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Influence of cytochrome P450 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke previously treated with clopidogrel.

ABSTRACT: This randomized double-blind crossover study aimed to investigate the influence of cytochrome P450 (CYP) 2C19 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke treated with clopidogrel. Patients received clopidogrel 75 mg/day for >?4 weeks. Subsequently, patients received prasugrel 3.75 mg/day (group A; n?=?64) or 2.5 mg/day (group B; n?=?65) for 4 weeks followed by a 4 week switched-dose regimen. To assess the influence of CYP2C19 polymorphisms, patients were classified as extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs). The primary endpoint was P2Y₁₂ reaction units (PRU) at the end of each 4 week treatment. A significant reduction in PRU was noted after treatment with prasugrel 3.75 mg/day compared with the pre-dose value (after treatment with clopidogrel) (p?

SUBMITTER: Kitazono T

PROVIDER: S-EPMC6182384 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Influence of cytochrome P450 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke previously treated with clopidogrel.

Kitazono Takanari T Ikeda Yasuo Y Nishikawa Masakatsu M Yoshiba Satoshi S Abe Kenji K Ogawa Akira A

Journal of thrombosis and thrombolysis 20181101 4

This randomized double-blind crossover study aimed to investigate the influence of cytochrome P450 (CYP) 2C19 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke treated with clopidogrel. Patients received clopidogrel 75 mg/day for > 4 weeks. Subsequently, patients received prasugrel 3.75 mg/day (group A; n = 64) or 2.5 mg/day (group B; n = 65) for 4 weeks followed by a 4 week switched-dose regimen. To assess the influence of CYP2C19 polymorphisms, pa ...[more]

PMID: 30074128

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Project description:Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75-325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65-5.26; p<0.001) and 11.26 (95%CI, 2.47-51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70-1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98 × 10(-6)). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

Project description:ContextClopidogrel therapy improves cardiovascular outcomes in patients with acute coronary syndromes and following percutaneous coronary intervention by inhibiting adenosine diphosphate (ADP)-dependent platelet activation. However, nonresponsiveness is widely recognized and is related to recurrent ischemic events.ObjectiveTo identify gene variants that influence clopidogrel response.Design, setting, and participantsIn the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), we administered clopidogrel for 7 days to 429 healthy Amish persons and measured response by ex vivo platelet aggregometry. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention.Main outcome measureADP-stimulated platelet aggregation in response to clopidogrel treatment and cardiovascular events.ResultsPlatelet response to clopidogrel was highly heritable (h(2) = 0.73; P < .001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P = 1.5 x 10(-13) for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P = 4.3 x 10(-11)). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P = .02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18-4.99; P = .02).ConclusionCYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.

Dataset Information

Influence of cytochrome P450 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke previously treated with clopidogrel.

Publications

Influence of cytochrome P450 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke previously treated with clopidogrel.

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