title: Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel.
abstract: BACKGROUND
  Certain alleles of the CYP2C19 gene are associated with higher platelet reactivity and increased ischemic events among patients treated with clopidogrel. However, the relationship of CYP2C19 genotype and outcomes in medically managed patients with acute coronary syndromes (ACS) is not known.
  
  
  OBJECTIVE
  This study sought to assess the effect of CYP2C19 genotype on ischemic outcomes in patients with ACS initially managed medically without revascularization who were randomized to either clopidogrel or prasugrel.
  
  
  METHODS
  We classified patients as extensive metabolizers (EM) or reduced metabolizers (RM) based on CYP2C19 genotype and evaluated ischemic outcomes and platelet reactivity. Among 9,326 patients enrolled from 2008 to 2011, 5,736 participated in the genetics cohort; of these, 2,236 had platelet function testing data.
  
  
  RESULTS
  There was no association between CYP2C19 metabolizer status (EM vs. RM) and the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio [HR]: 0.86). EM and RM patients had similar rates of the primary endpoint whether treated with prasugrel (HR: 0.82) or clopidogrel (HR: 0.91; p for interaction = 0.495). After adjusting for clinical and treatment variables, EM patients had a lower risk of MI versus RM patients (HR: 0.80), but risks of other outcomes were similar. RM patients had significantly higher mean P2Y12 reaction units versus EM patients when treated with clopidogrel (39.93), but not with prasugrel (3.87).
  
  
  CONCLUSIONS
  CYP2C19 metabolizer status is not associated with the composite outcome of cardiovascular death, MI, or stroke in medically managed ACS patients treated with clopidogrel or prasugrel. Our findings do not support routine CYP2C19 genetic testing in this population. (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects [TRILOGY ACS]; NCT00699998).
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Doll
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Neely
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Roe
authors.affiliation: Canadian VIGOUR Centre, Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.affiliation: Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Harvey D
authors.initials: HD
authors.lastname: White
authors.affiliation: Centre for Chronic Disease Control and Public Health Foundation of India, New Delhi, India.
authors.forename: Dorairaj
authors.initials: D
authors.lastname: Prabhakaran
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Suman
authors.initials: S
authors.lastname: Duvvuru
authors.affiliation: Cabernet Pharmaceuticals, Chapel Hill, North Carolina.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Sundseth
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.affiliation: Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, Virginia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
authors.affiliation: Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: E Magnus
authors.initials: EM
authors.lastname: Ohman
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom. Electronic address: k.a.a.fox@ed.ac.uk.
authors.forename: Keith A A
authors.initials: KAA
authors.lastname: Fox
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000368:Aged; D000483:Alleles; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D010979:Platelet Function Tests; D011110:Polymorphism, Genetic; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage; D012189:Retrospective Studies; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D004247:DNA; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
keywords: acute coronary syndrome; dual antiplatelet therapy; genetics; platelets