Abstract
Several clinical and genetic variables are associated with influencing high on treatment platelet reactivity (HTPR). The aim of the study was to propose a path model explaining a concurrent impact among variables influencing HTPR and ischemic events. In this prospective cohort study polymorphisms of CYP2C19*2, CYP2C19*17, ABCB1, PON1 alleles and platelet function assessed by Multiple Electrode Aggregometry were assessed in 416 patients undergoing percutaneous coronary intervention treated with clopidogrel and aspirin. The rates of major adverse cardiac events (MACE) were recorded during a 12-month follow up. The path model was calculated by a structural equation modelling. Paths from two clinical characteristics (diabetes mellitus and acute coronary syndrome (ACS)) and two genetic variants (CYP2C19*2 and CYP2C19*17) independently predicted HTPR (path coefficients: 0.11 0.10, 0.17, and -0.10, respectively; p<0.05 for all). By use of those four variables a novel score for prediction of HTPR was built: in a factor-weighted model the risk for HTPR was calculated with an OR of 3.8 (95%CI: 3.1–6.8, p<0.001) for a score level of ≥1 compared with a score of <1. While MACE was independently predicted by HTPR and age in the multivariate model (path coefficient: 0.14 and 0.13, respectively; p<0.05), the coexistence of HTPR and age ≥75 years emerged as the strongest predictor of MACE. Our study suggests a pathway, which might explain indirect and direct impact of variables on clinical outcome: ACS, diabetes mellitus, CYP2C19*2 and CYP2C19*17 genetic variants independently predicted HTPR. In turn, age ≥75 years and HTPR were the strongest predictors of MACE.
Highlights
Within the past years, platelet function studies have shown that up to 50% of clopidogrel treated patients have high on-treatment platelet reactivity (HTPR) [1]
Whether other polymorphisms of genes being involved in the metabolism or action of clopidogrel predict high on treatment platelet reactivity (HTPR) is a matter of debate [14,20,21,22,23]
Two third of patients underwent non-emergent percutaneous coronary intervention (PCI) and one third presented with an acute coronary syndromes (ACS) on admission
Summary
Platelet function studies have shown that up to 50% of clopidogrel treated patients have high on-treatment platelet reactivity (HTPR) [1]. Several clinical and genetic variables are associated with HTPR. From multiple candidate genes being involved in metabolism of clopidogrel, the CYP2C19*2 (loss-of-function allele) and the CYP2C19*17 (gainof-function mutation), have been associated with response variability to clopidogrel in some studies [12,14,15,16,17,18,19]. Whether other polymorphisms of genes being involved in the metabolism or action of clopidogrel (e.g. the intestinal efflux transport pump Pglycoprotein pump encoded by the ABCB1 gene or the paraoxonase-1, PON1 gene) predict HTPR is a matter of debate [14,20,21,22,23]
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