Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial
Savarese, Gianluigi; Uijl, Alicia; Lund, Lars H; Anker, Stefan D; Asselbergs, Folkert; Fitchett, David; Inzucchi, Silvio E; Koudstaal, Stefan; Ofstad, Anne Pernille; Schrage, Benedikt; Vedin, Ola; Wanner, Christoph; Zannad, Faiez; Zwiener, Isabella; Butler, Javed
(2021) Journal of Cardiac Failure, volume 27, issue 8, pp. 888 - 895
(Article)
Abstract
Background: In the EMPA-REG OUTCOME trial, ejection fraction (EF) data were not collected. In the subpopulation with heart failure (HF), we applied a new predictive model for EF to determine the effects of empagliflozin in HF with predicted reduced (HFrEF) vs preserved (HFpEF) EF vs no HF. Methods and Results:
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We applied a validated EF predictive model based on patient baseline characteristics and treatments to categorize patients with HF as being likely to have HF with mid-range EF (HFmrEF)/HFrEF (EF <50%) or HFpEF (EF ≥50%). Cox regression was used to assess the effect of empagliflozin vs placebo on cardiovascular death/HF hospitalization (HHF), cardiovascular and all-cause mortality, and HHF in patients with predicted HFpEF, HFmrEF/HFrEF and no HF. Of 7001 EMPA-REG OUTCOME patients with data available for this analysis, 6314 (90%) had no history of HF. Of the 687 with history of HF, 479 (69.7%) were predicted to have HFmrEF/HFrEF and 208 (30.3%) to have HFpEF. Empagliflozin's treatment effect was consistent in predicted HFpEF, HFmrEF/HFrEF and no-HF for each outcome (HR [95% CI] for the primary outcome 0.60 [0.31–1.17], 0.79 [0.51–1.23], and 0.63 [0.50–0.78], respectively; P interaction = 0.62). Conclusions: In EMPA-REG OUTCOME, one-third of the patients with HF had predicted HFpEF. The benefits of empagliflozin on HF and mortality outcomes were consistent in nonHF, predicted HFpEF and HFmrEF/HFrEF.
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Keywords: EMPA-REG OUTCOME, Heart failure with preserved ejection fraction, empagliflozin, heart failure with mid-range ejection fraction, heart failure with mildly reduced ejection fraction, heart failure with reduced ejection fraction, type 2 diabetes mellitus, Cardiology and Cardiovascular Medicine
ISSN: 1071-9164
Publisher: Churchill Livingstone
Note: Funding Information: The EMPA-REG OUTCOME trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. The sponsor of the EMPA-REG OUTCOME Trial (Boehringer Ingelheim) is committed to responsible sharing of clinical study reports, related clinical documents, and patient level clinical study data. Researchers are invited to submit inquiries via the following website: https://trials.boehringer-ingelheim.com. Dr. Savarese is a fellow of the Cardiovascular Clinical Trialists Forum, which received an unrestricted grant from Boehringer Ingelheim. He reports grants and personal fees from Vifor, grants and nonfinancial support from Boehringer Ingelheim, personal fees from Societa Prodotti Antibiotici, grants and personal fees from AstraZeneca, Roche and Servier, grants from Novartis, personal fees from GENESIS, Cytokinetics and Medtronic, and grants from Boston Scientific, outside the submitted work. Dr. Anker reports grants and personal fees from Vifor Int, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Brahms and grants and personal fees from Abbott Vascular, outside the submitted work. Dr. Butler reports consultant fees from Boehringer Ingelheim during the conduct of the study; consultant fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Sequana Medical, V-Wave Limited, and Vifor, outside the submitted work. Dr. Fitchett reports personal fees from Boehringer Ingelheim, Lilly and Astra Zeneca and other from Novo Nordisk outside the submitted work. Dr. Lund reports personal fees from Merck, grants and personal fees from Vifor-Fresenius, AstraZeneca and Relypsa, personal fees from Bayer, grants from Boston Scientific, personal fees from Pharmacosmos, Abbott, Medscape, Myokardia, grants and personal fees from Boehringer Ingelheim, Novartis, and personal fees from Sanofi and Lexicon, outside the submitted work. Drs. Ofstad, Vedin and Zwiener were employed by Boehringer Ingelheim during the conduct of the study. Dr. Schrage reports personal fees from Astra Zeneca, outside the submitted work. Dr. Zannad reports personal fees from Boehringer during the conduct of the study; personal fees from Janssen, Bayer, Boston Scientific, Amgen, CVRx, Novartis, AstraZeneca, Vifor Fresenius, Cardior, Applied Therapeutics, Cereno Pharmaceutical, and Merck; other from cardiorenal, other from CVCT, outside the submitted work. Dr. Inzucchi reports personal fees and nonfinancial support from Boehringer Ingelheim, during the conduct of the study; personal fees and nonfinancial support from AstraZeneca and Novo Nordisk, personal fees from Merck, Sanofi/Lexicon, vTv Therpeutics, Abbott/Alere, and Esperion outside the submitted work. All the other coauthors have no conflicts of interest to declare. Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Graphical assistance, supported financially by Boehringer Ingelheim, was provided by Charlie Bellinger of Elevate Scientific Solutions. Funding Information: Dr. Savarese is a fellow of the Cardiovascular Clinical Trialists Forum, which received an unrestricted grant from Boehringer Ingelheim. He reports grants and personal fees from Vifor, grants and nonfinancial support from Boehringer Ingelheim, personal fees from Societa Prodotti Antibiotici, grants and personal fees from AstraZeneca, Roche and Servier, grants from Novartis, personal fees from GENESIS, Cytokinetics and Medtronic, and grants from Boston Scientific, outside the submitted work. Dr. Anker reports grants and personal fees from Vifor Int, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Brahms and grants and personal fees from Abbott Vascular, outside the submitted work. Dr. Butler reports consultant fees from Boehringer Ingelheim during the conduct of the study; consultant fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Sequana Medical, V-Wave Limited, and Vifor, outside the submitted work. Dr. Fitchett reports personal fees from Boehringer Ingelheim, Lilly and Astra Zeneca and other from Novo Nordisk outside the submitted work. Dr. Lund reports personal fees from Merck, grants and personal fees from Vifor-Fresenius, AstraZeneca and Relypsa, personal fees from Bayer, grants from Boston Scientific, personal fees from Pharmacosmos, Abbott, Medscape, Myokardia, grants and personal fees from Boehringer Ingelheim, Novartis, and personal fees from Sanofi and Lexicon, outside the submitted work. Drs. Ofstad, Vedin and Zwiener were employed by Boehringer Ingelheim during the conduct of the study. Dr. Schrage reports personal fees from Astra Zeneca, outside the submitted work. Dr. Zannad reports personal fees from Boehringer during the conduct of the study; personal fees from Janssen, Bayer, Boston Scientific, Amgen, CVRx, Novartis, AstraZeneca, Vifor Fresenius, Cardior, Applied Therapeutics, Cereno Pharmaceutical, and Merck; other from cardiorenal, other from CVCT, outside the submitted work. Dr. Inzucchi reports personal fees and nonfinancial support from Boehringer Ingelheim, during the conduct of the study; personal fees and nonfinancial support from AstraZeneca and Novo Nordisk, personal fees from Merck, Sanofi/Lexicon, vTv Therpeutics, Abbott/Alere, and Esperion outside the submitted work. All the other coauthors have no conflicts of interest to declare. Funding Information: The EMPA-REG OUTCOME trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. Publisher Copyright: © 2021 The Author(s)
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