| Autor: |
Collet, Jean-Philippe, Hulot, Jean-Sébastien, Anzaha, Ghalia, Pena, Ana, Chastre, Thomas, Caron, Claire, Silvain, Johanne, Cayla, Guillaume, Bellemain-Appaix, Anne, Vignalou, Jean-Baptiste, Galier, Sophie, Barthélémy, Olivier, Beygui, Farzin, Gallois, Vanessa, Montalescot, Gilles |
| Jazyk: |
angličtina |
| Předmět: |
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| Zdroj: |
JACC: Cardiovascular Interventions. (4):392-402 |
| ISSN: |
1936-8798 |
| DOI: |
10.1016/j.jcin.2011.03.002 |
| Popis: |
ObjectivesThis study sought to determine whether the pharmacokinetic (PK) and pharmacodynamic (PD) responses to high or standard clopidogrel loading doses (LDs) differ according to CYP2C19*2 allele.BackgroundCYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses.MethodsYoung post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 43) or homozygous (*2/*2, n = 8) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel LD. The relative reduction in residual platelet aggregation (RR-RPA, %) and the area under the plasma concentration time curve of active metabolite from baseline to 6 h after loading (AUC0-6) were compared according to both LD and CYP2C19*2 carriage.ResultsThe 300-mg LD led to a gene-dose effect for RR-RPA (−65.7% ± 35.9% in wt/wt vs. −48.0% ± 38.4% in wt/*2 vs. −14.6% ± 32.4% in *2/*2; overall p value = 0.003, p = 0.03 for wt/wt versus wt/*2, p = 0.04 for wt/*2 versus *2/*2) with minor effect in *2/*2 carriers. After the 900-mg LD, the effect of the CYP2C19*2 variant on platelet inhibition was fully compensated in wt/*2 carriers but not in *2/*2 carriers (−83.6% ± 25.8% in wt/wt vs.−77.2% ± 26.9% in wt/*2 vs. −29.5% ± 26.8% in *2/*2; overall p value = 0.0003, p = 0.20 for wt/wt versus wt/*2, p < 0.001 for wt/*2 versus *2/*2). A similar pattern was observed for the active metabolite AUC0-6 according to carriage of CYP2C19*2 for both LDs. There was a significant correlation between PK and PD responses irrespective of the LD.ConclusionsCarriers of CYP2C19*2 display significantly lower responses to clopidogrel with a gene-dose effect. Clopidogrel resistance can be overcome by increasing the dose in heterozygous carriers but not in homozygous carriers. (Clopidogrel and Response Variability Investigation Study 2 [CLOVIS-2]; NCT00822666) |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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