title: Usefulness of high clopidogrel maintenance dose according to CYP2C19 genotypes in clopidogrel low responders undergoing coronary stenting for non ST elevation acute coronary syndrome.
abstract: The cytochrome P450 (CYP) 2C19*2 loss-of-function allele has been associated with impaired clopidogrel response and worse prognosis in clopidogrel-treated patients. The benefit of tailored therapy according to platelet function test results remains unclear, and the potential effect of genotypes on this benefit has not been addressed in unstable patients. The present study was designed to evaluate the benefit of tailored therapy with a higher maintenance dose according to CYP2C19 genotypes in patients identified as nonresponders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. Three hundred forty-six consecutive patients were enrolled and received a loading dose of 600 mg, including 86 *2 carriers (13 homozygotes and 73 heterozygotes) and 260 *2 noncarriers. Clopidogrel response, assessed with platelet reactivity index vasoactive-stimulated phosphoprotein, was significantly affected by genotype, with lower clopidogrel response in CYP2C19*2 allele carriers (p = 0.01). Accordingly, the rate of clopidogrel nonresponse was higher in CYP2C19*2 allele carriers (53% vs 41%, p = 0.04). All clopidogrel nonresponders (n = 151), including 105 *2 noncarriers and 46 *2 carriers, received high 150-mg clopidogrel maintenance doses at discharge to overcome initial low response. After 1 month, high maintenance doses overcame clopidogrel low response in only 44% of the whole population and significantly less frequently in *2 carriers than in noncarriers (28% vs 50%, p = 0.01). In conclusion, higher clopidogrel maintenance doses were able to overcome clopidogrel low response in fewer than half of clopidogrel low responders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. The benefit of this tailored therapy was significantly reduced in CYP2C19*2 carriers. Therefore, these patients might require alternative strategies with new P2Y₁₂ blockers.
authors.affiliation: Département de Cardiologie, CHU Timone, Marseille, France. thomascuisset@voila.fr
authors.forename: Thomas
authors.initials: T
authors.lastname: Cuisset
authors.forename: Jacques
authors.initials: J
authors.lastname: Quilici
authors.forename: William
authors.initials: W
authors.lastname: Cohen
authors.forename: Laurent
authors.initials: L
authors.lastname: Fourcade
authors.forename: Noémie
authors.initials: N
authors.lastname: Saut
authors.forename: Mathieu
authors.initials: M
authors.lastname: Pankert
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gaborit
authors.forename: Patrizia
authors.initials: P
authors.lastname: Carrieri
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Morange
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Bonnet
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Alessi
mesh_terms: D054058:Acute Coronary Syndrome / Q000235:genetics* / Q000628:therapy*; D000483:Alleles; D000704:Analysis of Variance; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004351:Drug Resistance / Q000235:genetics*; D023381:Endpoint Determination; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D010979:Platelet Function Tests; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D018709:Statistics, Nonparametric; D015607:Stents; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine