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Effectiveness and feasibility of cilostazol in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis

Journal of Neurology volume 267, pages 1577–1584 (2020)Cite this article

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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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References

  1. 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

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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

    Article  PubMed  Google Scholar 

  3. 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

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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)

    Article  PubMed  Google Scholar 

  6. 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

    CAS  Article  PubMed  Google Scholar 

  7. 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

    Article  Google Scholar 

  8. 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

    Article  PubMed  Google Scholar 

  9. Macdonald RL (2014) Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10:44–58. https://doi.org/10.1038/nrneurol.2013.246

    CAS  Article  PubMed  Google Scholar 

  10. 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

    CAS  Article  PubMed  Google Scholar 

  11. 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

    PubMed  Google Scholar 

  12. 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

    Article  PubMed  Google Scholar 

  13. 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

    CAS  Article  PubMed  Google Scholar 

  14. 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

    CAS  Article  PubMed  Google Scholar 

  15. 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

    Article  PubMed  Google Scholar 

  16. 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

    CAS  Article  Google Scholar 

  17. 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

    CAS  Article  PubMed  Google Scholar 

  18. 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

    CAS  Article  PubMed  Google Scholar 

  19. 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

    Article  PubMed  Google Scholar 

  20. 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

    Article  PubMed  Google Scholar 

  21. 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

    Article  Google Scholar 

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Acknowledgements

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.

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Author notes

  1. Tikun Shan and Tiejun Zhang contributed equally to the study as the co-first authors.

Affiliations

  1. Department of Neurosurgery, West China Hospital, Sichuan University and West China Brain Research Centre, No. 37 Guo Xue Xiang, Chengdu, Sichuan, China

    Tikun Shan, Tiejun Zhang, Weiqiang Qian, Lu Ma, Hao Li & Chao You

  2. Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Xiaoqi Xie

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  1. Tikun Shan
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  2. Tiejun Zhang
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Correspondence to Chao You or Xiaoqi Xie.

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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

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  • DOI: https://doi.org/10.1007/s00415-019-09198-z

Keywords

  • Cilostazol
  • Aneurysm
  • Subarachnoid hemorrhage
  • Treatment
  • Meta-analysis