The influence of genetic polymorphisms of CYP2C19 and ABCB1 on ADP-induced platelet aggregation in clopidogrel-treated patients: A comparison between the index hospitalization for myocardial infarction and the 3-month follow-up visit

Abstract

Background. Recent studies suggest that polymorphisms of genes involved in the clopidogrel metabolism may be associated with an impaired drug bioactivation and possibly with unfavourable clinical outcomes. The aim of this study was to assess the effect of selected genetic polymorphisms on adenosine diphosphate-induced platelet aggregation (ADP-PA) during the index hospitalization and after 3 months of clopidogrel therapy in patients presenting with myocardial infarction (MI).

Materials and methods. The study was designed as a single-center cohort trial with the 3-month follow-up. Genotyping for CYP2C19*2, CYP2C19*17, ABCB1 alleles and platelet reactivity assessment using the Multiplate Analyzer were performed in 157 patients.

Results. ADP-PA during the index hospitalization was significantly higher than at the 3-month follow-up visit regardless of the genotyp e [CYP2C19*1/*1 alleles (24.0 v. 15.5 U; p < 0.00001), CYP2C19*17 allele (CT: 25.0 v. 15.0 U; p = 0.000 2; TT: 35.0 v. 22.0 U; p = 0.02) and ABCB1 allele (CC: 27.0 v. 15.0 U; p < 0.0002; CT 24.0 v. 17.0 U; p < 0.0005)]. In univariate analysis we failed to demonstrate any impact of the analyzed genetic variants on both in-hospital and 3-month ADP-PA, except for CYP2C19*17/*17 homozygotes. Significantly higher values of ADP-PA were found in CYP2C19*17/*17 (TT homozygotes) allele carriers when compared with carriers of two wild alleles during the index hospitalization (CC: 20.0 U v. TT: 35.0 U; p = 0.02), but not at the 3-month follow-up visit. Multivariate regression analysis revealed increased mean platelet volume (β = 7.2), elevated platelet count (β = 0.2) and the presence of heart failure at discharge (β = 6.9), but not genetic polymorphisms, to be independent determinants of high ADP-PA during the index hospitalization. Similarly, elderly age (β = 3.3), high white blood cell count (β = 1.4), elevated platelet count (β = 0.4) and increased mean platelet volume (β = 0.1), but not genetic polymorphisms, were independently associated with the higher values of ADP-PA after 3 months of clopidogrel therapy.

Conclusions. On-clopidogrel platelet reactivity significantly decreases beyond the acute phase of MI regardless of the genotype. Additionally, our study indicates that in clopidogrel-treated MI patients genetic polymorphisms are not the major determinants of the interindividual variability in platelet reactivity. However, due to a limited sample size, their minor contribution cannot be excluded.