A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

John McMurray*, Milton Packer, Akshay Desai, Jianjian Gong, Nicola Greenlaw, Martin Lefkowitz, Adel Rizkala, Victor Shi, Jean Rouleau, Scott Solomon, Karl Swedberg, Michael R. Zile, Karl Andersen, Juan Luis Arango, Malcolm Arnold, Jan Bělohlávek, Michael Böhm, Sergey Boytsov, Lesley Burgess, Walter CabreraChen Huan Chen, Andrejs Erglis, Michael Fu, Efrain Gomez, Angel Gonzalez, Albert Alain Hagege, Tzvetana Katova, Songsak Kiatchoosakun, Kee Sik Kim, Edmundo Bayram, Felipe Martinez, Bela Merkely, Iván Mendoza, Arend Mosterd, Marta Negrusz-Kawecka, Keijo Peuhkurinen, Felix Ramires, Jens Refsgaard, Michele Senni, Antonio S. Sibulo, José Silva-Cardoso, Iain Squire, Randall C. Starling, Dragos Vinereanu, John R. Teerlink, Raymond Wong

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Aims 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. Methods and results We used the treatment-armof the Studies OfLeftVentricularDysfunction(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 LCZ696vs. aputativeplacebowasestimatedthroughtheproductof the hazardratioofLCZ696vs. 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 comparedwith a putative placebowas 28% (95%CI 15-39%; P< 0.0001). Putative placebo analyses based onCHARM-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. Conclusion 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.

Original languageEnglish
Pages (from-to)434-439
Number of pages6
JournalEuropean Heart Journal
Issue number7
StatePublished - 2015


  • Angiotensin II
  • Heart failure
  • Natriuretic peptides


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