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

Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Korea.
Circulation Cardiovascular Interventions (Impact Factor: 6.22). 11/2011; 4(6):585-94. DOI: 10.1161/CIRCINTERVENTIONS.111.962555
Source: PubMed


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.
Patients who survived an AMI (n=266) 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 3435C>T 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 3435C>T was not related to clopidogrel response or cardiovascular events. Carriage of the CYP2C19 LOF variant allele was relatively high (60.9%, n=162; *2/*17=2, *3/*17=1, *1/*2=96, *1/*3=29, *2/*2=20, and *2/*3=14). 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), 1.8; 95% confidence interval (CI), 0.8 to 4.2, P=0.152; and 2 LOF alleles; OR, 2.8; 95% CI, 1.2 to 6.5; P=0.016]; platelet reactivity and the rate of HPR did not differ between the CYP2C19*2 versus *3 allele carriage. In addition, cardiovascular event occurrence increased according to the number of the CYP2C19 LOF allele; compared with noncarriers, carriers of 1 [hazard ratio (HR), 3.1; 95% CI, 0.8 to 11.6; P=0.089] and 2 CYP2C19 LOF allele(s) (HR, 10.1; 95% CI, 1.8-58.8; P=0.008) were associated with clinical end point. The clinical impact of the CYP2C19*2 versus *3 allele carriage also did not differ.
Among East Asian patients who survived an AMI, the CYP2C19 LOF allele carriage appears to affect clopidogrel pharmacodynamics and cardiovascular events according to the number of the CYP2C19 LOF allele; the influence of the CYP2C19*2 and *3 alleles on clopidogrel response and long-term outcomes does not differ.

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    • "Bedsides, genetic assessment may be useful for the treatment of STEMI patients. Currently available scientific data suggest that the authors who urge these tests to be implemented and propagated are right about perceiving them as a chance to improve the results of emergency myocardial infarction treatment [32]. However, genetic test opponents point out that there is a lack of sufficient data of genetic conditioning responsible for clopidogrel metabolism as well as studies related to the influence of genes on treatment efficacy [33]. "
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    ABSTRACT: Antiplatelet drugs play a crucial role in the treatment of patients with myocardial infarction, particularly in association with percutaneous coronary intervention. Their main advantage is the reduction of adverse ischemic incidents and the major disadvantage is the increase in the frequency of hemorrhages. Thus, the choice of appropriate drug depends on the right risk assessment of the development of these complications in individual patients. The aim of this article is to provide an update of antiplatelet therapy in emergency myocardial infarction treatment. Currently, the most important role in the process of platelet inhibition is played by ADP P2Y12 blockers: clopidogrel, prasugrel and ticagrelor. Clopidogrel and prasugrel belong to thienopyridines, and ticagrelor, a drug of irreversible action, is an analogue of adenosine triphosphate. By 2011 clopidogrel, alongside aspirin, had the highest recommendations of world cardiology associations for acute coronary syndrome treatment. The position on clopidogrel was changed following the publication of European Society of Cardiology guidelines for STEMI in 2012 which advocate the administration of acetylsalicylic acid (ASA) and ADP receptor blocker (in combination with ASA). It needs to be stressed that prasugrel and ticagrelor received class IB recommendation, while clopidogrel received only IC. However, the most recent studies aimed at introducing a new generation of antiplatelet drugs of high efficacy in prevention of ischemic incidents and of reversible action: cangrelor and elinogrel, which raise hopes for better prognosis for myocardial infarction patients.
    Full-text · Article · Mar 2014 · Postepy w Kardiologii Interwencyjnej / Advances in Interventional Cardiology
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    • "The present study showed that PM and older age were independent predictors of HTPR in the late phase of ACS, consistent with the results of the Korean trial [8]. There are considerable ethnic differences in the distribution of CYP2C19 polymorphisms and the magnitude of response to clopidogrel, and CYP2C19 genotype is significantly associated with HTPR in Asian patients. "
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    ABSTRACT: It remains unknown whether the time course of the antiplatelet effects of clopidogrel differs according to cytochrome P450 (CYP) 2C19 phenotype in Japanese patients with acute coronary syndromes (ACS). Platelet reactivity was serially assessed by VerifyNow-P2Y12 assay (Accumetrics, San Diego, CA, USA). Results were expressed as P2Y12-reaction-units (PRU) in 177 patients with ACS who underwent stent implantation and received aspirin plus a 300-mg loading dose of clopidogrel followed by 75mg/day. High on-clopidogrel treatment platelet reactivity (HTPR) was defined as PRU>235. On the basis of the CYP2C19*2 and *3 alleles, 46 patients (26.0%) were classified as extensive metabolizers (EM), 103 (58.2%) as intermediate metabolizers (IM), and 28 (15.8%) as poor metabolizers (PM). At <7 days, the PRU level (232±102 vs. 279±70, 308±67, p<0.001) and the incidence of HTPR (49% vs. 74%, 86%, p=0.001) was lower in EM than in IM and PM. At 14-28 days the effects of CYP2C19 polymorphisms on PRU levels increased in a stepwise fashion (168±99 vs. 213±77 vs. 278±69, p<0.001), and EM and IM had lower percentages of HTPR than PM (28%, 37% vs. 73%, p<0.001). There was no significant difference in the cumulative frequency of 12-month adverse cardiovascular events among 3 phenotypes (16.5%, 14.1%, 9.2%; p=0.67). About three quarters of Japanese patients with ACS carried CYP2C19 variant alleles. The majority of IM and PM had increased platelet reactivity during the early phase of ACS. Although HTPR was frequently observed even 14-28 days after standard maintenance doses of clopidogrel in PM, the incidence of adverse outcomes did not differ, irrespective of CYP2C19 genotype.
    Preview · Article · Jul 2013 · Journal of Cardiology
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    • "There exists a marked interracial difference in the frequency of the CYP2C19 polymorphisms. Asians have a higher prevalence of CYP2C19 LOF alleles and PM phenotypes (from 13% to 23% in Asians and from 1% to 6% in Caucasians) [12, 13]. In this study, the prevalence of CYP2C19 PM, *2, and *3 alleles were 19.3%, 36.0%, and 12.3%, respectively. "
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    ABSTRACT: Clopidogrel is a prodrug which is converted into active metabolite by cytochrome P450 isoenzyme, CYP2C19. Numerous polymorphisms of CYP2C19 are reported, and a strong link exists between loss-of-function (LOF) or gain-of-function polymorphisms, clopidogrel metabolism, and clinical outcome. Hence, a fully automated point-of-care CYP2C19 genotyping assay is more likely to bring personalized antiplatelet therapy into real practice. We assessed the feasibility of the Verigene 2C19/CBS Nucleic Acid Test, a fully automated microarray-based assay, compared to bidirectional sequencing, and performed VerifyNow P2Y12 assay to evaluate the effect of CYP2C19 polymorphisms on on-treatment platelet reactivity in 57 Korean patients treated with clopidogrel after percutaneous coronary intervention. The Verigene 2C19/CBS assay identified ∗2, ∗3, and ∗17 polymorphisms with 100% concordance to bidirectional sequencing in 180 minutes with little hands-on time. Patients were classified into 4 groups: extensive (∗1/∗1; n = 12, 21.1%), intermediate (∗1/∗2, ∗1/∗3; n = 33, 57.9%), poor (∗2/∗2, ∗2/∗3, and ∗3/∗3; n = 11, 19.3%), and ultrarapid metabolizers (∗1/∗17; n = 1, 1.8%). The prevalence of the CYP2C19 ∗2, ∗3, and ∗17 alleles was 36.0%, 12.3%, and 0.9%. Platelet reactivity showed gene dose response according to the number of CYP2C19 LOF allele. In conclusion, the Verigene 2C19/CBS assay gave accurate CYP2C19 genotype results which were in well match with the differing on-treatment platelet reactivity.
    Full-text · Article · Mar 2013
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