title: Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction: A Network Meta-Analysis.
abstract: BACKGROUND
  Treatments that reduce mortality and morbidity in patients with heart failure with reduced ejection fraction, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), β-blockers (BB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNI), have not been studied in a head-to-head fashion. This network meta-analysis aimed to compare the efficacy of these drugs and their combinations regarding all-cause mortality in patients with heart failure with reduced ejection fraction.
  
  
  RESULTS
  A systematic literature review identified 57 randomized controlled trials published between 1987 and 2015, which were compared in terms of study and patient characteristics, baseline risk, outcome definitions, and the observed treatment effects. Despite differences identified in terms of study duration, New York Heart Association class, ejection fraction, and use of background digoxin, a network meta-analysis was considered feasible and all trials were analyzed simultaneously. The random-effects network meta-analysis suggested that the combination of ACEI+BB+MRA was associated with a 56% reduction in mortality versus placebo (hazard ratio 0.44, 95% credible interval 0.26-0.66); ARNI+BB+MRA was associated with the greatest reduction in all-cause mortality versus placebo (hazard ratio 0.37, 95% credible interval 0.19-0.65). A sensitivity analysis that did not account for background therapy suggested that ARNI monotherapy is more efficacious than ACEI or ARB monotherapy.
  
  
  CONCLUSIONS
  The network meta-analysis showed that treatment with ACEI, ARB, BB, MRA, and ARNI and their combinations were better than the treatment with placebo in reducing all-cause mortality, with the exception of ARB monotherapy and ARB plus ACEI. The combination of ARNI+BB+MRA resulted in the greatest mortality reduction.
authors.affiliation: From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.). hburnett@mapigroup.com.
authors.forename: Heather
authors.initials: H
authors.lastname: Burnett
authors.affiliation: From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.).
authors.forename: Amy
authors.initials: A
authors.lastname: Earley
authors.affiliation: From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.).
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.).
authors.forename: Michele
authors.initials: M
authors.lastname: Senni
authors.affiliation: From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.).
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.).
authors.forename: Celine
authors.initials: C
authors.lastname: Deschaseaux
authors.affiliation: From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.).
authors.forename: Shannon
authors.initials: S
authors.lastname: Cope
mesh_terms: D002908:Chronic Disease; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D013318:Stroke Volume; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology
keywords: drug combinations; drug therapy; heart failure; mortality; network meta-analysis