To retrospectively evaluate the effectiveness of buflomedil compared to a placebo in reducing the symptoms of intermittent claudication.

MEDLINE, International Pharmaceutical Abstracts, Cumulated Index Medicus and references from bibliographies of retrieved studies were searched. Articles on file at the authors' company (Abbott Laboratories, North Chicago) were also screened for inclusion.

Study designs of evaluations included in the review

Only prospective double-blind randomised controlled trials (RCTs) with a placebo control group, which measured improvement in claudication pain using treadmill exercise, were eligible for inclusion.

Specific interventions included in the review

Buflomedil treatment.

Participants included in the review

Patients with intermittent claudication. A majority (63 to 90%) of the patients in each study were male, and mean ages across studies ranged from 60 to 67 years. Smokers comprised 37 to 73% of the patients studied, and, where reported, the duration of claudication ranged from 21.1 to 40.8 months.

Outcomes assessed in the review

The outcomes were pain-free walking distance and maximum walking distance at 3 months of treatment. The averaged results were computed across all time periods.

How were decisions on the relevance of primary studies made?

One reviewer selected the papers for review.

Quality scores for each study were computed based on a predefined scale (included in an appendix to the paper) using patient selection, study design, treatment duration and compliance, study measurements and statistical methodology and reporting. The quality scores were then used in the meta-analyses to weight the individual studies. Linear regression and correlation were also used to examine the relationship between effect size and quality score. One reviewer performed the quality assessment.

The response to treatment in each study was transformed into a standardised effect size (ES), represented by the difference in response between treatment and placebo, divided by the pooled standard deviation of the outcome measures in the treatment and control groups. 'Response' was defined as the difference between the baseline and post-treatment walking distances. This analysis was computed for a 3-month outcome. Averaged results were also computed across all time periods.

How were the studies combined?

Meta-analyses were carried out according to the methods of Hedges and Olkin (see Other Publications of Related Interest). Four separate analyses were carried out: an unweighted analysis (method 1), and three weighted analyses in which the primary studies were weighted according to their quality scores (method 2), sample sizes (method 3), and both quality scores and sample sizes (method 4).

How were differences between studies investigated?

Subgroup analyses were not performed due to the small number of studies and the lack of data on study characteristics. The differences in quality between studies were explored using regression analysis and meta-analyses, both with and without weighting for study quality.

Ten studies with a total of 744 patients were included.

The quality scores ranged from 0.5 to 0.9 on a scale of 0 to 1.

Three-month results for each of the four analyses:

pain-free walking distance,

(1) ES 0.33 (95% confidence interval, CI: 0.14, 0.51, p<0.05),

(2) ES 0.32 (95% CI: 0.14, 0.50, p<0.05),

(3) ES 0.27 (95% CI: 0.11, 0.42, p<0.05), and

(4) ES 0.25 (95% CI: 0.09, 0.41, p<0.05);

maximum walking distance,

(1) ES 0.37 (95%CI: 0.16, 0.57, p<0.05),

(2) ES 0.37 (95% CI: 0.17, 0.56, p<0.05),

(3) ES 0.28 (95% CI: 0.12, 0.45, p<0.05), and

(4) ES 0.28 (95% CI: 0.11, 0.44, p<0.05).

Averaged results for each of the four analyses:

pain-free walking distance,

(1) ES 0.30 (95% CI: 0.11, 0.49, p<0.05),

(2) ES 0.29 (95% CI: 0.11, 0.47, p<0.05),

(3) ES 0.25 (95% CI: 0.09, 0.40, p<0.05), and

(4) ES 0.22 (95% CI: 0.07, 0.38, p<0.05);

maximum walking distance,

(1) ES 0.36 (95% CI: 0.15, 0.57, p<0.05),

(2) ES 0.36 (95% CI: 0.16, 0.55, p<0.05),

(3) ES 0.27 (95% CI: 0.11, 0.43, p<0.05), and

(4) ES 0.26 (95% CI: 0.10, 0.43, p<0.05).

The 3-month results show a statistically-significant improvement with buflomedil. The analysis weighted by both sample size and study quality found an overall ES of 0.25, which indicates that the average treated patient experiences a greater increase in pain-free walking distance than about 75% of the placebo-treated patients. The results for maximum walking distance show an overall ES of similar magnitude, and the averaged results for the two main outcomes are also similar: all four weighting methods demonstrate a significantly greater response with buflomedil treatment.

Study quality: the ESs differ little according to the weighting method used. This indicates that the ES is relatively independent of the study quality. Similarly there is no statistically-significant correlation between ES and quality score.

Buflomedil has a significant positive therapeutic effect in intermittent claudication patients, based on improvement in exercise duration.

The review is thorough and there is detailed consideration of the quality of the individual studies, even extending to examination of the validity of the quality scale used. However, one significant flaw is that there is little investigation of between-study heterogeneity. If the studies are heterogeneous in aspects other than sample size or quality, then the pooling itself may not have been appropriate. Moreover, as there are few details of the results of the primary studies, it is impossible for the reader to investigate heterogeneity of outcomes. Caution should be exercised when interpreting the above ESs.

Hedges LV, Olkin I. Statistical methods for meta-analysis. San Diego (CA): Academic Press; 1985.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.