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Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial

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Abstract

Background

Sodium changes are common in myocardial infarction (MI) complicated with left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). Sodium handling is fine-tuned in the distal nephron, were eplerenone exhibits some of its pleotropic effects. Little is known about the effect of eplerenone on serum sodium and the prognostic relevance of sodium alterations in patients with MI complicated with LVSD and/or HF.

Methods

The EPHESUS trial randomized 6632 patients to either eplerenone or placebo. Hyponatremia and hypernatremia were defined as sodium < 135 mmol/L or > 145 mmol/L, respectively. Linear mixed models and time updated Cox regression analysis were used to determine the effect of eplerenone on sodium changes and the prognostic importance of sodium changes, respectively. The primary outcomes were all-cause mortality and a composite of cardiovascular (CV) mortality and CV-hospitalization.

Results

A total of 6221 patients had a post-baseline sodium measurement, 797 patients developed hyponatremia (mean of 0.2 events/per patient) and 1476 developed hypernatremia (mean of 0.4 events/per patient). Patients assigned to eplerenone had a lower mean serum sodium over the follow-up (140 vs 141 mmol/L; p < 0.0001) and more often developed hyponatremia episodes (15 vs 11% p = 0.0001) and less often hypernatremia episodes (22 vs. 26% p = 0.0003). Hyponatremia, but not hypernatremia was associated with adverse outcome for all outcome endpoints in the placebo group but not in the eplerenone group (interaction p value < 0.05 for all). Baseline sodium values did not influence the treatment effect of eplerenone in reducing the various endpoints (interaction p value > 0.05 for all). Development of new-onset hyponatremia following eplerenone initiation did not diminish the beneficial eplerenone treatment effect.

Conclusion

Eplerenone induces minor reductions in serum sodium. The beneficial effect of eplerenone was maintained regardless of the baseline serum sodium or the development of hyponatremia. Sodium alterations should not refrain clinicians from prescribing eplerenone to patients who had an MI complicated with LVSD and/or HF.

Trail registry

ClinicalTrials.gov identifier: NCT00232180.

Graphic abstract

Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial.

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Funding

The EPHESUS trial was sponsored by Pfizer. BP, FZ and MB were members of the steering committees of this trial. PM has received a research grant from Vifor pharma and Fonds Wetenschappelijk Onderzoek (grant number: 1127917 N) and consultancy fees from AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, Novartis and Vifor pharma. JF, PR and FZ are supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program (reference: ANR-15-RHUS-0004). JV and PA are employees of Pfizer and report receiving stock options from Pfizer. MB reports fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Servier, Medtronic, ReCor, Vifor, Novartis and Abbott. MB is supported by the Deutsche Forschungsgemeinschaft (DFG, TTR 219, S-01). PR reports grants and personal fees from AstraZeneca, Bayer, Boehringer-Ingelheim, CVRx, Novartis, personal fees from Fresenius, Grunenthal, Sequana Medical, Servier, Stealth Peptides, Vifor, Vifor Fresenius Medical Care Renal Pharma, Idorsia, NovoNordisk, Ablative Solutions, G3P (stocks), Corvidia, Relypsa, outside the submitted work; and Cofounder: CardioRenal.

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Author notes

  1. Pieter Martens and JoãoPedro Ferreira equally contributed first authors.

Authors and Affiliations

  1. Department of Cardiology, Ziekenhuis Oost Limburg, Genk, Belgium

    Pieter Martens & Wilfried Mullens

  2. Department of Medicine and Life Sciences, University Hasselt, Hasselt, Belgium

    Pieter Martens & Wilfried Mullens

  3. Centre d’Investigation Clinique 1433 module Plurithematique, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, F-CRIN INI-CRCT Network, Universite de Lorraine, Inserm U1116, 4 rue du Morvan, 54500, Vandoeuvre les Nancy, France

    João Pedro Ferreira, Faiez Zannad & Patrick Rossignol

  4. Pfizer Inc., New York, NY, USA

    John Vincent, Paula Abreu & Martijn Busselen

  5. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA

    Wilson W. H. Tang

  6. Klinik Für Innere Medizin III, Saarland University, Saarbrücken, Germany

    Michael Böhm

  7. University of Michigan, Ann Arbor, MI, USA

    Bertram Pitt

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  1. Pieter Martens
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Correspondence to Patrick Rossignol.

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Martens, P., Ferreira, J.P., Vincent, J. et al. Serum sodium and eplerenone use in patients with a myocardial infarction and left ventricular dysfunction or heart failure: insights from the EPHESUS trial. Clin Res Cardiol 111, 380–392 (2022). https://doi.org/10.1007/s00392-021-01853-8

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  • DOI: https://doi.org/10.1007/s00392-021-01853-8

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