What is the clinical evidence from this study?

Study design: Observational. Population: Coronary heart disease (n=916). Intervention: CES1 G143E variant (143E-allele) vs. Non-carriers of the 143E-allele. Primary outcome: Clopidogrel active metabolite levels and on-clopidogrel ADP-stimulated platelet aggregation (p=0.001).

October 30, 2012Open Access

The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response

JLJoshua P. LewisUniversity of Maryland, Baltimore RHRichard B. HorensteinAustin College KRKathleen A. RyanUniversity of North Carolina at Chapel Hill

Key Result

Carriers of the CES1 143E-allele had significantly greater levels of clopidogrel active metabolite (P=0.001) and better clopidogrel response measured by platelet aggregation.

Study Design

Type

Observational (n=916)

Structured PICO

Does the CES1 G143E variant increase clopidogrel active metabolite levels and improve platelet response in patients treated with clopidogrel?

Population

916 individuals, comprising 566 participants from the PAPI study and 350 patients with coronary heart disease treated with clopidogrel.

Exposure

Presence of the CES1 G143E variant (143E-allele carrier status)

Comparator

Non-carriers of the CES1 143E-allele

Outcome

Bioactive metabolite levels, on-clopidogrel ADP-stimulated platelet aggregation, and cardiovascular outcomessurrogate

The CES1 G143E variant is associated with higher clopidogrel active metabolite levels and greater platelet inhibition, suggesting it is an important genetic determinant of clopidogrel efficacy.

Main Result

p-value: p=0.001

Abstract

INTRODUCTION: Carboxylesterase 1 (CES1) is the primary enzyme responsible for converting clopidogrel into biologically inactive carboxylic acid metabolites. METHODS: We genotyped a functional variant in CES1, G143E, in participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) study (n=566) and in 350 patients with coronary heart disease treated with clopidogrel, and carried out an association analysis of bioactive metabolite levels, on-clopidogrel ADP-stimulated platelet aggregation, and cardiovascular outcomes. RESULTS: The levels of clopidogrel active metabolite were significantly greater in CES1 143E-allele carriers (P=0.001). Consistent with these findings, individuals who carried the CES1 143E-allele showed a better clopidogrel response as measured by ADP-stimulated platelet aggregation in both participants of the PAPI study (P=0.003) and clopidogrel-treated coronary heart disease patients (P=0.03). No association was found between this single nucleotide polymorphism and baseline measures of platelet aggregation in either cohort. CONCLUSION: Taken together, these findings suggest, for the first time, that genetic variation in CES1 may be an important determinant of the efficacy of clopidogrel.

Ask AI

Helpful

Bookmark

View Full Paper