Platelet reactivity in the early and late phases of acute coronary syndromes according to cytochrome P450 2C19 phenotypes

Nagashima, Zenko; Tsukahara, Kengo; Morita, Satoshi; Endo, Tsutomu; Sugano, Teruyasu; Hibi, Kiyoshi; Himeno, Hideo; Fukui, Kazuki; Umemura, Satoshi; Kimura, Kazuo

doi:10.1016/j.jjcc.2013.03.006

Cited by 31 publications

(32 citation statements)

References 49 publications

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“…The sample size was calculated on the basis of previous reports that assessed PRU levels in Japanese CAD patients [23,24]. On the basis of the proportions of patients in our hospital, we estimated that the study subjects should include eight patients who were not treated with clopidogrel for every 10 patients treated with aspirin/clopidogrel.…”

Section: Discussionmentioning

confidence: 99%

“…Second, we did not measure aspirin reaction units with the VerifyNow Aspirin assay, and therefore could not compare the PL 24 -AUC 10 measured with the T-TAS and aspirin reaction units measured with the VerifyNow Aspirin assay. Third, because we did not measure serial changes in PL 24 -AUC 10 values in the aspirin/clopidogrel group after clopidogrel loading, it is possible that the on-clopidogrel platelet thrombus formation might not be sufficiently downregulated in the aspirin/clopidogrel group treated with a maintenance dose of clopidogrel.…”

Section: Discussionmentioning

confidence: 99%

“…To assess the effects of CYP2C19 phenotype on PL 24 -AUC 10 levels, we compared the PL 24 -AUC 10 and PRU values in patients in the aspirin/clopidogrel group classified as EMs carrying normal-function alleles (CYP2C19*1/CYP2C19*1), IMs carrying one loss-offunction allele (CYP2C19*1/CYP2C19*2; CYP2C19*1/ CYP2C19*3), and PMs carrying two loss-of-function alleles (CYP2C19*2/CYP2C19*2; CYP2C19*2/CYP2C19*3; CYP2C19*3/CYP2C19*3). Table S2 (Fig.…”

Section: Effects Of Cyp2c19 Phenotype On Pl 24 -Auc 10 Levelsmentioning

confidence: 99%

“…Multiple regression analysis identified high PL 24 -AUC 10 as an independent and significant determinant of PM status (OR 3.868, 95% CI 1.314-11.39, P = 0.014) ( Table 3). The PRU, PL 24 BNP, B-type natriuretic peptide; CI, confidence interval; CRP, C-reactive protein; EF, left ventricular ejection fraction; eGFR, estimated glomerular filtration rate; Hct, hematocrit; OR, odds ratio; PRU, P2Y12 reaction unit. *Data for this parameter were divided into two groups on the basis of the median value.…”

Section: Effects Of Cyp2c19 Phenotype On Pl 24 -Auc 10 Levelsmentioning

confidence: 99%

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Assessment of platelet‐derived thrombogenicity with the total thrombus‐formation analysis system in coronary artery disease patients receiving antiplatelet therapy

Arima

Kaikita

Ishii

et al. 2016

Journal of Thrombosis and Haemostasis

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Total thrombus‐formation analysis system (T‐TAS) quantitatively measures platelet thrombus formation. We examined the utility of T‐TAS in patients with coronary artery disease. T‐TAS can discriminate different types of the antiplatelet therapy in the same measuring method. Genetic background, cytochrome P‐450 2C19 genotypes, also influenced T‐TAS parameters. Summary BackgroundAccurate evaluation of thrombogenicity helps to prevent thrombosis and excessive bleeding. The total thrombus‐formation analysis system (T‐TAS) was developed for quantitative analysis of platelet thrombus formation by the use of microchips with thrombogenic surfaces (collagen, platelet chip [PL‐chip]; collagen plus tissue factor, atherome chip [AR‐chip]). We examined the utility of the T‐TAS in the assessment of the efficacy of antiplatelet therapy in patients with coronary artery disease (CAD). Methods and ResultsIn this cross‐sectional study, 372 consecutive patients admitted to the cardiovascular department were divided into three groups: patients not receiving any antiplatelet therapy (control, n = 56), patients receiving aspirin only (n = 69), and patients receiving aspirin and clopidogrel (n = 149). Blood samples were used for the T‐TAS to measure the platelet thrombus‐formation area under the curve (AUC) at various shear rates (1500 s−1 [PL18‐AUC10] and 2000 s−1 [PL24‐AUC10] for the PL‐chip; 300 s−1 [AR10‐AUC30] for the AR‐chip). The on‐clopidogrel platelet aggregation was measured by the use of P2Y12 reaction units (PRUs) with the VerifyNow system. The mean PL24‐AUC10 levels were 358 ± 111 (± standard deviation) (95% confidence interval [CI] 328.9–387.1) in the control group, 256 ± 108 (95% CI 230.5–281.5) in the aspirin group, and 113 ± 91 (95% CI 98.4–127.6) in the aspirin/clopidogrel group. In the aspirin/clopidogrel group, the PL24‐AUC10 was higher in poor metabolizers (PMs) with cytochrome P450 2C19(CYP2C19) polymorphisms (152 ± 112, 95% CI 103.4–200.6) than in the non‐PM group (87 ± 74, 95% CI 73.8–100.2). ConclusionsOur findings suggest that the PL24‐AUC10 level measured by the T‐TAS is a potentially suitable index for the assessment of antiplatelet therapy in CAD patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Cyp2c19 Phenotype On Pl 24 -Auc 10 Levelsmentioning

confidence: 99%

Section: Effects Of Cyp2c19 Phenotype On Pl 24 -Auc 10 Levelsmentioning

confidence: 99%

See 2 more Smart Citations

Assessment of platelet‐derived thrombogenicity with the total thrombus‐formation analysis system in coronary artery disease patients receiving antiplatelet therapy

Arima

Kaikita

Ishii

et al. 2016

Journal of Thrombosis and Haemostasis

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“…Although the efficacy of clopidogrel is linked to several enzymes, transporters and acceptors, such as CYP2B6, CYP3A4, CYP3A5, ABCB1, PON1, and P2Y12, the most important factors suggested to be associated with low response to the drug are CYP2C19 * 2 and CYP2C19 * 3 variants (Nagashima et al, 2013; Jiang et al, 2015; Sabaté et al, 2015; Ma et al, 2016). The impact of CYP2C19 variants on risk of MACE is controversial (Mega et al, 2009, 2010b; Bauer et al, 2011; Han et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention

Sun

Chen

et al. 2016

Front. Pharmacol.

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The impact of pharmacogenetic variants of cytochrome P450 2C19 (CYP2C19) on clopidogrel-mediated effects on platelet inhibition, inflammatory response and endothelial function, as well as risk of major adverse cardiovascular events (MACE), in coronary heart patients undergoing percutaneous coronary intervention (PCI) was investigated. To this end, we assessed the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 h of PCI in 559 patients treated with clopidogrel and followed up for 1 year for evidence of MACE. CYP2C19 *2 and *3 variants were identified using a clopidogrel-sensitive gene detection kit. Our results showed higher RPA and MAR as well as increased sE-selectin, sCD40L, sP-selectin, MMP-9, and sVCAM-1 levels in CYP2C19 intermediate metabolizer (IM, CYP2C19*1/*2, or *1/*3), poor metabolizer (PM, CYP2C19*2/*2, *2/*3, or *3/*3) and combined IM+PM groups, relative to those in extensive metabolizers (EM, CYP2C19*1/*1). In total, 519 patients completed 1 year of follow-up, among which 69 (13.3%) experienced MACE. The risk of MACE in CYP2C19 IM+PM patients was 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664 (1.397–5.193), P = 0.004). The data suggest that CYP2C19*2 and *3 variants modulate the drug efficacy of clopidogrel in coronary heart patients undergoing PCI and further enhance the risk of MACE. Accordingly, CYP2C19 pharmacogenetic profiling may be beneficial for coronary heart patients undergoing PCI to predict the efficacy of treatment with clopidogrel. We propose that IM and PM patients should benefit from treatment with higher clopidogrel doses to improve efficacy and reduce the incidence of MACE.

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A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

Duong

Nand

Patel

et al. 2022

Pharmacology Res & Perspec

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Treatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population‐specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady‐state AUC0‐τ of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26–9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4–30.1] ng·h/ml, p < .001) population. In addition to CYP2C19‐poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity.

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Platelet reactivity in the early and late phases of acute coronary syndromes according to cytochrome P450 2C19 phenotypes

Cited by 31 publications

References 49 publications

Assessment of platelet‐derived thrombogenicity with the total thrombus‐formation analysis system in coronary artery disease patients receiving antiplatelet therapy

Assessment of platelet‐derived thrombogenicity with the total thrombus‐formation analysis system in coronary artery disease patients receiving antiplatelet therapy

Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention

A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

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