The EMPHASIS-HF trial: Eplerenone in mild systolic heart failure [Classics Series]

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1. Eplerenone significantly reduces mortality in patients suffering from heart failure with reduced systolic function (LVEF≤30%, or 30-35% if QRS>130 ms) and mild symptoms (NYHA class II) when compared with placebo

2. The incidence of hyperkalemia was significantly higher in the eplerenone group

Original Date of Publication: January 6, 2011

Study Rundown: Mineralocorticoid antagonists significantly improved survival in patients with severe systolic heart failure (i.e., LVEF<35% and NYHA class III/IV symptoms) in the RALES trial and in patients with heart failure after myocardial infarction in the EPHESUS trial. The purpose of the EMPHASIS-HF trial was to explore the effects of adding eplerenone, a type of mineralocorticoid antagonist, to evidence-based therapy in patients with systolic heart failure and only mild symptoms (i.e., LVEF<35% and NYHA class II symptoms). The findings demonstrated that eplerenone significantly reduces the risk of death from cardiovascular causes and hospitalization for heart failure (HR 0.63; 95%CI 0.54-0.74). While there was a significantly higher risk of hyperkalemia in the eplerenone group, there were no significant differences between the two groups in the rate of drug withdrawal for hyperkalemia.

This study, along with the RALES and EPHESUS trials, demonstrate that mineralocorticoid antagonism in patients with symptomatic systolic heart failure improves mortality and reduces hospitalization. One criticism of the trial was that the study population only differed from the RALES population based on their subjective NYHA classification. Thus, critics argued that it was difficult to determine whether there was really a true enough difference between the study populations. While it is true that the NYHA classification is subjective, it is one of the best prognostic tools for heart failure patients, and the rates of mortality observed in the EMPHASIS-HF trials were much lower than those seen in the RALES trial, suggesting there was a difference in the severity of disease.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: Originally published in NEJM in 2011, this randomized, controlled trial involved 2,737 patients recruited at 278 centres in 29 countries. Patients were considered eligible for the trial if they were ≥55 years of age, had NYHA class II symptoms, LVEF≤30% (or 30-35% if QRS>130 ms), and were being treated with ACE-I/ARB and a beta-blocker at recommended or maximal tolerated doses, unless contraindicated. Patients were excluded if they were having acute myocardial infarction, NYHA class III/IV symptoms, serum potassium >5.0 mmol/L, glomerular filtration rate <30 mL/min/1.73m², a need for potassium-sparing diuretic, or any other clinically significant coexisting condition. The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. Secondary outcomes included hospitalization for heart failure or death from any cause, death from any cause, and death from cardiovascular causes, among others.

A total of 1,364 patients were randomized to the eplerenone group, while 1,373 were randomized to the placebo group. At 3 years after randomization, the eplerenone group experienced a significantly lower rate of the primary outcome (HR 0.63; 95%CI 0.54-0.74) when compared to placebo. Notably, the eplerenone group experienced significantly lower rates of both death from cardiovascular causes (HR 0.76; 95%CI 0.61-0.94) as well as hospitalization for heart failure (HR 0.58; 95%CI 0.47-0.70). Moreover, patients treated with eplerenone also experienced significantly lower rates of death from any cause (HR 0.76; 95%CI 0.62-0.93) and hospitalization for any reason (HR 0.77; 95%CI 0.67-0.88). While rates of hyperkalemia were significantly higher in the eplerenone group (8.0% vs 3.7%, P<0.001), there were no significant differences in the rates of study drug withdrawal for hyperkalemia between the two groups.

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