Effect of CYP2C19*2 and *17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications

Grosdidier, Charlotte; Quilici, Jacques; Loosveld, Marie; Camoin, Laurence; Moro, Pierre-Julien; Saut, Noémie; Gaborit, Bénédicte; Pankert, Mathieu; Cohen, William; Lambert, Marc; Beguin, Shirley; Morange, Pierre‐Emmanuel; Bonnet, Jean‐Louis; Alessi, Marie‐Christine; Cuisset, Thomas

doi:10.1016/j.amjcard.2012.12.013

Cited by 61 publications

(38 citation statements)

References 31 publications

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“…5,6 Yet, recent reports have shown some residual interindividual variability, despite prasugrel that could be because of other signaling pathways or genetic polymorphisms. 8,9 In this study, we corroborate with previous work that the presence of the CYP2C19*2 loss-of-function allele influences on treatment P2Y12-mediated platelet responses, and provide novel insights that α 2A -AR polymorphism mediates P2Y12-mediated platelet responses in stable coronary artery disease patients taking clopidogrel. Furthermore, in those individuals who carry both mutations, it is notable that there is an additive effect on the P2Y12-mediated platelet responses.…”

Section: Discussionsupporting

confidence: 79%

“…[1][2][3][4] Although the interindividual variability has been reduced with the introduction of more potent P2Y12 inhibitors, such as prasugrel or ticagrelor, 5,6 variability continues to exist, 7 suggesting that other signaling pathways or genetic polymorphisms may be important. 8,9 Variability in platelet response has been partly attributed to the influence of environmental factors, such as smoking, body weight, and alcohol; however, genetic polymorphisms may play a crucial role as well. The cytochrome P450 2C19*2 (CYP2C19*2) loss-of-function allele exemplifies this with its known influence on ADP-induced platelet aggregation.…”

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confidence: 99%

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α _2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant

Peace

Mangiacapra

Bailleul

et al. 2014

ATVB

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Objective-Platelet α 2A -adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation.The 6.3-kb variant of α 2A -AR gene is associated with increased epinephrine-induced platelet aggregation in healthy volunteers. The cytochrome P450 2C19*2 (CYP2C19*2) loss-of-function allele influences P2Y12-mediated platelet inhibition and hence the rate of major adverse cardiovascular events. We assessed the influence of 6.3-kb α 2A -AR gene variant on platelet aggregation and its interaction with CYP2C19*2 loss-of-function allele in patients with stable angina on aspirin and clopidogrel (dual antiplatelet therapy). Approach and Results-Aggregation to 5 increasing doses of epinephrine (from 0.156 to 10 μmol/L) was assessed in aggregation units by Multiplate Analyzer and platelet reactivity in P2Y12 reactivity units and % inhibition by VerifyNow P2Y12 assay before percutaneous revascularization. Gene polymorphisms were analyzed with TaqMan Drug Metabolism assay. Of 141 patients, aggregation was higher in 6.3-kb carriers (n=52) when compared with wild types (n=89) at all epinephrine doses (P<0.05) apart from 10 μmol/L (P=0.077). Percentage inhibition was lower (P=0.048) in 6.3-kb α 2A -AR carriers. Percentage inhibition was lower (P=0.005) and P2Y12 reactivity units was higher (P=0.012) in CYP2C19*2 allele carriers. Higher P2Y12 reactivity units (P=0.037) and lower percentage inhibition (P=0.009) were observed in carriers of both 6.3-kb α 2A -AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own.

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

α _2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant

Peace

Mangiacapra

Bailleul

et al. 2014

ATVB

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“…Data revealed that prasugrel inhibited platelets better than clopidorgel, despite the genotype. Results showed that more patients taking prasugrel had low on-treatment platelet reactivity and this fact was also associated with an elevated bleeding risk [24].…”

Section: Genotyping -The Influence Of Gene Profile On Platelet Reactimentioning

confidence: 89%

Most Recent Evidence Behind Aggregometry and Genotyping Methods as Platelet Function Testing for Tailored Anti-Platelet Treatment Among PCI Patients

Gajda¹,

Kołtowski²,

Tomaniak³

2015

Adv Clin Exp Med

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Aggregometry and genotyping are methods of platelet function testing, which can be beneficial for high-risk patients undergoing invasive cardiac procedures. An optimal level of platelet reactivity (PR) should be maintained. There are discrepancies between individuals and their response to clopidogrel, accounting for the incidence of poor responders from 5% to 44%. This phenomenon predisposes the patients to increased risk of ischaemic events and thereby overall poorer clinical outcome. Prasugrel and tricagrelor are newer without genetic correlation to their action, however associated with increased bleeding risk. Aggregometry methods assess platelet reactivity at the exact moment of blood sampling. They reflect "phenotype" of the patient and vary after drug administration or dose change. The most popular tests are Light Transmission Aggregometry, Vasodilator-Stimulated Protein, VerifyNow, Multiple Electrode Aggregometry and Thrombelastography. There is proven genetic correlation between some cytochrome enzymes on clopidogrel response. The most widely tested is gene CYP2C19, which produces the enzyme transforming clopidogrel into an active metabolite. The CYP2C19*2 allele carriers have higher PR which can result in more thrombotic events. The manuscript shows the most recent evidence behind platelet function testing. Aggregometry is shown to be beneficial in 5 trials and 1 meta-analysis, while one paper was of different opinion. Ten studies show a positive clinical effect of genotyping on patients' outcome, while one does not support it. The best method of identifying high-risk individuals could be both methods and personalisation of antiplatelet therapy may decrease adverse ischaemic outcomes (Adv Clin Exp Med 2015, 24, 4, 687-693).

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“…U osób będących nosicielami mutacji CYP2C19*17 rzadziej niż u osób z allelem CYP2C19*1*1 jest obserwowana HTPR [55]. Obecność CYP2C19*17 może się wiązać z niższym ryzkiem wystąpienia niepożądanych zdarzeń zakrzepowych, lecz jednocześnie wyższe jest ryzyko krwawienia [56].…”

Section: Cyp2c19*17unclassified

Genetyczne aspekty farmakokinetyki i farmakodynamiki klopidogrelu

Laskowska¹,

Kubica²,

Kubica³

2015

Folia Cardiologica

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Effect of CYP2C192 and 17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications

Cited by 61 publications

References 31 publications

α _2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant

α _2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant

Most Recent Evidence Behind Aggregometry and Genotyping Methods as Platelet Function Testing for Tailored Anti-Platelet Treatment Among PCI Patients

Genetyczne aspekty farmakokinetyki i farmakodynamiki klopidogrelu

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Effect of CYP2C19*2 and *17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications

Cited by 61 publications

References 31 publications

α 2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant

α 2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant

Most Recent Evidence Behind Aggregometry and Genotyping Methods as Platelet Function Testing for Tailored Anti-Platelet Treatment Among PCI Patients

Genetyczne aspekty farmakokinetyki i farmakodynamiki klopidogrelu

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Effect of CYP2C192 and 17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications

α _2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant

α _2A -Adrenergic Receptor Polymorphism Potentiates Platelet Reactivity in Patients With Stable Coronary Artery Disease Carrying the Cytochrome P450 2C19*2 Genetic Variant