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Acute Pain | Chronic Pain | General

Cilostazol for intermittent claudication

 

Clinical bottom line

Cilostazol at 50 or 100 mg twice daily increased maximum and pain free walking distances substantially more than did placebo over 12-24 weeks in patients with intermittent claudication.

See updated review below


Reference

PD Thompson et al. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. American Journal of cardiology 2002 90: 1314-1319.

Study

Inclusion criteria were randomised controlled trials of cilostazol for intermittent claudication due to peripheral arterial occlusive disease in the lower extremities; walking distance as an outcome; use of treadmill for evaluations. Reviewers extracted data on pain-free or maximum walking times or distances, and used pre- and post-intervention scores to calculate a percent change from baseline. The analysis was an intention to treat based on patients who had a baseline and at least one post treatment evaluation. The duration of the studies was 12 to 24 weeks.

Results

Doses of cilostazol were 50 mg or 100 mg twice a day. Quality of trials was not reported, though all were randomised and all appeared to be properly blinded; withdrawals were reported, and reasons given, so it is likely that all trials scored at least 3/5 on a common quality reporting scale. Patients were well matched at baseline. Their mean age was 65 years, 75% were men, about 60% had intermittent claudication for at least five years, and about a quarter had diabetes. Walking distances at baseline were not given.

The effects of placebo and cilostazol on walking distance and pain-free walking distance are given in Table 1, as mean percentage improvements from baseline. Both doses of cilostazol produced significantly better increases in walking distance than did placebo.

Table 1: Improvement in walking distance over baseline

Treatment

Walking distance (% increase)

Pain free walking distance (% increase)

Placebo

21

40

Cilostazol 50 mg twice a day

44

60

Cilostazol 100 mg twice a day

50

67

Plasma lipids

Cilostazol 50 and 100 mg reduced serum triglycerides by 13 and 16%, and raised HDL cholesterol by 6 and 13% respectively. Only the 100 mg dose was significantly better than placebo or pentoxifylline. LDL cholesterol was unchanged.

SF-36

Cilostazol at end of treatment improved mean scores by 4.4 points more than placebo for the physical function subscale in six trials., but not for general health.

Adverse events

Adverse event discontinuations were 13% and 16% for the 50 and 100 mg doses of cilostazol, compared with 9% for placebo and 21% for pentoxifylline. Common adverse events were headache (32%), diarrhoea (17%), abnormal stools (14%), rhinitis (8%) and peripheral oedema (6%), all significantly higher incidence than placebo.

Comment

Cilostazol is a selective phosphodiesterase inhibitor. The results appear to be reasonable and better in the two trials that compared it to pentoxifylline.

The review is unclear about the source of the information, but suggests that it came from individual patients or trial reports, as no search strategy is given. If so, it is a pity that the authors were unable to declare some level of increase as being clinically significant, and tell us the number of patients who achieved that benefit. What we have is average results only.

Update review

A new review [1] largely repeats this one, but perhaps with more detail. It concludes, on the basis of only using randomised, double blind studies, that cilostazol improves maximum and pain free walking distance. This review has much more information of adverse events, and records higher adverse event rates for headache, palpitations, dizziness, and diarrhoea, but not serious adverse events, and with only a small increased dropout rate compared with placebo.

  1. M Hashiguchi et al. Studies on the effectiveness and safety of cilostazol, beraprost sodium, prostaglandin E1 for the treatment of intermittent claudication. Yakugaku Zasshi 2004 124: 321-332.