TY - JOUR
T1 - Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI
T2 - A meta-analysis
AU - Mega, Jessica L.
AU - Simon, Tabassome
AU - Collet, Jean Philippe
AU - Anderson, Jeffrey L.
AU - Antman, Elliott M.
AU - Bliden, Kevin
AU - Cannon, Christopher P.
AU - Danchin, Nicolas
AU - Giusti, Betti
AU - Gurbel, Paul
AU - Horne, Benjamin D.
AU - Hulot, Jean Sebastian
AU - Kastrati, Adnan
AU - Montalescot, Gilles
AU - Neumann, Franz Josef
AU - Shen, Lei
AU - Sibbing, Dirk
AU - Steg, P. Gabriel
AU - Trenk, Dietmar
AU - Wiviott, Stephen D.
AU - Sabatine, Marc S.
PY - 2010/10/27
Y1 - 2010/10/27
N2 - 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 clinicaloutcomesin 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.
AB - 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 clinicaloutcomesin 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.
UR - http://www.scopus.com/inward/record.url?scp=78049326068&partnerID=8YFLogxK
U2 - 10.1001/jama.2010.1543
DO - 10.1001/jama.2010.1543
M3 - Article
C2 - 20978260
AN - SCOPUS:78049326068
SN - 0098-7484
VL - 304
SP - 1821
EP - 1830
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 16
ER -