Letter by De Backer et al regarding article, "Oral buflomedil in the prevention of cardiovascular events in patients with peripheral arterial obstructive disease: a randomized, placebo-controlled, 4-year study".

Buflomedil in the Prevention of Cardiovascular Events in Patients With Peripheral Arterial Obstructive Disease: A Randomized, Placebo-Controlled, 4-Year Study” To the Editor: We read with interest the publication of a randomized clinical trial of Buflomedil in intermittent claudication (the Limbs International Medicinal Buflomedil [LIMB] study1) and the accompanying editorial.2 The protocol of this trial was written in 1999, in response to a request of the French health authorities to reassess the risk/benefit ratio. A first report of the trial was given in 2005 at the late-breaking clinical trial session of the Annual Meeting of the American College of Cardiology. This congress presentation gave rise to much interest because randomized clinical trials of long duration and focusing on hard end points with vasoactive agents are exceptional in the field of peripheral arterial obstructive disease. However, full expert review of the results was not yet possible because of lack of detail in initial reporting. In the recent publication of the study,1 the authors state that the use of buflomedil should be considered in addition to an antiplatelet agent in patients with peripheral arterial obstructive disease and intermittent claudication. In the accompanying editorial,2 Michael S. Conte, MD, questions the clinical relevance of the difference between placebo and buflomedil for the primary outcome measure (a composite measure of cardiovascular death and morbidity, including a composite measure of symptomatic deterioration from peripheral arterial obstructive disease). With regard to the efficacy of buflomedil in the symptomatic treatment of intermittent claudication, this study does not provide new valuable information, because walking distance was measured with a patient interview and not with the more objective standardized treadmill test. Therefore, the conclusions of our recent update of the Cochrane systematic review on this issue remain unchanged.3 We concluded that only 2 studies of more-or-less acceptable quality exist. The moderately positive results of the 2 studies are undermined by publication bias, which we documented by identifying traces of 4 unpublished irretrievable studies that were inconclusive. We agree with Conte that the LIMB trial provides limited evidence for a clinically meaningful benefit of buflomedil, both with regard to hard and soft cardiovascular end points and with regard to symptomatic improvement in walking distance. However, we would like to add information on the safety issue. The potential toxicity of the product, stemming from a series of case reports, is worrisome. In 2005, the French National Commission for Pharmacovigilance conducted a historical review of case series of voluntary and involuntary (such as in patients with renal insufficiency) overdose with neurological (primarily myoclonic twitches and convulsions) and cardiovascular adverse reactions (mainly arrhythmias and cardiac arrest), with lethal dosages starting at 5 to 6 g. The French authorities decided in 2006 to withdraw the 600-mg and 300-mg formulations of buflomedil because of its narrow therapeutic margin and to impose major restrictions in the labeling. Similar actions were taken in other countries where buflomedil is marketed. In our opinion, the balance between benefit and risk for buflomedil is unsatisfactory and insufficient evidence exists to integrate buflomedil routinely into the guidelines for treatment of intermittent claudication.