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Title: A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure
Authors: McMurray, J.
Packer, M.
Desai, A.
Gong, J.
Greenlaw, N.
Lefkowitz, M.
Rizkala, A.
Shi, V.
Rouleau, J.
Solomon, S.
Swedberg, K.
Zile, M. R.
Andersen, K.
Arango, J. L.
Arnold, M.
Belohlavek, J.
Boehm, M.
Boytsov, S.
Burgess, L.
Cabrera, W.
Chen, C. -. H.
Erglis, A.
Fu, M.
Gomez, E.
Gonzalez, A.
Hagege, A. -. A.
Katova, T.
Kiatchoosakun, S.
Kim, K. -. S.
Bayram, E.
Martinez, F.
Merkely, B.
Mendoza, I.
Mosterd, A.
Negrusz-Kawecka, M.
Peuhkurinen, K.
Ramires, F.
Refsgaard, J.
Senni, M.
Sibulo, A. S.
Silva-Cardoso, J.
Squire, Iain Boland
Starling, R. C.
Vinereanu, D.
Teerlink, J. R.
Wong, R.
First Published: 21-Nov-2014
Publisher: Oxford University Press (OUP)
Citation: European Heart Journal, 2015, 36 (7), pp. 434-439 (6)
Abstract: 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-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. 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.
DOI Link: 10.1093/eurheartj/ehu455
ISSN: 0195-668X
eISSN: 1522-9645
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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