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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.
The investigators propose to conduct a multicenter randomized trial to test the primary hypothesis of whether cilostazol reduces the incidence of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and improves patients' neurological prognosis, while assessing its safety. The investigators will recruit 316 patients from 30 hospitals in China. Eligibility criteria for the trial participants include Aged 18-80 years. Diagnosed with subarachnoid hemorrhage (SAH) by computed tomography (CT) scan, and the responsible aneurysm is identified by computed tomography angiography (CTA) or digital subtraction angiography (DSA). Received aneurysm coil embolization or craniotomy clipping within 72 hours of symptom onset. Hunt-Hess grade II-IV. No rebleeding or new intracranial hemorrhage is shown on head CT within 6 hours after surgery. Understand and follow the procedures of clinical trial, participate voluntarily and sign the informed consent (the informed consent can be signed voluntarily by the person or guardian). Patients with multiple aneurysms, Modified Rankin Scale (mRS) score ≥ 3 before onset, contraindications to cilostazol use, severe organic diseases and an expected survival time of less than 90 days, severe liver insufficiency or renal insufficiency before randomization, aneurysm treatment requiring the use of other antiplatelet drugs after interventional therapy, receiving treatment with other investigational drugs or device trials currently will be excluded. Patients will be randomly assigned to the experimental group or control group at a 1:1 ratio. Experimental Group patients will receive cilostazol 100 mg twice daily for 14 consecutive days, in addition to the standard aSAH treatment. Control Group patients will receive a placebo twice daily (bid) for 14 consecutive days, in addition to the standard aSAH treatment. The primary study endpoint is incidence of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) within 14±2 days after randomization. Other secondary endpoints include neurological function prognosis at 90±7 days after randomization, incidence of intracranial rebleeding events within 90±7 days after randomization, incidence of other severe bleeding events within 90±7 days after randomization. This trial will provide important information for the development of clinical guidelines for reducing delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cilostazol Group | Experimental | Administer 100 mg cilostazol, twice daily for 14 days and the standard aneurysmal subarachnoid treatment pathway. |
|
| Control Group | Placebo Comparator | Implement placebo 100mg twice daily for 14 days and the standard aneurysmal subarachnoid treatment pathway. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cilostazol 100 mg BID | Drug | Within 24 hours after randomization, patients will receive cilostazol 100 mg twice daily (BID) for 14 consecutive days, in addition to the standard aSAH treatment. |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of delayed cerebral ischemia (DCI) | Delayed cerebral ischemia (DCI) was defined as the occurrence of clinical deterioration, including new-onset focal neurological deficits (e.g., hemiplegia, aphasia, apraxia, hemianopia, or neglect) and/or a decrease in the consciousness (a Glasgow Coma Scale [GCS] score reduction of at least 2 points, either in the total score or any individual subscore), with symptoms lasting for at least 1 hour and not occurring immediately after aneurysm surgery. Other potential causes of clinical deterioration (e.g., hydrocephalus, rebleeding, fever, infection, metabolic disturbance, epilepsy, etc.) were excluded. Alternatively, DCI was defined as the presence of new infarct lesions on follow-up brain CT/MRI that were not detected on the initial admission brain CT or post-operative follow-up brain CT. | At 14±2 days after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Neurological function prognosis | The modified Rankin Scale (mRS) score and Glasgow Outcome Scale (GOS) score were evaluated at 90 days after randomization. Favorable outcome was defined as an mRS score of 0-3 (0-3 indicating no disability to moderate disability; 4-6 indicating moderately severe disability to death) and a GOS score of 3-5 (3-5 indicating severe disability to good recovery). | At 90 days after randomization |
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Inclusion Criteria:
Exclusion Criteria:
Multiple aneurysms (>1aneurysms confirmed by CTA/DSA)
Modified Rankin Scale (mRS) score ≥ 3 before onset
Patients with contraindications to cilostazol use:
Patients with severe organic diseases and an expected survival time of less than 90 days
Severe liver insufficiency or renal insufficiency before randomization
Aneurysm treatment requiring the use of other antiplatelet drugs after interventional therapy
Currently receiving treatment with other investigational drugs or device trials
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Liping Liu | Contact | +86-010-59978328 | lipingsister@gmail.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beijing Tiantan Hospital, Capital Medical University | Beijing | Beijing Municipality | 100070 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35902229 | 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. | |
| 29778364 | Result |
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There is not a plan to make IPD available. Sharing IPD will require IRB approval from Tiantan Hospital and other participating institutes in China.
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| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D000077407 | Cilostazol |
| C494814 | BID protein, human |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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Patients will be randomly assigned to the following treatment groups at a 1:1 ratio:
Experimental Group： Within 24 hours after randomization, patients will receive cilostazol 100 mg twice daily for 14 consecutive days, in addition to the standard aSAH treatment.
Control Group： Within 24 hours after randomization, patients will receive a placebo twice daily (bid) for 14 consecutive days, in addition to the standard aSAH treatment.
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| placebo | Drug | Within 24 hours after randomization, patients will receive a placebo twice daily (BID) for 14 consecutive days, in addition to the standard aSAH treatment. |
|
| Incidence of intracranial rebleeding events | Any new intracranial hemorrhage occurring within 90 days after randomization (whether rebleeding in the surgical area or new intracranial hemorrhage events following cilostazol administration), confirmed by comparing non-contrast CT scan results during follow-up with those of the last post-operative non-contrast CT scan before randomization. | At 90±7 days after randomization |
| Incidence of other severe bleeding events | Any new symptomatic intracranial hemorrhage or any new moderate or severe hemorrhage occurring within 90 days after randomization (defined according to the Bleeding Academic Research Consortium [BARC] criteria as hemorrhage requiring endoscopic treatment, surgical intervention, or blood transfusion [Types 2-3] and fatal hemorrhage [Type 5]). | At 90 days after randomization |
| 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. |
| 21677432 | Result | 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. |
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| 27494819 | Result | 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. |
| 30341966 | Result | 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. |
| 36450971 | Result | 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. |
| 19506373 | Result | 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. |
| 21125444 | Result | 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. |
| 20350366 | Result | 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. |
| Result | 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 |
| 33860901 | Result | 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. |
| 18779447 | Result | 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. |
| 20150545 | Result | 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. |
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| 37665377 | Result | 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. |
| 1830180 | Result | 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. |
| 22879655 | Result | 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. |
| 31394993 | Result | 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. |
| 21640651 | Result | 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. |
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| 17636626 | Result | 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. |
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| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011804 |
| Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |