title: Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study.
abstract: BACKGROUND
  Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies.
  
  
  OBJECTIVE
  To compare different assays for prediction of events during long-term follow-up.
  
  
  METHODS
  In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA-100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up.
  
  
  RESULTS
  Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status.
  
  
  CONCLUSIONS
  Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping.
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria. jolanta.siller-matula@meduniwien.ac.at
authors.forename: J M
authors.initials: JM
authors.lastname: Siller-Matula
authors.forename: G
authors.initials: G
authors.lastname: Delle-Karth
authors.forename: I M
authors.initials: IM
authors.lastname: Lang
authors.forename: T
authors.initials: T
authors.lastname: Neunteufl
authors.forename: M
authors.initials: M
authors.lastname: Kozinski
authors.forename: J
authors.initials: J
authors.lastname: Kubica
authors.forename: G
authors.initials: G
authors.lastname: Maurer
authors.forename: K
authors.initials: K
authors.lastname: Linkowska
authors.forename: T
authors.initials: T
authors.lastname: Grzybowski
authors.forename: K
authors.initials: K
authors.lastname: Huber
authors.forename: B
authors.initials: B
authors.lastname: Jilma
mesh_terms: D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects / Q000401:mortality; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001317:Austria; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D015815:Cell Adhesion Molecules / Q000097:blood; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D010641:Phenotype; D010750:Phosphoproteins / Q000097:blood; D010766:Phosphorylation; 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; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013927:Thrombosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine