Effects of genetic variants on platelet reactivity and one-year clinical outcomes after percutaneous coronary intervention: A prospective multicentre registry study

Hyung Joon Joo,Do-Sun Lim,Soon Jun Hong,Ji Young Park,Junghan Yoon,Seok-Yeon Kim,Yangsoo Jang,Scot Garg,Woong Chol Kang,Wonyong Shin,Myeong-Ki Hong,Jae Hyoung Park,Young-Hyo Lim,Yun-Hyeong Cho,Sung Gyun Ahn,Weon Kim,Woonggil Choi,Yong Hoon Kim,Hyeoncheol Gwon

doi:10.1038/s41598-017-18134-y

Abstract

Clopidogrel is the mainstay for antiplatelet treatment after percutaneous coronary intervention (PCI). The relationship of platelet reactivity and genetic polymorphism with clinical outcomes with newer-generation drug-eluting stents is unclear. We analysed 4,587 patients for the most powerful single-nucleotide polymorphisms (CYP2C19, CYP2C9, ABCB1, PON1, and P2Y12) related to on-treatment platelet reactivity (OPR). The optimal cut-off value of high OPR for major adverse thrombotic events was 266. CYP2C19 was significantly associated with high OPR and the number of CYP2C19*R (*2 or *3) alleles was proportional to the increased risk of high OPR. Death, myocardial infarction (MI), stroke, stent thrombosis, and bleeding events were assessed during a 1-year follow-up period. Primary endpoints were death and non-fatal MI. The cumulative 1-year incidence of death and stent thrombosis was significantly higher in patients with CYP2C19*2/*2, CYP2C19*2/*3, and CYP2C19*3/*3 (Group 3) than in patients with CYP2C19*1/*1 (Group 1). Multivariate Cox proportional hazard model showed that cardiac death risk was significantly higher in Group 3 than in Group 1 (hazard ratio 2.69, 95% confidence interval 1.154–6.263, p = 0.022). No association was reported between bleeding and OPR. Thus, CYP2C19 may exert a significant impact on the prognosis of PCI patients even in the era of newer-generation drug-eluting stents.

Highlights

Clopidogrel is the mainstay for antiplatelet treatment after percutaneous coronary intervention (PCI)
The main findings from Analysis 1 are as follows: (1) higher on-treatment platelet reactivity (OPR) was significantly associated with a higher incidence of thrombotic events after PCI; the optimal cut-off value for high OPR was a P2Y12 reaction unit (PRU) value of 266; and (2) among five single nucleotide polymorphisms (SNPs), only CYP2C19 gene variants was associated with the increased risk of high OPR in a dose-dependent manner
The main findings from Analysis 2 are as follows: (1) the 1-year incidence rate of death was significantly higher in patients with CYP2C19*R/*R (Group 3) as compared to other groups; (2) the incidence of stent thrombosis was higher in patients with CYP2C19*R/*R; and (3) CYP2C19*R/*R was an independent risk predictor for cardiac death

Summary

Introduction

Clopidogrel is the mainstay for antiplatelet treatment after percutaneous coronary intervention (PCI). The “East Asian paradox” refers to the increased prevalence of high on-treatment platelet reactivity (OPR) but similar or lower thrombotic event rates after PCI in East Asian patients and has raised questions over the optimal antiplatelet strategy for the East Asian patients[4]. The proposed mechanism underlying these phenomena includes differences in genetic predisposition such as the higher prevalence of CYP2C19 loss-of-function alleles, which has been observed in East Asian patients[5]. These data indicate that the discrepancy between thrombogenicity characteristics and genotyping may affect clinical outcomes after PCI. In the era of newer-generation, drug-eluting stents (DES), it is still unclear whether OPR and its associated genetic polymorphisms may affect clinical outcomes, including both ischemic and bleeding events. The present study, enrolled approximately 5,000 patients undergoing PCI and determined the relationship between OPR as well as genotypes and the subsequent major adverse events in Korean patients

Methods

Results

Conclusion