www.thelancet.com/neurology Vol 18 June 2019 539 Articles Lancet Neurol 2019; 18: 539–48 See Comment page 515 Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Centre, Osaka, Japan (K Toyoda MD, T Yamaguchi MD); Clinical Research Centre for Medicine, International University of Health and Welfare, Tokyo, Japan (S Uchiyama MD); Centre for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Centre, Tokyo, Japan (S Uchiyama); Department of Neurology, University of California, San Francisco, CA, USA (J D Easton MD); Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan (K Kimura MD); Department of Neurology, Tokyo Saiseikai Central Hospital, Tokyo, Japan (H Hoshino MD); Department of Neurosurgery, Kobe City Medical Centre General Hospital, Kobe, Japan (N Sakai MD); Clinical Research Institute and Department of Cerebrovascular Medicine and Neurology, National Hospital Organisation Kyushu Medical Centre, Fukuoka, Japan (Y Okada MD); Department of Neurology (K Tanaka MD) and Division of Biostatistics and Clinical Epidemiology (H Origasa PhD), University of Toyama, Toyama, Japan; Department of Neurology, Senri Chuo Hospital, Toyonaka, Japan (H Naritomi MD); Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan (K Houkin MD); Department of Neurology, Ichinomiya Nishi Hospital, Ichinomiya, Japan (K Yamaguchi MD); Department of Neurosurgery, Kushiro Rosai Hospital, Kushiro, Japan (M Isobe MD); and Headquarters of the Iseikai Medical Corporation, Osaka, Japan (K Minematsu MD) Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial Kazunori Toyoda, Shinichiro Uchiyama, Takenori Yamaguchi, J Donald Easton, Kazumi Kimura, Haruhiko Hoshino, Nobuyuki Sakai, Yasushi Okada, Kortaro Tanaka, Hideki Origasa, Hiroaki Naritomi, Kiyohiro Houkin, Keiji Yamaguchi, Masanori Isobe, Kazuo Minematsu, on behalf of the CSPS.com Trial Investigators Summary Background Although dual antiplatelet therapy with aspirin and clopidogrel reduces early recurrence of ischaemic stroke, with long-term use this type of therapy is no longer efective and the risk of bleeding increases. Given that cilostazol prevents stroke recurrence without increasing the incidence of serious bleeding compared with aspirin, we aimed to establish whether dual antiplatelet therapy involving cilostazol is safe and appropriate for long-term use. Methods In a multicentre, open-label, randomised controlled trial across 292 hospitals in Japan, patients with high- risk non-cardioembolic ischaemic stroke identifed on MRI were randomly assigned to two groups in a 1:1 ratio to receive monotherapy with either oral aspirin (81 or 100 mg, once per day) or clopidogrel (50 or 75 mg, once per day) alone, or a combination of cilostazol (100 mg, twice per day) with aspirin or clopidogrel. Randomisation was done centrally (using block randomisation with a block size of six per each participating hospital) through a web-based registration system and was done by EPS Corporation. The patients were required to have at least 50% stenosis of a major intracranial or extracranial artery or two or more of the vascular risk factors. Trial medication was continued for half a year or longer, for a maximum of 3·5 years. The primary efcacy outcome was the rate of frst recurrence of symptomatic ischaemic stroke. Safety outcomes were severe or life-threatening bleeding; any adverse events; serious adverse events; and any bleeding events. Efcacy analyses were done in the intention-to-treat population and safety analyses were done in the as-treated population. This trial was registered with ClinicalTrials.gov (number NCT01995370) and UMIN Clinical Trials Registry (number 000012180). Findings Participants were recruited from Dec 13, 2013, to March 31, 2017. 932 patients assigned to the dual therapy group and 947 patients assigned to the monotherapy group were included in the intention-to-treat analysis. The trial was stopped after the enrolment of 1884 patients of an anticipated 4000 patients because of the delay in recruitment. Ischaemic stroke recurred in 29 (3%) of 932 patients (annualised rate 2·2%) on dual therapy including cilostazol and 64 (7%) of 947 patients (annualised rate 4·5%) on monotherapy during a median 1·4 years follow-up (hazard ratio [HR] 0·49, 95% CI 0·31–0·76, p=0·0010). Severe or life-threatening bleeding occurred in eight patients (annualised rate 0·6%) on dual therapy and 13 patients (annualised rate 0·9%) on monotherapy (HR 0·66, 95% CI 0·27–1·60, p=0·35). Occurrence of any type of adverse event was similar between the groups (255 [28%] of 910 patients in the dual therapy group vs 219 [24%] of 921 patients in the monotherapy group); as was occurrence of serious adverse events (87 [10%] vs 142 [15%]) and bleeding events (38 [4%] vs 33 [4%]). Gastrointestinal bleeding, which afected nine (<1%) of 910 patients in the monotherapy group and nine (<1%) of 921 patients in the dual therapy group, was the most common type of bleeding. Interpretation The combination of cilostazol with aspirin or clopidogrel had a reduced incidence of ischaemic stroke recurrence and a similar risk of severe or life-threatening bleeding compared with treatment with aspirin or clopidogrel alone in patients at high risk for recurrent ischaemic stroke. Funding Otsuka Pharmaceutical. Copyright © 2019 Elsevier Ltd. All rights reserved. Introduction Patients with non-cardioembolic ischaemic stroke have a higher risk of recurrence when they have carotid steno- sis, 1 intracranial arterial stenosis, 2 or multiple vascular risk factors than when they do not have these com- plications. 3,4 For such patients, comprehensive preventive therapy, including antiplatelet medication, has been proven benefcial. However, newer antiplatelet agents that are promising for patients with coronary artery disease and have been in commercial use for around 10 years, such as ticagrelor and prasugrel, did not show advantages over conventional antiplatelet agents for patients with stroke in randomised controlled trials (RCTs). 5,6