CYP2C19 loss-of-function alleles, but not PON1 variants, increased the risk of major cardiovascular events in young post-MI patients on clopidogrel (HR 2.26; 95% CI 1.15-4.41; P=0.02).
Cohort (n=477)
Randomized crossover for PK/PD phase
Do PON1 and CYP2C19 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients?
CYP2C19 loss-of-function variants, but not PON1 variants, significantly predict reduced clopidogrel active metabolite generation, lower platelet inhibition, and a higher risk of major cardiovascular events in post-MI patients.
Hazard Ratio: 2.26 (95% CI 1.15–4.41)
p-value: p=0.02
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.
Hulot et al. (Sat,) conducted a cohort in Post-myocardial infarction (n=477). CYP2C19 loss-of-function allele vs. Noncarrier was evaluated on Major cardiovascular events (death, MI, and urgent coronary revascularization) (HR 2.26, 95% CI 1.15-4.41, p=0.02). CYP2C19 loss-of-function alleles, but not PON1 variants, increased the risk of major cardiovascular events in young post-MI patients on clopidogrel (HR 2.26; 95% CI 1.15-4.41; P=0.02).