Abstract 17658: CYP2C19 Polymorphism and PON-1 Activity in NSTE ACS: Vorapaxar Effect in Relation to Clopidogrel Metabolism in the TRACER Trial
Background: CYP2C19 genotypes influence response to clopidogrel and paraoxonase-1 (PON-1) has been proposed as a key enzyme for clopidogrel activation. In the TRACER trial, where there was frequent use of clopidogrel, vorapaxar was associated with a nonsignificant reduction of the primary endpoint and a nominal reduction of CV death, myocardial infarction (MI), or stroke. We investigated association of CYP2C19 genotype and PON-1 activity with outcomes and whether each modified vorapaxar efficacy.
Methods: DNA samples were obtained from TRACER pts and were genotyped for CYP2C19 loss-of-function (LOF) alleles (*2, *3, *4, *5, *6, *7, *8) and the CYP2C19 gain-of-function allele *17 and were classified by predicted phenotypes: extensive (EM) (*1 *1, *1*17, *17 /*17) and reduced (RM) (*1/*2-*8; *2-*8/*2-*8) metabolizers. Undetermined metabolizer (*17/*2-*8) were excluded. PON-1 activity was measured from plasma obtained at baseline and classified as high, moderate, or low according to tertiles. The outcome was the composite of CV death, MI, or stroke (median follow-up 1.2 yrs).
Results: Of 12,944 pts, 9990 were discharged on clopidogrel, of which 4590 were genotyped for the CYP2C19 polymorphism and 6651 had plasma PON-1 activity measured at randomization. PON-1 activity was not significantly associated with CV death, MI, or stroke (HR for 50 u/L 0.97; 95% CI 0.93-1.00; p=0.063). CYP2C19 phenotypes were not associated with the outcome (HR for EM vs RM 0.99; 95% CI 0.79-1.25; p=0.93). The effect of vorapaxar was not significantly modified by CYP2C19 phenotype or PON-1 activity (Table).
Conclusion: In this large NSTE ACS cohort, we did not find a significant association of CYP2C19 genotypes and PON-1 activity with long-term ischemic outcomes, and no changes in vorapaxar efficacy were observed. These subgroup results do not support use of CYP2C19 genotyping or PON-1 activity assay for ischemic risk stratification and identification of those who may benefit from vorapaxar.
- © 2013 by American Heart Association, Inc.