Effect of Cytochrome P450 Polymorphisms on Platelet Reactivity After Treatment With Clopidogrel in Acute Coronary Syndrome

doi:10.1016/j.amjcard.2007.11.065

The American Journal of Cardiology

Volume 101, Issue 8, 15 April 2008, Pages 1088-1093

https://doi.org/10.1016/j.amjcard.2007.11.065 Get rights and content

Genetic polymorphisms of cytochrome P450 (CYP) isoforms may promote variability in platelet response to clopidogrel. This study was conducted to analyze, in 603 patients with non–ST elevation acute coronary syndromes, the effect of CYP3A4, CYP3A5, and CYP2C19 gene polymorphisms on clopidogrel response and post-treatment platelet reactivity assessed by adenosine diphosphate (ADP)–induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression. The CYP2C19*2 polymorphism was significantly associated with ADP-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression in recessive (p <0.01, p <0.007, and p <0.06, respectively) and codominant (p <0.08, p <0.0001, and p <0.009, respectively) models, but the CYP3A4*1B and CYP3A5*3 polymorphisms were not. The CYP2C19*2 allele carriers exhibited the highest platelet index levels in multivariate analysis (p = 0.03). After covariate adjustment, the CYP2C19*2 allele was more frequent in clopidogrel nonresponders, defined by persistent high post-treatment platelet reactivity (ADP-induced platelet aggregation >70%; p = 0.03). In conclusion, the present data suggest that the CYPC19*2 allele influences post-treatment platelet reactivity and clopidogrel response in patients with non–ST elevation acute coronary syndromes.

Section snippets

Methods

Consecutive patients admitted for non–ST elevation acute coronary syndromes to the Department of Cardiology of Timone Hospital (Marseille, France) from October 2004 to June 2006 were eligible for this prospective study. Non–ST elevation acute coronary syndromes were defined as clinical symptoms compatible with acute myocardial ischemia <12 hours before admission and ≥1 of the following: a new finding of ST-segment depression >0.05 mV, transient (<20 minutes) ST-segment elevation >0.1 mV, T-wave

Results

Six hundred three unrelated participants were included in our study. We assessed ADP-Ag, PRI VASP, and ADP-PS. PRI VASP and ADP-PS were evaluated in 455 and 600 participants, respectively. Table 2 lists the clinical characteristics of participants. All platelet parameters studied were correlated. The associations between ADP-Ag and PRI VASP (r = 0.62, p <0.0001) and between PRI VASP and ADP-PS (r = 0.52, p <0.0001) appeared stronger than the association between ADP-Ag and ADP-PS (r = 0.36, p

Discussion

The results of this study of a large population suggest that CYP2C19 gene polymorphisms participate in the variability of platelet response to clopidogrel in patients with non–ST elevation acute coronary syndromes treated with high loading doses of clopidogrel. First, we found that CYP2C19*2 allele carriers had higher platelet reactivity to ADP, whatever the studied platelet index. This result is consistent with previous findings in healthy subjects from Hulot et al.²¹ The association remained

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Coronary artery diseaseEffect of Cytochrome P450 Polymorphisms on Platelet Reactivity After Treatment With Clopidogrel in Acute Coronary Syndrome

Section snippets

Methods

Results

Discussion

Biochem Pharmacol

Lancet

Thromb Res

J Am Coll Cardiol

J Am Coll Cardiol

J Thromb Haemost

J Am Coll Cardiol

J Am Coll Cardiol

Blood

J Biol Chem

J Thromb Haemost

The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A

Thromb Haemost

Identification of the platelet ADP receptor targeted by antithrombotic drugs

Nature

Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial InvestigatorsEffects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation

N Engl J Med

Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity

Circulation

Coronary artery disease
Effect of Cytochrome P450 Polymorphisms on Platelet Reactivity After Treatment With Clopidogrel in Acute Coronary Syndrome