title: Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients.
abstract: OBJECTIVE
  The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the prospective comparison of ARNI with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of LCZ696 on mode of death.
  
  
  RESULTS
  PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure, New York Heart Association Class II-IV symptoms, and left ventricular ejection fraction ≤40% receiving guideline-recommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72-0.89, P < 0.001). Among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68-0.94, P = 0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64-0.98, P = 0.034) were reduced by treatment with LCZ696 compared with enalapril. Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and distributed evenly between treatment groups, as were non-cardiovascular deaths.
  
  
  CONCLUSIONS
  LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths.
  
  
  BACKGROUND
  https://clinicaltrials.gov/, NCT01035255.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: British Heart Foundation Cardiovascular Research Center, University of Glasgow, Glasgow, UK.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.affiliation: Institut de Cardiologie, Université de Montréal, Montreal, Canada.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: Chen
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, USA.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Gong
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, USA.
authors.forename: Adel R
authors.initials: AR
authors.lastname: Rizkala
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Abdel
authors.initials: A
authors.lastname: Brahimi
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Claggett
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Finn
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Loren Howard
authors.initials: LH
authors.lastname: Hartley
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Lefkowitz
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Shi
authors.affiliation: Medical University of South Carolina and Ralph H. Johnston Veterans Administration Medical Center, Charleston, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA ssolomon@rics.bwh.harvard.edu.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
mesh_terms: D000368:Aged; D000613:Aminobutyrates / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D002423:Cause of Death; D004311:Double-Blind Method; D004338:Drug Combinations; D004656:Enalapril / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; 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; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Angiotensin-receptor blocker; Clinical trial; Heart failure; Mortality; Neprilysin inhibition; Pharmacotherapy