Translational Stroke Research

, Volume 10, Issue 4, pp 381–388 | Cite as

Dose-Dependent Inhibitory Effects of Cilostazol on Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage

  • Hidenori SuzukiEmail author
  • Yoshinari Nakatsuka
  • Ryuta Yasuda
  • Masato Shiba
  • Yoichi Miura
  • Mio Terashima
  • Yume Suzuki
  • Koichi Hakozaki
  • Fuki Goto
  • Naoki Toma
Original Article


Cilostazol is a selective inhibitor of phosphodiesterase type III that downregulates tenascin-C (TNC), a matricellular protein, which may cause delayed cerebral infarction after aneurysmal subarachnoid hemorrhage (SAH). The authors increased the dosage and evaluated the dose-dependent effects of cilostazol on delayed cerebral infarction and outcomes in SAH patients. This was a retrospective cohort study in a single center. One hundred fifty-six consecutive SAH patients including 67 patients of admission World Federation of Neurological Surgeons grades IV–V who underwent aneurysmal obliteration within 48 h post-SAH from 2007 to 2017 were analyzed. Cilostazol (0 to 300 mg/day) was administered from 1-day post-clipping or post-coiling to day 14 or later. Cilostazol treatment dose-dependently decreased delayed cerebral infarction and tended to improve outcomes, although cilostazol did not affect other outcome measures including angiographic vasospasm. On multivariate analyses, 300 mg/day (100 mg three times) cilostazol independently decreased delayed cerebral infarction and improved 3-month outcomes, but other regimens including 200 mg/day (100 mg twice) cilostazol were not independent prognostic factors. Propensity score-matched analyses showed that the 300 mg/day cilostazol cohort had lower plasma TNC levels and a lower incidence of delayed cerebral infarction associated with better outcomes compared with the non-cilostazol cohort. The 300 mg/day cilostazol may improve post-SAH outcomes by reducing plasma TNC levels and delayed cerebral infarction, but not vasospasm. Further studies are warranted to investigate if 300 mg/day cilostazol is more beneficial to post-SAH outcomes than a usual dose of 200 mg/day cilostazol that was demonstrated to be effective in randomized controlled trials.


Cerebral infarction Cerebral vasospasm Cilostazol Delayed cerebral ischemia Subarachnoid hemorrhage Tenascin-C 



We thank Ms. Chiduru Yamamoto (Department of Neurosurgery, Mie University Graduate School of Medicine) for her technical assistance.


This work was funded by a grant-in-aid for Scientific Research from Japan Society for the Promotion of Science (grant number 17K10825) to Dr. Suzuki.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

This article does not contain any studies with animals performed by any of the authors.

Informed Consent

Informed consent was obtained from all individual participants included in the study as to TNC measurements. For other retrospective analyses, formal consent is not required.

Supplementary material

12975_2018_650_MOESM1_ESM.pdf (127 kb)
ESM 1 (PDF 126 kb)


  1. 1.
    Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389:655–66.CrossRefGoogle Scholar
  2. 2.
    Suzuki H. What is early brain injury? Transl Stroke Res. 2015;6:1–3.CrossRefGoogle Scholar
  3. 3.
    Vergouwen MDI, Vermeulen M, van Gijn J, Rinkel GJE, Wijdicks EF, Muizelaar JP, et al. 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. 2010;41:2391–5.CrossRefGoogle Scholar
  4. 4.
    Suzuki H, Shiba M, Nakatsuka Y, Nakano F, Nishikawa H. Higher cerebrospinal fluid pH may contribute to the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Transl Stroke Res. 2017;8:165–73.CrossRefGoogle Scholar
  5. 5.
    Suzuki H, Kawakita F. Tenascin-C in aneurysmal subarachnoid hemorrhage: deleterious or protective? Neural Regen Res. 2016;11:230–1.CrossRefGoogle Scholar
  6. 6.
    Fujimoto M, Shiba M, Kawakita F, Liu L, Shimojo N, Imanaka-Yoshida K, et al. Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice. J Neurosurg. 2016;124:1693–702.CrossRefGoogle Scholar
  7. 7.
    Liu L, Fujimoto M, Kawakita F, Nakano F, Imanaka-Yoshida K, Yoshida T, et al. Anti-vascular endothelial growth factor treatment suppresses early brain injury after subarachnoid hemorrhage in mice. Mol Neurobiol. 2016;53:4529–38.CrossRefGoogle Scholar
  8. 8.
    Liu L, Kawakita F, Fujimoto M, Nakano F, Imanaka-Yoshida K, Yoshida T, et al. Role of periostin in early brain injury after subarachnoid hemorrhage in mice. Stroke. 2017;48:1108–11.CrossRefGoogle Scholar
  9. 9.
    Fujimoto M, Shiba M, Kawakita F, Liu L, Shimojo N, Imanaka-Yoshida K, et al. Effects of tenascin-C knockout on cerebral vasospasm after experimental subarachnoid hemorrhage in mice. Mol Neurobiol. 2017;55:1951–8. Scholar
  10. 10.
    Liu L, Fujimoto M, Nakano F, Nishikawa H, Okada T, Kawakita F, et al. Deficiency of tenascin-C alleviates neuronal apoptosis and neuroinflammation after experimental subarachnoid hemorrhage in mice. Mol Neurobiol. 2018;
  11. 11.
    Suzuki H, Kanamaru K, Suzuki Y, Aimi Y, Matsubara N, Araki T, et al. Tenascin-C is induced in cerebral vasospasm after subarachnoid hemorrhage in rats and humans: a pilot study. Neurol Res. 2010;32:179–84.CrossRefGoogle Scholar
  12. 12.
    Fujinaga K, Onoda K, Yamamoto K, Imanaka-Yoshida K, Takao M, Shimano T, et al. Locally applied cilostazol suppresses neointimal hyperplasia by inhibiting tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts. J Thorac Cardiovasc Surg. 2004;128:357–63.CrossRefGoogle Scholar
  13. 13.
    Nishino A, Umegaki M, Fujinaka T, Yoshimine T. Cilostazol attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. Neurol Res. 2010;32:873–8.CrossRefGoogle Scholar
  14. 14.
    Ito H, Fukunaga M, Suzuki H, Miyakoda G, Ishikawa M, Yabuuchi Y, et al. Effect of cilostazol on delayed cerebral vasospasm after subarachnoid hemorrhage in rats: evaluation using black blood magnetic resonance imaging. Neurobiol Dis. 2008;32:157–61.CrossRefGoogle Scholar
  15. 15.
    Boulouis G, Labeyrie MA, Raymond J, Rodriguez-Régent C, Lukaszewicz AC, Bresson D, et al. Treatment of cerebral vasospasm following aneurysmal subarachnoid haemorrhage: a systematic review and meta-analysis. Eur Radiol. 2017;27:3333–42.CrossRefGoogle Scholar
  16. 16.
    Senbokuya N, Kinouchi H, Kanemaru K, Ohashi Y, Fukamachi A, Yagi S, et al. Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial. J Neurosurg. 2013;118:121–30.CrossRefGoogle Scholar
  17. 17.
    Matsuda N, Naraoka M, Ohkuma H, Shimamura N, Ito K, Asano K, et al. Effect of cilostazol on cerebral vasospasm and outcome in patients with aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled trial. Cerebrovasc Dis. 2016;42:97–105.CrossRefGoogle Scholar
  18. 18.
    Suzuki S, Sayama T, Nakamura T, Nishimura H, Ohta M, Inoue T, et al. Cilostazol improves outcome after subarachnoid hemorrhage: a preliminary report. Cerebrovasc Dis. 2011;32:89–93.CrossRefGoogle Scholar
  19. 19.
    Konczalla J, Seifert V, Beck J, Güresir E, Vatter H, Raabe A, et al. Outcome after Hunt and Hess grade V subarachnoid hemorrhage: a comparison of pre-coiling era (1980-1995) versus post-ISAT era (2005-2014). J Neurosurg. 2018;128:100–10.CrossRefGoogle Scholar
  20. 20.
    Yoo AR, Koh SH, Cho GW, Kim SH. Inhibitory effects of cilostazol on proliferation of vascular smooth muscle cells (VSMCs) through suppression of the ERK1/2 pathway. J Atheroscler Thromb. 2010;17:1009–18.CrossRefGoogle Scholar
  21. 21.
    Niki T, Mori H. Phase I study of cilostazol: safety evaluation at increasing single doses in healthy volunteers. Arzneimittelforschung. 1985;35(7A):1173–85.Google Scholar
  22. 22.
    Drake CG. Report of World Federation of Neurological Surgeons Committee on a universal subarachnoid hemorrhage grading scale [letter]. J Neurosurg. 1988;68:985–6.Google Scholar
  23. 23.
    Suzuki H, Muramatsu M, Tanaka K, Fujiwara H, Kojima T, Taki W. Cerebrospinal fluid ferritin in chronic hydrocephalus after aneurysmal subarachnoid hemorrhage. J Neurol. 2006;253:1170–6.CrossRefGoogle Scholar
  24. 24.
    Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57:289–300.Google Scholar
  25. 25.
    Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat. 2011;10:150–61.CrossRefGoogle Scholar
  26. 26.
    Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–107.CrossRefGoogle Scholar
  27. 27.
    Frontera JA, Claassen J, Schmidt JM, Wartenberg KE, Temes R, Connolly ES Jr, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery. 2006;59:21–7.CrossRefGoogle Scholar
  28. 28.
    Yamaguchi-Okada M, Nishizawa S, Mizutani A, Namba H. Multifaceted effects of selective inhibitor of phosphodiesterase III, cilostazol, for cerebral vasospasm after subarachnoid hemorrhage in a dog model. Cerebrovasc Dis. 2009;28:135–42.CrossRefGoogle Scholar
  29. 29.
    Uchida H, Mishima Y, Tanabe T, Furukawa K, Ohashi S, Sakaguchi S, et al. Therapeutic effect of OPC-13013 on chronic arterial occlusive diseases. Cardioangiology. 1985;17:421–32.Google Scholar
  30. 30.
    Nakatsuka Y, Kawakita F, Yasuda R, Umeda Y, Toma N, Sakaida H, et al. Preventive effects of cilostazol against the development of shunt-dependent hydrocephalus after subarachnoid hemorrhage. J Neurosurg. 2017;127:319–26.CrossRefGoogle Scholar
  31. 31.
    Ahn SH, Savarraj JP, Pervez M, Jones W, Park J, Jeon SB, et al. The subarachnoid hemorrhage early brain edema score predicts delayed cerebral ischemia and clinical outcomes. Neurosurgery. 2017;83:137–45. Scholar
  32. 32.
    Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH. Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl Stroke Res. 2013;4:432–46.CrossRefGoogle Scholar
  33. 33.
    Suzuki H, Kanamaru K, Shiba M, Fujimoto M, Imanaka-Yoshida K, Yoshida T, et al. Cerebrospinal fluid tenascin-C in cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2011;23:310–7.CrossRefGoogle Scholar
  34. 34.
    Suzuki H, Nishikawa H, Kawakita F. Matricellular proteins as possible biomarkers for early brain injury after aneurysmal subarachnoid hemorrhage. Neural Regen Res. 2018;13:1175–8.Google Scholar
  35. 35.
    Okada T, Suzuki H. Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage. Neural Regen Res. 2017;12:193–6.CrossRefGoogle Scholar
  36. 36.
    Al-Mufti F, Amuluru K, Smith B, Damodara N, El-Ghanem M, Singh IP, et al. Emerging markers of early brain injury and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage. World Neurosurg. 2017;107:148–59.CrossRefGoogle Scholar
  37. 37.
    Zheng YK, Dong XQ, Du Q, Wang H, Yang DB, Zhu Q, et al. Comparison of plasma copeptin and multiple biomarkers for assessing prognosis of patients with aneurysmal subarachnoid hemorrhage. Clin Chim Acta. 2017;475:64–9.CrossRefGoogle Scholar
  38. 38.
    Satoh S, Ikegaki I, Kawasaki K, Asano T, Shibuya M. Pleiotropic effects of the rho-kinase inhibitor fasudil after subarachnoid hemorrhage: a review of preclinical and clinical studies. Curr Vasc Pharmacol. 2014;12:758–65.CrossRefGoogle Scholar
  39. 39.
    Chapados R, Abe K, Ihida-Stansbury K, McKean D, Gates AT, Kern M, et al. ROCK controls matrix synthesis in vascular smooth muscle cells: coupling vasoconstriction to vascular remodeling. Circ Res. 2006;99:837–44.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurosurgeryMie University Graduate School of MedicineTsuJapan
  2. 2.Center for Vessels and HeartMie University HospitalTsuJapan

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