title: Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in predicting clinical outcome following drug-eluting stent implantation in patients with stable coronary artery disease.
abstract: OBJECTIVE
  This study sought to assess the usefulness of clopidogrel-pathway genotyping and on-treatment platelet reactivity (OTR) testing in predicting major adverse cardiac events (MACE) in stable coronary artery disease (CAD) patients receiving drug-eluting stents (DES) under dual antiplatelet (clopidogrel plus aspirin) therapy.
  
  
  BACKGROUND
  The role of pharmacogenetics and OTR in predicting MACE-death, myocardial infarction, or stent thrombosis-in stable CAD patients scheduled for DES implantation is still debated.
  
  
  METHODS
  Patients with stable CAD treated by DES implantation (n = 1,432) were genotyped with a TaqMan OpenArray (Applied Biosystems, Carlsbad, California) and assessed for OTR with the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, California). Genes tested were ABCB1, CYP1A2, CYP2B6*9, CYP2C8*3, CYP2C9*2, CYP2C19, CYP3A4, CYP3A5*3, P2RY12, and PON1CYP2C19. High OTR was defined as P2Y12 reaction units ≥230. The endpoint at 12-month follow-up was MACE occurring during antiplatelet therapy.
  
  
  RESULTS
  All groups that were stratified for loss-of-function variants of the cytochrome P450 gene CYP2C19 had significant hazard ratios (HR) for MACE (genotypic HR: 1.41, 95% confidence interval [CI]: 1.06 to 1.89, p = 0.01; allelic HR: 1.56, 95% CI: 2.26 to 1.2, p = 0.01). Variants of other clopidogrel-pathway genes were not significantly associated with MACE. When OTR was assessed, clinical significance was found only in high-risk diabetic (HR: 2.11, 95% CI: 1.29 to 3.45, p < 0.001) and chronic kidney disease (HR: 2.03, 95% CI: 1.03 to 4.02, p = 0.04) patients.
  
  
  CONCLUSIONS
  CYP2C19 metabolizer status is an independent predictor of MACE after DES implantation and can be used for prognostication in all stable CAD patients. High OTR, as assessed by the VerifyNow P2Y12 test, is an independent predictor of MACE only for high-risk subsets, that is, patients with diabetes or chronic kidney disease.
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Multimedica, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Viviani Anselmi
authors.forename: Carlo
authors.initials: C
authors.lastname: Briguori
authors.forename: Roberta
authors.initials: R
authors.lastname: Roncarati
authors.forename: Laura
authors.initials: L
authors.lastname: Papa
authors.forename: Gabriella
authors.initials: G
authors.lastname: Visconti
authors.forename: Amelia
authors.initials: A
authors.lastname: Focaccio
authors.forename: Francesca
authors.initials: F
authors.lastname: De Micco
authors.forename: Michael V G
authors.initials: MV
authors.lastname: Latronico
authors.forename: Paolo
authors.initials: P
authors.lastname: Pagnotta
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use; D001711:Biotransformation / Q000235:genetics; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D003328:Coronary Thrombosis / Q000209:etiology; D065731:Cytochrome P-450 CYP2C19; D003661:Decision Support Techniques; D004359:Drug Therapy, Combination; D054855:Drug-Eluting Stents; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology; D018579:Patient Selection; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects / Q000295:instrumentation* / Q000401:mortality; D010597:Pharmacogenetics; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010979:Platelet Function Tests; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013997:Time Factors; 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; D001241:Aspirin
keywords: CAD; CKD; CYP; DES; DM; HR; LVEF; MACE; OTR; P2Y(12); P2Y(12) reaction units; PRU; SNP; angioplasty; chronic kidney disease; clopidogrel; coronary artery disease; cytochrome P450; diabetes mellitus; drug-eluting stent(s); genetics; hazard ratio(s); left ventricular ejection fraction; major adverse cardiac events; negative outcome; on-treatment platelet reactivity; platelet reactivity; predictive test; purinergic receptor P2Y, G-protein coupled, 12; single-nucleotide polymorphism