Article Text

Download PDFPDF

Randomised controlled trial
Eplerenone reduces risk of cardiovascular death or hospitalisation in heart failure patients with reduced ejection fraction
  1. Andrew Ambrosy1,
  2. Mihai Gheorghiade1
  1. 1Center for Cardiovascular Innovation, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Mihai Gheorghiade
    Cardiovascular Center for Drug Development, Duke University, 645 North Michigan Avenue, Suite 1006, Chicago, IL 60611, USA; m-gheorghiade{at}

Statistics from

Commentary on: OpenUrlCrossRefPubMedWeb of Science


Mineralocorticoid receptor antagonists (MRAs) have been shown to decrease all-cause mortality and cardiovascular (CV) hospitalisation in patients with moderate-to-severe heart failure (HF) (ie, New York Heart Association (NYHA) class III and IV symptoms) with a reduced ejection fraction (EF)1 and in patients with acute myocardial infarction complicated by HF with systolic dysfunction.2 The aim of EMPHASIS-HF was to investigate the effects of eplerenone, in addition to evidence-based background therapy, on clinical outcomes in patients with mild HF (ie, NYHA class II symptoms) with a reduced EF.


Patients ≥55 years of age with NYHA functional class II symptoms, an EF ≤30%, treated with an ACE inhibitor/angiotensin receptor blocker and a β-blocker, and a history of CV-related hospitalisation within the past 6 months were enrolled. Patients without a recent CV hospitalisation were eligible for enrolment if they had a measured b-type natriuretic peptide (BNP) level ≥250 pg/ml or N-terminal-proBNP ≥500 pg/ml in men or ≥750 pg/ml in women. Patients with a baseline serum K+ >5.0 mmol/l or an estimated glomerular filtration rate <30 ml/min/1.73 m2 were excluded.

Patients were randomised in a double-blind fashion to receive either 25 mg (uptitrated to 50 mg after 4 weeks) of eplerenone once daily or matching placebo. Patients were revaluated every 4 months, and study investigators were instructed to decrease the dose if serum K+ was 5.5–5.9 mmol/l and to withhold the study drug if serum K+ was ≥6.0 mmol/l. The primary outcome was the composite of CV mortality (CVM) and first HF hospitalisation. The study was terminated early after a prespecified interim analysis revealed an overwhelming benefit (p<0.001) associated with eplerenone treatment.


A total of 2737 patients were randomised (1364 to eplerenone and 1373 to placebo) for a median follow-up of 21 months (4783 patient-years). The primary outcome occurred in 249 patients (18.3%) in the eplerenone group and 356 patients (25.9%) in the placebo group, representing an absolute risk reduction of 7.6% and a HR of 0.63 (95% CI 0.54 to 0.74, p<0.001). The number needed to treat was 19 (95% CI 15 to 27) to prevent one primary outcome event and 51 (95% CI 32 to 180) to prevent one death from occurring per year of follow-up.

Patients randomised to eplerenone and placebo, respectively, reported hyperkalaemia (defined as serum K+ level >5.5 mmol/l) in 158 (11.8%) and 96 (7.2%) patients (p<0.001) and hypokalaemia (defined as serum K+ <4.0 mmol/l) in 519 (38.8%) and 648 (48.4%) patients (p<0.001).


Although eplerenone-treated patients reported a robust improvement in the primary end point, some limitations of the data should be addressed. First, the results cannot be generalised to all HF patients with mild symptoms, as this study selectively enrolled patients ≥55 years of age with an EF ≤30% and a recent history of CV-related hospitalisation. The study investigators attempted to minimise the risk of hyperkalaemia by excluding patients with baseline K+ >5.0 mmol/l and severe renal dysfunction, serially measuring potassium and adjusting the dose of study medication. The risk of hyperkalaemia is likely to be greater in a general population of ambulatory HF patients and may be a potential barrier to incorporating MRAs into everyday clinical practice,3 particularly in patients hospitalised for acute HF syndromes (AHFS) who may have an increase in serum K+ and often experience worsening renal function during hospitalisation and/or soon after discharge.4

Despite the promise of MRAs, the mechanism by which this class of drugs decreases HF-related morbidity and mortality remains to be determined. There was an early and greater between-group difference in first HF hospitalisation and a delayed and smaller between-group difference in CVM. It is unlikely that fluid removal contributed significantly to the early decrease in HF hospitalisation, as this study utilised a non-natriuretic dose of eplerenone.5 Similarly, the late reduction in CVM is unlikely to be explained by decreased or reverse remodelling, as prior research found a comparable dose of eplerenone administered once daily for 9 months had no discernible effect on remodelling.6 Given the high postdischarge mortality and rehospitalisation rate characteristic of acute HF syndromes (AHFS), future research should focus on the use of MRAs in this high-risk patient population.4 Novel MRAs with superior selectivity for the mineralocorticoid receptor and enhanced anti-remodelling effects in preclinical studies are currently under development.


View Abstract


  • Competing interests MG has received consulting fees from Bayer Schering Pharma AG, DebioPharm SA, Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals and Pericor Therapeutics. He is also a consultant for Abbott Labs, Astellas, Astra Zeneca, Bayer Schering Pharma AG, CorThera, Cytokinetics, DebioPharm SA, Errekappa Terapeutici (Milan, Italy), GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Otsuka Pharmaceuticals, Pericor Therapeutics, Protein Design Laboratories, Sanofi Aventis, Sigma Tau, Solvay Pharmaceuticals. AA has no competing interests.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.