Influence of CYP2C19*2 and *3 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

Abstract

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...

Effect of high-dose clopidogrel according to CYP2C19*2 genotype in patients undergoing percutaneous coronary intervention– a systematic review and meta-analysis

“…Both higher loading dose (600 mg) and maintenance dose (150 mg/day) were administrated to 693 patients in 3 studies [24][25][26]. A total of 9 studies with 3068 patients provided data for the association of high-dose clopiogrel with OTPR in CYP2C19*2 carriers [10][11][12]14,18,[25][26][27][28]. Seven studies with 2,266 patients presented the data on the risk for HTPR [12][13][14]16,17,23,24], and 6 studies with 6,811 patients reported the risk for clinical events [18][19][20][21][22][23].…”

“…Of these studies, 36 studies conducted without high-dose clopidogrel strategy were excluded. Finally, a total of 19 investigations were included in the meta-analysis, with 15 from Caucasians [11][12][13][16][17][18][19][20][21][22][23][24][25]27,28], and 4 from Asians [10,14,15,26] (Table 1). Among these 19 investigations (10,960 patients), 5 studies applied higher maintenance dose of clopidogrel (150 mg/day) in CYP2C19*2 carriers with a total sample size of 801 patients [10,11,[14][15][16].…”

“…Finally, a total of 19 investigations were included in the meta-analysis, with 15 from Caucasians [11][12][13][16][17][18][19][20][21][22][23][24][25]27,28], and 4 from Asians [10,14,15,26] (Table 1). Among these 19 investigations (10,960 patients), 5 studies applied higher maintenance dose of clopidogrel (150 mg/day) in CYP2C19*2 carriers with a total sample size of 801 patients [10,11,[14][15][16]. Eleven studies applied higher loading dose (600 mg or 900 mg) with a sample size reaching to 9,466 patients [12,13,[17][18][19][20][21][22][23]27,28].…”

“…Thrombosis Research xxx (2014) xxx-xxx The effect of high-dose clopidogrel on the improvement of the response to clopidogrel in the setting of LOF CYP2C19 genotype has been investigated in two randomized trials [10,11]. One study found that compared with standard dose of 75 mg/day clopidogrel, better platelet inhibition could be achieved in CYP2C19*2 carriers treated with 150 mg/day high-dose clopidogrel [10]. In another study (ELE-VATE-TIMI 56 trial), when the maintenance dose of clopidogrel was tripled to 225 mg/day in stable heart disease patients, one CYP2C19*2 allele carriers achieved levels of platelet reactivity similar to that seen in non-carriers with the standard 75 mg/day dose; However, in patients with two CYP2C19*2 alleles, clopidogrel dose as high as 300 mg/day did not result in the similar platelet inhibition degree to that seen in non-carriers with 75 mg/day dose [11].…”

“…Therefore, in 2010, the US Food and Drug Administration (FDA) added a boxed warning to the clopidogrel label which suggests that individuals with poor metabolizer genotypes may be at increased risk for adverse cardiovascular events, and should consider other antiplatelet medications or alternative dosing strategies, such as high-dose clopidogrel administration [9]. Thrombosis Research xxx (2014) xxx-xxx The effect of high-dose clopidogrel on the improvement of the response to clopidogrel in the setting of LOF CYP2C19 genotype has been investigated in two randomized trials [10,11]. One study found that compared with standard dose of 75 mg/day clopidogrel, better platelet inhibition could be achieved in CYP2C19*2 carriers treated with 150 mg/day high-dose clopidogrel [10].…”