Key result
Adding cilostazol to aspirin or clopidogrel cuts recurrent stroke ~56% compared with antiplatelet monotherapy.
Why the study?
Cilostazol reduces stroke recurrence in noncardioembolic ischemic stroke and may lower SBP, raising the question of whether its benefit is mediated by blood pressure reduction.
Does dual therapy with cilostazol and aspirin or clopidogrel reduce the risk of stroke recurrence compared to monotherapy in patients with noncardioembolic ischemic stroke, and is this effect mediated by a reduction in systolic blood pressure?
RCT (n=1,795)
Open-label
Randomized
Yes
Does dual therapy with cilostazol and aspirin or clopidogrel reduce the risk of stroke recurrence compared to monotherapy in patients with noncardioembolic ischemic stroke, and is this effect mediated by a reduction in systolic blood pressure?
Cilostazol reduces the risk of stroke recurrence in patients with noncardioembolic ischemic stroke through pleiotropic pathways independent of systolic blood pressure reduction.
This hypothesis-generating analysis suggests cilostazol's stroke prevention benefits do not rely on blood.
AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our results indicate that cilostazol reduced stroke recurrence without lowering SBP, likely through other pleiotropic pathways.
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Miwa et al. (2025) conducted an RCT in Non-cardioembolic ischemic stroke (n=1,795). Cilostazol plus aspirin or clopidogrel vs. Aspirin or clopidogrel alone was evaluated on First recurrence of ischemic stroke (cumulative hazard rate difference -0.043, 95% CI -0.070 to -0.015). Cilostazol added to aspirin or clopidogrel reduced stroke recurrence compared to monotherapy (cumulative hazard rate difference -0.043) without mediating a reduction in systolic blood pressure.
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