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Aims: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization., Methods and Results: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004)., Conclusions: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Frailty is a severe, common co-morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co-transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period., Methods: We calculated a cumulative deficit-derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR-Preserved. Patients were classified into four groups: non-frail (FI < 0.21), mild frailty (0.21 to <0.30), moderate frailty (0.30 to <0.40) and severe frailty (≥0.40). Clinical outcomes and health-related quality of life were evaluated according to baseline FI along with the effect of empagliflozin on chronological changes in FI (at 12, 32 and 52 weeks)., Results: The patient distribution was 1514 (25.3%), 2100 (35.1%), 1501 (25.1%) and 873 (14.6%) in non-frail, mild frailty, moderate frailty and severe frailty, respectively. Severe frailty patients tended to be female and have low Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more co-morbidities and more polypharmacy. Incidence rates of the primary outcome of cardiovascular death or HF hospitalization increased as frailty worsened (hazard ratio [HR] of each FI category compared with the non-frail group: 1.10 [95% confidence interval, CI, 0.89-1.35], 2.00 [1.63-2.47] and 2.61 [2.08-3.27] in the mild frailty, moderate frailty and severe frailty groups, respectively; P trend < 0.001). Compared with placebo, empagliflozin reduced the risk for the primary outcome across the four FI categories, HR: 0.59 [95% CI 0.42-0.83], 0.79 [0.61-1.01], 0.77 [0.61-0.96] and 0.90 [0.69-1.16] in non-frail to severe frailty categories, respectively (P value for trend = 0.097). Empagliflozin also improved other clinical outcomes and KCCQ score across frailty categories. Compared with placebo, empagliflozin-treated patients had a higher likelihood of being in a lower FI category at Weeks 12, 32 and 52 (P < 0.05), odds ratio: 1.12 [95% CI 1.01-1.24] at Week 12, 1.21 [1.09-1.34] at Week 32 and 1.20 [1.09-1.33] at Week 52., Conclusions: Empagliflozin improved key efficacy outcomes with a possible diminution of effect in very frail patients. Empagliflozin also improved frailty status during follow-up., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF)., Objectives: The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy., Methods: The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline., Results: A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; P trend test  = 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents., Conclusions: Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, PhaseBio, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial; has served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Butler has received research support from the National Institutes of Health, Patient Centered Outcomes Research, and the European Union; has served on the Speakers Bureau for Novartis, Janssen, and Novo Nordisk; and has served as a consultant and has served on steering committee, clinical events committee, or data safety monitoring boards for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin-Cures, Boehringer Ingelheim, Bristol Myers Squib, Cardiocell, CVRx, G3 Pharmaceutical, Innolife, Janssen, Lantheus, LinaNova, Luitpold, Medscape, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Stealth-Peptide, SC Pharma, V-Wave Limited, Vifor, and ZS Pharma. Dr Anker has received grants and personal fees from Vifor International and Abbott Vascular; and has received personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International. Dr Ferreira is a consultant for Boehringer Ingelheim. Dr Filippatos has received lecture fees and/or committee member contributions in trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Amgen, and Boehringer Ingelheim; and has received research support from the European Union. Dr Januzzi is a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, Applied Therapeutics, Innolife, Novartis Pharmaceuticals and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has received fees as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research and Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and holds a position as co-founder and nonexecutive director of Us2.ai. Dr Sattar has received personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp and Dohme, Novo Nordisk, Pfizer, and Sanofi; and has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside of the submitted work. Dr Zaremba-Pechmann is a contractor to Boehringer Ingelheim via Elderbrook Solutions Gmbh. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Drs Nordaby and Brueckmann are employees of Boehringer Ingelheim International GmbH. Dr Pocock is a consultant for Boehringer Ingelheim. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Dr Packer has received personal fees from Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Data Sharing Statement: To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript and secondary analyses in a peer-reviewed journals and regulatory and reimbursement activities are completed, normally within 1 year after the marketing application has been granted by major Regulatory Authorities. Researchers should use https://vivli.org/ to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. This study aimed to evaluate the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751)., Methods and Results: In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, heart failure events, and a ≥5 point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at 90 days, assessed using the win ratio (WR). First heart failure hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRAs at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR 1.46, 95% confidence interval [CI] 1.08-1.97 and WR 1.27, 95% CI 0.93-1.73 in MRA users and non-users, respectively; interaction p = 0.52). The effect of empagliflozin on first heart failure hospitalization or cardiovascular death was not modified by MRA use (hazard ratio [HR] 0.58, 95% CI 0.30-1.11 and HR 0.85, 95% CI 0.47-1.52 in MRA users and non-users, respectively; interaction p = 0.39). Investigator-reported and severe hyperkalaemia events were infrequent (<6%) irrespective of MRA use., Conclusions: In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF., (© 2023 European Society of Cardiology.)

Background: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies., Methods: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977., Findings: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p interaction =0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p interaction =0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p interaction =0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups., Interpretation: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy., Funding: Boehringer Ingelheim and Eli Lilly and Company., Competing Interests: Declaration of interests SV holds a tier 1 Canada Research Chair in cardiovascular surgery; and reports receiving research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio, and Pfizer; and receiving 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 organisation. JB 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, and Vifor. SDA has received grants from Vifor; personal fees from Vifor, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Thermo Fisher Scientific; and grants and personal fees from Abbott Vascular. JPF reports consulting fees from Boehringer Ingelheim. GF reports honoraria for lectures for Medtronic, Vifor, Servier, Novartis, Bayer, Amgen, and Boehringer Ingelheim, and committee member contributions in trials sponsored by Boehringer Ingelheim. JLJ reports grant support, consulting income, and participation in clinical endpoint committees and data safety monitoring boards from Janssen; participation in clinical endpoint committees and data safety monitoring boards from Boehringer Ingelheim; grant support from Novartis, Innolife, Applied Therapeutics, and Siemens Diagnostics; and consultancy fees from Novartis, Roche Diagnostics, and Abbott Diagnostics. CSPL reports research grants from Bayer, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research and Development, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global, Radcliffe Group, and Corpus; and serves as co-founder and non-executive director of eKo.ai. NS reports personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk, Pfizer, and Sanofi; and grant income from Boehringer Ingelheim. BP, MN, and MB are employees of Boehringer Ingelheim. SJP reports personal fees from Boehringer Ingelheim. FZ reports personal fees from Boehringer Ingelheim, Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera; and other support from cardiovascular clinical trialists and Cardiorenal. MP reports personal fees from AbbVie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Lilly, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance. NKD declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF)., Methods and Results: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported., Conclusion: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)