Oral buflomedil in the prevention of cardiovascular events in patients with peripheral arterial obstructive disease: a randomized, placebo-controlled, 4-year study

Background: Cardiovascular-related morbidity and mortality in patients with peripheral arterial obstructive disease remain high. We performed an international, multicenter, randomized, double-blind, placebo-controlled trial to investigate whether long-term administration of oral buflomedil could reduce the rate of cardiovascular events in patients with intermittent claudication.

Methods and results: Patients >40 years of age with documented peripheral arterial obstructive disease, intermittent claudication, and an ankle-brachial index between 0.30 and 0.80 were eligible for inclusion and were randomized to receive orally either buflomedil or placebo for 2 to 4 years. Aspirin was recommended for all patients (unless they were receiving other antithrombotic treatments at inclusion). The primary efficacy outcome was critical cardiovascular events, defined as the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, symptomatic deterioration of peripheral arterial obstructive disease, or leg amputation. A total of 2078 patients were recruited. Mean treatment duration was 33 months. The rate of critical cardiovascular events was significantly lower in buflomedil-randomized patients than in placebo-randomized patients (9.1% versus 12.4%; hazard ratio, 0.742; 95% confidence interval, 0.603 to 0.915; P=0.0163). Ankle-brachial index increased by 9.2% in buflomedil-randomized patients and decreased by 3.6% in placebo-randomized patients (P<0.001). Tolerance of buflomedil and placebo was comparable.

Conclusions: Compared with placebo, buflomedil administered for 3 years reduced the occurrence of symptomatic cardiovascular events by 26%. The main contributor to the difference in the composite outcome was the reduction in symptomatic deterioration of peripheral arterial disease. The use of buflomedil should be considered in addition to an antiplatelet agent in patients with peripheral arterial obstructive disease and intermittent claudication.