Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction Are Independent From its Diuretic and Potassium-Sparing Effects: Insights From an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) Substudy

Study Questions:

Are the beneficial effects of eplerenone following myocardial infarction due to its diuretic and potassium-sparing properties?


This is a secondary analysis from the EPHESUS trial, which examined the impact of the mineral corticoid antagonist, eplerenone, versus placebo following myocardial infarction in patients with systolic heart failure (HF) (left ventricular ejection fraction [LVEF] ≤40%). Of 6,632 enrolled patients, 552 were excluded due to lack of data at 1 month. These patients were older and sicker. The diuretic effect endpoint was defined as: 1) a weight reduction of >0.05 kg at 1 month, or 2) a plasma volume reduction >1.4% at 1 month. The K-sparing effect was defined as a change from baseline >0.11 mmol/L, which was the median change in the placebo group. Several outcomes were assessed including all-cause death, cardiovascular death or hospitalization, all-cause death or cardiovascular hospitalization, and hospitalization for HF.


The mean ± standard deviation patient age was 64 ± 12 years, 71% were male, mean estimated glomerular filtration rate was 69 ± 19 ml/min/1.73 m2, mean potassium was 4.3 ± 0.4 mmol/L, and mean LVEF was 33 ± 6%. After 1 month of therapy, patients in the eplerenone group demonstrated a greater diuretic effect with greater weight loss (<0.0001), and a decrease in an estimated plasma volume (p < 0.047). By month 3, there was no difference in diuretic effect between the two groups (p = 0.74). While both groups had an increase in potassium at follow-up, patients in the eplerenone group had overall higher potassium levels at months 1 (p < 0.0001) and 3 (p < 0.009) than placebo, and placebo patients were more likely to be on potassium supplements (p < 0.0006). Irrespective of treatment group, a diuretic effect manifested as a decrease in plasma volume was associated with an 11-19% reduction in the tested cardiovascular outcomes, excluding sudden cardiac death and cardiovascular death. Likewise, patients with a follow-up potassium above the baseline median had a 12-34% improvement in outcomes excluding all-cause death or hospitalization and HF hospitalization. There was no interaction between cardiovascular outcomes and treatment with eplerenone.


The authors concluded that eplerenone’s impact on outcomes in patients with HF development post-myocardial infarction are independent of its effects on potassium and volume.


This is a very nice analysis of both eplerenone’s potential role in post-myocardial infarction outcomes as well as the role of patient volume status and electrolytes. The authors demonstrate three important findings. First, plasma volume reduction (but not body weight reduction) is associated with better outcomes. They suggest that this may be secondary to fluid redistribution rather than retention. Second, hypokalemia is detrimental. Finally, while eplerenone had both a diuretic and potassium-sparing effect, its early benefits in the post-myocardial infarction population are independent of these two factors. This supports eplerenone’s role in modulating the neurohormonal axis, rather than electrolytes, for outcome impact. However, this conclusion regarding its benefits only apply to those patients who survived the first month.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, SCD/Ventricular Arrhythmias, Acute Heart Failure, Chronic Heart Failure

Keywords: Myocardial Infarction, Ventricular Function, Left, Weight Loss, Diuretics, Body Weight, Spironolactone, Heart Failure, Systolic, Heart Diseases, Cause of Death, Hypokalemia, Cardiovascular Diseases, Stroke Volume, Hospitalization, Death, Sudden, Cardiac

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