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, B. 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

Research output: Contribution to journalArticle

58 Citations (Scopus)

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-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
Volume36
Issue number7
DOIs
Publication statusPublished - 2015

Fingerprint

Placebo Effect
Heart Failure
Placebos
Hospitalization
Enalapril
Neprilysin
Angiotensin Receptors
Mortality
Risk Reduction Behavior
Mineralocorticoid Receptor Antagonists
Investigational Therapies
LCZ 696
Angiotensins
Angiotensin-Converting Enzyme Inhibitors
Renin
Morbidity
Therapeutics

Keywords

  • Angiotensin II
  • Heart failure
  • Natriuretic peptides

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

McMurray, J., Packer, M., Desai, A., Gong, J., Greenlaw, N., Lefkowitz, M., ... Wong, R. (2015). A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure. European Heart Journal, 36(7), 434-439. https://doi.org/10.1093/eurheartj/ehu455

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure. / McMurray, John; Packer, Milton; Desai, Akshay; Gong, Jianjian; Greenlaw, Nicola; Lefkowitz, Martin; Rizkala, Adel; Shi, Victor; Rouleau, Jean; Solomon, Scott; Swedberg, Karl; Zile, Michael R.; Andersen, Karl; Arango, Juan Luis; Arnold, Malcolm; Bělohlávek, Jan; Böhm, Michael; Boytsov, Sergey; Burgess, Lesley; Cabrera, Walter; Chen, Chen Huan; Erglis, Andrejs; Fu, Michael; Gomez, Efrain; Gonzalez, Angel; Hagege, Albert Alain; Katova, Tzvetana; Kiatchoosakun, Songsak; Kim, Kee Sik; Bayram, Edmundo; Martinez, Felipe; Merkely, B.; Mendoza, Iván; Mosterd, Arend; Negrusz-Kawecka, Marta; Peuhkurinen, Keijo; Ramires, Felix; Refsgaard, Jens; Senni, Michele; Sibulo, Antonio S.; Silva-Cardoso, José; Squire, Iain; Starling, Randall C.; Vinereanu, Dragos; Teerlink, John R.; Wong, Raymond.

In: European Heart Journal, Vol. 36, No. 7, 2015, p. 434-439.

Research output: Contribution to journalArticle

McMurray, J, Packer, M, Desai, A, Gong, J, Greenlaw, N, Lefkowitz, M, Rizkala, A, Shi, V, Rouleau, J, Solomon, S, Swedberg, K, Zile, MR, Andersen, K, Arango, JL, Arnold, M, Bělohlávek, J, Böhm, M, Boytsov, S, Burgess, L, Cabrera, W, Chen, CH, Erglis, A, Fu, M, Gomez, E, Gonzalez, A, Hagege, AA, Katova, T, Kiatchoosakun, S, Kim, KS, Bayram, E, Martinez, F, Merkely, B, Mendoza, I, Mosterd, A, Negrusz-Kawecka, M, Peuhkurinen, K, Ramires, F, Refsgaard, J, Senni, M, Sibulo, AS, Silva-Cardoso, J, Squire, I, Starling, RC, Vinereanu, D, Teerlink, JR & Wong, R 2015, 'A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure', European Heart Journal, vol. 36, no. 7, pp. 434-439. https://doi.org/10.1093/eurheartj/ehu455
McMurray, John ; Packer, Milton ; Desai, Akshay ; Gong, Jianjian ; Greenlaw, Nicola ; Lefkowitz, Martin ; Rizkala, Adel ; Shi, Victor ; Rouleau, Jean ; Solomon, Scott ; Swedberg, Karl ; Zile, Michael R. ; Andersen, Karl ; Arango, Juan Luis ; Arnold, Malcolm ; Bělohlávek, Jan ; Böhm, Michael ; Boytsov, Sergey ; Burgess, Lesley ; Cabrera, Walter ; Chen, Chen Huan ; Erglis, Andrejs ; Fu, Michael ; Gomez, Efrain ; Gonzalez, Angel ; Hagege, Albert Alain ; Katova, Tzvetana ; Kiatchoosakun, Songsak ; Kim, Kee Sik ; Bayram, Edmundo ; Martinez, Felipe ; Merkely, B. ; Mendoza, Iván ; Mosterd, Arend ; Negrusz-Kawecka, Marta ; Peuhkurinen, Keijo ; Ramires, Felix ; Refsgaard, Jens ; Senni, Michele ; Sibulo, Antonio S. ; Silva-Cardoso, José ; Squire, Iain ; Starling, Randall C. ; Vinereanu, Dragos ; Teerlink, John R. ; Wong, Raymond. / A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure. In: European Heart Journal. 2015 ; Vol. 36, No. 7. pp. 434-439.
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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-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.",
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author = "John McMurray and Milton Packer and Akshay Desai and Jianjian Gong and Nicola Greenlaw and Martin Lefkowitz and Adel Rizkala and Victor Shi and Jean Rouleau and Scott Solomon and Karl Swedberg and Zile, {Michael R.} and Karl Andersen and Arango, {Juan Luis} and Malcolm Arnold and Jan Bělohl{\'a}vek and Michael B{\"o}hm and Sergey Boytsov and Lesley Burgess and Walter Cabrera and Chen, {Chen Huan} and Andrejs Erglis and Michael Fu and Efrain Gomez and Angel Gonzalez and Hagege, {Albert Alain} and Tzvetana Katova and Songsak Kiatchoosakun and Kim, {Kee Sik} and Edmundo Bayram and Felipe Martinez and B. Merkely and Iv{\'a}n Mendoza and Arend Mosterd and Marta Negrusz-Kawecka and Keijo Peuhkurinen and Felix Ramires and Jens Refsgaard and Michele Senni and Sibulo, {Antonio S.} and Jos{\'e} Silva-Cardoso and Iain Squire and Starling, {Randall C.} and Dragos Vinereanu and Teerlink, {John R.} and Raymond Wong",
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T1 - A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

AU - McMurray, John

AU - Packer, Milton

AU - Desai, Akshay

AU - Gong, Jianjian

AU - Greenlaw, Nicola

AU - Lefkowitz, Martin

AU - Rizkala, Adel

AU - Shi, Victor

AU - Rouleau, Jean

AU - Solomon, Scott

AU - Swedberg, Karl

AU - Zile, Michael R.

AU - Andersen, Karl

AU - Arango, Juan Luis

AU - Arnold, Malcolm

AU - Bělohlávek, Jan

AU - Böhm, Michael

AU - Boytsov, Sergey

AU - Burgess, Lesley

AU - Cabrera, Walter

AU - Chen, Chen Huan

AU - Erglis, Andrejs

AU - Fu, Michael

AU - Gomez, Efrain

AU - Gonzalez, Angel

AU - Hagege, Albert Alain

AU - Katova, Tzvetana

AU - Kiatchoosakun, Songsak

AU - Kim, Kee Sik

AU - Bayram, Edmundo

AU - Martinez, Felipe

AU - Merkely, B.

AU - Mendoza, Iván

AU - Mosterd, Arend

AU - Negrusz-Kawecka, Marta

AU - Peuhkurinen, Keijo

AU - Ramires, Felix

AU - Refsgaard, Jens

AU - Senni, Michele

AU - Sibulo, Antonio S.

AU - Silva-Cardoso, José

AU - Squire, Iain

AU - Starling, Randall C.

AU - Vinereanu, Dragos

AU - Teerlink, John R.

AU - Wong, Raymond

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Angiotensin II

KW - Heart failure

KW - Natriuretic peptides

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