Effect of CYP2C19*2 and *3 Loss-of-Function Alleles on Platelet Reactivity and Adverse Clinical Events in East Asian Acute Myocardial Infarction Survivors Treated With Clopidogrel and Aspirin

Abstract

Background-As compared with whites, East Asians more often carry the cytochrome P450 (CYP) 2C19 loss-of-function (LOF) allele with the CYP2C19*3 variant. The influence of the CYP2C19 LOF alleles (*2 and *3) on clopidogrel response and clinical outcomes in East Asians with acute myocardial infarction (AMI) has not been reported. We sought to evaluate the effect of the CYP2C19 variants on clopidogrel pharmacodynamics and long-term prognosis in these patients. Methods and Results-Patients who survived an AMI (nϭ266) were enrolled in a single-center registry. Predischarge platelet reactivity was assessed with light transmittance aggregometry and the VerifyNow P2Y12 assay; the CYP2C19*2, *3, *17 and ABCB1 3435CϾT variants were determined. The primary clinical end point was the composite of cardiovascular death, nonfatal MI, and ischemic stroke. The median exposure to clopidogrel was 21 months (interquartile range, 13-29). The ABCB1 3435CϾT was not related to clopidogrel response or cardiovascular events. Carriage of the CYP2C19 LOF variant allele was relatively high (60.9%, nϭ162; *2/*17ϭ2, *3/*17ϭ1, *1/*2ϭ96, *1/*3ϭ29, *2/*2ϭ20, and *2/*3ϭ14). Platelet reactivity increased proportionally according to the number of the CYP2C19 LOF alleles. In a multivariate regression analysis, the risk of high on-treatment platelet reactivity (HPR) increased depending on the number of CYP2C19 LOF allele [1 LOF allele; odds ratio (OR), 1.

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

“…[10][11][12][13][14] Of note, individuals carrying two LOF alleles, who are considered CYP2C19 poor metabolizers (PMs), showed the worst pharmacokinetic/pharmacodynamic profiles for clopidogrel and the highest risk of cardiovascular outcomes compared with those with one LOF allele or none. 10,13,14 Because the metabolizing enzyme and drug transporter function together instead of separately in pharmacokinetics, it may be reasonable to assume that the evaluation of both the CYP2C19 PM status and ABCB1 3435 TT might improve the ability to predict adverse clinical outcomes in patients taking clopidogrel after PCI. However, there is a paucity of data on the combined effect of these two at-risk variants.…”

Association of CYP2C19 Genotype With Periprocedural Myocardial Infarction After Uneventful Stent Implantation in Chinese Patients Receiving Clopidogrel Pretreatment

“…CYP2C19*2 (containing a splicing defect) and CYP2C19*3 (containing a premature stop codon), are 2 major LOF alleles of CYP2C19. A recent Korean study 12 suggested that CYP2C19 LOF alleles had a gene-dose effect on post-clopidogrel platelet reactivity and that the effect of the CYP2C19*2 vs. *3 LOF allele carriage on platelet reactivity did not differ in East Asians. Additionally, there is no difference in the prevalence of HPR between CYP2C19*2/*2 and CYP2C19*2/*3 carriers.…”

“…Additionally, there is no difference in the prevalence of HPR between CYP2C19*2/*2 and CYP2C19*2/*3 carriers. 12 The fact that the magnitude of platelet reactivity increased by the presence of CYP2C19 LOF alleles encourages the search for the additional effect of CYP2C19 genotype on periprocedural outcome during PCI.…”

A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users

“…42 The percentage of patients who had undergone percutaneous coronary intervention varied from 0 to 100%, and the proportion of smokers ranged from Volume 17 | Number 1 | January 2015 | GENETIcS in MEDIcINE 8 to 56%, with three studies including more than 50% of smokers. [42][43][44] All 30 studies addressed clinical end points, and 17 studies also investigated ST. The definition of the composite clinical outcome and the event rates varied between primary studies.…”