BARCELONA — The combination of warfarin plus aspirin provided no benefit over aspirin alone in a major randomized trial involving more than 2,100 patients with peripheral arterial disease, Dr. Sonia Anand reported at the joint congress of the European Society of Cardiology and the World Heart Federation.
Moreover, the combination resulted in a 3.4-fold increase in life-threatening bleeding, compared with standard low-dose aspirin, added Dr. Anand of McMaster University, Hamilton, Ont.
She reported on 2,161 patients with peripheral arterial disease (PAD) at 80 centers in seven countries who participated in the Warfarin Antiplatelet Vascular Evaluation (WAVE) trial. Patients were randomized to low-dose aspirin at 81–325 mg/day or to aspirin plus warfarin with a target international normalized ratio of 1.8–3.5. The mean achieved INR was 2.2.
During 3 years of follow-up, the combined end point of cardiovascular death, MI, stroke, or severe coronary or peripheral arterial ischemia occurred in 15.9% of the combined therapy group and 17.4% on aspirin alone, a nonsignificant difference.
Life-threatening bleeding occurred in 4.0% of patients in the warfarin-aspirin arm and 1.2% with aspirin alone. Hemorrhagic stroke was 15 times more frequent in the combined therapy arm. Moderate bleeding occurred in 2.9% of patients on combination therapy, compared with 1.0% of those on aspirin alone.
Discussant Dr. Freek W.A. Verheugt observed there is good evidence showing aspirin plus warfarin is superior to aspirin alone for the prevention of death, MI, and stroke in patients recovering from acute coronary syndromes. This was recently underscored in a metaanalysis by cardiologists at Catholic University, Rome, involving 14 randomized trials totaling more than 25,000 patients. The analysis concluded that combination therapy with a target INR of 2–3 conferred a 27% reduction in risk that dwarfed the doubled risk of major bleeding compared with aspirin alone (Eur. Heart J. 2006;27:519–26).
So why didn't aspirin plus warfarin show more benefit in the WAVE trial? Probably because the baseline risk in PAD patients was substantially lower than in the patients in the post-MI studies, meaning the potential for therapeutic benefit was less as well, said Dr. Verheugt, professor and head of cardiology at University Medical Center, Nijmegen, the Netherlands.
The negative WAVE findings leave PAD patients with a dearth of treatment options. Warfarin alone was of no benefit over aspirin in a large Dutch PAD trial. Clopidogrel plus aspirin provided no advantage over aspirin alone in the 15,603-patient Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, in which one-third of participants had PAD.
And while clopidogrel alone resulted in a 24% reduction in vascular events compared with aspirin in patients with PAD in the nearly 20,000-patient Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, the number needed to treat for 1 year to prevent one vascular event was 165. Moreover, CAPRIE is an old trial conducted in the prestatin, pre-ACE inhibitor era and is no longer relevant in contemporary practice, the cardiologist continued.
The best hope for patients with PAD, Dr. Verheugt added, probably lies in the improved antithrombotics now in the developmental pipeline. The investigational oral thrombin blockers and oral factor Xa inhibitors, either alone or with aspirin, are worthy of study in the PAD population. Unfortunately, the ongoing large clinical trials of these agents don't involve patients with PAD.
The WAVE trial was sponsored by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.
The combination resulted in a 3.4-fold increase in life-threatening bleeding, compared with low-dose aspirin. DR. ANAND