, Volume 64, Issue 23, pp 2689-2707
Date: 19 Sep 2012

Eplerenone

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Summary

Abstract

Eplerenone (Inspra™) is a selective aldosterone blocker. Oral eplerenone is approved for use in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI) in the US and in European countries (e.g. the UK and The Netherlands).

The addition of eplerenone to standard medical therapy significantly improved mortality and morbidity in patients with LV systolic dysfunction and clinical evidence of heart failure following acute MI in the large, well designed EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study) trial. The beneficial effects of eplerenone on all-cause mortality and cardiovascular mortality were seen within 30 days of randomisation. Eplerenone was generally well tolerated. Although a higher incidence of hyperkalaemia occurred with eplerenone than with placebo, the incidence of hypokalaemia was significantly lower with eplerenone treatment. Thus, the addition of eplerenone to standard medical therapy is an important new strategy for further improving mortality and morbidity in post-MI patients with LV systolic dysfunction and heart failure.

Pharmacological Properties

Eplerenone is a 9α, 11α-epoxy-derivative of mexrenone that binds preferentially to the mineralocorticoid receptor. Compared with spironolactone, eplerenone was ≈370-fold less potent at inhibiting activation of the androgen receptor and devoid of agonist activity at the progesterone receptor in vitro and, unlike spironolactone, eplerenone did not have antiandrogenic or progestagenic effects in animal models.

Eplerenone ameliorated maladaptive LV remodelling in rat models of MI, with the greatest benefits occurring in rats receiving eplerenone plus the ACE inhibitor trandolapril compared with rats receiving placebo. Increases in LV end-diastolic pressure and volume were significantly attenuated with eplerenone versus placebo. Moreover, eplerenone attenuated reactive fibrosis, without exacerbating infarct expansion or impairing infarct healing. Eplerenone demonstrated additional effects in animal models that may contribute to its cardioprotective effects, including attenuating increases in neurohormone and natriuretic peptide levels, and ameliorating platelet activation, endothelial dysfunction and Superoxide production.

In healthy volunteers, a mean maximum plasma concentration (Cmax) of 1.72 μg/mL was reached after 1.3 hours with a mean area under the plasma concentration-time curve (AUC) of 9.54 μg · h/mL following a single oral dose of eplerenone 100mg. Steady-state eplerenone concentrations are reached within 2 days. In patients with stable heart failure receiving eplerenone 50mg, the steady-state Cmax and AUC were 30% and 38% higher than in healthy volunteers receiving the same dose. Eplerenone is extensively metabolised; this metabolism is primarily mediated by the cytochrome P450 (CYP) isozyme CYP3A4, with no active metabolites detected in human plasma. The eplerenone elimination half-life was ≈4–6 hours. The potent CYP3A4 inhibitor ketoconazole increased the eplerenone AUC 5-fold; concomitant administration of eplerenone and potent CYP3A4 inhibitors is contraindicated. European prescribing information recommends that eplerenone not be coadministered with strong inducers of CYP3A4 such as St John’s wort, rifampicin (rifampin), carbamazepine, phenytoin and phenobarbital, due to the risk of decreased efficacy.

Therapeutic Efficacy

The addition of eplerenone (target dosage 50 mg/day) to standard medical therapy significantly improved mortality and morbidity in patients with LV systolic dysfunction and clinical evidence of heart failure following acute MI, according to the results of the large (n = 6632), well designed EPHESUS study. Compared with placebo recipients, eplerenone recipients had significant reductions in all-cause mortality and the combined endpoint of cardiovascular mortality or first hospitalisation for a cardiovascular event (primary endpoints) and in cardiovascular mortality and the combined endpoint of all-cause mortality or any hospitalisation (major secondary endpoints) after a mean 16 months of follow-up. The reduction in cardiovascular mortality was largely due to a significantly lower incidence of sudden death from cardiac causes with eplerenone than with placebo. The beneficial effects of eplerenone on all-cause mortality and cardiovascular mortality were seen within 30 days of randomisation.

Eplerenone recipients were significantly less likely than placebo recipients to be hospitalised for heart failure, and eplerenone recipients experienced significantly fewer hospitalisation episodes for cardiovascular events than placebo recipients.

Additional retrospective analyses of the EPHESUS study revealed that the mean length of hospital stay was significantly shorter with eplerenone than with placebo, and that eplerenone had beneficial effects on morbidity and mortality in patients with a history of hypertension at baseline and in patients with diabetes mellitus and signs of heart failure. In addition, eplerenone improved morbidity and mortality to a similar extent regardless of whether or not patients received reperfusion therapy. Moreover, eplerenone was a cost-effective option in patients with LV systolic dysfunction and heart failure following acute MI.

Tolerability

Eplerenone was generally well tolerated in patients with LV systolic dysfunction and heart failure following acute MI in the EPHESUS study. Gastrointestinal disorders occurred significantly more frequently in eplerenone than in placebo recipients, and respiratory disorders such as cough, dyspnoea and pneumonia occurred significantly less frequently.

There were no significant differences between eplerenone and placebo recipients in the proportion of men experiencing gynaecomastia or impotence, or women experiencing breast pain (incidence <1%).

Overall, metabolic and nutritional disorders occurred significantly less frequently in eplerenone than in placebo recipients; specifically, hypokalaemia, serious hypokalaemia and hypoglycaemia occurred significantly less frequently with eplerenone than with placebo. Hyperkalaemia and serious hyperkalaemia occurred significantly more frequently with eplerenone than with placebo. A post hoc analysis found that the hyperkalaemia that occurred with eplerenone in the EPHESUS study was predictable, manageable and nonfatal.