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.
Similar content being viewed by others
References
Shah V, Jahan N (2019) Prognostic significance of hyponatremia in ST-elevation myocardial infarction/heart failure patients. Cureus 11:e5673
Plakht Y, Gilutz H, Shiyovich A (2018) Sodium levels during hospitalization with acute myocardial infarction are markers of in-hospital mortality: Soroka acute myocardial infarction II (SAMI-II) project. Clin Res Cardiol 107:956–964
Choi JS, Kim CS, Bae EH et al (2017) Prognostic impact of hyponatremia occurring at various time points during hospitalization on mortality in patients with acute myocardial infarction. Medicine (Baltimore) 96:e7023
Burkhardt K, Kirchberger I, Heier M et al (2015) Hyponatraemia on admission to hospital is associated with increased long-term risk of mortality in survivors of myocardial infarction. Eur J Prev Cardiol 22:1419–1426
Balling L, Kober L, Schou M, Torp-Pedersen C, Gustafsson F (2013) Efficacy and safety of angiotensin-converting enzyme inhibitors in patients with left ventricular systolic dysfunction and hyponatremia. J Card Fail 19:725–730
Lazzeri C, Valente S, Chiostri M, Attana P, Picariello C, Gensini GF (2012) Usefulness of hyponatremia in the acute phase of ST-elevation myocardial infarction as a marker of severity. Am J Cardiol 110:1419–1424
Madan VD, Novak E, Rich MW (2011) Impact of change in serum sodium concentration on mortality in patients hospitalized with heart failure and hyponatremia. Circ Heart Fail 4:637–643
Klein L, O’Connor CM, Leimberger JD et al (2005) Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure (OPTIME-CHF) study. Circulation 111:2454–2460
Shea AM, Hammill BG, Curtis LH, Szczech LA, Schulman KA (2008) Medical costs of abnormal serum sodium levels. J Am Soc Nephrol 19:764–770
Schou M, Valeur N, Torp-Pedersen C, Gustafsson F, Kober L (2011) Plasma sodium and mortality risk in patients with myocardial infarction and a low LVEF. Eur J Clin Invest 41:1237–1244
Balling L, Schou M, Videbaek L, Hildebrandt P, Wiggers H, Gustafsson F (2011) Prevalence and prognostic significance of hyponatraemia in outpatients with chronic heart failure. Eur J Heart Fail 13:968–973
Verbrugge FH, Grodin JL, Mullens W, Taylor DO, Starling RC, Tang WH (2016) Transient hyponatremia during hospitalization for acute heart failure. Am J Med 129:620–627
Hirth RA, Messana JM (2008) What does a serum sodium cost? J Am Soc Nephrol 19:654–655
Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WH, Mullens W (2015) Hyponatremia in acute decompensated heart failure: depletion versus dilution. J Am Coll Cardiol 65:480–492
Ponikowski P, Voors AA, Anker SD et al (2016) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC) developed with the special contribution of the heart failure association (HFA) of the ESC. Eur Heart J 37:2129–2200
Collet JP, Thiele H, Barbato E et al 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 42(14):1289–1367. https://doi.org/10.1093/eurheartj/ehaa575
Pitt B, Remme W, Zannad F et al (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348:1309–1321
Ferreira JP, Eschalier R, Duarte K et al (2020) Reduced diuretic dose in patients treated with eplerenone: data from the EPHESUS trial. Circ Heart Fail 13:e006597
Gheorghiade M, Abraham WT, Albert NM et al (2007) Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the optimize-HF registry. Eur Heart J 28:980–988
Levy WC, Mozaffarian D, Linker DT et al (2006) The Seattle heart failure model: prediction of survival in heart failure. Circulation 113:1424–1433
Packer M, Medina N, Yushak M (1984) Correction of dilutional hyponatremia in severe chronic heart failure by converting-enzyme inhibition. Ann Intern Med 100:782–789
Dzau VJ, Packer M, Lilly LS, Swartz SL, Hollenberg NK, Williams GH (1984) Prostaglandins in severe congestive heart failure. Relation to activation of the renin—angiotensin system and hyponatremia. N Engl J Med 310:347–352
Mullens W, Verbrugge FH, Nijst P, Tang WHW (2017) Renal sodium avidity in heart failure: from pathophysiology to treatment strategies. Eur Heart J 38:1872–1882
Goldsmith SR, Francis GS, Cowley AW Jr, Levine TB, Cohn JN (1983) Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol 1:1385–1390
Gottschalk CW, Mylle M (1959) Micropuncture study of the mammalian urinary concentrating mechanism: evidence for the countercurrent hypothesis. Am J Physiol 196:927–936
Bavishi C, Ather S, Bambhroliya A et al (2014) Prognostic significance of hyponatremia among ambulatory patients with heart failure and preserved and reduced ejection fractions. Am J Cardiol 113:1834–1838
Sligl W, McAlister FA, Ezekowitz J, Armstrong PW (2004) Usefulness of spironolactone in a specialized heart failure clinic. Am J Cardiol 94:443–447
Greenblatt DJ, Koch-Weser J (1973) Adverse reactions to spironolactone. A report from the Boston collaborative drug surveillance program. JAMA 225:40–43
Mullens W, Damman K, Harjola VP et al (2019) The use of diuretics in heart failure with congestion—a position statement from the heart failure association of the European society of cardiology. Eur J Heart Fail 21:137–155
Lee WH, Packer M (1986) Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 73:257–267
Ljungman S, Kjekshus J, Swedberg K (1992) Renal function in severe congestive heart failure during treatment with enalapril [the cooperative North Scandinavian enalapril survival study (CONSENSUS) Trial]. Am J Cardiol 70:479–487
Mullens W, Damman K, Testani JM et al (2020) Evaluation of kidney function throughout the heart failure trajectory—a position statement from the heart failure association of the European society of cardiology. Eur J Heart Fail 22:584–603
Vardeny O, Claggett B, Anand I et al (2014) Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail 7:573–579
Yusuf S, Pitt B, Davis CE, Hood WB Jr, Cohn JN (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327:685–691
Bauersachs J, Jaisser F, Toto R (2015) Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases. Hypertension 65:257–263
Kovesdy CP, Lott EH, Lu JL et al (2012) Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation 125:677–684
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Data sharing policy
Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (a) for indications that have been approved in the US and/or EU or (b) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00392-021-01853-8