title: A putative placebo analysis of the effects of   LCZ696 on clinical outcomes in heart failure.
abstract: OBJECTIVE
  Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos.
  
  
  RESULTS
  We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality.
  
  
  CONCLUSIONS
  These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.
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authors.lastname: McMurray
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authors.lastname: Fu
authors.forename: Efrain
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authors.lastname: Gomez
authors.forename: Angel
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authors.forename: Albert-Alain
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authors.lastname: Hagege
authors.forename: Tzvetana
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authors.lastname: Katova
authors.forename: Songsak
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authors.lastname: Kiatchoosakun
authors.forename: Kee-Sik
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authors.lastname: Kim
authors.forename: Edmundo
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authors.lastname: Bayram
authors.forename: Felipe
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authors.lastname: Martinez
authors.forename: Bela
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authors.lastname: Merkely
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authors.lastname: Mendoza
authors.forename: Arend
authors.initials: A
authors.lastname: Mosterd
authors.forename: Marta
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authors.lastname: Negrusz-Kawecka
authors.forename: Keijo
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authors.lastname: Peuhkurinen
authors.forename: Felix
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authors.lastname: Ramires
authors.forename: Jens
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authors.lastname: Refsgaard
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authors.forename: Antonio S
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authors.lastname: Sibulo
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authors.lastname: Silva-Cardoso
authors.forename: Iain
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authors.lastname: Squire
authors.forename: Randall C
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authors.lastname: Starling
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mesh_terms: D000368:Aged; D000613:Aminobutyrates / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D004338:Drug Combinations; D004656:Enalapril / Q000627:therapeutic use; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; C081643:candesartan; C549068:sacubitril and valsartan sodium hydrate drug combination