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Randomized Controlled Trial
. 2021 Mar 23;77(11):1397-1407.
doi: 10.1016/j.jacc.2021.01.044.

Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced

João Pedro Ferreira  1 , Faiez Zannad  2 , Stuart J Pocock  3 , Stefan D Anker  4 , Javed Butler  5 , Gerasimos Filippatos  6 , Martina Brueckmann  7 , Waheed Jamal  8 , Dominik Steubl  8 , Elke Schueler  9 , Milton Packer  10
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Free article
Randomized Controlled Trial

Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced

João Pedro Ferreira et al. J Am Coll Cardiol. .
Free article

Abstract

Background: Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction.

Objectives: This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).

Methods: Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization.

Results: The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group.

Conclusions: In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Keywords: empagliflozin; heart failure; mineralocorticoid receptor antagonists.

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Conflict of interest statement

Funding Support and Author Disclosures EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly. Dr. Ferreira has received consulting fees from Boehringer Ingelheim during the conduct of the study. Dr. Zannad has received personal fees from Boehringer Ingelheim during the conduct of the study; has received personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera outside the submitted work; and has received other support from CardioVascular Clinical Trialists and Cardiorenal, outside the submitted work. Dr. Pocock has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr. Anker 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. Dr. Butler has received consultancy fees from Boehringer Ingelheim during the conduct of the study; and has received consultancy fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave, and Vifor, outside the submitted work. Dr. Filippatos has received payment for being a trial committee member from Boehringer Ingelheim during the conduct of the study; and has received payment for being a trial committee member from Medtronic, Vifor, Servier, and Novartis, outside the submitted work. Dr. Brueckmann has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and Novo Nordisk, outside the submitted work. Drs. Brueckmann, Steubl, Jamal, and Steubl are employees of Boehringer Ingelheim. Dr. Schueler is an employee of mainanalytics, contracted by Boehringer Ingelheim. Dr. Packer has reported that he has no relationships relevant to the contents of this paper to disclose.

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