Cilostazol Contributes to Risk Reduction of Stroke Recurrence without Mediating a Reduction of Blood Pressure:...

Cilostazol, a phosphodiesterase III inhibitor, reduces the risk of stroke recurrence among patients with noncardioembolic ischemic stroke through inhibition of the platelet function and its pleiotropic effects. Its potential mechanisms include inhibiting angiotensin II-induced endothelial cell apoptosis and promoting vasodilation, which may lower systolic blood pressure (SBP). We hypothesized that the decreased risk of stroke recurrence could be attributed to a reduction in SBP.

In a post hoc analysis of CSPS.com, we defined change in SBP as its change at the last visit compared with baseline and treated it as a time-dependent mediator. We performed causal mediation analyses to separate the overall effects of cilostazol on the first recurrence of ischemic stroke into indirect effects (mediated by change in SBP on cilostazol) and direct effects (mediated through pathways other than a change in SBP on cilostazol). The effects were summarized by cumulative hazard rate difference.

Ischemic stroke recurred in 27 (3%) of 889 patients on dual therapy with cilostazol and aspirin or clopidogrel and 62 (6.8%) of 906 patients on monotherapy with aspirin or clopidogrel alone during a median follow-up period of 1.4 years. The mediation analysis showed that the positive effect of dual therapy was not mediated by the association between SBP change and stroke recurrence. The estimated direct and indirect effects of cilostazol on stroke recurrence during the same follow-up period were cumulative hazard rate differences of -0.043 (95% CI, -0.070 to -0.015) and -0.0008 (-0.0024 to 0.00035), respectively.

Our results indicate that cilostazol reduced stroke recurrence without lowering SBP, likely through other pleiotropic pathways.