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Clinical Trial
. 2022 Dec;28(12):2512-2520.
doi: 10.1038/s41591-022-02041-5. Epub 2022 Dec 5.

Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved

Stefan D Anker  1   2 , Javed Butler  3   4 , Muhammad Shariq Usman  5 , Gerasimos Filippatos  6 , João Pedro Ferreira  7   8 , Edimar Bocchi  9 , Michael Böhm  10 , Hans Pieter Brunner-La Rocca  11   12 , Dong-Ju Choi  13 , Vijay Chopra  14 , Eduardo Chuquiure  15 , Nadia Giannetti  16 , Juan Esteban Gomez-Mesa  17 , Stefan Janssens  18 , James L Januzzi  19 , José R González-Juanatey  20 , Bela Merkely  21 , Stephen J Nicholls  22 , Sergio V Perrone  23   24 , Ileana L Piña  25 , Piotr Ponikowski  26 , Michele Senni  27 , David Sim  28 , Jindrich Spinar  29 , Iain Squire  30 , Stefano Taddei  31 , Hiroyuki Tsutsui  32 , Subodh Verma  33 , Dragos Vinereanu  34   35 , Jian Zhang  36 , Tomoko Iwata  37 , Janet M Schnee  38 , Martina Brueckmann  39   40 , Stuart J Pocock  41 , Faiez Zannad  42
Affiliations
Clinical Trial

Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved

Stefan D Anker et al. Nat Med. 2022 Dec.

Abstract

The EMPEROR-Preserved trial showed that the sodium-glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF) > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41-49%). In patients with LVEF ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71-0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66-1.04, P = 0.11). For patients with an LVEF of 41-49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57-0.88, P = 0.002) for the primary outcome (Pinteraction = 0.27), and 0.57 (95%CI: 0.42-0.79, P < 0.001) for total HHF (Pinteraction = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.

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Conflict of interest statement

S.D.A. has received grants from Vifor; has received personal fees from Vifor, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions and Thermo Fisher Scientific; and has received grants and personal fees from Abbott Vascular, outside the submitted work. J.B. reports consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd and Vifor. G.F. reports lectures and/or Committee Member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, Bayer, Amgen and Boehringer Ingelheim. J.P.F. reports consulting fees from Boehringer Ingelheim during the conduct of the study. E.B. reports consultant fees from AstraZeneca, Boehringer Ingelheim, Servier Affaires Medicales; research grants from Bayer, Boehringer Ingelheim, Merck, Novartis; and travel grants from Laboratorios Baldacci. M.Bö. reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor, Servier and Vifor during the conduct of the study. H.P.B.-L.R. reports research grants from Medtronic, Novartis Pharma, Roche Diagnostics Corporation and Vifor Pharma. V.C. reports speaking fees from AstraZeneca, Boehringer Ingelheim and Novartis. N.G. reports consulting fees from Amgen Canada, AstraZeneca Canada, Boehringer Ingelheim Canada, Merck, Novartis and Servier Canada; and research grants from Amgen Canada, Boehringer Ingelheim, Merck and Novartis. S.J. reports advisory board contributions in trials sponsored by Boehringer Ingelheim. J.L.J. reports consulting fees from Applied Therapeutics, Boehringer Ingelheim, Janssen Global Services; research grants from Novartis Pharma, Roche Diagnostics; stock options from Imbria Pharmaceuticals; and Committee Member contributions in trials sponsored by AbbVie, Bayer Healthcare Pharmaceuticals Inc., Intercept Pharmaceuticals Inc. and Siemens Medical Solutions USA Inc. J.R.G.-J. reports personal fees from Boehringer Ingelheim. B.M. reports consulting fees from AstraZeneca, Boehringer Ingelheim and Novartis. S.J.N. reports research grants from Amgen, Anthera, AstraZeneca, Boehringer Ingelheim, Cerenis, Eli Lilly and Company, Esperion, F Hoffmann-La Roche, InfaReDx, LipScience, Novartis, Resverlogix, Sanofi-Regeneron and The Medicines Company. S.V.P. reports consulting fees from Abbott and Laboratorios Bago. I.L.P. reports personal fees from Boehringer Ingelheim. P.P. reports personal fees from Boehringer Ingelheim, AstraZeneca, Servier, BMS, Amgen, Novartis, Merck, Pfizer and Berlin Chemie; and grants and personal fees from Vifor Pharma. M.S. reports consultancy fees from Abbot, Bayer, Bayer Healthcare, Merck, Novartis and Vifor Pharma. I.S. reports research grants from Boehringer Ingelheim. H.T. reports personal fees from Boehringer Ingelheim, Astellas Pharma Inc., Pfizer Japan Inc., Bristol-Myers Squibb Company, Otsuka Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Kowa Pharmaceutical Co. Ltd and Teijin Pharma Ltd; grants from Actelion Pharmaceuticals Japan Ltd, Japan Tobacco Inc., Daiichi Sankyo Co., Ltd, IQVIA Services Japan, Omron Healthcare, Astellas Pharma Inc. and Teijin Pharma Ltd; grants and personal fees from Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited and MSD KK; and grants, personal fees and other from Nippon Boehringer Ingelheim Co., Ltd and Novartis Pharma K.K, outside the submitted work. S.V. reports research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, NovoNordisk, PhaseBio and Pfizer; and honoraria from Sanofi, Sun Pharmaceuticals and the Toronto Knowledge Translation Working Group. He is a member of the scientific excellence committee of the EMPEROR-Reduced trial and served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. D.V. reports consulting fees from AstraZeneca, Boehringer Ingelheim and Novartis Pharma. T.I., J.M.S. and M.Br. are employees of Boehringer Ingelheim. S.J.P. reports personal fees from Boehringer Ingelheim during the conduct of the study. F.Z. reports personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer and Cellprothera outside of the submitted work; and other support from cardiovascular clinical trialists and Cardiorenal, outside of the submitted work. All other authors have no competing interests.

Figures

Fig. 1
Fig. 1. Effect of empagliflozin versus placebo on time-to-first-event outcomes and total heart failure hospitalizations by LVEF category.
Hazard ratios for the primary endpoint, first hospitalization for heart failure (HHF), cardiovascular (CV) death and all-cause mortality were calculated using a multivariable Cox regression model, whereas the hazard ratio for total HHF was calculated using a joint frailty model with CV death as competing risk, as described in the Methods. Data are presented as point estimates and 95% CIs with two-sided P values. No adjustments for multiple testing were made.
Fig. 2
Fig. 2. Comparison of effects of empagliflozin versus placebo on outcomes by LVEF category.
Effects are shown for the primary outcome (cardiovascular death or hospitalization for heart failure) (a), first hospitalization for heart failure (b), cardiovascular death (c) and total hospitalizations for heart failure (d). Detailed results for all related modeled analyses are shown in Fig. 1.
Fig. 3
Fig. 3. Comparison of empagliflozin versus placebo for change in eGFR over time and eGFR slope by LVEF category.
Effects are shown for LVEF ≥ 50% (a) and LVEF 41–49% (b). a, Between-group difference in slope: 1.24 ml min−1 1.73 m−2 per year (95% CI: 0.87–1.61, P < 0.0001). b, Between-group difference in slope: 1.61 ml min−1 1.73 m−2 per year (95% CI: 1.09–2.13, P < 0.0001). Data are presented as adjusted mean and standard error. Change in eGFR was analyzed using a mixed model for repeated measures while the eGFR slope (that is, the rate of change in the decrease in eGFR) was analyzed using a random coefficient model, as described in the Methods.
Fig. 4
Fig. 4. Comparison of empagliflozin versus placebo for outcomes by LVEF subgroups in patients with LVEF ≥ 50%.
Effects are shown for the first event of cardiovascular (CV) death or hospitalization for heart failure (HHF), first HHF, CV death and total HHF (a), and the slope of change in eGFR (b) for patients in subgroups of LVEF from 50% to 70%. Data for the clinical events are presented as point estimates and 95% confidence intervals (CIs); data for the difference in slope of eGFR are presented as mean values and 95% CIs.
Extended Data Fig. 1
Extended Data Fig. 1. Effect of empagliflozin versus placebo on changes in NYHA functional class in patients with LVEF ≥ 50%.
Odds ratios were calculated using a multivariable Cox regression model. Data are presented as point estimates and 95% CIs with two-sided P values. No adjustments for multiple testing were made. Patients treated with empagliflozin had higher odds of improving NYHA class at week 52 (odds ratio 1.32 [95% CI: 1.10–1.56]; P = 0.0033) and lower odds of worsening NYHA class at week 52 (odds ratio 0.74 [95% CI: 0.54–1.01]; P = 0.0606). LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
Extended Data Fig. 2
Extended Data Fig. 2. The effect of different heart failure therapies tested in specific trials aiming to recruit HFpEF patients.
Known and estimated treatment effects for the composite endpoint of the time to a first event of cardiovascular death or HHF are displayed for the subgroup of patients with LVEF ≥ 50%. Panel A shows treatment effect sizes, and Panel B provide hazard ratios and event rates as are available. CI, confidence interval; CV, cardiovascular; HF, heart failure; HHF, hospitalization for heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction.
See this image and copyright information in PMC

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