BMJ Confidential: For Review Only Ticagrelor with Aspirin for Platelet Reactivity in Minor Stroke or Transient Ischemic Attack Patients: A Randomized, Open-label, Blinded-endpoint Trial Journal: BMJ Manuscript ID BMJ-2018-047607 Article Type: Research BMJ Journal: BMJ Date Submitted by the 22-Oct-2018 Author: Complete List of Authors: WANG, YILONG; Tiantan Comprehensive Stroke Center, Tiantan Hospital, Capital Medical University, Beijing, China, Chen, Weiqi; Beijing Tiantan Hospital, Capital Medical University Lin, Yi; Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University Meng, Xia; Beijing Tiantan Hospital Capital Medical University, Department of Neurology Chen, Guohua; Department of Neurology, Wuhan No.1 Hospital Wang, zhimin; Department of Neurology, Taizhou First People's Hospital, Huangyan Hospital of Wenzhou Medical University Wu, Jialing; Department of Neurology, Tianjin Huanhu Hospital Wang, Dali; Department of Neurology, North China University of Science and Technology Affiliated Hospital, Li, Jianhua; Department of Neurology, the First Hospital of Fangshan District Cao, Yibin; Department of Neurology, Tangshan Gongren Hospital Xu, Yu-ming ; The First Affiliated Hospital of Zhengzhou University, Department of Neurology Zhang, Guohua; Department of Neurology, the Second Hospital of Hebei Medical University, Li, Xiaobo; Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School, Yangzhou University PAN, YUESONG; Beijing Tiantan Hospital, Capital Medical University, Department of Neurology LI, HAO; Tiantan Comprehensive Stroke Center, Tiantan Hospital, Capital Medical University, Beijing, China, Zhao, Xingquan; Beijing Tiantan Hospital Capital Medical University, Department of Neurology Liu, Liping; Beijing Tiantan Hospital Capital Medical University, Department of Neurology Lin, Jinxi; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Dong, Kehui; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Jing, Jing; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, https://mc.manuscriptcentral.com/bmj Page 1 of 32 BMJ 1 2 3 Johnston, S Claiborne; University of Texas, Austin, Neurology 4 Wang, David; INI Stroke Network, OSF Healthcare System, University of 5 Illinois College of Medicine, 6 Wang, Yongjun; Department of Neurology, Beijing Tiantan Hospital, 7 Capital Medical University, 8 9 Keywords: Platetlet Reactivity, Ticagrelor, Stroke, TIA, CYP2C19 10 11 Confidential: For Review Only 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 2 of 32 Wang Page 1 1 2 3 Ticagrelor with Aspirin for Platelet Reactivity in Minor Stroke or Transient 4 5 6 Ischemic Attack Patients: A Randomized, Open-label, Blinded-endpoint Trial 7 Yilong Wang, MD, PhD1,2,3,4*, Weiqi Chen, MD, PhD1,2,3,4*, Yi Lin, MD, PhD5, Xia Meng, MD, 8 PhD1,2,3,4, Guohua Chen, MD6, Zhimin Wang, MD7, Jialing Wu, MD8, Dali Wang, MD9, Jianhua 9 10 11 12 13 14 10 Li, MD , Yibin Cao , MD, Yuming Xu , MD, Guohua Zhang , MD, Xiaobo Li , MD, 1,2,3,4 1,2,3,4 1,2,3,4 11 YuesongConfidential: Pan, PhD , Hao Li, PhD ,For Xingquan Review Zhao, MD, PhD Only, Liping Liu, MD, 12 PhD1,2,3,4, Jinxi Lin, MD, PhD1,2,3,4, Kehui Dong, MD1,2,3,4, Jing Jing, MD, PhD1,2,3,4, S. 13 Claiborne Johnston, MD, PhD15, David Wang, DO, FAHA, FAAN16, Yongjun Wang, MD1,2,3,4; 14 On Behalf of the PRINCE Protocol Steering Group 15 16 17 Yilong Wang and Weiqi Chen contributed equally to the manuscript. 18 19 1 Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 20 2 China National Clinical Research Center for Neurological Diseases, Beijing, China 21 3 Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China 22 4 Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China 23 5 Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical 24 25 University, Fuzhou, China 6 26 Department of Neurology, Wuhan No.1 Hospital, Wuhan, China 27 7 Department of Neurology, Taizhou First People's Hospital, Huangyan Hospital of Wenzhou 28 Medical University, Taizhou, China 29 8 Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China 30 9 Department of Neurology, North China University of Science and Technology Affiliated 31 Hospital, Tangshan, China 32 10 33 Department of Neurology, the First Hospital of Fangshan District, Beijing, China 11 34 Department of Neurology, Tangshan Gongren Hospital, Tangshan, China 35 12 Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 36 China 37 13 Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang, 38 China 39 14 40 Department of Neurology, Northern Jiangsu People's Hospital, Clinical Medical School, 41 Yangzhou University, Yangzhou, China 42 15 Dell Medical School, University of Texas at Austin, USA 43 16 INI Stroke Network, OSF Healthcare System, University of Illinois College of Medicine, 44 Peoria, USA 45 46 Corresponding author: Yongjun Wang and Yilong Wang 47 48 E-mail address: [email protected] and [email protected] 49 Address: No.6 Tiantanxili, Dongcheng District, Beijing, China, 100050 50 Business telephone: 0086-010-67098350 51 Fax numbers: 0086-010-67013383 52 Tables: 3; Figures: 4; Word count: 3846 (not including title page, figure legends, references, 53 tables and figures) 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 3 of 32 BMJ Wang Page 2 1 2 3 ABSTRACT 4 5 6 OBJECTIVE 7 8 To test the hypothesis that ticagrelor plus aspirin is safe and superior to clopidogrel plus aspirin 9 10 for reducing the 90-day high platelet reactivity and stroke recurrence in patients with minor 11 Confidential: For Review Only 12 stroke or transient ischemic attack (TIA), particularly in carriers of the CYP2C19 loss-of- 13 14 15 function allele and patients with large-artery atherosclerosis. 16 17 DESIGN 18 19 Randomized, open-label, controlled, blinded-endpoint trial. 20 21 22 SETTING 23 24 Prospective studies conducted at 26 centres in China. 25 26 PARTICIPANTS 27 28 29 A total of 675 acute minor stroke or TIA patients. 30 31 INTERVENTION 32 33 Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 mg loading 34 35 dose, 75 mg daily thereafter) on a background of aspirin (100 mg daily for the first 21 days) 36 37 38 within 24 h of symptom onset. 39 40 MAIN OUTCOME MEASURES 41 42 The primary outcome of the trial was the proportion of patients with high platelet reactivity at 90 43 44 45 days. High platelet reactivity was defined as a P2Y12 reaction unit of >208 measured using the 46 47 VerifyNow P2Y12 assay. The secondary outcomes included high platelet reactivity at 90±7 days 48 49 in patients carrying genetic variants that would affect clopidogrel metabolism and any stroke 50 51 52 (ischemic or haemorrhagic) recurrence at 90±7 days, 6 months, and 1 year. 53 54 RESULTS 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj BMJ Page 4 of 32 Wang Page 3 1 2 3 At 90 days, high platelet reactivity occurred in 35 of 280 patients (12.5%) in the 4 5 6 ticagrelor/aspirin group and 86 of 290 patients (29.7%) in the clopidogrel/aspirin group (odds 7 8 ratio [OR], 0.34; 95% confidence interval [CI], 0.22-0.52; P<0.001), and 10.8% versus 35.4% 9 10 (OR, 0.22, 95% CI, 0.12-0.40; P<0.001) of patients carrying CYP2C19 loss-of-function alleles 11 Confidential: For Review Only 12 (P=0.04 for interaction). Stroke occurred in 21 of 336 patients (6.3%) in the ticagrelor/aspirin 13 14 15 group and 30 of 339 patients (8.8%) in the clopidogrel/aspirin group (hazard ratio, 0.70; 95% CI, 16 17 0.40-1.22; P=0.20). Patients with large-artery atherosclerosis in the ticagrelor/aspirin group had 18 19 lower stroke recurrence at 90 days (6.0%) than did those in the clopidogrel/aspirin group (13.1%, 20 21 22 hazard ratio, 0.45; 95% CI, 0.20-0.98; P=0.04). No difference was observed in the rates of major 23 24 or minor haemorrhagic events between the ticagrelor and clopidogrel groups (4.8% and 3.5%, 25 26 respectively; P=0.42). 27 28 29 CONCLUSION 30 31 Minor stroke or TIA patients who were treated with ticagrelor had a lower rate of high platelet 32 33 reactivity than did those who were treated with clopidogrel, particularly those who were carriers 34 35 of the CYP2C19 loss-of-function allele and lower recurrent stroke in patients with large-artery 36 37 38 atherosclerosis. 39 40 TRIAL REGISTRATION 41 42 Clinicaltrials.gov NCT02506140 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmj Page 5 of 32 BMJ Wang Page 4 1 2 3 Introduction 4 5 6 Acute minor ischemic stroke and transient ischemic attack (TIA) patients are at high risk of 7 8 recurrent stroke and cardiovascular events.1 The Clopidogrel in High-risk patients with Acute 9 10 Non-disabling Cerebrovascular Events (CHANCE) trial indicated that combined clopidogrel and 11 Confidential: For Review Only 12 aspirin treatment is superior to aspirin alone in reducing the risk of stroke,2 but may increase the 13 14 15 risk of non-intracranial haemorrhage.1, 3 The CHANCE genetic sub-study demonstrated that 16 17 patients who were carriers of the cytochrome P450 (CYP) 2C19*2 and *3 loss-of-function 18 19 alleles benefitted more from using aspirin alone than from using dual antiplatelet therapy.4 20 21 22 Additionally, a previous study found that Asian stroke patients had a higher risk of intracranial 23 24 large-artery atherosclerosis (LAA), and there was a higher rate of recurrent stroke in patients 25 26 with intracranial arterial stenosis with minor stroke or a high risk of TIA than in those without.5 27 28 6 29 Ticagrelor is primarily metabolized via the CYP3A4 enzyme.