Clinical trial NCT00125671: Warfarin and Antiplatelet Vascular Evaluation
Official title: A Phase III Randomized Trial of Warfarin Plus Antiplatelet Therapy Versus Antiplatelet Therapy Alone in Patients With Peripheral Vascular Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Peripheral Vascular Diseases
Cardiovascular Diseases
Keywords: Warfarin and Antiplatelet Vascular Evaluation
Peripheral vascular disease
Atherosclerosis
cardiovascular events
Ischemia
oral anticoagulants
low ankle-brachial index
moderate intensity warfarin
International normalized ratio [INR]
Lead sponsor: Warfarin and Antiplatelet Vascular Evaluation
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Heart and Stroke Foundation of Ontario
First posted: 2005-08-01
Enrollment: 2400
Sex: ALL
Minimum age (years): 35
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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

Eligibility 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.

Primary outcomes:
measure: The composite of cardiovascular (CV) death, first occurrence of myocardial infarction (MI), or stroke
measure: 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:
measure: CV death, MI, stroke, amputation, revascularization of the coronary or peripheral arteries, or admission to hospital for unstable angina with electrocardiogram (ECG) changes
measure: CV death, MI, stroke, transient ischemic attack (TIA), amputation or revascularization of the coronary, carotid, or leg arteries
measure: All cause death, MI, TIA, stroke, amputation, or revascularization of the coronary or peripheral arteries
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: Population Health Research Institute, McMaster University
state: Ontario
Study officials:
affiliation: Population Health Research Institute, McMaster University
name: Sonia Anand, MD PhD FRCPc
role: PRINCIPAL_INVESTIGATOR
References:
citation: WAVE Investigators. The effects of oral anticoagulants in patients with peripheral arterial disease: rationale, design, and baseline characteristics of the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, including a meta-analysis of trials. Am Heart J. 2006 Jan;151(1):1-9. doi: 10.1016/j.ahj.2005.03.021.
citation: Warfarin Antiplatelet Vascular Evaluation Trial Investigators; Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A, Sussex B, Liu L, Guzman R, Cina C, Crowell R, Keltai M, Gosselin G. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007 Jul 19;357(3):217-27. doi: 10.1056/NEJMoa065959.