Factors associated with the failure of clopidogrel dose-adjustment according to platelet reactivity monitoring to optimize P2Y12-ADP receptor blockade

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• 作者：Laurent Bonello^a ; ^{laurentbonello@yahoo.fr} ; Laurence Camoin-Jau^b ; ^c ; Julien Mancini^d ; ^e ; Jacques Bessereau^f ; Charlotte Grosdidier^g ; Marie-Christine Alessi^g ; Michel Ostorero^h ; Franç ; oise Dignat-George^b ; ^c ; Franck Paganelli^a
• 关键词：Acute coronary syndrome ; genetic polymorphism ; high on-treatment platelet reactivity ; P2Y12-ADP receptor ; vasodilator-stimulated phosphoprotein
• 刊名：Thrombosis Research
• 出版年：2012
• 期刊代码：247_00493848
• 类别：med
• 出版时间：July, 2012
• 卷：130
• 期：1
• 页码：70-74
• 文件大小：334 K

摘要

Introduction

Inter-individual variability in clopidogrel responsiveness is dependent on genetic polymorphisms. We aimed to investigate the impact of 3 genetic polymorphisms involved in clopidogrel metabolism on a strategy of dose-adjustment according to platelet reactivity (PR) monitoring.

Materiel and methods

This prospective multicenter study enrolled 498 ACS patients undergoing PCI. PR was measured using the Vasodilator-Stimulated Phosphoprotein index (VASP) and a cut-off value of 鈮?#xA0;50%defined high on-treatment platelet reactivity (HTPR). Genetic polymorphisms of cytochrome (CYP) 2C19, Paraxonase-1 (PON1) and ABCB1 were determined by allele specific PCR. Dose-adjustment was performed using up-to 3 additional loading doses (LD) of 600 mg clopidogrel in order to obtain a VASP < 50%in patients with HTPR following the first LD.

Results

CYP 2C19 2*polymorphism (p = 0.02), but neither PON1 (p = 0.8) nor ABCB1 genotype (p = 0.9), was significantly associated with HTPR. The dose-adjustment strategy failed in 11%of patients. ABCB1 polymorphism was significantly associated with a failed dose-adjustment (FDA) (p = 0.04). No relation was found between the other genotypes and the efficacy of LD adjustment. In multivariate analysis, BMI and ABCB1 polymorphism were the only factors significantly associated with FDA (p = 0.005 and p = 0.04 respectively).

Conclusion

While CYP 2C19 2* is associated with HTPR after 600 mg of clopidogrel, ABCB1 is responsible for the failure of a strategy of loading dose-adjustment according to PR monitoring. These findings may help to define a therapeutic strategy to optimize anti-platelet therapy in ACS patients undergoing PCI.