PS-C28-8: CILOSTAZOL CONTRIBUTES TO RISK REDUCTION OF STROKE RECURRENCE WITHOUT LOWERING BLOOD PRESSURE: RESULTS FROM CSPS.COM

Abstract

Background: The Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com) found that the dual therapy with cilostazol plus aspirin or clopidogrel reduced the risks of recurrent ischemic stroke compared with monotherapy with aspirin or clopidogrel alone in patients with non-cardioembolic ischemic stroke. As its putative mechanisms, cilostazol can serve a role in the inhibition of angiotensin 2-induced endothelial cell apoptosis and vasodilation, which may yield lower systolic blood pressure (SBP). We aimed to determine to what extent the effect on ischemic stroke recurrence was mediated through blood pressure reduction due to cilostazol. Methods: In a post hoc analysis of CSPS.com, we defined change in SBP as the change in SBP 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 the cilostazol on the first recurrence of the symptomatic ischemic stroke into indirect effects (mediated by change in SBP on cilostazol) and direct effects (mediated through pathways other than change in SBP on cilostazol). The effects were summarized by cumulative hazard rate difference. Results: In the ITT population, ischemic stroke recurred in 29 (3%) of 932 patients on dual therapy and 64 (7%) of 947 patients on monotherapy during a median 1.4-year follow-up. The estimates for effect of SBP (per 1mmHg increase) on the stroke recurrence at 24-months follow-up was 0.0007 (95% confidence interval [95% CI] 0.00018 to 0.0013). The effect estimates for direct effect and indirect effect of the cilostazol on the stroke recurrence at the same follow-up were -0.045 (95% CI, -0.071 to -0.015) and -0.0007 (95% CI, -0.0023 to 0.00053), respectively. The results of the adjusted model with age were similar. Conclusions: Although it was shown that change of SBP was associated with an increased risk of stroke recurrence, there was no evidence that change in SBP mediated the association between cilostazol and ischemic stroke recurrence, indicating that cilostazol contributed to risk reduction of stroke recurrence without through change in SBP.