title: Angiotensin-neprilysin inhibition versus enalapril in heart failure.
abstract: BACKGROUND
  We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients.
  
  
  METHODS
  In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.
  
  
  RESULTS
  The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.
  
  
  CONCLUSIONS
  LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
authors.affiliation: From the British Heart Foundation (BHF) Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); the Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas (M.P.); the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharmaceuticals, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie de Montréal, Université de Montréal, Montreal (J.L.R.); the Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Heart and Lung Institute, Imperial College London, London (K.S.); and the Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston (M.R.Z.).
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.forename: Jianjian
authors.initials: J
authors.lastname: Gong
authors.forename: Martin P
authors.initials: MP
authors.lastname: Lefkowitz
authors.forename: Adel R
authors.initials: AR
authors.lastname: Rizkala
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.forename: Victor C
authors.initials: VC
authors.lastname: Shi
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
mesh_terms: D000368:Aged; D000613:Aminobutyrates / Q000009:adverse effects / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D001713:Biphenyl Compounds; D004311:Double-Blind Method; D004338:Drug Combinations; D004656:Enalapril / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D013318:Stroke Volume; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination