The results of this pooled analysis from nine randomized, multi-center, placebo-controlled trials demonstrate that at 24 week follow-up cilostazol produced significant improvements in maximal walking distance in patients with intermittent claudication, benefits that correlated with improvements in quality of life measures. Specifically, cilostazol 100 mg bid increased MWD by 42.1 meters compared to placebo, with the benefits of cilostazol achieved in all subgroups examined and correlating with improvements in quality of life measures. Furthermore, analysis of the temporal effects of cilostazol on walking ability showed that continued increases could be achieved with cilostazol 100 mg bid over 24 weeks of therapy. Improvements in pain-free walking distance were demonstrable as well.
An advantage of the present analysis was the ability to combine the patient-level data from nine trials with identical inclusion and exclusion criteria. Based on that, we are able to demonstrate in a large pooled sample that cilostazol achieves benefits in maximal walking time not only in the overall population, but also amongst multiple subgroups. However, the present study must be evaluated in the context of its limitations. First, given that the goals of treatment in intermittent claudication include improved exercise performance, assessment of treadmill walking ability is central to establishment of clinical efficacy. These nine cilostazol trials employed two different exercise tests, constant load and graded exercise protocols, and walking distances measured on the graded test tend to be greater than distances measured with the constant load protocol.19
However, the comparability of the two protocols has been previously established, particularly in patients able to walk greater than 100m.19
Moreover, to further account for potential effects of having different treadmill protocols, we used a value that incorporated both baseline walking distance and post-treatment walking distance in our analysis and we demonstrated using a test for interaction that there was no significant difference in treatment response based on the different treadmill exercise protocols. Second, as with all pooled analyses, it is important to recognize the potential limitations of combining data from different studies. Due to heterogeneity across these nine studies, we chose a random effects model to be most conservative the estimate of the treatment effect of cilostazol. Heterogeneity in these studies was felt to be due in large part to the widely varying point estimates for the treatment effect of cilostazol. Given that the studies had identical inclusion and exclusion criteria, similar outcome measures and similar periods of follow-up, we did not feel that the heterogeneity seen here was related to differences in patient characteristics. We may also have been limited in our ability to detect a greater response to cilostazol. The assessment of exercise capacity on a treadmill has been shown to underestimate actual patient walking distance,20
given that patients tend to walk at greater intensity levels on treadmill protocols than they would otherwise use for regular activities of daily living. Despite these limitations, these data demonstrate that cilostazol does produce a sustained improvement in walking distance over 24 weeks and among all subgroups analyzed.
The walking improvements observed with cilostazol in this meta-analysis were significant as assessed by objective parameters (treadmill exercise performance) and associated with subjective patient-based improvements in functional capacity. How these clinical benefits compare to other established therapies for claudication, such as a formal exercise program or a successful limb revascularization, remain to be determined. Comparative trials assessing these different treatment modalities need to be performed. These data also highlight the limitations in our treatment options for stable claudication and remind us of the critical need for continued research to seek novel therapies to improve symptoms and quality of life in patients with PAD.
Furthermore, the mechanisms of cilostazol’s benefit in intermittent claudication also remain unclear. By inhibiting phosphodiesterase 3 and increasing intracellular cAMP levels, cilostazol has been shown to cause vasodilation and improve peripheral blood flow.1–4
However, although flow limitation in PAD is a primary cause of intermittent claudication, PAD is not simply a hemodynamic disorder and severity of claudication pain cannot simply be explained by reduction in perfusion pressure and flow. Indeed, studies have shown a poor correlation between diminished calf blood flow and walking distance in patients with PAD.22
Additionally, restoration of flow via revascularization does not completely improve claudication symptoms,23
and the symptomatic improvements known to result from exercise training programs in patients with PAD do not occur solely as a result of increase blood flow.24
Compelling reasons therefore exist for the exploration of novel paradigms to explain the symptomatic limitation in patients with intermittent claudication.
In conclusion, the current analysis demonstrated that administration of cilostazol can achieve sustained improvements in walking distance and quality of life in patients with intermittent claudication. However, the improvements seen here should encourage us to continue to focus on the fundamental mechanisms of intermittent claudication as a guide to the development of novel therapies for this life-limiting condition. These efforts are essential in order to broaden the currently limited therapeutic options for patients with PAD and intermittent claudication.