Buflomedil for intermittent claudication.
BACKGROUND
Intermittent claudication is pain, caused by chronic occlusive arterial disease, that develops in a limb during exercise and is relieved with rest. Buflomedil is a vasoactive agent claimed to have beneficial effects on the microcirculation. It is used chiefly to treat peripheral vascular disease and to a lesser extent for cerebrovascular arterial disease. However, its clinical efficacy for intermittent claudication has not yet been critically examined.


OBJECTIVE
To evaluate the available evidence on the efficacy of buflomedil for intermittent claudication.


METHODS
We searched Medline, International Pharmaceutical Abstracts (IPA) and the Cochrane Controlled Trials Register. Abbott Laboratories, the distributor of buflomedil, was asked to provide reports of controlled clinical trials. Reference lists of retrieved articles were checked, and enquiries sent to authors of known trials, to identify additional trials. Finally, we conducted a Science Citation Index search.


METHODS
Trial reports had to be double-blinded, randomized, and conformed to our PIO-criteria (Patients, Intervention, Outcome) to be considered for inclusion. Patients were required to have proven intermittent claudication (Fontaine stage II); the intervention was to be oral administration of buflomedil compared to placebo; and outcomes had to include pain-free walking distance (PFWD) and maximum walking distance (MWD) analysed by standardized exercise test.


METHODS
Searches of bibliographic databases yielded three eligible randomized controlled trials (RCTs) and a meta-analysis referring to nine eligible trials. Two of these nine trials had already been identified; two had been published in journals not referenced in traditional bibliographic indexes; and five were unpublished. Despite multiple requests, only one of the five unpublished trials was provided by the author of the meta-analysis, the other four could not be retrieved. Four of the six eligible trials retrieved were subsequently excluded after quality evaluation. Data on walking distances were extracted from the two remaining trials. Differences in incremental gain between active and placebo groups for PFWD and MWD with their confidence intervals were calculated.


RESULTS
Both RCTs showed moderate improvements in PFWD for patients on buflomedil. In one trial this improvement (75 m, 95% CI 37-114) was statistically significant, but in the other, with a wholly diabetic population, it was non-significant (81m, 95% CI -9-170) compared to placebo. For both RCTs the gains in MWD were statistically significant, but with wide confidence intervals (81 m, 95% CI 30-131; and 171 m, 95% CI 27-316 respectively). Pooling of the data was not attempted.


CONCLUSIONS
There is little evidence available to evaluate the efficacy of buflomedil for intermittent claudication. Most available trials are of poor quality and were excluded. The two trials included showed moderately positive results but these are undermined by publication bias since we know of another four unpublished, irretrievable, and inconclusive studies. There is a lack evidence for the efficacy of buflomedil in intermittent claudication.
De Backer
T L
TL
Heymans Institute of Pharmacology - Medical School, University of Gent, De Pintelaan 185, Gent, Belgium, B-9000. Marc.Bogaert@rug.ac.be
Vander Stichele
R H
RH
Bogaert
M G
MG
D000284:Administration, Oral; D004311:Double-Blind Method; D006801:Humans; D007383:Intermittent Claudication / Q000188:drug therapy*; D017594:Publication Bias; D011759:Pyrrolidines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*
D011759:Pyrrolidines; D014665:Vasodilator Agents; C010651:buflomedil