Efficacy and Safety of Dual Antiplatelet Therapy Using Cilostazol with Aspirin or Clopidogrel to Reduce the Rate of Recurrent Ischemic Stroke in Asia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
DOI:
https://doi.org/10.33192/smj.v77i5.271759Keywords:
Aspirin, Cilostazol, Clopidogrel, Dual Antiplatelet, Ischemic StrokeAbstract
Objective: The stroke mortality rate in Asia is higher than in other regions worldwide. As an antiplatelet medication and phosphodiesterase-3 inhibitor, cilostazol lacks approval for use in ischemic stroke. We intended to analyze the efficacy and safety of cilostazol dual antiplatelet therapy (DAPT) with clopidogrel or aspirin compared to aspirin or clopidogrel monotherapy.
Materials and Methods: This review was carried out under the PRISMA 2020 guidelines, using sources from PubMed, Cochrane Library, EBSCOhost, Proquest, and the Lancet database. The Cochrane Risk of Bias 2 (RoB2) tool for randomized controlled trials was used to grade the quality of studies and Review Manager (RevMan) 5.4 for the meta-analysis.
Results: Eight studies were included in this analysis, with four undergoing quantitative evaluation through metaanalysis, involving 3,328 patients. The risk of recurrent ischemic stroke for patients treated with cilostazol DAPT was significantly lower compared to those receiving monotherapy (risk ratio, RR: 0.49; 95% CI: 0.32–0.71; p: 0.0001) and (hazard ratio, HR: 0.48; 95% CI: 0.32–0.74; p: 0.0008). There were no significant differences in any hemorrhagic adverse events between the treatment groups (RR: 0.98; 95% CI: 0.71-1.36; p: 0.91). Acute neurological deterioration showed no significant differences (RR: 0.55; 95% CI: 0.11-2.77; p: 0.47).
Conclusion: Cilostazol DAPT is more effective than clopidogrel or aspirin alone in preventing recurrent ischemic strokes without significantly increasing hemorrhagic risks or acute neurological decline. However, the study’s exclusive focus on a Japanese population limits the generalizability of the findings, highlighting the need for more diverse clinical trials across Asia.
References
Feigin VL, Brainin M, Norrving B, Martins S, Sacco RL, Hacke W, et al. World Stroke Organization (WSO): Global Stroke Fact Sheet 2022. Int J Stroke. 2022;17(1):18-29.
Kongkar R, Pinyopasakul W, Pongthavornkamol K, Dajpratham P, Orathai P. The determinants of quality of life in Thai family caregivers of stroke survivors. Siriraj Med J. 2019;71(4):290-6.
Venketasubramanian N, Yoon BW, Pandian J, Navarro JC. Stroke Epidemiology in South, East, and South-East Asia: A Review. J Stroke. 2017;19(3):286-94.
Chudapongse R, Sangpetngam B, Chankaew E, Aurboonyawat T, Churojana A, Withayasuk P. Comparative Evaluation of Imaging Modalities for Eligibility in Endovascular Treatment of Delayed Onset Acute Anterior Circulation Ischemic Stroke in Siriraj Hospital: A Retrospective Analysis. Siriraj Med J. 2024;76(9):573-80.
Ananchaisarp T, Sa-a K. Knowledge of stroke and planned response among patients living with diabetes mellitus and hypertension in a primary care unit. Siriraj Med J. 2022;74(2):75-84.
Flach C, Muruet W, Wolfe CDA, Bhalla A, Douiri A. Risk and Secondary Prevention of Stroke Recurrence: A Population-Base Cohort Study. Stroke. 2020;51(8):2435-44.
Skajaa N, Adelborg K, Horváth-Puhó E, Rothman KJ, Henderson VW, Thygesen LC, et al. Risks of Stroke Recurrence and Mortality After First and Recurrent Strokes in Denmark: A Nationwide Registry Study. Neurology. 2022;98(4):e329-e342.
Dajpratham P, Udompanturak S, Karawek J. Factors associated with functional improvement at discharge in stroke rehabilitation. Siriraj Med J. 2007;59(5):222-5.
Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm J, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018;379(3):215-25.
Havenon A, Sheth KN, Madsen TE, Johnston KC, Turan TN, Toyoda K, et al. Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities. Stroke. 2021;52(10):e635-e45.
Chai E, Chen J, Li C, Zhang X, Fan Z, Yang S, et al. The Efficacy and Safety of Cilostazol vs. Aspirin for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis. Front Neurol. 2022;13:814654.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10:89.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024). Cochrane, 2024. Available from: www.training.cochrane.org/handbook.
Aoki J, Iguchi Y, Urabe T, Yamagami H, Todo K, Fujimoto S, et al. Acute Aspirin Plus Cilostazol Dual Therapy for Noncardioembolic Stroke Patients within 48 Hours of Symptom Onset. J Am Heart Assoc. 2019;8(15):e012652.
Uchiyama S, Sakai N, Toi S, Ezura M, Okada Y, Takagi M, et al. Final results of cilostazol-aspirin therapy against recurrent stroke with intracranial artery stenosis (CATHARSIS). Cerebrovasc Dis Extra. 2015;5(1):1-3.
Nakamura T, Tsuruta S, Uchiyama S. Cilostazol combined with aspirin prevents early neurological deterioration in patients with acute ischemic stroke: a pilot study. J Neurol Sci. 2012;313(1-2):22-26.
Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial. Lancet Neurol. 2019;18(6):539-48.
Hoshino H, Toyoda K, Omae K, Ishida N, Uchiyama S, Kimura K, et al. Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial. Stroke. 2021;52(11):3430-9.
Uchiyama S, Toyoda K, Omae K, Saita R, Kimura K, Hoshino H, et al. Dual Antiplatelet Therapy Using Cilostazol in Patients With Stroke and Intracranial Arterial Stenosis. J Am Heart Assoc. 2021;10(20):e022575.
Toyoda K, Omae K, Hoshino H, Uchiyama S, Kimura K, Miwa K, et al. Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke: A CSPS.com Trial Post Hoc Analysis. Neurology. 2022;98(10):e983-e92.
Nishiyama Y, Kimura K, Otsuka T, Toyoda K, Uchiyama S, Hoshino H, et al. Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke: Subanalysis of the CSPS.com Trial. Stroke. 2023;54(3):697-705.

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