The purpose of this study is to evaluate whether the addition of warfarin (a blood-thinning medication) to an antiplatelet therapy like aspirin is better than antiplatelet therapy alone (i.e. usual treatment) for the prevention of leg surgery, heart attacks, stroke and death in people with peripheral vascular disease.

Condition	Intervention	Phase
Peripheral Vascular Diseases Cardiovascular Diseases	Drug: Warfarin	Phase III

Further Study Details: 

Primary Outcomes: The composite of cardiovascular (CV) death, first occurrence of myocardial infarction (MI), or stroke; The composite of CV death, first occurrence of MI, stroke, or severe ischemia requiring urgent intervention of the coronary (PTCA, CABG) or peripheral artery circulation (thrombolytic therapy, angioplasty, bypass surgery, limb amputation)
Secondary Outcomes: CV death, MI, stroke, amputation, revascularization of the coronary or peripheral arteries, or admission to hospital for unstable angina with electrocardiogram (ECG) changes; CV death, MI, stroke, transient ischemic attack (TIA), amputation or revascularization of the coronary, carotid, or leg arteries; All cause death, MI, TIA, stroke, amputation, or revascularization of the coronary or peripheral arteries
Expected Total Enrollment:  2400

Atherosclerosis is the underlying cause of peripheral vascular disease (PVD) of the lower extremities, and leads to intermittent claudication, leg ulceration and gangrene. More importantly, symptomatic PVD is an ominous sign that widespread atherosclerosis is present and patients with this condition suffer a threefold increase in myocardial infarction (MI), stroke, and CV death. These CV events are a consequence of rupture of an atherosclerotic plaque, which leads to platelet activation and thrombin generation, thrombus formation and occlusion of a critical blood vessel. Antiplatelet therapy has been clearly demonstrated to reduce major CV events. It is also reasonable to expect that this process may be further attenuated by the addition of an anti-thrombin agent (such as warfarin) in combination with antiplatelet agents.

WAVE is a large, international, multicentre, randomized clinical trial in high-risk PVD patients to evaluate the additional benefit of moderate intensity warfarin (target INR of 2.4-3.0) to antiplatelet therapy compared to antiplatelet therapy alone in reducing serious cardiovascular events.

There are currently 80 active centres following participants in Canada, Poland, Australia, Hungary, China, Ukraine, and the Netherlands. Following randomization to one of the two treatment groups, participants will require clinic or phone follow-up visits every 3 months for 2.5 or 3.5 years. For participants on warfarin, INRs will be measured monthly or more frequently if required. For participants who stop warfarin therapy prematurely, every attempt will be made to have them restart it

Ages Eligible for Study:  35 Years   -   85 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Intermittent claudication with objective evidence of PVD (e.g. ankle-brachial index [ABI] < 0.90)
• Ischemic rest pain of the lower limbs
• Ischemic non-healing ulcers or focal gangrene
• Amputation for vascular causes
• Previous peripheral vascular revascularization (angioplasty or bypass surgery)
• Blue toe syndrome
• Other significant peripheral arterial disease (e.g. carotid stenosis)
• Vascular disease and evidence of asymptomatic peripheral arterial disease [PAD] (i.e. ABI < 0.90)

Exclusion Criteria:

Temporary:

• Potential subjects will be temporarily excluded if they need to undergo:

  • vascular diagnostic (angiography) or interventional procedures (arterial bypass graft surgery or angioplasty); or
  • limb amputation for vascular insufficiency.

Permanent:

• Subjects will be excluded for the following:

  • active bleeding or high risk bleeding;
  • clear indication for long-term warfarin use (i.e. atrial fibrillation);
  • previous allergy or intolerance to warfarin;
  • stroke in the last 6 months;
  • renal failure requiring dialysis;
  • known significant abdominal aortic or cerebral aneurysm;
  • peripheral arterial aneurysms (iliac or femoral) without evidence of lower limb ischemia;
  • significant liver disease (i.e. cirrhosis);
  • cancer with a life expectancy < 6 months;
  • anticipated non-adherence to warfarin;
  • excessive alcohol use;
  • pregnancy or planning to become pregnant; or
  • failure to provide informed consent.

Canada, Ontario
      Population Health Research Institute, McMaster University, Hamilton,  Ontario,  L8L 2X2,  Canada

Study chairs or principal investigators

Sonia Anand, MD PhD FRCPc,  Principal Investigator,  Population Health Research Institute, McMaster University   

Study ID Numbers:  MCT-37413; T4913
Last Updated:  August 11, 2005
Record first received:  July 29, 2005
ClinicalTrials.gov Identifier:  NCT00125671
Health Authority: Canada: Health Canada
ClinicalTrials.gov processed this record on 2005-08-23