title: Individualized Angiotensin-Converting Enzyme (ACE)-Inhibitor Therapy in Stable Coronary Artery Disease Based on Clinical and Pharmacogenetic Determinants: The PERindopril GENEtic (PERGENE) Risk Model.
abstract: BACKGROUND
  Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model.
  
  
  RESULTS
  Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 to 2. As a consequence, estimated annual numbers needed to treat ranged from as low as 29 (clinical risk score ≥10 and PGXscore of 0) to 521 (clinical risk score ≤6 and PGXscore of 2). Furthermore, our data suggest that long-term perindopril prescription in patients with a PGXscore of 0 to 2 is cost-effective.
  
  
  CONCLUSIONS
  Both baseline clinical phenotype, as well as genotype determine the efficacy of widely prescribed ACE inhibition in stable CAD. Integration of clinical and pharmacogenetic determinants in a combined risk prediction model demonstrated a very wide range of gradients of absolute treatment benefit.
authors.affiliation: Thoraxcenter, Department of Cardiology, Erasmus MC and Cardiovascular Research Institute COEUR, Rotterdam, The Netherlands Netherlands Heart Institute, Utrecht, The Netherlands.
authors.forename: Rohit M
authors.initials: RM
authors.lastname: Oemrawsingh
authors.affiliation: Thoraxcenter, Department of Cardiology, Erasmus MC and Cardiovascular Research Institute COEUR, Rotterdam, The Netherlands.
authors.forename: K Martijn
authors.initials: KM
authors.lastname: Akkerhuis
authors.affiliation: Thoraxcenter, Department of Cardiology, Erasmus MC and Cardiovascular Research Institute COEUR, Rotterdam, The Netherlands.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Van Vark
authors.affiliation: Institute for Medical Technology Assessment, Erasmus University Rotterdam, Rotterdam, The Netherlands.
authors.forename: W Ken
authors.initials: WK
authors.lastname: Redekop
authors.affiliation: Thoraxcenter, Department of Cardiology, Erasmus MC and Cardiovascular Research Institute COEUR, Rotterdam, The Netherlands.
authors.forename: Goran
authors.initials: G
authors.lastname: Rudez
authors.affiliation: STICARES Cardiovascular Research Foundation, Rhoon, The Netherlands.
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Remme
authors.affiliation: Lille Heart Institute, Lille, France.
authors.forename: Michel E
authors.initials: ME
authors.lastname: Bertrand
authors.affiliation: National Heart and Lung Institute, Imperial College and ICMS, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Fox
authors.affiliation: Department of Cardiology and LTTA Center, University Hospital of Ferrara and Salvatore Maugeri Foundation, IRCCS, Lumezzane, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Department of Hematology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Moniek
authors.initials: M
authors.lastname: de Maat
authors.affiliation: Thoraxcenter, Department of Cardiology, Erasmus MC and Cardiovascular Research Institute COEUR, Rotterdam, The Netherlands.
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Simoons
authors.affiliation: Thoraxcenter, Department of Cardiology, Erasmus MC and Cardiovascular Research Institute COEUR, Rotterdam, The Netherlands.
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: Brugts
authors.affiliation: Thoraxcenter, Department of Cardiology, Erasmus MC and Cardiovascular Research Institute COEUR, Rotterdam, The Netherlands h.boersma@erasmusmc.nl.
authors.forename: Eric
authors.initials: E
authors.lastname: Boersma
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*; D003324:Coronary Artery Disease / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000191:economics / Q000235:genetics / Q000401:mortality; D003362:Cost-Benefit Analysis; D003661:Decision Support Techniques; D004311:Double-Blind Method; D016527:Drug Costs; D005260:Female; D005838:Genotype; D006323:Heart Arrest / Q000209:etiology / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000209:etiology; D018579:Patient Selection; D020913:Perindopril / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*; D010597:Pharmacogenetics / Q000191:economics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine / Q000191:economics; D016016:Proportional Hazards Models; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D043783:Receptor, Bradykinin B1 / Q000235:genetics*; D012151:Resuscitation; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: C544065:AGTR1 protein, human; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D043783:Receptor, Bradykinin B1; D020913:Perindopril
keywords: angiotensin‐converting enzyme inhibitor; coronary artery disease; individualized therapy; pharmacogenetics; risk model