Cilostazol for Preventing Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

Summary

The investigators propose to conduct a multicenter randomized trial to test whether cilostazol reduces the incidence of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and improves patients' neurological prognosis, while assessing its safety.

Timeline

Start

2025-11-30

Primary completion

2027-05-31

Completion

2027-08-31

Publications

• Background SVIN COVID-19 Global SAH Registry. Global impact of the COVID-19 pandemic on subarachnoid haemorrhage hospitalisations, aneurysm treatment and in-hospital mortality: 1-year follow-up. J Neurol Neurosurg Psychiatry. 2022 Jul 28:jnnp-2022-329200. doi: 10.1136/jnnp-2022-329200. Online ahead of print.
• Results Kim BJ, Lee EJ, Kwon SU, Park JH, Kim YJ, Hong KS, Wong LKS, Yu S, Hwang YH, Lee JS, Lee J, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Navarro JC, Kang DW; PICASSO investigators. Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial. Lancet Neurol. 2018 Jun;17(6):509-518. doi: 10.1016/S1474-4422(18)30128-5.
• Results Suzuki S, Sayama T, Nakamura T, Nishimura H, Ohta M, Inoue T, Mannoji H, Takeshita I. Cilostazol improves outcome after subarachnoid hemorrhage: a preliminary report. Cerebrovasc Dis. 2011;32(1):89-93. doi: 10.1159/000327040. Epub 2011 Jun 11.
• Results Matsuda N, Naraoka M, Ohkuma H, Shimamura N, Ito K, Asano K, Hasegawa S, Takemura A. 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(1-2):97-105. doi: 10.1159/000445509. Epub 2016 Apr 13.
• Results Nakatsuka Y, Kawakita F, Yasuda R, Umeda Y, Toma N, Sakaida H, Suzuki H; , on behalf of the Prospective Registry for Searching Mediators of Neurovascular Events After Aneurysmal Subarachnoid Hemorrhage (pSEED) Group. Preventive effects of cilostazol against the development of shunt-dependent hydrocephalus after subarachnoid hemorrhage. J Neurosurg. 2017 Aug;127(2):319-326. doi: 10.3171/2016.5.JNS152907. Epub 2016 Aug 5.
• Results Sugimoto K, Nomura S, Shirao S, Inoue T, Ishihara H, Kawano R, Kawano A, Oka F, Suehiro E, Sadahiro H, Shinoyama M, Oku T, Maruta Y, Hirayama Y, Hiyoshi K, Kiyohira M, Yoneda H, Okazaki K, Dreier JP, Suzuki M. Cilostazol decreases duration of spreading depolarization and spreading ischemia after aneurysmal subarachnoid hemorrhage. Ann Neurol. 2018 Dec;84(6):873-885. doi: 10.1002/ana.25361. Epub 2018 Nov 29.
• Results Qureshi AI, Akhtar IN, Ma X, Lodhi A, Bhatti I, Beall J, Broderick JP, Cassarly CN, Martin RH, Sharma R, Thakkar M, Suarez JI. Effect of Cilostazol in Animal Models of Cerebral Ischemia and Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis. Neurocrit Care. 2023 Jun;38(3):698-713. doi: 10.1007/s12028-022-01637-6. Epub 2022 Nov 30.
• Results 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(2):135-42. doi: 10.1159/000223439. Epub 2009 Jun 5.
• Results Onal MB, Bilginer B, Narin F, Ziyal MI, Soylemezoglu F, Ozgen T. Comparison of intrathecal cilostazol and nimodipine treatments in subarachnoid hemorrhage: an experimental study in rabbits. Acta Neurochir Suppl. 2011;110(Pt 2):43-8. doi: 10.1007/978-3-7091-0356-2_9.
• Results Nishino A, Umegaki M, Fujinaka T, Yoshimine T. Cilostazol attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. Neurol Res. 2010 Oct;32(8):873-8. doi: 10.1179/016164109X12608733393791. Epub 2010 Mar 26.
• Results Boulouis G, Labeyrie MA, Raymond J, et al. Treatment of cerebral vasospasm following aneurysmal subarachnoid haemorrhage: a systematic review and meta-analysis. Eur Radiol. 2017;27(8):3333-3342. doi:10.1007/s00330-016-4702-ySenbokuya N, Kinouchi H, Kanemaru K, et al. Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: A multicenter prospective, randomized, open-label blinded end point trial - Clinical article. J Neurosurg. 2013;118(1):121-130. doi:10.3171/2012.9.JNS12492
• Results Kherallah RY, Khawaja M, Olson M, Angiolillo D, Birnbaum Y. Cilostazol: a Review of Basic Mechanisms and Clinical Uses. Cardiovasc Drugs Ther. 2022 Aug;36(4):777-792. doi: 10.1007/s10557-021-07187-x. Epub 2021 Apr 16.
• Results Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation. 2008 Sep 23;118(13):1358-65. doi: 10.1161/CIRCULATIONAHA.107.735985. Epub 2008 Sep 8.
• Results Kim SG, Hong JM, Kim HY, Lee J, Chung PW, Park KY, Kim GM, Lee KH, Chung CS, Bang OY. Ischemic stroke in cancer patients with and without conventional mechanisms: a multicenter study in Korea. Stroke. 2010 Apr;41(4):798-801. doi: 10.1161/STROKEAHA.109.571356. Epub 2010 Feb 11.
• Results Bedenis R, Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G. Cilostazol for intermittent claudication. Cochrane Database Syst Rev. 2014 Oct 31;2014(10):CD003748. doi: 10.1002/14651858.CD003748.pub4.
• Results Lee KS, Lee C, Dhillon PS, Kirollos R, Nga VDW, Yeo TT, Henkes H, Arthur AS, Yeo LLL, Bhogal P. Antiplatelet therapy in aneurysmal subarachnoid hemorrhage: an updated meta-analysis. Neurosurg Rev. 2023 Sep 4;46(1):221. doi: 10.1007/s10143-023-02120-2.
• Results Ohkuma H, Suzuki S, Kimura M, Sobata E. Role of platelet function in symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke. 1991 Jul;22(7):854-9. doi: 10.1161/01.str.22.7.854.
• Results Rowland MJ, Hadjipavlou G, Kelly M, Westbrook J, Pattinson KT. Delayed cerebral ischaemia after subarachnoid haemorrhage: looking beyond vasospasm. Br J Anaesth. 2012 Sep;109(3):315-29. doi: 10.1093/bja/aes264.
• Results Mayer SA, Aldrich EF, Bruder N, Hmissi A, Macdonald RL, Viarasilpa T, Marr A, Roux S, Higashida RT. Thick and Diffuse Subarachnoid Blood as a Treatment Effect Modifier of Clazosentan After Subarachnoid Hemorrhage. Stroke. 2019 Oct;50(10):2738-2744. doi: 10.1161/STROKEAHA.119.025682. Epub 2019 Aug 9.
• Results Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011 Jul;10(7):618-25. doi: 10.1016/S1474-4422(11)70108-9. Epub 2011 Jun 2.
• Results Hoh BL, Ko NU, Amin-Hanjani S, Chou SH-Y, Cruz-Flores S, Dangayach NS, Derdeyn CP, Du R, Hanggi D, Hetts SW, Ifejika NL, Johnson R, Keigher KM, Leslie-Mazwi TM, Lucke-Wold B, Rabinstein AA, Robicsek SA, Stapleton CJ, Suarez JI, Tjoumakaris SI, Welch BG. 2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2023 Jul;54(7):e314-e370. doi: 10.1161/STR.0000000000000436. Epub 2023 May 22.
• Results Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007 Jul 18;2007(3):CD000277. doi: 10.1002/14651858.CD000277.pub3.
• Results Dorhout Mees SM, Kerr RS, Rinkel GJ, Algra A, Molyneux AJ. Occurrence and impact of delayed cerebral ischemia after coiling and after clipping in the International Subarachnoid Aneurysm Trial (ISAT). J Neurol. 2012 Apr;259(4):679-83. doi: 10.1007/s00415-011-6243-2. Epub 2011 Sep 24.
• Results Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017 Feb 11;389(10069):655-666. doi: 10.1016/S0140-6736(16)30668-7. Epub 2016 Sep 13.

Drugs

Indications