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Randomized Controlled Trial
. 2023 Jan 1;44(1):41-50.
doi: 10.1093/eurheartj/ehac530.

Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial

Jan Biegus  1 , Adriaan A Voors  2 , Sean P Collins  3   4 , Mikhail N Kosiborod  5   6 , John R Teerlink  7 , Christiane E Angermann  8 , Jasper Tromp  9 , Joao Pedro Ferreira  10   11 , Michael E Nassif  12 , Mitchell A Psotka  13 , Martina Brueckmann  14   15 , Afshin Salsali  16   17 , Jonathan P Blatchford  18 , Piotr Ponikowski  1
Affiliations
Randomized Controlled Trial

Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial

Jan Biegus et al. Eur Heart J. .

Abstract

Aims: Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated.

Methods and results: A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL -1.97 (-2.86, -1.08), -1.74 (-2.73, -0.74); -1.53 (-2.75, -0.31) kg; for WL-adjusted: -2.31 (-3.77, -0.85), -2.79 (-5.03, -0.54), -3.18 (-6.08, -0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001).

Conclusion: Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90.

Keywords: Acute heart failure; Decongestion; Empagliflozin; SGLT-2 inhibitor.

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Conflict of interest statement

Conflict of interest: A.A.V. has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. S.P.C. is a consultant for Aiphia, Siemens, Bristol Myers Squibb, Boehringer Ingelheim, and Vixiar and receives research support from the NIH, PCORI, AstraZeneca, and Beckman Coulter. M.N.K. has received research grants from AstraZeneca and Boehringer Ingelheim, and has served as a consultant for Alnylam, AstraZeneca, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Sanofi, and Vifor. J.R.T. has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. C.E.A. has received research support from and/or has been a consultant for Abbott, Boehringer Ingelheim, Medtronic, Novartis, ResMed, Thermo Fisher, Vifor, and German Federal Ministry of Education and Research. J.T. is supported by the National University of Singapore Start-up grant, the tier 1 grant from the ministry of education and the CS-IRG New Investigator Grant from the National Medical Research Council; has received consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche diagnostics, and Us2.ai, owns patent US-10702247-B2 unrelated to the present work. J.P.F. is a consultant for Boehringer Ingelheim and receives research support from AstraZeneca. M.E.N. has received speaking honoraria from Abbott, and is a consultant for Vifor, Roche, and Amgen. P.P. reports personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, Berlin Chemie, and grants and personal fees from Vifor Pharma. J.P.B. is an employee of Elderbrook Solutions. M.B. and A.S. are employees of Boehringer Ingelheim. J.B. and M.A.P. have no competing interests.

Figures

Structured Graphical Abstract
Structured Graphical Abstract
Empagliflozin in acute heart failure: the EMPULSE Trial. CI, confidence interval. Data shown for the treatment effect graphs are adjusted mean change from baseline, with error bars representing standard error. *The units of weight changes per mean daily loop diuretic dose are presented in kg/40 mg of intravenous furosemide (or 80 mg of oral furosemide) or equivalent. The equivalent to 40 mg of furosemide was defined as 20 mg of torasemide or 1 mg of bumetanide. †Measured as changes in haematocrit (%). ‡Calculated as a sum of the points allocated for dyspnoea, orthopnoea and fatigue. For each variable, a 0- to 3-point scale has been used, where points were allocated for: absence (0 points), seldom (1 point), frequent (2 points), and continuous (3 points) based on the frequency of the clinical sign. §The hierarchy and the components of the primary outcome measured by the win ratio: 1. Time to all-cause death; 2. Number of heart failure (HF) events (including hospitalizations for HFs, urgent HF visits and unplanned outpatient visits); 3. Time to first HF event; 4. ≥5 point difference in change from baseline in KCCQ total symptom score (KCCQ-TSS) after 90 days of treatment.
Figure 1
Figure 1
The trajectories of adjusted mean changes in body weight during the study in empagliflozin and placebo arms.
Figure 2
Figure 2
The trajectories of adjusted mean changes in body weight per mean daily dose of loop diuretics during the study in empagliflozin and placebo arms.
Figure 3
Figure 3
The trajectories of adjusted mean changes in haematocrit during the study in empagliflozin and placebo arms.
Figure 4
Figure 4
The win ratios for primary efficacy outcome* at Day 90 by median weight change at Days 15 and 30 in (A) the entire population (stratified by treatment group), (B) the placebo arm only (unstratified), and (C) the empagliflozin arm only (unstratified). *Hierarchical composite of death, number of heart failure events, time to first heart failure event and change from baseline in KCCQ-TSS after 90 days of treatment. The win ratio was calculated using a non-parametric generalized pairwise comparison procedure; data are presented as the point estimate and 95% CI with a two-sided P-value.
Figure 5
Figure 5
The win ratios for primary efficacy outcome* at Day 90 by median haematocrit change at Days 15 and 30 in (A) the entire population (stratified by treatment group), (B) the placebo arm only (unstratified), and (C) the empagliflozin arm only (unstratified). *Hierarchical composite of death, number of heart failure events, time to first heart failure event and change from baseline in KCCQ-TSS after 90 days of treatment. The win ratio was calculated using a non-parametric generalized pairwise comparison procedure; data are presented as the point estimate and 95% CI with a two-sided P-value.
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