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October 27, 2010

Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel Predominantly for PCI: A Meta-analysis

Author Affiliations

Author Affiliations: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Drs Mega, Antman, Cannon, Wiviott, and Sabatine); Department of Pharmacology, Assistance Publique-Hôpitaux de Paris and Universite Pierre et Marie Curie, Paris, France (Dr Simon); INSERM U-937, Institut de Cardiologie, Group Hospitalier Pitié-Salpétrière, and Universite Pierre et Marie Curie, Paris, France (Dr Collett); Cardiovascular Department, Intermountain Medical Center, Murray, Utah (Drs Anderson and Horne); Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, Maryland (Drs Bliden and Gurbel); Division of Coronary Artery Disease, Hopital Europeen Georges Pompidou and Universite Paris Rene Descartes, Paris, France (Dr Danchin); Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy (Dr Giusti); Institut de Cardiologie and Pharmacology Department, Pitié-Salpétrière University Hospital, Paris, France (Dr Hulot); Department of Cardiology, Deutsches Herzzentrum München, Munich, Germany (Drs Kastrati and Sibbing); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpétrière, Paris, France (Dr Montalescot); Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (Dr Neumann); Eli Lilly, Indianapolis, Indiana (Dr Shen); INSERM U-698, Universite Paris 7, and Hopital Bichat Assistance Publique, Paris, France (Dr Steg); and Department of Clinical Pharmacology, Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (Dr Trenk).

JAMA. 2010;304(16):1821-1830. doi:10.1001/jama.2010.1543

Content Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes.

Objective To define the risk of major adverse cardiovascular outcomes among carriers of 1 (≈ 26% prevalence in whites) and carriers of 2 (≈ 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel.

Data Sources and Study Selection A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained.

Data Extraction Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype.

Results Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P = .01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P = .002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P < .0001) and 2 (HR, 3.97; 95% CI, 1.75-9.02; P = .001) CYP2C19 reduced-function alleles, as compared with noncarriers.

Conclusion Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.

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