title: Combined neprilysin and renin-angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis.
abstract: OBJECTIVE
  The combined neprilysin/renin-angiotensin system (RAS) inhibitor sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization, cardiovascular death, and all-cause mortality in a large outcomes trial. While sacubitril/valsartan is the only currently available drug in its class, there are two prior clinical trials in heart failure with omapatrilat, another combined neprilysin/RAS inhibitor. Using all available evidence can inform clinicians and policy-makers.
  
  
  RESULTS
  We performed a meta-analysis using data from three trials in heart failure with reduced EF that compared combined neprilysin/RAS inhibition with RAS inhibition alone and reported clinical outcomes: IMPRESS (n = 573), OVERTURE (n = 5770), and PARADIGM-HF (n = 8399). We assessed the pooled hazard ratio (HR) for all-cause death or heart failure hospitalization, and for all-cause mortality in random-effects models, comparing combined neprilysin/RAS inhibition with ACE inhibition alone. The composite outcome of death or heart failure hospitalization was reduced numerically in patients receiving combined neprilysin/RAS inhibition in all three trials, with a pooled HR of 0.86, 95% confidence interval (CI) 0.76-0.97, P = 0.013. For the endpoint of all-cause mortality, the pooled HR was 0.88, 95% CI 0.80-0.98, P = 0.021. Combined neprilysin/RAS inhibition compared with ACE inhibition was associated with more hypotension, but less renal dysfunction and hyperkalaemia in all three trials.
  
  
  CONCLUSIONS
  Pooled estimates from three trials with two separate drugs of combined neprilysin/RAS inhibition support the use of combined neprilysin/RAS inhibition in heart failure with reduced EF.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ssolomon@rics.bwh.harvard.edu.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Claggett
authors.affiliation: University of Glasgow, Glasgow, UK.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: Duke University, Durham, NC, USA.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Hernandez
authors.affiliation: Ronald Reagan-UCLA Medical Center, Los Angeles, CA, USA.
authors.forename: Gregg C
authors.initials: GC
authors.lastname: Fonarow
mesh_terms: D000613:Aminobutyrates / Q000008:administration & dosage*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D004338:Drug Combinations; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D015260:Neprilysin / Q000008:administration & dosage*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013318:Stroke Volume; D013777:Tetrazoles / Q000008:administration & dosage*; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Heart failure; Meta-analysis; Neprilysin; Renin-angiotensin system