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

JAMA. 2016 Jul 5;316(1):70-8. doi: 10.1001/jama.2016.8662.

Abstract

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles*
  • Asian Continental Ancestry Group
  • Aspirin / therapeutic use*
  • China
  • Clopidogrel
  • Cytochrome P-450 CYP2C19 / genetics*
  • Cytochrome P-450 CYP2C19 / metabolism
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Gene Silencing
  • Genotype
  • Hemorrhage / chemically induced
  • Heterozygote
  • Humans
  • Ischemic Attack, Transient / genetics
  • Ischemic Attack, Transient / prevention & control*
  • Male
  • Middle Aged
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Secondary Prevention*
  • Stroke / genetics
  • Stroke / prevention & control*
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / therapeutic use
  • Time Factors
  • Treatment Outcome

Substances

  • Platelet Aggregation Inhibitors
  • Clopidogrel
  • Cytochrome P-450 CYP2C19
  • Ticlopidine
  • Aspirin

Associated data

  • ClinicalTrials.gov/NCT00979589