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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Kim BJ, Lee E-J, Kwon SU, et al on behalf of the 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; 17:

2 Web-Appendix Prevention of Cardiovascular Events in Ischemic Stroke Patients with High Risk of Cerebral Hemorrhage (PICASSO): a multicenter, randomized controlled trial Correspondence to: Professor Sun U Kwon, MD, PhD, Department of Neurology, Asan Medical Center, University of Ulsan, College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, Korea, Tel: sukwon@amc.seoul.kr

3 Supplementary methods Sample size for probucol arm According to the prespecified protocol, we adopted the sample size of the antiplatelet study arm, which was determined as a total of 1596 patients (798 for each group).24 Before the end-point evaluation, we examined whether the adopted sample size has sufficient power to test the superiority of probucol over non-probucol. The annual event-rate of the primary composite vascular endpoint was estimated at 15%.24 To estimate the degree of risk reduction by probucol, we referenced a recent data which showed that succinobucol, the monosuccinic acid ester of probucol, has a hazard ratio of 0.81 (vs. non-succinobucol) for the composite endpoint (cardiovascular death, cardiac arrest, myocardial infarction, or stroke, in patients with acute coronary syndrome).18 Because we included patients with high risk for both ischemic and hemorrhagic vascular events, we hypothesized that the benefit of probucol would be more prominent in these patients, and thus estimated a 25% reduction of risk in the primary endpoint. Based on these values, a total sample size of 1596 patients guaranteed 87% of power to demonstrate the superiority of probucol. Primary endpoints Composite of vascular events include stroke, myocardial infarction, and cardiovascular death. The definition of stroke, myocardial infarction, and cardiovascular death are as follows: 1. Stroke Focal neurological deficit (>24 hours) from cerebrovascular causes or transient focal neurological deficit ( 24 hours) with a new evidence of stroke in brain imagings. Transient cerebral ischemia without the evidence of new stroke by appropriate brain imaging studies is not included in stroke. Ischemic stroke, hemorrhagic stroke, and unclassified stroke are included. 2. Myocardial infarction The following criteria were used in the diagnosis: Detection of a rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit(url) together with evidence of myocardial ischemia with at least one of the following criteria: Symptoms of ischemia ECG changes indicative of new ischemia [new ST-T changes or new left bundle branch block (LBBB)] Development of pathological Q waves in the ECG Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

4 Sudden unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at autopsy. For percutaneous coronary interventions (PCI) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of periprocedural myocardial necrosis. By convention, increases of biomarkers greater than 3 x 99th percentile URL have been designated as defining PCI-related myocardial infarction. A subtype related to a documented stent thrombosis is recognized. For coronary artery bypass grafting (CABG) in patients with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of periprocedural myocardial necrosis. By convention, increases of biomarkers greater than 5 x 99th percentile URL plus either new pathological Q waves or new LBBB, or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable myocardium have been designated as defining CABG-related myocardial infarction. Pathological findings of an acute myocardial infarction. 3. Cardiovascular death Fatal stroke, fatal myocardial infarction, and vascular death. Deaths within 28 days after the onset of stroke or myocardial infarction are designated as fatal stroke or myocardial infarction. Sudden deaths without clear non-vascular etiology (e.g., cancer, infection, and suicide) are also included under vascular deaths.

5 Supplemental table 1 Characteristic of the Patients at Baseline according to 4 groups Cilostazol + Probucol Aspirin + Probucol Cilostazol Aspirin N Demographics Age (years) 65 3 ± ± ± ± 10 5 Male 238 (63%) 227 (60%) 229 (61%) 243 (64%) Medical history Hypertension 338 (89%) 341 (91%) 333 (89%) 335 (88%) Diabetes 120 (32%) 112 (30%) 118 (31%) 135 (35%) Dyslipidemia 175 (46%) 172 (46%) 153 (41%) 161 (42%) Coronary artery disease 19 (5%) 21 (6%) 11 (3%) 20 (5%) Current smoking 74 (19%) 78 (21%) 66 (18%) 79 (21%) Family history of stroke 88 (23%) 78 (21%) 83 (22%) 79 (21%) Qualifying ischemic event Ischemic stroke 366 (96%) 356 (95%) 352 (94%) 359 (94%) Transient ischemic attack 14 (4%) 20 (5%) 23 (6%) 22 (6%) Time-to-randomization (days) 18 (8-43) 17 (7-34) 17 (8-40) 17 (7-38) Index of high risk of ICH Prior history of ICH 64 (17%) 71 (19%) 75 (20%) 73 (19%) Radiological findings of ICH 83 (22%) 83 (22%) 84 (22%) 76 (20%) Multiple microbleeds 233 (61%) 222 (59%) 216 (58%) 232 (61%) Vital signs Systolic blood pressure (mmhg) 135 ± ± ± ± 17 Diastolic blood pressure (mmhg) 80 ± ± ± ± 12

6 Heart rate (beats/min) 83 ± ± ± ± 14 Body-mass index (kg/m 2 ) 25 ± 4 24 ± 3 24 ± 4 24 ± 4 Fazekas score (27%) 103 (29%) 100 (29%) 122 (33%) (50%) 163 (45%) 148 (43%) 151 (41%) 3 81 (22%) 93 (26%) 100 (29%) 92 (25%) NIHSS score 2 (1-3) 2 (1-3) 2 (0-3) 1 (0-3) MMSE score 26 (22-28) 25 (20-28) 26 (21-28) 26 (21-28) Follow-up duration (years) 2 0 ( ) 2 0 ( ) 1 8 ( ) 1 8 ( ) Concomitant therapy Statin 285 (75%) 285 (76%) 284 (76%) 290 (76%) High intensity 4 (1%) 4 (1%) 4 (1%) 5 (1%) Moderate intensity 184 (48%) 187 (50%) 183 (49%) 179 (47%) Low intensity 97 (26%) 94 (25%) 97 (26%) 106 (28%) ARB/ACEI 221 (58%) 196 (52%) 223 (59%) 199 (52%) Dihydropyridine 181 (48%) 174 (46%) 181 (48%) 188 (49%) Beta blockers 52 (14%) 46 (12%) 41 (11%) 42 (11%) Thiazide 53 (14%) 41 (11%) 45 (12%) 46 (12%) Lipids (mg/dl) Total cholesterol ± ± ± ± 40 5 LDL cholesterol ± ± ± ± 33 5 HDL cholesterol 44 7 ± ± ± ± 11 9 Results are presented as number (%) and mean±sd, or median (IQR). To convert cholesterol values to millimoles per liter, multiply by P-value by Chi-square test, Fisher s exact test, ANOVA or Kruskal-Wallis test as appropriate

7 SD = standard deviation, HDL = high-density lipoprotein, ICH = intracerebral hemorrhage, IQR = interquartile range, NIHSS = National Institutes of Health Stroke Scale, LDL = low-density lipoprotein, MMSE = Mini Mental State Examination

8 Supplemental table 2 Primary and Secondary Outcome Measures and interaction between the two arms (antiplatelet and probucol arms) Cilostazol + Probucol Aspirin + Probucol Cilostazol Aspirin P-value Primary Endpoints Composite vascular event a No. of event Incidence (95% CI) 3 01 ( ) 4 81 ( ) 5 63 ( ) 5 87 ( ) Cerebral hemorrhage No. of event Incidence rate (95% CI) 0 52 ( ) 0 91 ( ) 0 70 ( ) 1 50 ( ) Secondary Endpoints Stroke No. of event Incidence rate (95% CI) 1 96 ( ) 4 03 ( ) 4 64 ( ) 5 74 ( ) Ischemic stroke No. of event Incidence rate (95% CI) 1 44 ( ) 3 12 ( ) 4 08 ( ) 4 23 ( ) Myocardial infarction No. of event Incidence rate (95% CI) 0 39 ( ) 0 65 ( ) 0 70 ( ) 0 14 ( ) Cardiovascular death No. of event Incidence rate (95% CI) 0 39 ( ) 0 65 ( ) 0 70 ( ) 0 14 ( )

9 Other vascular events No. of event Incidence rate (95% CI) 0 66 ( ) 0 78 ( ) 0 56 ( ) 0 82 ( ) All-cause death No. of event Incidence rate (95% CI) 1 31 ( ) 2 08 ( ) 2 53 ( ) 2 04 ( ) P-value for interaction effect between antiplatelet arm and probucol arm. Incidence presented as event / 100-person year.

10 We would like to specially thank all the investigators of PICASSO listed below. Steering committee Kwon, SU Lee, JY Park KY Kang, DW Rha, JH Park, JM Lee, YS Heo, JH Lee, JH Kim YJ Hong, KS Cho, YJ Yu, KH Bae, HJ Sohn, SI Ahn, SH Cha, JK Song, HJ (Asan Medical Center, Korea) (Korea University College of Medicine, Korea) (Chung-Ang University Hospital, Korea) (Asan Medical Center, Korea) (Inha University Hospital, Korea) (Eulji General Hospital, Korea) (Seoul National University Boramae Hospital, Korea) (Severance Hospital, Korea) (National Health Insurance Corporation Ilsan Hospital, Korea) (Ewaha Womans University Mokdong Hospital, Korea) (Inje University Ilsan Paik Hospital, Korea) (Inje University Ilsan Paik Hospital, Korea) (Hallym University Sacred Heart Hospital, Korea) (Seoul National University Boramae Hospital, Korea) (KeiMyung University Dongsan Medical Center, Korea) (Chosun University Hospital, Korea) (Dong-A University Medical Center, Korea) (Chungnam National University Hospital, Korea) Data Safety Monitoring Board Kim, JS Yoon, BW Lee, BC Nam, CM (Asan Medical Center, Korea) (Seoul National University Hospital, Korea) (Hallym University Sacred Heart Hospital, Korea) (Severance Hospital, Korea) Central Independent Adjudication Committee Koo, JS Nam, HS Park KY Park, JM Lee, JH Kim, DH Rha, JH Nah, HW Cho, KH (Seoul St.Mary s Hospital, Korea) (Severance Hospital, Korea) (Chung-Ang University Hospital, Korea) (Eulji General Hospital, Korea) (Kangdong Sacred Heart Hospital, Korea) (Dong-A University Medical Center, Korea) (Inha University Hospital, Korea) (Dong-A University Medical Center, Korea) (Korea University Anam Hospital, Korea)

11 Investigators Kwon, SU Lee, SH Yu, KH Lee, YS Cho, YJ Kim, DE Han, MK Park, JM Lee, JH Lee, KB Rha, JH Kim YJ Park KY Heo, SH Cho, KH Kim, HY Kim, YD Cho, AH Baik, JS Lee, KY Lee, JS Lee, JY Park, J Seo, WK Park, TH Kim, EG Koh, IS Cha, JK Choi, NC Kwon, JH Sohn, SI Lee, J Hwang, YH Song, HJ Shin, BS Kim, JT Lee, SJ Park, HY Ahn, SH Chung, PW Koo, JS Kim, HY Kwon, SB Kim, SH Lee, JH Sin, DI (Asan Medical Center, Korea) (Seoul National University Hospital, Korea) (Hallym University Sacred Heart Hospital, Korea) (Seoul National University Boramae Hospital, Korea) (Inje University Ilsan Paik Hospital, Korea) (Dongguk University Ilsan Hospital, Korea) (Seoul National University Bundang Hospital, Korea) (Eulji General Hospital, Korea) (Kangdong Sacred Heart Hospital, Korea) (Soonchunhyang University Hospital, Korea) (Inha University Hospital, Korea) (Ewha Womans University Mokdong Hospital, Korea) (Chung-Ang University Hospital, Korea) (Kyung Hee University Hospital, Korea) (Korea University Anam Hospital, Korea) (Konkuk University Medical Center, Korea) (Severance Hospital, Korea) (Catholic University of Korea, St.Mary's Hospital, Korea) (Inje University Sanggye Paik Hospital, Korea) (Gangnam Severance Hospital, Korea) (Ajou University Hospital, Korea) (Yonsei University Wonju Serverance Hospital, Korea) (Myongji Hospital, Korea) (Korea University Guro Hospital, Korea) (Seoul Medical Center, Korea) (Inje University Pusan Paik Hospital, Korea) (National Medical Center, Korea) (Dong-A University Medical Center, Korea) (Gyeongsang National University Hospital, Korea) (Ulsan University Hospital, Korea) (KeiMyung University Dongsan Medical Center, Korea) (Yeungnam University Hospital, Korea) (Kyungbuk National University Hospital, Korea) (Chungnam National University Hospital, Korea) (Chonbuk National University Hospital, Korea) (Chonnam National University Hospital, Korea) (Eulji University Hospital, Korea) (Wonkwang University Hospital, Korea) (Chosun University Hospital, Korea) (Kangbuk Samsung Hospital, Korea) (Seoul St.Mary Hospital, Korea) (Hanyang University Hospital, Korea) (Kangnam Sacred Heart Hospital, Korea) (Kangwon National University Hospital, Korea) (National Health Insurance Corporation Ilsan Hospital, Korea) (Chungbuk National University Hospital, Korea)

12 Do, JK (Catholic University of Daegu, Korea) Lee, SB (Daejeon St.Mary's Hospital, Korea) Lee, YB (Gachon University Gil Hospital, Korea) Yoo, BG (Kosin University Gospel Hospital, Korea) Sung, SM (Pusan National University Hospital, Korea) Kim, O (Bundang CHA Medical Center, Korea) Jung, JM (Korea University Anshan Hospital, Korea) Park, JW (Uijeongbu St. Mari Hospital, Korea) Lee, KY (Hanyang University Guri Hospital, Korea) Jung, YH (Changwon Fatima Hospital, Korea) Kim, JS (Fatima general Hospital Daegu, Korea) Lee, TK (Soonchunhyang University Bucheon Hospital, Korea) Kim, SR (Dongkang Medical Center, Korea) Jose C. Navarro (UST Hospital, Philippines) Maria C San Jose (St. Luke's Medical Center, Philippines) Artemio Roxas Jr. (The Medical City, Philippines) Raquel Mallarl-Alvarez (Makati Medical Center, Philippines) Ma. EV. Collantes (Manila Doctors Hospital, Philippines) Lawrence K.S. WONG (Prince of Wales Hospital, Hong Kong) FONG Wing-Chi (Queen Elizabeth Hospital, Hong Kong) TSOI Tak Hong (Pamela Youde Nethersole Eastern Hospital, Hong Kong) NG Ping Wing (United Christian Hospital, Hong Kong) Kim, BJ (Kyung Hee University Hospital, Korea)\ Lee, EJ (Asan Medical Center, Korea)

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