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


In China, there are approximately 3 million new strokes every year, and approximately 30% of them are minor ischemic strokes. TIA is even more common with an estimated 23.9 million occurring in 2010, based on a Chinese national survey. Understanding the relationship between CYP2C19 variants and clinical effect of clopidogrel (Plavix; Bristol-Myers Squibb Co. and Sanofi SA) is critically important to optimize treatment for patients with minor stroke or TIA.


The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial showed that the combination of clopidogrel with aspirin compared with aspirin alone reduced the risk of stroke among patients with transient ischemic attack (TIA) or minor ischemic stroke who can be treated within 24 hours after the onset of symptoms. Clopidogrel, in combination with aspirin, has become a recommended treatment option for patients with TIA or acute minor stroke. Clopidogrel requires conversion to an active metabolite by hepatic cytochrome p450 (CYP) isoenzymes to exert an antiplatelet effect, and polymorphisms of the CYP2C19 gene (OMIM 124020) have been identified as strong predictors of clopidogrel nonresponsiveness. In the clinical setting the association between CYP2C19 loss-of-function alleles (especially the most common *2 and *3 variants) and clinical efficacy of clopidogrel has been studied extensively with discordant results and Very limited data are available addressing the effect of CYP2C19 variants on clopidogrel efficacy in stroke, especially in Asian populations, in which the rates of stroke incidence and mortality are higher compared with white populations. The prevalence of CYP2C19 loss-of-function variants is also high in Asian populations.


As a result, a study published online in JAMA (23 June 2016) examined the efficacy and safety of dual therapy of clopidogrel and aspirin compared with aspirin alone according to genotype status among patients in the trial. For the study, Three CYP2C19 major alleles (*2, *3, *17) were genotyped among 2933 Chinese patients from 73 sites who were enrolled in the CHANCE trial conducted from January 2, 2010, to March 20, 2012.


For the study, 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. 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.


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; events among carriers, 80 (9.4%) with clopidogrel-aspirin vs 94 (10.8%) with aspirin; HR, 0.93. 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; carriers: 80 (9.4%) with clopidogrel-aspirin vs 95 (10.9%) with aspirin; HR, 0.92; 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).


According to the authors, 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.



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