Cilostazol plus aspirin for secondary prevention of non-cardioembolic stroke: a systematic review and meta-analysis

Abstract

Abstract Background Stroke recurrence remains a major concern following non-cardioembolic ischemic stroke. Dual antiplatelet therapy has shown benefit in certain populations, but the optimal regimen is unclear. Cilostazol, a phosphodiesterase-III inhibitor with antiplatelet and vasodilatory properties and a potentially lower bleeding risk, has been proposed as an alternative to clopidogrel. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of cilostazol combined with aspirin versus aspirin alone for secondary prevention after non-cardioembolic ischemic stroke. Results Four RCTs (Kwon and colleagues, 2005; Nakamura and colleagues, 2012; Uchiyama and colleagues, 2015; Aoki and colleagues, 2019) met inclusion criteria, involving 1570 participants. Pooled analysis showed no significant reduction in stroke recurrence with the aspirin–cilostazol combination (AC) compared with aspirin alone at ≤ 2 weeks (risk difference [RD]: −0.01; 95% CI −0.02 to 0.01; p = 0.48) or at 6 months (RD: −0.02; 95% CI −0.06 to 0.01; p = 0.15). There was no increase in intracerebral hemorrhage, gastrointestinal bleeding, hematuria, or serious adverse events. AC was associated with a small but significant increase in palpitations (RD: 0.02; 95% CI 0.001−0.03; p = 0.04). Numerical data on functional outcomes were not consistently reported, but qualitative assessment suggested possible benefits in neurological recovery and disability reduction. Conclusions Cilostazol plus aspirin does not significantly reduce recurrent stroke compared with aspirin monotherapy, though it maintains a comparable safety profile with only a slight increase in palpitations. This regimen may be considered for patients at high risk of hemorrhage or with clopidogrel intolerance, but current evidence does not support its routine use over standard therapy. Larger, multi-ethnic randomized trials are needed to clarify benefits in specific subgroups, such as those with intracranial stenosis, and to evaluate functional outcomes using standardized reporting. PROSPERO Registration Number : CRD42021238520.