title: Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00979589.
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Xingquan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Jinxi
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Dell Medical School, University of Texas at Austin, Austin.
authors.forename: S Claiborne
authors.initials: SC
authors.lastname: Johnston
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Yuesong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.affiliation: Illinois Neurological Institute Stroke Network, OSF Healthcare System, University of Illinois College of Medicine, Peoria, Illinois.
authors.forename: David
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Chunxue
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Xia
authors.initials: X
authors.lastname: Meng
authors.affiliation: Fudan Institute of Urology, Hushan Hospital, Fudan University, Shanghai, China9Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000368:Aged; D000483:Alleles; D044466:Asian People; D001241:Aspirin / Q000627:therapeutic use*; D002681:China; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D020868:Gene Silencing; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006579:Heterozygote; D006801:Humans; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D055502:Secondary Prevention; D020521:Stroke / Q000235:genetics / Q000517:prevention & control*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin