title: Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial.
abstract: BACKGROUND
  The angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and reduced ejection fraction (EF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. We evaluated the influence of EF on clinical outcomes and on the effectiveness of sacubitril/valsartan compared with enalapril.
  
  
  RESULTS
  Eight thousand three hundred ninety-nine patients with New York Heart Association class II to IV HF with reduced EF [left ventricular EF (LVEF) ≤40%] were randomized to sacubitril/valsartan 97/103 mg twice daily versus enalapril 10 mg twice daily and followed for a median of 27 months. The primary study end point was cardiovascular death or HF hospitalization. LVEF was assessed at the sites and recorded on case report forms. We related LVEF to study outcomes and assessed the effectiveness of sacubitril/valsartan across the LVEF spectrum. The mean LVEF in PARADIGM-HF, reported by sites, was 29.5 (interquartile range, 25-34). The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with a 9% increased risk of cardiovascular death or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.05-1.13; P<0.001), a 9% increased risk for CV death (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14), a 9% increased risk in HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14) and a 7% increased risk in all-cause mortality (hazard ratio, 1.07; 95% confidence interval, 1.03-1.12) in adjusted analyses. Sacubitril/valsartan was effective across the LVEF spectrum, with no evidence of heterogeneity, when modeled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95).
  
  
  CONCLUSIONS
  In patients with HF and reduced EF enrolled in PARADIGM-HF, LVEF was a significant and independent predictor of all outcomes. Sacubitril/valsartan was effective at reducing cardiovascular death and HF hospitalization throughout the LVEF spectrum.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.). ssolomon@rics.bwh.harvard.edu.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Brian
authors.initials: B
authors.lastname: Claggett
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Michael
authors.initials: M
authors.lastname: Zile
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Victor C
authors.initials: VC
authors.lastname: Shi
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Randall C
authors.initials: RC
authors.lastname: Starling
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Ömer
authors.initials: Ö
authors.lastname: Kozan
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Andrej
authors.initials: A
authors.lastname: Dukat
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: Martin P
authors.initials: MP
authors.lastname: Lefkowitz
authors.affiliation: From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
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; D002423:Cause of Death; D004338:Drug Combinations; D004656:Enalapril / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000503:physiopathology; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D020127:Recovery of Function; D013318:Stroke Volume / Q000187:drug effects*; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D000068756:Valsartan; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004338:Drug Combinations; D011480:Protease Inhibitors; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: heart; heart failure; humans; mineralocorticoid receptor antagonists; neprilysin