Journal
CIRCULATION-CARDIOVASCULAR INTERVENTIONS
Volume 4, Issue 5, Pages 422-428Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCINTERVENTIONS.111.963025
Keywords
clopidogrel; genetic polymorphisms; pharmacokinetics; cytochrome P450; paraoxonase-1; coronary artery disease; platelets; coronary stenting; myocardial infarction
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Funding
- Delegation a la Recherche Clinique
- Assistance Publique-Hopitaux de Paris (AP-HP)
- French Ministry of Health [PHRC P070117]
- APHP [CRC 97109]
- Fondation de France
- INSERM
- Federation Francaise de Cardiologie
- Biotronik
- Medco Research Institute
- Biotronik and Medco Health Solutions
- Daiichi Sankyo
- Eli Lilly
- Bristol-Myers Squibb
- Sanofi-Aventis, Eli Lilly
- Guerbet Medical
- Medtronic
- Boston Scientific
- Cordis
- Stago
- Societe Francaise de Cardiologie
- Federation Franc, aise de Cardiologie
- Abbott Vascular
- Servier
- CSL Behring
- Astra Zeneca
- Federation Franc
- aise de Cardiologie
- ITC Edison
- Pfizer
- Bayer
- Boehringer Ingelheim
- Cardiovascular Research Foundation
- Cleveland Clinic Research Foundation
- Daichi Snakyo
- Duke Institute
- The Medicines Company, Europa
- GlaxoSmith-Kline
- Institut de Cardiologie de Montreal
- Menarini
- Nanospheres
- Novartis
- Portola
- Sanofi-Aventis
- TIMI Study Group
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Background-Reduced concentrations of clopidogrel active metabolite have been associated with diminished platelet inhibition and higher rates of adverse cardiovascular events. Paraoxonase-1 (PON1) has recently been proposed as a key enzyme for clopidogrel metabolic activation. We tested the effects of PON1 polymorphisms on clopidogrel pharmacokinetics and pharmacodynamics and the occurrence of cardiovascular outcomes in young post-myocardial infarction (MI) patients treated with clopidogrel. Methods and Results-We genotyped PON1 (Q192R and L55M) and CYP2C19 variants in 106 patients enrolled in the PK/PD CLOVIS-2 trial. Patients were randomly exposed to a 300-mg or 900-mg clopidogrel loading dose in a crossover study design. Clopidogrel active metabolite isomer H4 (clopi-H4) and platelet function testing were measured serially after loading dose. There was no significant association between PON1 Q192R or L55M and clopi-H4 formation or antiplatelet response to clopidogrel after either loading dose. Using multivariable linear regression analyses, the CYP2C19*2 allele was the only predictor of clopi-H4 generation and platelet response irrespective of the platelet function assay. CYP2C19 loss-of-function but not PON1 variants were significantly associated with increased risk of major cardiovascular events (death, MI, and urgent coronary revascularization) occurring during long-term clopidogrel exposure in 371 young post-MI patients (age <45 years) enrolled in the AFIJI cohort (CYP2C19 loss-of-function allele carrier versus noncarrier: hazard ratio, 2.26; 95% confidence interval, 1.15-4.41, P=0.02; PON1 QQ192 versus QR/RR192: hazard ratio, 1.03; 95% confidence interval, 0.50-2.11, P=0.93; PON1 LL55 versus LM/MM55: hazard ratio, 1.52; 95% confidence interval, 0.75-3.08, P=0.24). Conclusions-Our study does not confirm that PON1 Q192R or L55M can influence clopidogrel pharmacokinetics or pharmacodynamics in post-MI patients.
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