WAVE: Give Antiplatelets in PAD, Hold the Warfarin

July 20, 2007 — The addition of oral anticoagulation to antiplatelet therapy for peripheral artery disease (PAD) doesn't further reduce the likelihood of cardiovascular (CV) events, but it does raise the risk of serious bleeding complications, including hemorrhagic stroke, according to a randomized study appearing in the July 19, 2007 New England Journal of Medicine.
The Warfarin Antiplatelet Vascular Evaluation (WAVE) also cautions against extrapolating therapies that have passed clinical-trial muster in one arterial bed to the treatment of disease in another, its investigators say.
In this case, for example, combined antiplatelet and oral anticoagulant therapy has been found effective and safe for myocardial infarction (MI) secondary prevention, but in WAVE it raised the risk of life-threatening complications, observed the trial's principal investigator, Dr Sonia S Anand (McMaster University, Hamilton, ON). The trial, she told heartwire, "points to the need for doing carefully conducted trials within each vascular subgroup rather than assuming the risk-benefit ratio is the same when you go from coronary to peripheral to cerebrovascular disease."
But the trial's primary message, she said, is that "In patients with PAD who don't have a clear indication for oral anticoagulants, such as a mechanical heart valve or atrial fibrillation, using an oral anticoagulant on top of antiplatelets as a prevention method is not indicated at this point."
In an accompanying editorial, Dr Emile R Mohler (University of Pennsylvania, Philadelphia) agrees. WAVE, in combination with other, smaller studies, "shows clearly that the addition of an anticoagulant to an antiplatelet drug results in increased rates of bleeding complications," and that outcomes are superior with antiplatelet therapy alone in the long-term management of PAD.
As previously reported by heartwire, Anand presented WAVE in preliminary form at the World Congress of Cardiology 2006.
The seven-country trial had randomized 2161 patients with PAD to receive antiplatelet therapy (primarily aspirin) either with or without an oral vitamin-K antagonist (primarily warfarin). The PAD could be in the lower extremities, the carotids, or the subclavian arteries.
An attempt had been made to exclude patients with a propensity for bleeding or who were unlikely to tolerate combined therapy, according to the authors. To that end, eligibility required that patients first receive both agents without untoward side effects for two to four weeks and achieve a stable international normalized ratio (INR) of 2.0 to 3.0. Randomized patients also could not have a specific indication for anticoagulation, active or recent bleeding, recent stroke, renal failure, or chronic nonsteroidal anti-inflammatory drug (NSAID) use.
Even with those entry criteria plus INR monitoring that was probably more careful than what is generally done in clinical practice, Anand said, "we observed this excess risk of bleeding. In the real world, it's likely to be much higher."
No significant difference was seen in the primary endpoint of MI, stroke, or CV death over a follow-up averaging 35 months, nor in a second primary composite endpoint that consisted of the first one or severe ischemia in the coronary or peripheral arterial beds. Nor were there significant differences for primary endpoints' individual components; a closer look, however, showed a significant increase in hemorrhagic strokes with combination therapy. In addition, rates of minor, moderate, and "life-threatening" bleeding complications were significantly higher with double antithrombotic therapy.
Although WAVE doesn't address why its combination therapy caused more serious bleeding complications than has been observed in secondary-prevention MI and stroke trials, Anand speculated that the PAD patients were older and sicker. "They had more comorbid conditions, such as diabetes or other vascular disease, and were more likely to be smokers," she said. "All of those comorbid conditions increase both the vascular event risk and bleeding event risk."
WAVE "was sponsored by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Ontario, and the Population Health Research Institute. Donations were also provided by Roche Diagnostics (in kind) and DuPont Pharma. In Hungary, acenocoumarol was provided by ICN Pharma." Mohler reports receiving lecture fees from Bristol-Myers Squibb, Sanofi, and Astra-Zeneca and grant support from Bristol-Myers Squibb and Sanofi.
N Engl J Med. 2007;357:217-227, 293-296.