loss-of-function alleles on the pharmacodynamic effects of standard-and high-dose clopidogrel in East Asians undergoing percutaneous coronary intervention: the results of the ACCEL-DOUBLE-2N3 study. J Thromb Haemost 2013; 11: 1194-7.Carriage of the cytochrome P450 (CYP) 2C19 loss-of-function (LoF) polymorphism has been associated with high on-treatment platelet reactivity (HPR) and an increased risk of ischemic event occurrence in clopidogrel-treated patients undergoing a percutaneous coronary intervention (PCI) [1]. Although there are multiple CYP2C19 alleles associated with null function (i.e. *2-*8), the treatment strategy to overcome the LoF allele effect was mostly based on the CYP2C19*2 LoF allele [2]. There is a marked interethnic difference in the frequency of poor metabolizers between East Asians (13-30%) and Caucasians (< 5%). The CYP2C19*2 (rs4244285, c.681G>A in exon 5, splice site mutation) and *3 (rs4986893, c.636G>A in exon 4, a premature stop codon) alleles account for the LoF polymorphism in East Asians, whereas most of the LoF polymorphism in Caucasians consist of the CYP2C19*2 allele with extremely rare *3 carriage. The effect of the CYP2C19*3 allele on the enzyme activity appeared greater than the CYP2C19*2 allele in several previous studies [3,4].In this pilot study, we analyzed the association between platelet reactivity and the CYP2C19 genotype in East Asians during standard-and high-dose clopidogrel, and compared the gene-dose effect of the CYP2C19*2 and *3 alleles.Baseline platelet function measurement was performed during standard-dose clopidogrel therapy (n = 155) (Data S1): for elective PCI, patients received a 300-mg clopidogrel load at least 12 h before PCI or ingested a daily 75-mg clopidogrel therapy (≥ 5 days), and acute myocardial infarction patients were treated with emergent PCI after a 600-mg clopidogrel load, followed by daily 75-mg clopidogrel administration (≥ 5 days). Immediately before discharge, patients started high-dose clopidogrel administration (150-mg daily). Follow-up platelet measurement was performed after patients took high-dose clopidogrel during at least 30 days.The platelet function test (AggRAM aggregometer; Helena Laboratories Corp., Beaumont, TX, USA) and genotyping were performed (Data S1). The primary endpoint was the level of 20 lM ADP-induced platelet aggregation (PA) during clopidogrel treatment according to the CYP2C19 metabolizer status. Secondary endpoints were DPA between standard-and high-dose clopidogrel, and the frequency of HPR according to the CYP2C19 metabolizer status. We also evaluated differences in these parameters across the CYP2C19 genotype. HPR was defined as 20 lM ADP-induced PA ≥ 59% [1].To adjust the influence of covariates on PA, a multivariate linear and binary logistic regression analysis was performed using known relevant clinical characteristics as fixed covariates [5] (Data S1). P < 0.05 was considered to indicate a significant difference, and all statistical analyzes were performed using SPSS 18.0 (SPSS Inc., Chicago, IL, U...

The thrombotic risk profile between premenopausal and postmenopausal women is similar. However, improved management of cholesterol may be of clinical benefit. Large-scale studies are required to validate these findings.

High platelet reactivity (HPR) and suboptimal response to dual antiplatelet therapy (DAPT) may explain high recurrent rates of ischemic events in Type II diabetes mellitus (DM) patients undergoing percutaneous coronary intervention (PCI). The aim of this study was to examine the effect of clopidogrel on platelet reactivity, and thrombogenecity between DM and non-DM PCItreated patients (n = 138). Patients were categorized according to clopidogrel treatment and DM status. Patients received a maintenance-dose clopidogrel of 75 mg/d (C75 group, n = 72) or a 600 mg clopidogrel loading-dose in clopidogrel naïve patients (C600 group, n = 66). Platelet function was assessed by thrombelastography, flow cytometry, VerifyNow™ aspirin assay and light transmittance aggregometry (LTA). Aspirin response was similar between treatments and DM status. In the C75 group, DM patients had higher 5 and 20 M ADP, 2 g/ml collagen-induced LTA; and p-selectin expression compared to non-DM patients (p ≤ 0.05 for all). DM patients in the C600 group had higher 5 and 20 M ADPinduced LTA post dosing (p < 0.04) and higher maximum induced platelet-fibrin clot strength at baseline and post dosing timepoints (p < 0.05 for all). The present study provides further evidence that DM patients on DAPT are characterized by persistently higher platelet reactivity and thrombogenecity, making them potential candidates for more potent P2Y 12 receptor antagonists.

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