A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication

Abstract

Pharmacologic therapy for intermittent claudication in patients with peripheral artery disease (PAD) is limited. We aimed to determine the durability of cilostazol treatment response over time, treatment effects in various subpopulations, and long-term safety. This analysis pooled original data from nine randomized, controlled trials evaluating cilostazol in intermittent claudication, including 1258 subjects treated with cilostazol 100 mg bid. Analysis of covariance was used to compare differences in walking distance, and a pooled random-effects weighted mean difference in maximal walking distance (MWD) was determined. Temporal effects were analyzed by compiling data at 4-week intervals in studies of 24 weeks in duration. Cilostazol was associated with a 50.7% improvement from baseline in MWD compared with placebo (24.3%), with an absolute improvement of 42.1 meters greater than the improvement with placebo (p < 0.001) over a mean follow-up period of 20.4 weeks. Continued increases were demonstrated over the 24-week treatment period. These benefits were seen in all subgroups, after stratifying by age, sex, smoking status, duration of PAD, diabetes, hypertension, prior myocardial infarction, or beta-blocker use. Cilostazol did not increase the risk of all-cause mortality (RR 0.95 [0.68-1.35]). In conclusion, treatment with cilostazol achieves benefits in walking distance that are sustained at 24 weeks and observed irrespective of baseline clinical characteristics. Cilostazol demonstrated no increased risk of all-cause mortality.

Figure 1

Meta-analysis of randomized, controlled trials evaluating the effect of cilostazol versus placebo. Due to underlying heterogeneity, cilostazol analyses are performed using the random-effects weighted mean difference in maximal walking distance (MWD) with corresponding 95% confidence interval (CI).

Figure 2

Analysis of treatment effects over time for cilostazol versus placebo. Data are shown as the estimated treatment effect, a comparison of geometric means. Statistical comparison is achieved by ANCOVA.

Figure 3

Meta-analysis of all-cause mortality in cilostazol trials. Data are shown as a risk ratio with corresponding 95% confidence interval (CI) for the CASTLE study and the nine cilostazol randomized controlled trials (RCTs).