Delayed cerebral ischemia seriously affects the prognosis of patients surviving the initial aneurysmal subarachnoid hemorrhage. Application of cilostazol was reported to ameliorate vasospasm and improve outcomes in series and clinical trials. But the effectiveness and feasibility of cilostazol on aneurysmal subarachnoid hemorrhage remained controversial. We performed a systematic review to clarify this issue.
PubMed, Ovid and Cochrane library database were systematically searched up to May 2018 for eligible publications in English. Quality assessment was conducted for included studies. Meta-analysis was conducted to evaluate the overall effect on events of interest. Subgroup analyses and sensitivity analyses were used to check whether the results were robust. Publication bias was evaluated with the funnel plot.
Pooled analyses found cilostazol significantly reduced incidences of severe angiographic vasospasm (p = 0.0001), symptomatic vasospasm (p < 0.00001), new cerebral infarction (p < 0.00001) and the poor outcome (p < 0.0001). Subgroup and sensitivity analyses achieved consistent results. There was no statistical difference between cilostazol and the control group in reducing mortality (p = 0.07). But sensitivity analysis changed the result after excluding one study. Under the prescribed dosage, complication was few and non-lethal.
Cilostazol was effective and safe to reduce incidences of severe angiographic vasospasm, symptomatic vasospasm, new cerebral infarction and poor outcome in patients after aneurysmal subarachnoid hemorrhage. However, its effect on mortality and the interactive effect with nimodipine warranted further research.
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Connolly ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P, Council AHAS, Int CCR, Nursing CC, Anesthes CCS, Cardiology CC (2012) Guidelines for the management of aneurysmal subarachnoid hemorrhage a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 43:1711–1737. https://doi.org/10.1161/STR.0b013e3182587839
Crowley RW, Medel R, Dumont AS, Ilodigwe D, Kassell NF, Mayer SA, Ruefenacht D, Schmiedek P, Weidauer S, Pasqualin A, Macdonald RL (2011) Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke 42:919–923. https://doi.org/10.1161/STROKEAHA.110.597005
Dankbaar JW, Rijsdijk M, van der Schaaf IC, Velthuis BK, Wermer MJH, Rinkel GJE (2009) Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology 51:813–819. https://doi.org/10.1007/s00234-009-0575-y
Dorhout Mees S, Rinkel GJE, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J (2007) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD000277.pub3
Ferguson S, Macdonald RL (2007) Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 60:658–667. https://doi.org/10.1227/01.NEU.0000255396.23280.31(discussion 667)
Huang YI, Cheng Y, Wu J, Li YS, Xu E, Hong Z, Li ZY, Zhang WW, Ding MP, Gao XG, Fan DS, Zeng JS, Wong KS, Lu CZ, Xiao J, Yao C, Investigators CC (2008) Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 7:494–499. https://doi.org/10.1016/S1474-4422(08)70094-2
Junichi K, Yongge L, Bing S, Yasmin S, Masuhiro Y, Frank C (2003) Cilostazol as a unique antithrombotic agent. Curr Pharm Des 9:2289–2302. https://doi.org/10.2174/1381612033453910
Kimura H, Okamura Y, Chiba Y, Shigeru M, Ishii T, Hori T, Shiomi R, Yamamoto Y, Fujimoto Y, Maeyama M, Kohmura E (2015) Cilostazol administration with combination enteral and parenteral nutrition therapy remarkably improves outcome after subarachnoid hemorrhage. Acta Neurochir Suppl 120:147–152. https://doi.org/10.1007/978-3-319-04981-6_25
Macdonald RL (2014) Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10:44–58. https://doi.org/10.1038/nrneurol.2013.246
Matsuda N, Naraoka M, Ohkuma H, Shimamura N, Ito K, Asano K, Hasegawa S, Takemura A (2016) Effect of cilostazol on cerebral vasospasm and outcome in patients with aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled trial. Cerebrovasc Dis 42:97–105. https://doi.org/10.1159/000445509
Murahashi T, Kamiyama K, Hara K, Ozaki M, Mikamoto M, Nakagaki Y, Nakagaki Y, Nakamura H (2013) The efficiency of cilostazol for cerebral vasospasm following subarachnoid hemorrhage. No Shinkei Geka 41:393–400
Nakatsuka Y, Kawakita F, Yasuda R, Umeda Y, Toma N, Sakaida H, Suzuki H (2016) Preventive effects of cilostazol against the development of shunt-dependent hydrocephalus after subarachnoid hemorrhage. J Neurosurg 127:319–326. https://doi.org/10.3171/2016.5.JNS152907
Niu PP, Yang G, Xing YQ, Guo ZN, Yang Y (2014) Effect of cilostazol in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurol Sci 336:146–151. https://doi.org/10.1016/j.jns.2013.10.027
Rinkel GJ, Algra A (2011) Long-term outcomes of patients with aneurysmal subarachnoid haemorrhage. Lancet Neurol 10:349–356. https://doi.org/10.1016/j.jns.2013.10.027
Saber H, Desai A, Palla M, Mohamed W, Seraji-Bozorgzad N, Ibrahim M (2018) Efficacy of cilostazol in prevention of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a meta-analysis. J Stroke Cerebrovasc Dis 27:2979–2985. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.06.027
Senorita N, Kinouchi H, Kanemaru K, Ohashi Y, Fukamachi A, Yagi S, Shimizu T, Furuya K, Uchida M, Takeuchi N, Nakano S, Koizumi H, Kobayashi C, Fukasawa I, Takahashi T, Kuroda K, Nishiyama Y, Yoshioka H, Horikoshi T (2013) Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial. J Neurosurg 118:121–130. https://doi.org/10.3171/2012.9.JNS12492
Suzuki S, Sayama T, Nakamura T, Nishimura H, Ohta M, Inoue T, Mannoji H, Takeshita I (2011) Cilostazol improves outcome after subarachnoid hemorrhage: a preliminary report. Cerebrovasc Dis 32:89–93. https://doi.org/10.1159/000327040
Takagi T, Imai T, Mishiro K, Ishisaka M, Tsujimoto M, Ito H, Nagashima K, Matsukawa H, Tsuruma K, Shimazawa M, Yoshimura S, Kozawa O, Iwama T, Hara H (2017) Cilostazol ameliorates collagenase-induced cerebral hemorrhage by protecting the blood-brain barrier. J Cereb Blood Flow Metab 37:123–139. https://doi.org/10.1177/0271678X15621499
Tan L, Margaret B, Zhang JH, Hu R, Yin Y, Cao L, Feng H, Zhang Y (2015) Efficacy and safety of cilostazol therapy in ischemic stroke: a meta-analysis. J Stroke Cerebrovasc Dis 24:930–938. https://doi.org/10.1016/j.jstrokecerebrovasdis.2014.12.002
Vergouwen MDI, Vermeulen M, van Gijn J, Rinkel GJE, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YBWEM (2010) Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies proposal of a multidisciplinary research group. Stroke 41:2391–2395. https://doi.org/10.1161/STROKEAHA.110.589275
Yoshimoto T, Shirasaka T, Fujimoto S, Yoshidumi T, Yamauchi T, Tokuda K, Kaneko S, Kashiwaba T (2009) Cilostazol may prevent cerebral vasospasm following subarachnoid hemorrhage. Neurol Med Chir 49:235–240. https://doi.org/10.2176/nmc.49.235
Study was funded by the “1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University” (No. ZY2016102), and National Natural Science Foundation of China (No. 81501003). We are grateful to Dr. Zhong Yao for his work in the early literature screening.
Conflicts of interest
I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under the consideration for publication elsewhere, in whole or in part. In addition, no conflict of interest exists in our study. This article is a meta-analysis with all analyses based on previous published studies, thus no ethical approval and patient consent are required.
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Shan, T., Zhang, T., Qian, W. et al. Effectiveness and feasibility of cilostazol in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurol 267, 1577–1584 (2020). https://doi.org/10.1007/s00415-019-09198-z
- Subarachnoid hemorrhage