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Association Between ABCB1 Polymorphisms and Outcomes of Clopidogrel Treatment in Patients With Minor Stroke or Transient Ischemic AttackSecondary Analysis of a Randomized Clinical Trial

Educational Objective
To determine whether ABCB1 genetic variants are associated with efficacy of clopidogrel bisulfate for minor stroke or transient ischemic attack.
1 Credit CME
Key Points

Question  Are ABCB1 genetic variants associated with the efficacy of clopidogrel bisulfate for minor stroke or transient ischemic attack?

Findings  In this secondary analysis of a randomized clinical trial that included 2836 adults, clopidogrel plus aspirin was associated with a significant reduction in the risk of new stroke in patients with ABCB1 –154 TT and 3435 CC genotype but not in those with ABCB1 -154 TC/CC or 3435 CT/TT genotype compared with aspirin alone.

Meaning  ABCB1 genetic variants may be associated with the efficacy of clopidogrel for treatment of minor stroke or transient ischemic attack.

Abstract

Importance  Genetic variants of ABCB1 may affect intestinal absorption of clopidogrel bisulfate. However, it is unclear whether ABCB1 polymorphisms are associated with clopidogrel efficacy for minor ischemic stroke or transient ischemic attack (TIA).

Objectives  To investigate the association between ABCB1 polymorphisms and clopidogrel efficacy for minor stroke or TIA.

Design, Setting, and Participants  In this prespecified secondary analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) randomized clinical trial, 3010 patients with minor stroke or TIA at 73 sites in China with experience in conducting genetic studies were included from October 1, 2009, to July 30, 2012. The analysis was conducted on March 20, 2018. Four single-nucleotide polymorphisms (ABCB1 –154T>C [rs4148727], ABCB1 3435C>T [rs1045642], CYP2C19*2 [681G>A, rs4244285], and CYP2C19*3 [636G>A, rs4986893]) were genotyped among 2836 patients treated with clopidogrel plus aspirin (n = 1414) or aspirin alone (n = 1422). The association of ABCB1 genetic variants (–154 TC/CC and 3435 CT/TT) with clopidogrel efficacy was evaluated in the context of CYP2C19 status, another gene associated with clopidogrel efficacy.

Interventions  Patients in the CHANCE trial were randomized to treatment with clopidogrel combined with aspirin or to aspirin alone.

Main Outcomes and Measures  Primary efficacy outcome was stroke recurrence after 3 months. The safety outcome was any bleeding risk after 3 months.

Results  Among 2836 patients, the median age was 61.8 years (interquartile range, 54.4-71.1 years) and 1887 patients (66.5%) were male. A total of 2146 (75.7%) patients were carriers of ABCB1 –154 TC/CC (570 [20.1%]) or 3435 CT/TT (1851 [65.3%]) genotype. Clopidogrel plus aspirin treatment was associated with reduced risk of new stroke in patients with ABCB1 –154 TT and 3435 CC genotype (hazard ratio [HR], 0.43; 95% CI, 0.26-0.71) but not in those with ABCB1 –154 TC/CC or 3435 CT/TT genotype (HR, 0.78; 95% CI, 0.60-1.03) compared with aspirin (P = .04 for interaction). A combined association of ABCB1 and CYP2C19 polymorphisms with new stroke was observed. The risk of bleeding for clopidogrel plus aspirin treatment was not associated with the ABCB1 genotypes (2.3% and 1.3% vs 1.9% and 2.2%; P = .25 for interaction in patients with or without ABCB1 –154 TC/CC or 3435 CT/TT genotype)

Conclusions and Relevance  The ABCB1 polymorphism was associated with the reduced efficacy of clopidogrel plus aspirin treatment compared with aspirin among patients with minor ischemic stroke or TIA. Genetic polymorphism of ABCB1 should be considered when prescribing clopidogrel for these patients.

Trial Registration  ClinicalTrials.gov identifier: NCT00979589

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Article Information

Accepted for Publication: October 16, 2018.

Corresponding Author: Yongjun Wang, MD, No. 119, South 4th Ring West Road, Fengtai District, Beijing, China, 100070 (yongjunwang@ncrcnd.org.cn).

Published Online: February 11, 2019. doi:10.1001/jamaneurol.2018.4775

Author Contributions: Dr Yongjun Wang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Pan, Chen, Yilong Wang, Li, Zhao, Liu, Yongjun Wang.

Acquisition, analysis, or interpretation of data: Johnston, Simon, D. Wang, Meng, Yongjun Wang.

Drafting of the manuscript: Pan, D. Wang.

Critical revision of the manuscript for important intellectual content: Chen, Yilong Wang, Li, Johnston, Simon, Zhao, Liu, Meng, Yongjun Wang.

Statistical analysis: Pan.

Obtained funding: Zhao, Yongjun Wang.

Administrative, technical, or material support: Chen, Zhao, Meng.

Supervision: Chen, Yilong Wang, Li, Johnston, Zhao, Liu, D. Wang, Yongjun Wang.

Conflict of Interest Disclosures: Dr Johnston reported being the principal investigator of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, a National Institutes of Health–sponsored trial, with clopidogrel and placebo donated by Sanofi. Dr Simon reported receiving personal fees from board membership, consultancy, or lecture from AstraZeneca, Astellas, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, and Pfizer.

Funding/Support: This study was supported by grants 2016YFC0901001, 2016YFC0901002, 2017YFC1310901, 2018YFC1311700, and 2018YFC1311706 from the Ministry of Science and Technology of the People’s Republic of China and grants 2016-1-2041 and SML20150502 from the Beijing Municipal Commission of Health and Family Planning.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Members: Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) Investigators: Beijing Tiantan Hospital, Beijing, China: Yongjun Wang, MD; Yilong Wang, MD, PhD; Xingquan Zhao, MD, PhD; Dell Medical School, University of Texas at Austin, Austin: S. Claiborne Johnston, MD, PhD; Taizhou First People’s Hospital, Taizhou, China: Zhimin Wang, MD; Taiyuan Iron And Steel (Group) Co., Ltd., General Hospital, Taiyuan, China: Haiqin Xia, MD; Penglai People’s Hospital, Yantai, China: Guiru Zhang, MD; The Third People’s Hospital of Datong, Datong, China: Xudong Ren, MD; The Fourth Central Hospital of Tianjin, Tianjin, China: Chunling Ji, MD; The Second Hospital of Hebei Medical University, Shijiazhuang, China: Guohua Zhang, MD; The First Hospital of Fangshan District, Beijing, China: Jianhua Li, MD; Beijing Puren Hospital, Beijing, China: Bohua Lu, MD; Tianjin Ninghe District Hospital, Tianjin, China: Liping Wang, MD; The People’s Hospital of Zhengzhou, Zhengzhou, China: Shutao Feng, MD; Affiliated Hospital of North China Coal Medical College, Tangshan, China: Dali Wang, MD; Zhejiang Zhoushan Hospital, Zhoushan, China: WeiguoTang, MD, PhD; HanDan Central Hospital, Handan, China: Juntao Li, MD; Zhecheng People’s Hospital, Zhecheng, China: Hongtian Zhang, MD; Shanxi Medical University Second Hospital, Taiyuan, China: Guanglai Li, MD; Baotou Central Hospital, Baotou, China: Baojun Wang, MD, PhD; The General Hospital of Changjiang River Shipping, Wuhan, China: Yuhua Chen, MD; Dalian Economic And Technological Development Zone Hospital, Dalian, China: Ying Lian, MD; First Neurology Department, Affiliated Hospital of North China Coal Medical College, Tangshan, China: Bin Liu, MD; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China: Junfang Teng, MD; First Affiliated Hospital of Liaoning Medical University, Jinzhou, China: Rubo Sui, MD; Lianyungang Municipal Hospital of TCM, Lianyungang, China: Lejun Li, MD; Central Hospital In Qiu County, Handan, China: Zhiling Yuan, MD; Tianjin First Center Hospital, Tianjin, China: Dawei Zang, MD; Renmin Hospital of Wuhan University, Wuhan, China: Zuneng Lu, MD; Qingdao Central Hospital, Qingdao, China: Li Sun, MD; Baogang Hospital, Baotou, China: Dong Wang, MD; Changzhi City People’s Hospital of Shanxi Province, Changzhi, China: Liying Hou, MD; Harrison International Peace Hospital, Hengshui, China: Dongcai Yuan, MD; People’s Hospital of Linzi District, Zibo, China: Yongliang Cao, MD; Yantai Mountain Hospital, Yantai, China: Hui Li, MD; Beijing Pinggu District Hospital, Beijing, China: Xiuge Tan, MD; Taiyuan Central Hospital, Taiyuan, China: Huicong Wang, MD; Chengde Central Hospital, Chengde, China: Haisong Du, MD; Shijiazhuang Central Hospital, Shijiazhuang, China: Mingyi Liu, MD; First Neurology Department, Dalian Municipal Central Hospital, Dalian, China: Suping Wang, MD; Xi’an 141 Hospital, Xi’an, China: Qiuwu Liu, MD; Chengdu Third Municipal People’s Hospital, Chengdu, China: Zhong Zhang, MD; Affiliated Hospital of Chifeng University, Chifeng, China: Qifu Cui, MD; Zhengzhou Central Hospital, Zhengzhou, China: Runqing Wang, MD; Lihuili Hospital Medical Center, Ningbo, China: Jialin Zhao, MD; Henan Provincial People’s Hospital, Zhengzhou, China: Jiewen Zhang, MD; Jinzhong City Second Hospital, Jinzhong, China: Jianping Zhao, MD; Beijing Anzhen Hospital, Capital Medical University, Beijing, China: Qi Bi, MD, PhD; Beijing Huairou District Chinese Medicine Hospital, Beijing, China: Xiyou Qi, MD; Hebei Medical University Third Hospital, Shijiazhuang, China: Junyan Liu, MD; First Affiliated Hospital Shanxi Medical University, Taiyuan, China: Changxin Li, MD; Hebei Provincial People’s Hospital, Shijiazhuang, China: Ling Li, MD; Guangzhou First Municipal Peoples Hospital, Guangzhou, China: Xiaoping Pan, MD; Central Hospital In Cangzhou, Cangzhou, China: Junling Zhang, MD; The Chinese People’s Armed Police Force Medical School Affiliated Hospital, Tianjin, China: Derang Jiao, MD; Zhejiang Wenzhou Medical College First Affiliated Hospital, Wenzhou, China: Zhao Han, MD; Jilin Central Hospital, Jilin, China: Dawei Qian, MD; Anhui Maanshan Central Hospital, Maanshan, China: Jin Xiao, MD; Beijing Aviation Industry Central Hospital, Beijing, China: Yan Xing, MD; Luhe Hospital, Beijing, China: Huishan Du, MD; Beijing Fuxing Hospital, Capital Medical University, Beijing, China: Guang Huang, MD; The 306th Hospital of P.L.A, Beijing, China: Yongqiang Cui, MD; The First Affiliated Hospital of Tianjin University of Chinese Medicine, Tianjin, China: Yan Li, MD; Baiqiuen International Peace Hospital of People’s Liberation Army, Shijiazhuang, China: Lianyuan Feng, MD; Fourth Affiliated Hospital of China Medical University, Shenyang, China: Lianbo Gao, MD; Xiangya Hospital Central-South University, Xiangya, China: Bo Xiao, MD; Tangshan Worker’s Hospital, Tangshan, China: Yibin Cao, MD; The 1st Hospital in Handan, Handan, China: Yiping Wu, MD; Yangquan Coal (Group) Co., Ltd. General Hospital, Yangquan, China: Jinfeng Liu, MD; Tianjin Tianhe Hospital, Tianjin, China: Zhiming Zhang, MD; Nantong First People’s Hospital, Nantong, China: Zhengxie Dong, MD; The 1st Hospital of Zhangjiakou City, Zhangjiakou, China: Limin Wang, MD; West China Hospital, Chengdu, China: Li He, MD, PhD; The Second Affiliated Hospital of Shandong University of TCM, Jinan, China: Xinchen Wang, MD; Fenyang Hospital of Shanxi Province, Fenyang, China: Xueying Guo, MD; Zhejiang Zhoushan Putuo District People’s Hospital, Zhoushan, China: Ming Wang, MD; Xiyuan Hospital of China Academy of Chinese Traditional Medicine, Beijing, China: Xiaosha Wang, MD; No.2 People’s Hospital East in Lianyungang City, Lianyungang, China: Jiandong Jiang, MD; Affiliated Hospital of Qingdao University Medical College, Qingdao, China: Renliang Zhao, MD, PhD; Qilu Hospital of Shandong University, Jinan, China: Shengnian Zhou, MD, PhD; Zibo Hospital of Traditional Chinese Medicine, Zibo, China: HaoHu, MD; Beijing Shijitan Hospital, Beijing, China: Maolin He, MD, PhD; Beijing Haidian Hospital, Beijing, China: Fengchun Yu, MD; Beijing Shunyi District Hospital, Beijing, China: Quping Ouyang, MD; Dalian Third Municipal Hospital, Dalian, China: Jingbo Zhang, MD; The First Affliated Hospital of Jinan University, Guangzhou, China: Anding Xu, MD, PhD; Navy Genaral Hospital of P.L.A, Beijing, China: Xiaokun Qi, MD; Beijing Second Artillery General Hospital, Beijing, China: Lei Wang, MD; Beijing Daxing District Hospital, Beijing, China: Fuming Shi, MD; Sichuan Province People’s Hospital, Chengdu, China: Fuqiang Guo, MD; Dalian Municipal Central Hospital, Dalian, China: Jianfeng Wang, MD; The Second Hospital in Baoding, Baoding, China: Fengli Zhao, MD; The Hospital Combine Traditional Chinese and Western Medicine in Cangzhou, Cangzhou, China: Ronghua Dou, MD; The 309th Hospital Of P.L.A, Beijing, China: Dongning Wei, MD; Liangxiang Hospital Of Fangshan District, Beijing, China: Qingwei Meng, MD; HuaXin Hospital First Hospital of Tsinghua University, Beijing, China: Yilu Xia, MD; Tianjin Huanhu Hospital, Tianjin, China, ShiminWang, MD; Shijiazhuang First Hospital, Shijiazhuang, China: Zhangcang Xue, MD; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China: Yuming Xu, MD, PhD; Xinzhou City People’s Hospital, Xinzhou, China: Liping Ma, MD; Sichuan Province People’s Hospital of Deyang City, Deyang, China: Chun Wang, MD; First Hospital, Jilin University, Jilin, China: Jiang Wu, MD; Shandong Provincial Hospital, Jinan, China: Yifeng Du, MD; Fujian Province Hospital, Fuzhou, China: Yinzhou Wang, MD; Liaoyang City Third People’s Hospital, Liaoyang, China: Lijun Xiao, MD; Handan City Center Hospital, Handan, China: Fucong Song, MD; Beijing Chaoyang Hospital, Capital Medical University, Beijing, China: Wenli Hu, MD; Beijing University of Chinese Medicine East Hospital, Beijing, China: Zhigang Chen, MD; Hebei Medical University Fourth Hospital, Shijiazhuang, China: Qingrui Liu, MD; The Fourth Affiliated Hospital of Soochow University, Suzhou, China: Jiemin Zhang, MD; Zhejiang University of Chinese Medicine Affiliated First Hospital, Hangzhou, China: Mei Chen, MD; Affiliated Hospital of Kailuan Company Ltd, Tangshan, China, Xiaodong Yuan, MD; Affiliated Hospital of Weifang Medical University, Weifang, China: Zhihui Liu, MD; The First Hospital of Harbin Medical University, Harbin, China: Guozhong Li, MD; Dalian Friendship Hospital, Dalian, China: Xiaohong Li, MD; Tianjin Dagang Hospital, Tianjin, China: Tingchen Tian, MD.

Meeting Presentation: This paper was presented at the 11th World Stroke Congress; October 20, 2018; Montreal, Quebec, Canada.

Data Sharing Statement: See Supplement 3.

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