Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel Predominantly for PCI: A Meta-analysis.
Mega, Jessica L. MD, MPH; Simon, Tabassome MD, PhD; Collet, Jean-Philippe MD, PhD; Anderson, Jeffrey L. MD; Antman, Elliott M. MD; Bliden, Kevin BS; Cannon, Christopher P. MD; Danchin, Nicolas MD, PhD; Giusti, Betti PhD; Gurbel, Paul MD; Horne, Benjamin D. PhD; Hulot, Jean-Sebastian MD, PhD; Kastrati, Adnan MD; Montalescot, Gilles MD, PhD; Neumann, Franz-Josef MD; Shen, Lei PhD; Sibbing, Dirk MD; Steg, P. Gabriel MD; Trenk, Dietmar PhD; Wiviott, Stephen D. MD; Sabatine, Marc S. MD, MPH
[Review]
JAMA.
304(16):1821-1830, October 27, 2010.
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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 ([almost equal to] 26% prevalence in whites) and carriers of 2 ([almost equal to] 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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