Long-Term Comparison of Cilostazol versus Clopidogrel in Secondary Prevention of Noncardioembolic Ischemic Stroke

Background Cilostazol is a widely used antiplatelet drug for secondary stroke prevention in Asia, but its comparison with clopidogrel, another commonly used antiplatelet drug, is not well understood. This study aims to investigate the effectiveness and safety of cilostazol compared to clopidogrel for the secondary prevention of noncardioembolic ischemic stroke. Methods A retrospective comparative effectiveness research analysis was conducted using 1:1 propensity-matched data from insured individuals between Jan 1, 2012, and Dec 31, 2019. The study used administrative claims data in Health Insurance and Review Assessment in Korea. Patients with diagnosis codes for ischemic stroke without atrial fibrillation, heart failure, valvular diseases, and myocardial infarction were included and divided into two groups, those receiving cilostazol and those receiving clopidogrel. The primary outcome was a recurrent ischemic stroke. Secondary outcomes included all-cause death, myocardial infarction, hemorrhagic stroke, and a composite of these outcomes. The safety outcome was major gastrointestinal bleeding. Results A total of 4754 patients were included in the propensity-matched population, with a median age of 67 years, 3080 (40.7%) were male, and 4480 (59.3%) were female. The study found no statistically significant difference in recurrent ischemic stroke (cilostazol group vs clopidogrel group, 2.7% vs 3.2%; 95% CI, 0.62-1.21), the composite outcome of recurrent ischemic stroke, all-cause death, myocardial infarction, and hemorrhagic stroke (5.1% vs 5.5%; 95% CI 0.75-1.22), and major gastrointestinal bleeding (1.3% vs 1.5%; 95% CI 0.57-1.47) between cilostazol and clopidogrel use patients. In subgroup analysis, cilostazol was associated with a lower incidence of recurrent ischemic stroke compared to clopidogrel in hypertensive patients (2.5% vs 3.9%; interaction P = 0.41). Conclusions This real-world, comparative effectiveness research study suggests that cilostazol is effective and safe for noncardioembolic ischemic stroke and may be associated with better effectiveness in hypertensive patients compared to clopidogrel over an 8-year period. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement None ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: . This study protocol was approved by the institutional review board of the Pusan national university (No. PNU IRB/2022\_114\_HR) with a waiver of informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable The data used for this study were obtained from the HIRA research database (M20220628003) and were stored on a separate server managed by the HIRA. All authors had full access to all the data in the study and take responsibility for its integrity and the data analysis. * CASISP : Cilostazol versus Aspirin for Secondary Ischaemic Stroke Prevention CSPS : Cilostazol for Prevention of Secondary Stroke CT : computed tomography CYP : cytochrome P450 DAPT : dual antiplatelet therapy EVT : endovascular treatment GI : gastrointestinal HIRA : Health Insurance and Review Assessment IVT : intravenous thrombolytic therapy MRI : magnetic resonance imaging PDE : phosphodiesterase PICASSO : Prevention of Cardiovascular Events in Ischemic Stroke Patients with High Risk of Cerebral Hemorrhage PSM : propensity score matching SAPT : single antiplatelet therapy TIA : transient ischemic attack