Heart Failure After Myocardial Infarction
Eplerenone is used to improve survival following acute myocardial infarction in clinically stable patients with left ventricular dysfunction (i.e., left ventricular ejection fraction [LVEF] 40% or less) who have demonstrated clinical evidence of heart failure. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend therapy with an aldosterone antagonist (i.e., spironolactone, eplerenone) to reduce morbidity and mortality following acute myocardial infarction in patients with reduced LVEF (40% or less) who develop symptoms of heart failure or who have a history of diabetes mellitus, unless contraindicated. Efficacy of eplerenone for improving survival has been evaluated in a multicenter, randomized, double-blind, placebo-controlled study (the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; EPHESUS) involving 6632 patients with acute myocardial infarction complicated by congestive heart failure and left-ventricular dysfunction. Results of this study indicate that the addition of eplerenone (25-50 mg daily; mean dosage: 43 mg daily) to standard therapy (e.g., aspirin, nitrates, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, β-adrenergic blocking agents (β-blockers), hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors, loop diuretics) 3-14 days (mean: 7 days) after acute myocardial infarction reduced the risk of mortality from any cause, and of hospitalization or mortality from cardiovascular causes by 15 and 13%, respectively, compared with standard therapy and placebo. In addition, eplerenone reduced the risk of mortality or hospitalization from any cause by 8% and mortality from cardiovascular causes by 17%. Eplerenone did not appear to affect the rates of re-infarction.
Chronic Heart Failure
Eplerenone has been used in the management of chronic heart failure (New York Heart Association [NYHA] class II-IV) with reduced ejection fraction in conjunction with standard therapy for heart failure to increase survival and reduce heart failure-related hospitalizations.
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. ACCF and AHA recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure and reduced LVEF who are already receiving a β-blocker and an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, ARNI); careful patient selection is required to minimize the risk of hyperkalemia and renal insufficiency.
Aldosterone receptor antagonists are also recommended, unless contraindicated, in conjunction with standard heart failure therapy to reduce morbidity and mortality following acute myocardial infarction in patients with reduced LVEF who develop symptoms of heart failure or who have a history of diabetes mellitus. ACCF and AHA state that there are limited data to support or refute whether spironolactone and eplerenone are interchangeable. The perceived difference between eplerenone and spironolactone is attributed to the selectivity of aldosterone receptor antagonism and not the effectiveness of mineralocorticoid-blocking activity.
In a randomized, double-blind study (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure [EMPHASIS-HF]), in patients with mild heart failure symptoms (NYHA class II), eplerenone (in addition to therapy with an ACE inhibitor and/or angiotensin II receptor antagonist and β-blocker) reduced the risk of death and heart failure-related hospitalization compared with placebo. Patients enrolled in the study were at least 55 years of age, had an ejection fraction of 30% or less (mean: 26%), and were receiving treatment with a β-blocker and an ACE inhibitor and/or an angiotensin II receptor antagonist at the recommended or maximally tolerated dosage. Approximately 50% of patients had been previously hospitalized for heart failure and had a history of myocardial infarction. In patients with serum potassium concentration of 5 mEq/L or less, eplerenone was administered in a dosage of 25 mg once daily, which was increased after 4 weeks of therapy to 50 mg once daily; patients with decreased renal function (estimated glomerular filtration rate [eGFR] 30-49 mL/minute per 1.73 m) received an initial eplerenone dosage of 25 mg once every other day with an increase to 25 mg once daily after 4 weeks. Eplerenone substantially reduced the primary composite end point of death from cardiovascular causes or hospitalization for heart failure compared with placebo (18.3 versus 25.9%, respectively). Hyperkalemia (serum potassium exceeding 5.5 mEq/L) developed in approximately 12% of patients receiving eplerenone.
Eplerenone is used orally in the management of hypertension. The drug may be used as monotherapy or in combination with other classes of antihypertensive agents.
Because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics generally are considered the preferred drugs for the initial management of hypertension in adults; however, aldosterone antagonists (e.g., eplerenone, spironolactone) may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs. Aldosterone antagonists may be particularly useful in selected patients with heart failure or following myocardial infarction. For information on antihypertensive therapy for patients with heart failure or following myocardial infarction,
Safety and efficacy of eplerenone, given alone or in combination with other antihypertensive agents, in the treatment of hypertension have been evaluated in several placebo-controlled studies. In 2 studies of 8-12 weeks' duration, patients with baseline diastolic pressure of 95-114 mm Hg were randomized to receive eplerenone (25-400 mg daily, administered as a single dose or in 2 divided doses) monotherapy (611 patients) or placebo (140 patients). In these patients, eplerenone (50-400 mg daily) decreased placebo-corrected seated and standing trough systolic blood pressure (determined 4 hours before morning dose) by about 5-13 mm Hg and diastolic blood pressure by about 3-7 mm Hg. Antihypertensive effect of eplerenone was maintained through 8-24 weeks. Results of other studies indicate that in patients not receiving other antihypertensive drugs, blood pressure may return to pretreatment levels within 1 week following discontinuance of eplerenone. Although eplerenone has lowered blood pressure in all races studied, monotherapy with the drug has produced a smaller reduction in blood pressure during the initial dosage titration period in black hypertensive patients, a population associated with low-renin hypertension; however, this population difference in response does not appear to occur during continued therapy.
Eplerenone may be used in combination with other antihypertensive agents (e.g., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blocking agents, β-blockers, thiazide diuretics).
For information on overall principles and expert recommendations for the management of hypertension,