title: Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis.
abstract: Residual platelet reactivity (RPR) to adenosine 5' diphosphate (ADP) was an independent predictor of stent thrombosis (ST) in patients receiving drug-eluting stents on dual-antiplatelet treatment and was associated with the cytochrome P450 (CYP)2C19*2 polymorphism. The aim was to evaluate the role of the CYP2C19*2 polymorphism in the occurrence of ST or the composite end point of ST and cardiac mortality within a 6-month follow-up in patients undergoing percutaneous coronary interventions with drug-eluting stent implantation on dual-antiplatelet treatment enrolled in the RECLOSE trial. Seven hundred seventy-two patients were studied for the CYP2C19*2 polymorphism and RPR (using 10-muM ADP-induced platelet aggregation). Patients with ST or the composite of ST and cardiac mortality showed a higher prevalence of carriers of the rare allele (54.1% vs 31.3%; p = 0.025 and 51.7% vs 31.2%; p = 0.020, respectively). At multivariate logistic regression analysis with ST or ST and cardiac mortality as dependent variables and the CYP2C19*2 polymorphism, ADP RPR, and additional previously shown clinical and procedural risk factors for ST as independent variables, the CYP2C19*2 allele (ST odds ratio [OR] 3.43, 95% confidence interval [CI] 1.01 to 12.78, p = 0.047; ST and cardiac mortality OR 2.70, 95% CI 1.00 to 8.42, p = 0.049) and ADP RPR (ST OR 3.08, 95% CI 1.23 to 7.72, p = 0.016; ST and cardiac mortality OR 2.90, 95% CI 1.08 to 12.98, p = 0.019) were independent risk factors. Subjects with the contemporary presence of the CYP2C19*2 allele and ADP RPR showed a strong risk of ST or ST and cardiac mortality (OR 5.79, 95% CI 1.04 to 39.01, p = 0.033 and OR 11.45, 95% CI 1.84 to 71.27, p = 0.009, respectively). In conclusion, the CYP2C19*2 allele was associated with the occurrence of ST or ST and cardiac mortality in high-risk vascular patients on dual-antiplatelet treatment. These findings could impact on the future design of pharmacogenetic antiaggregant strategies.
authors.affiliation: Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy. betti.giusti@unifi.it
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gori
authors.forename: Rossella
authors.initials: R
authors.lastname: Marcucci
authors.forename: Claudia
authors.initials: C
authors.lastname: Saracini
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sestini
authors.forename: Rita
authors.initials: R
authors.lastname: Paniccia
authors.forename: Piergiovanni
authors.initials: P
authors.lastname: Buonamici
authors.forename: David
authors.initials: D
authors.lastname: Antoniucci
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Gensini
mesh_terms: D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001241:Aspirin / Q000008:administration & dosage; D000077144:Clopidogrel; D003328:Coronary Thrombosis / Q000209:etiology / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D054855:Drug-Eluting Stents / Q000009:adverse effects*; D005260:Female; D006083:Graft Occlusion, Vascular / Q000209:etiology* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000628:therapy*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011110:Polymorphism, Genetic; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin