Bum Joon Kim1, Eun-Jae Lee2, Sun U Kwon3, Jong-Ho Park4, Yong-Jae Kim5, Keun-Sik Hong6, Lawrence K S Wong7, Sungwook Yu8, Yang-Ha Hwang9, Ji Sung Lee10, Juneyoung Lee11, Joung-Ho Rha12, Sung Hyuk Heo1, Sung Hwan Ahn13, Woo-Keun Seo14, Jong-Moo Park15, Ju-Hun Lee16, Jee-Hyun Kwon17, Sung-Il Sohn18, Jin-Man Jung19, Jose C Navarro20, Dong-Wha Kang2. 1. Department of Neurology, Kyung Hee University Medical Center, Seoul, South Korea. 2. Department of Neurology, University of Ulsan, Ulsan, South Korea. 3. Department of Neurology, University of Ulsan, Ulsan, South Korea. Electronic address: sukwon@amc.seoul.kr. 4. Department of Neurology, Myogji Hospital, Goyang, South Korea. 5. Department of Neurology, Ewha Womans University, Seoul, South Korea. 6. Department of Neurology, Ilsan Paik Hospital, Inje University, Goyang, South Korea. 7. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China. 8. Department of Neurology, Anam Hospital, Korea University, Seoul, South Korea. 9. Department of Neurology, Kyungpook National University Hospital, Daegu, South Korea. 10. Clinical Research Centre, University of Ulsan, Ulsan, South Korea. 11. Department of Biostatistics, Korea University, Seoul, South Korea. 12. Department of Neurology, Inha University Hospital, Incheon, South Korea. 13. Department of Neurology, Chosun University Hospital, Gwangju, South Korea. 14. Department of Neurology, Samsung Medical Centre, Sunkyunkwan University, Seoul, South Korea. 15. Department of Neurology, Eulji General Hospital, Eulji University, Seoul, South Korea. 16. Department of Neurology, Sacred Heart Hospital, Hallym University, Seoul, South Korea. 17. Asan Medical Centre, and Department of Neurology, Ulsan University Hospital, University of Ulsan, Ulsan, South Korea. 18. Department of Neurology, Dongsan Medical Centre, Keimyung University, Daegu, South Korea. 19. Department of Neurology, Ansan Hospital, Korea University, Seoul, South Korea. 20. University of Santo Tomas Hospital, Manila, Philippines.
Abstract
BACKGROUND: The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. METHODS: In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. FINDINGS: Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0-3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57-1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20-1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50-0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27-1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. INTERPRETATION: In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior toaspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. FUNDING: Korea Otsuka Pharmaceutical.
RCT Entities:
BACKGROUND: The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. METHODS: In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. FINDINGS: Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0-3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57-1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20-1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50-0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27-1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. INTERPRETATION: In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. FUNDING: Korea Otsuka Pharmaceutical.
Authors: Adam de Havenon; Kevin N Sheth; Tracy E Madsen; Karen C Johnston; Tanya N Turan; Kazunori Toyoda; Jordan J Elm; Joanna M Wardlaw; S Claiborne Johnston; Olajide A Williams; Ashkan Shoamanesh; Maarten G Lansberg Journal: Stroke Date: 2021-09-14 Impact factor: 10.170