripheral Arterial Disease. N Engl J Med 2007;357:217-27.

Presented by S. Anand, European Society of Cardiology Scientific Congress, September 2006.

Keywords: Intermittent Claudication, Risk, Myocardial Infarction, Stroke, Gangrene, Ankle Brachial Index, Warfarin, Peripheral Arterial Disease, Carotid Artery Diseases, Pain, Lower Extremity, Angioplasty, International Normalized Ratio, Ulcer, Hemorrhage

< Back to Listings