title: Ivabradine in stable coronary artery disease without clinical heart failure.
abstract: BACKGROUND
  An elevated heart rate is an established marker of cardiovascular risk. Previous analyses have suggested that ivabradine, a heart-rate-reducing agent, may improve outcomes in patients with stable coronary artery disease, left ventricular dysfunction, and a heart rate of 70 beats per minute or more.
  
  
  METHODS
  We conducted a randomized, double-blind, placebo-controlled trial of ivabradine, added to standard background therapy, in 19,102 patients who had both stable coronary artery disease without clinical heart failure and a heart rate of 70 beats per minute or more (including 12,049 patients with activity-limiting angina [class ≥II on the Canadian Cardiovascular Society scale, which ranges from I to IV, with higher classes indicating greater limitations on physical activity owing to angina]). We randomly assigned patients to placebo or ivabradine, at a dose of up to 10 mg twice daily, with the dose adjusted to achieve a target heart rate of 55 to 60 beats per minute. The primary end point was a composite of death from cardiovascular causes or nonfatal myocardial infarction.
  
  
  RESULTS
  At 3 months, the mean (±SD) heart rate of the patients was 60.7±9.0 beats per minute in the ivabradine group versus 70.6±10.1 beats per minute in the placebo group. After a median follow-up of 27.8 months, there was no significant difference between the ivabradine group and the placebo group in the incidence of the primary end point (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% confidence interval, 0.96 to 1.20; P=0.20), nor were there significant differences in the incidences of death from cardiovascular causes and nonfatal myocardial infarction. Ivabradine was associated with an increase in the incidence of the primary end point among patients with activity-limiting angina but not among those without activity-limiting angina (P=0.02 for interaction). The incidence of bradycardia was higher with ivabradine than with placebo (18.0% vs. 2.3%, P<0.001).
  
  
  CONCLUSIONS
  Among patients who had stable coronary artery disease without clinical heart failure, the addition of ivabradine to standard background therapy to reduce the heart rate did not improve outcomes. (Funded by Servier; SIGNIFY Current Controlled Trials number, ISRCTN61576291.).
authors.affiliation: From the National Heart and Lung Institute, Imperial College, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, London (K.F., P.G.S.), and the Robertson Centre for Biostatistics, University of Glasgow, Glasgow (I.F.) - both in the United Kingdom; Département Hospitalo-Universitaire Fibrosis Inflammation Remodeling, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, INSERM Unité 1148, and Université Paris-Diderot, Sorbonne Paris Cité - all in Paris (P.G.S.); the Montreal Heart Institute Coordinating Centre, Université de Montréal, Montreal (J.-C.T.); the Third Division of Cardiology, Medical University of Silesia, Katowice, Poland (M.T.); and the Department of Cardiology and Laboratory for Technologies of Advanced Therapies Center, University Hospital of Ferrara and Maria Cecilia Hospital, GVM Care and Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy (R.F.).
authors.forename: Kim
authors.initials: K
authors.lastname: Fox
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.forename: Philippe Gabriel
authors.initials: PG
authors.lastname: Steg
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Michal
authors.initials: M
authors.lastname: Tendera
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrari
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000368:Aged; D060050:Angina, Stable / Q000188:drug therapy; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001552:Benzazepines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D057194:Intention to Treat Analysis; D000077550:Ivabradine; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012306:Risk
chemical_list: D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000077550:Ivabradine