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Original Investigation |

Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack

Yilong Wang, MD, PhD1,2,3,4; Xingquan Zhao, MD, PhD1,2,3,4; Jinxi Lin, MD, PhD1,2,3,4; Hao Li, PhD1,2,3,4; S. Claiborne Johnston, MD, PhD5; Yi Lin, MD, PhD6; Yuesong Pan, MD1,2,3,4; Liping Liu, MD, PhD1,2,3,4; David Wang, DO, FAHA, FAAN7; Chunxue Wang, MD, PhD1,2,3,4; Xia Meng, MD, PhD1,2,3,4; Jianfeng Xu, MD, PhD8,9; Yongjun Wang, MD1,2,3,4 ; for the CHANCE investigators
[+] Author Affiliations
1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
2China National Clinical Research Center for Neurological Diseases, Beijing, China
3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
4Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
5Dell Medical School, University of Texas at Austin, Austin
6Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
7Illinois Neurological Institute Stroke Network, OSF Healthcare System, University of Illinois College of Medicine, Peoria, Illinois
8Fudan Institute of Urology, Hushan Hospital, Fudan University, Shanghai, China
9Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
JAMA. 2016;316(1):70-78. doi:10.1001/jama.2016.8662.
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Importance  Data are limited regarding the association between CYP2C19 genetic variants and clinical outcomes of patients with minor stroke or transient ischemic attack treated with clopidogrel.

Objective  To estimate the association between CYP2C19 genetic variants and clinical outcomes of clopidogrel-treated patients with minor stroke or transient ischemic attack.

Design, Setting, and Participants  Three CYP2C19 major alleles (*2, *3, *17) were genotyped among 2933 Chinese patients from 73 sites who were enrolled in the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) randomized trial conducted from January 2, 2010, to March 20, 2012.

Interventions  Patients with acute minor ischemic stroke or transient ischemic attack in the trial were randomized to treatment with clopidogrel combined with aspirin or to aspirin alone.

Main Outcomes and Measures  The primary efficacy outcome was new stroke. The secondary efficacy outcome was a composite of new composite vascular events (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death). Bleeding was the safety outcome.

Results  Among 2933 patients, 1948 (66.4%) were men, with a mean age of 62.4 years. Overall, 1207 patients (41.2%) were noncarriers and 1726 patients (58.8%) were carriers of loss-of-function alleles (*2, *3). After day 90 follow-up, clopidogrel-aspirin reduced the rate of new stroke in the noncarriers but not in the carriers of the loss-of-function alleles (P = .02 for interaction; events among noncarriers, 41 [6.7%] with clopidogrel-aspirin vs 74 [12.4%] with aspirin; hazard ratio [HR], 0.51 [95% CI, 0.35-0.75]; events among carriers, 80 [9.4%] with clopidogrel-aspirin vs 94 [10.8%] with aspirin; HR, 0.93 [95% CI, 0.69 to 1.26]). Similar results were observed for the secondary composite efficacy outcome (noncarriers: 41 [6.7%] with clopidogrel-aspirin vs 75 [12.5%] with aspirin; HR, 0.50 [95% CI, 0.34-0.74]; carriers: 80 [9.4%] with clopidogrel-aspirin vs 95 [10.9%] with aspirin; HR, 0.92 [95% CI, 0.68-1.24]; P = .02 for interaction). The effect of treatment assignment on bleeding did not vary significantly between the carriers and the noncarriers of the loss-of-function alleles (2.3% for carriers and 2.5% for noncarriers in the clopidogrel-aspirin group vs 1.4% for carriers and 1.7% for noncarriers in the aspirin only group; P = .78 for interaction).

Conclusions and Relevance  Among patients with minor ischemic stroke or transient ischemic attack, the use of clopidogrel plus aspirin compared with aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss-of-function alleles. These findings support a role of CYP2C19 genotype in the efficacy of this treatment.

Trial Registration  clinicaltrials.gov Identifier: NCT00979589

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Figure 1.
Clopidogrel-Aspirin vs Aspirin on Clinical Outcome Stratified by Metabolizer Phenotype

NE indicates not estimable. Patients with two *2 or *3 alleles (ie, *2/*2, *2/*3, or *3/*3) were classified as having the poor metabolizer phenotype, those with one *2 or *3 allele (ie, *1/*2 or *1/*3) were classified as having the intermediate metabolizer phenotype, those without a *2, *3, or *17 allele (ie, *1/*1) were classified as having the extensive metabolizer phenotype, those with a single *17 allele (ie, *1/*17) and *17 homozygotes were classified as having the ultra metabolizer phenotype. Composite event was defined as a new clinical vascular event, including ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death. The size of the data markers indicate the sample size of the subgroup.

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Figure 2.
Cumulative Probability of Stroke, Composite Event, and Bleeding According to Loss-of-Function Allele Carrier Status

Loss-of-function allele carriers were defined as patients with at least 1 loss-of-function allele (ie, *2 or *3): *1/*2, *1/*3, *2/*2, *2/*3, *3/*3, *2/*17, or *3/*17; loss-of-function allele noncarriers were defined as patients with no loss-of-function allele: *1/*1, *1/*17, or *17/*17. Composite event was defined as a new clinical vascular event, including ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death.

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