Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study

Collet, Jean‐Philippe; Hulot, Jean‐Sébastien; Pena, Anna; Villard, Eric; Estève, Jean-Baptiste; Silvain, Jean‐François; Payot, Laurent; Brugier, Delphine; Cayla, Guillaume; Beygui, Farzin; Bensimon, Gilbert; Funck‐Brentano, Christian; Montalescot, Gilles

doi:10.1016/s0140-6736(08)61845-0

Cited by 855 publications

(600 citation statements)

References 43 publications

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“…On the other hand, prasugrel is metabolized by esterases in the intestines and is subsequently metabolized by the CYP450 3A, 2B6, 2C9, and 2C19 isoforms 9, 10. In previous clinical studies, 20% to 30% of the patients treated with clopidogrel showed low or no inhibition of ADP‐induced platelet aggregation by CYP2C19 polymorphisms, as measured by ex vivo aggregometry 11, 12…”

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confidence: 99%

The Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Japanese Volunteers

Umemura

Iwaki

2016

Clinical Pharm in Drug Dev

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The dosing regimen of prasugrel adjusted for Japanese patients was compared with that of clopidogrel by analyzing the pharmacokinetics and pharmacodynamics in 40 healthy Japanese subjects in a randomized, single‐blind crossover study. In period 1, the subjects received either 300 mg clopidogrel or 20 mg prasugrel; after a >2‐week interval (period 2), the drug was switched. Blood samples of 36 of the 40 subjects were collected for analysis of pharmacokinetics, pharmacodynamics, and CYP2C19 genotypes. The plasma concentration of the active metabolite of prasugrel increased rapidly and reached its peak 30 minutes postadministration, whereas that of the active metabolite of clopidogrel reached its peak 1 hour postadministration. The mean AUC and Cmax of the active metabolite of clopidogrel, but not those of prasugrel, were CYP2C19 genotype dependent. Prasugrel rapidly inhibited platelet aggregation, reaching its maximum effect 1 hour postadministration. Clopidogrel, on the other hand, showed maximum inhibition 2 hours postadministration. Platelet aggregation inhibition by clopidogrel was significantly lower in the poor‐metabolizer subjects than in the extensive‐metabolizer subjects. Overall, prasugrel inhibited platelet aggregation more rapidly and more effectively in healthy Japanese subjects than was observed for clopidogrel.

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confidence: 99%

The Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Japanese Volunteers

Umemura

Iwaki

2016

Clinical Pharm in Drug Dev

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“…Besides the CYP2C19*2 polymorphism, there may be other factors influencing the antiplatelet effect of clopidogrel including drug interaction involving the cytochrome P450 enzyme, insulin resistance or poor bioavailability [12]. Consequently, a higher risk of adverse thrombotic events has been found after clopidogrel treatment [10,13].…”

Section: Discussionmentioning

confidence: 99%

Early double stent thrombosis associated with clopidogrel hyporesponsivenesss

2011

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A 57-year-old male patient without cardiovascular history suffered an acute myocardial infarction and underwent drug-eluting stent implantation in the left anterior descending artery. A few days later, the right coronary artery was also stented (drug-eluting stent). Three days later, he was re-admitted to our hospital in cardiogenic shock. Emergent coronary angiography showed total occlusion of both stents. Platelet function analysis (PFA) showed attenuated platelet inhibition in response to clopidogrel treatment. The patient was the carrier of a loss-of-function polymorphism in the CYP2C19 gene, which has been associated with increased incidence of adverse thrombotic events. Antiplatelet therapy was switched to prasugrel and PFA revealed an adequate antiplatelet effect.

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“…All PCR analyses were performed in 384-well plates using a Dual 384-Well GeneAmp PCR System 9700 (ABI, Foster City, CA, USA), and the end point fluorescent readings were obtained using an ABI PRISM 7900HT Sequence Detection System (ABI, Foster City, CA, USA). Duplicate samples and negative controls were betes mellitus and a decreased renal function are associated with poor responsiveness to clopidogrel [4][5][6][7][8] .…”

Section: Genotypingmentioning

confidence: 99%

“…The primary metabolic mediators are CYP2C19, CYP3A and CYP1A2 2) . A decreased function of CYPs as a result of drug interactions or genetic polymorphisms reduces the antiplatelet effects of clopidogrel, which is associated with poor outcomes after acute myocardial infarction and percutaneous coronary intervention (PCI) [2][3][4][5] . Previous studies have suggested that the CYP2C19 genotype, a female gender, an old age, dia-…”

Section: Introductionmentioning

confidence: 99%

Relationship Between Statin Type and Responsiveness to Clopidogrel in Patients Treated with Percutaneous Coronary Intervention: A Subgroup Analysis of the CILON-T Trial

Suh

Jin

Lee

et al. 2014

JAT

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Aim:To compare the responsiveness to clopidogrel in patients who were prescribed two different types of statins, atorvastatin vs. rosuvastatin, following percutaneous coronary intervention. Methods: A total of 915 patients were randomized according to the antiplatelet therapy strategy in the CILON-T trial. In this subgroup analysis, we included patients who took atorvastatin (20 mg/day, n = 295) or rosuvastatin (10 mg/day, n = 261) during the entire study period and underwent measurement of the P2Y12 reaction unit (PRU) values at both discharge and six months. We compared the P2Y12 reaction unit (PRU) values at six months and investigated the relationship between the genotypes of cytochrome P450 (CYP) 3A4, 3A5 and 2C19 with the PRU values at six months in both groups. Results: The baseline characteristics did not differ between the groups. There were no significant differences in the PRU values at discharge (atorvastatin 221.0±87.3 vs. rosuvastatin 217.1±84.7, p=0.59). However, the rosuvastatin group had higher PRU values than the atorvastatin group at six months (atorvastatin 226.4±79.3 vs. rosuvastatin 241.5±88.2, p = 0.033). In the genotype analysis, the number of CYP2C19 loss-of-function (LOF) alleles ( ＊ 2 or ＊ 3) was positively associated with a higher PRU value in both statin groups, and there were no significant interactions regarding the PRU values between the number of CYP 2C19 LOF alleles and the type of statin (p for interaction = 0.56). In the multivariate analysis, the use of rosuvastatin was a significant predictor of a PRU value of ＞273 (the highest tertile) (OR 1.67, 95% confidence interval 1.05-2.65, p= 0.031). Conclusions: Rosuvastatin is associated with high on-treatment platelet reactivity compared with atorvastatin following the coadministration of clopidogrel for six months. Further studies are therefore warranted to clarify the mechanism underlying this relationship.

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Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study

Cited by 855 publications

References 43 publications

The Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Japanese Volunteers

The Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Japanese Volunteers

Early double stent thrombosis associated with clopidogrel hyporesponsivenesss

Relationship Between Statin Type and Responsiveness to Clopidogrel in Patients Treated with Percutaneous Coronary Intervention: A Subgroup Analysis of the CILON-T Trial

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