To assess the effectiveness of physical training, smoking cessation, pentoxifylline, or nafronyl in the treatment of intermittent claudication.

The authors searched the MEDLINE database (January 1976 to December 1996) using the keywords: 'atherosclerosis', 'arteriosclerosis obliterans', 'peripheral vascular disease', and 'intermittent claudication'. The authors also scanned the reference lists of retrieved articles to identify additional relevant studies. The search was limited to English-language publications.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs), and, if there were no level I studies, then data from non-randomised controlled trials were considered. Reviews or meta-analysis of the literature, case reports and uncontrolled or retrospective studies, double reports were excluded. Treatment duration ranged from 3 to 6 months, while follow-up varied from 3 to 12 months in the physical treatment trials. Treatment duration on smoking cessation was 10 months to 10 years. Treatment duration for pentoxifylline was 1 to 12 months, and for nafronyl 3 to 6 months. Trials were excluded if they did not have a control group or compared one of the four interventions with another active treatment, or if they were trials without clinically meaningful outcomes.

Specific interventions included in the review

Physical training, smoking cessation, pentoxifylline (400-1200 mg/day), or nafronyl (400-800 mg/day) in the intervention groups and placebo, nothing, or usual activity in the control groups.

Participants included in the review

Patients with intermittent claudication. Studies were included which evaluated primary treatment of patients with intermittent claudication at stage II of the disease independent of study design. Studies conducted on selected populations (diabetic patients, hypertensive patients) were excluded.

Outcomes assessed in the review

Pain-free and total walking distance were the main outcome measures. For these two outcomes, the criterion was the use of a device that forced the patients to walk at a set speed. Studies were excluded if they did not define or assess adequately any of the following outcomes: pain-free and total walking distance or time, ankle- brachial index before or after exercise, rest and peak blood flow, and ankle pressure.

How were decisions on the relevance of primary studies made?

The quality of the selection process was evaluated on a random sample of 100 articles analysed by 3 independent researchers achieving a k- value ranging from 0.90 to 0.95.

Included studies were graded level 1 (randomised and double- or assessor-blind), level 2 (open randomised) or level 3 (non-randomised). Trials were graded for quality of their design by 2 independent observers.

Data were extracted by 2 independent observers using a standardised form. In case of disagreement, consensus was reached by adding a third observer. Only results obtained at the end of the treatment period were compared, provided that baseline values for the outcomes considered were comparable among studies.

How were the studies combined?

Results were expressed as common differences of the means with 95% confidence intervals (CIs). Summary calculations were not feasible for smoking cessation trials because of dis-similar outcomes.

How were differences between studies investigated?

The authors state that tests for homogeneity were performed and no heterogeneity was found.

There were 6 level-2 trials (76 participants in the intervention group and 70 participants in the control group) and 4 level-3 trials (60 participants in the intervention group and 45 participants in the control group) for physical treatment interventions.

There were 4 level-3 trials (183 participants in the intervention group and 683 participants in the control group) for smoking cessation interventions.

There were 12 level-1 (419 participants in the intervention group and 415 participants in the control group) and 1 level-2 trials (15 participants in the intervention group and 15 participants in the control group) for pentoxifylline and 6 level-1 trials for nafronyl (323 participants in the intervention group and 306 participants in the control group).

In five level-2 studies, physical training increased pain-free (4 studies) and total walking distance (5 studies) by 139.0 m, 95% CI: 31.0, 246.9 m, and total walking distance by 179.1 m, 95% CI: 60.2, 298.1 m, which were both statistically significant.

In a level 3 study, smoking cessation resulted in total walking distance of 46.7 m, 95% CI: -19.3 to 112.7 m, which was not statistically significant.

In six level-1 studies, pentoxifylline increased pain-free distance by 21.0 m, 95% CI: 0.7, 41.3 m (statistically significant) and total walking distance (7 level-I studies) by 43.8 m, 95% CI: 14.1, 73.6 m (which was statistically significant).

In four level-1 studies, nafronyl increased pain-free distance by 58.6 m, 95% CI: 30.4, 86.8 m (which was statistically significant) and total walking distance (from 2 trials) by 71.2 m, 95% CI: 13.3, 129.0 m (which was statistically significant).

Physical training increased pain-free and total walking distance in level 2 studies. Only level 3 studies support the usefulness of smoking cessation. In level 1 studies, pentoxifylline and nafronyl increased pain-free and total walking distance, but the average effects were relatively small.

The authors conclude that physical training is a potentially effective treatment modality, as is smoking cessation. However, available evidence is week and it is therefore unclear whether prescribing supervised physical training programmes is cost- effective, since this intervention is expensive and time-consuming.

The authors have clearly stated their research question and their inclusion and exclusion criteria. The literature search is good but the authors may have missed additional relevant studies by searching only one database and by restricting their search to English language publications.

The quality of the included studies was formally assessed and the authors have reported on how the articles were selected, and how many of the reviewers were involved in the data selection and extraction. The data extraction is reported in tables and text and the statistical pooling was appropriate and the authors tested for homogeneity although the method is not stated.

The authors have discussed the limitations of their review and their conclusions appear to follow from the results.

Practice: The authors state that in practice, although the effectiveness of pentoxifylline and nafronyl is convincingly demonstrated, it is questionable whether their prescription to patients with intermittent claudication at stage II of disease would be clinically relevant. In current clinical practice, the administration of these drugs should therefore be evaluated on a patient-by-patient basis.

Research: The authors state that data are needed from larger properly designed clinical trials, assessing also the degree of disability and quality of life.

These additional published commentary may also be of interest. Hiatt WR. Intermittent claudication revisited: the value of medical therapy. Arch Intern Med 1999:159;1955-1956. Intermittent claudication treatments. Bandolier 2000:74;3-4.

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.