Continuing Education Activity

Eplerenone is a medication used in the management and treatment of heart failure with reduced ejection fraction and hypertension. It is in the aldosterone antagonist class of drugs. This activity outlines the indications, action, and contraindications for eplerenone as a valuable agent in managing heart failure and hypertension. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, and monitoring) pertinent for members of the interprofessional team in treating patients with hypertension, heart failure, and related conditions.

Objectives:

• Identify the mechanism of action and administration of eplerenone as regards its use in heart failure and hypertension.
• Describe the potential adverse effects of eplerenone.
• Outline appropriate monitoring for patients on therapy with eplerenone.
• Review interprofessional team strategies for improving care coordination and communication to support optimal medication outcomes for patients prescribed eplerenone.

Indications

Eplerenone is classified as an aldosterone antagonist and has been available in the United States since 2002.  Eplerenone’s key advantage over its older and less expensive drug in its class, spironolactone, is its increased selectivity for the mineralocorticoid receptor relative to glucocorticoid, progesterone, and androgen receptors.

Eplerenone is approved by the Food and Drug Administration (FDA) for:

• The improvement of survival of stable patients with left ventricular (LV) systolic dysfunction (left ventricular ejection fraction less than or equal to 40%) and congestive heart failure (CHF) after an acute myocardial infarction (MI)
• Hypertension, alone or combined with other agents.[1][2]

Though the FDA specifies eplerenone’s use in heart failure specifically to those status-post myocardial infarctions (MI), it also has off-label use for general heart failure patients with an ejection fraction (EF) less than or equal to35%, especially when they have experienced an adverse effect to spironolactone. The use of eplerenone in these populations has support from the EPHESUS and EMPHASIS-HF randomized controlled trials, respectively.[3][4] 

Concerning its use in hypertension, eplerenone is not a recommended agent for the initial treatment of hypertension. However, eplerenone and spironolactone are preferred agents for patients with hypertension due to primary aldosteronism or resistant hypertension. Eplerenone has not been subject to prospective comparisons to spironolactone or other agents in head-to-head trials of resistant hypertension but may be used as an alternative to spironolactone, especially when a patient has experienced antiandrogen adverse effects from spironolactone.

As an aldosterone antagonist, it is also used off-label to treat primary aldosteronism and ischemic heart disease.[5][6][7]

Mechanism of Action

Aldosterone is a mineralocorticoid that acts on both epithelial (e.g., kidney) and nonepithelial (e.g., heart and blood vessels) receptors to induce sodium and water reabsorption. In addition to its hypertensive effects, aldosterone is implicated in the progression of myocardial fibrosis, especially following myocardial infarction. Eplerenone binds to mineralocorticoid receptors competitively, antagonizing aldosterone. Eplerenone’s main mechanistic advantage relative to spironolactone is that it has a 100 to 1000-fold lower binding affinity to glucocorticoid, progesterone, and androgen receptors.[8]          

Administration

Eplerenone is only administered orally without regard to food. It achieves peak plasma concentrations 1.5 hours after oral administration with a bioavailability of approximately 70%. Though some sources state that 25 mg of spironolactone is equivalent to 50 mg of eplerenone, there are no head-to-head clinical trials of these agents.  

For patients with heart failure, the 2013 ACCF/AHA Guideline for the Management of Heart Failure (HF) recommends a starting dose of 25 mg once daily and titrate to a goal dose of 50 mg once daily after four weeks of treatment, potassium less than or equal to 5 mEq/L and adequate renal function (estimated glomerular filtration rate, eGFR greater than or equal to 50 mL/minute/1.73 m^2).[9]

Due to its shorter half-life of 3 to 6 hours, the 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, as well as the 2016 Endocrine Society guideline on primary aldosteronism, admonish that twice-daily dosing may be necessary for optimal effect.[10][5] 

Renal dose adjustments are necessary with the use of eplerenone as described below:

For hypertension (manufacturer's labeling)

• Contraindicated in creatinine clearance (CrCl) less than 50 mL/minute or serum creatinine greater than 2mg/dL (males) or over 1.8 mg/dL (females)
• HF, post-MI (manufacturer's labeling)
• Use with caution in CrCl 31 to 50 mL/minute or serum creatinine exceeding 2mg/dL (males) or 1.8 mg/dL (females)
• Contraindicated in CrCl less than or equal to 30 mL/minute

According to the 2013 ACCF/AHA Guideline for the Management of Heart Failure recommendation for HF (including post-MI)[9]:

• eGFR 30 to 49 mL/min/1.73m2 initiate a starting dose of 25 mg once every other day and titrate to a goal dose of 25 mg once daily after four weeks of treatment and potassium less than or equal to 5 mEq/L
• Contraindicated in eGFR below 30 mL/min

Adverse Effects

Hyperkalemia is by far the most common adverse effect of eplerenone. Clinical trial experience indicates an approximately 1.5 to 2.0 fold risk of hyperkalemia, with a number needed to harm ranging from 23 to 62. While serious hyperkalemia (greater than or equal to 6 mEq/L) was more common in both the EMPHASIS and EPHESUS trials, the adverse effect was usually manageable by reducing the dose or temporarily discontinuing the drug. In contrast, hypokalemia—which correlates with an increased risk of death from any cause among heart failure patients—was significantly reduced. Though serum creatinine may rise on eplerenone, the EMPHASIS-HF trial found no increased risk of renal failure.

Notably absent as a side effect is gynecomastia, which occurred in about 9% of the patients taking spironolactone in the RALES trial.[11] In both the EMPHASIS-HF and EPHESUS trials, gynecomastia was no more common in patients taking eplerenone compared to placebo. Indeed, researchers have used eplerenone to reverse the effects of spironolactone-induced gynecomastia in small trials of patients with cirrhosis or primary hyperaldosteronism.[12][13]  

Contraindications

Clinicians should not start eplerenone therapy in patients with potassium greater than 5.5 mEq/L or a CrCl less than 30 mL/min, as these increase the risk of serious hyperkalemia. Since eplerenone metabolism is via CYP3A4, potent CYP3A4 inhibitors (including specific protease inhibitors, azole antifungals, and clarithromycin) may increase eplerenone to unsafe blood concentrations. 

Of note, when used for hypertension, more stringent contraindications are applied:

• Types 2 diabetes with microalbuminuria
• Serum creatinine over 2.0 mg/dL in males and 1.8 mg/dL in females or a CrCl below 50mL/min
• Concomitant use of potassium supplementation or potassium-sparing diuretics

Since Addison disease characteristically demonstrates an aldosterone deficiency, eplerenone is also contraindicated in these patients.

Monitoring

Though eplerenone's indications include the treatment of hypertension, its effects on blood pressure likely depend on the population studied.  For example, in the EMPHASIS-HF study, systolic blood pressure decreased by a mean of 2.2 mmHg relative to the placebo group.  In contrast, systolic blood pressure increased in the EPHESUS trial by 3 mmHg relative to the placebo group (presumably), reflecting the improved recovery of cardiac output).

Serum creatinine and potassium require monitoring for all indications, but patients with HF are most vulnerable to hyperkalemia.  To this end, the 2013 ACCF/AHA Guideline for the Management of Heart Failure recommends serum potassium, and renal function check occurs on the following schedule after initiation: 3 days, one week, monthly for the first three months of therapy and every three months thereafter. If either of these parameters worsens, hold eplerenone until the potassium is less than 5 mEq/L and consider restarting with a reduced dose after confirming resolution of the metabolic abnormality for at least 72 hours.[9]

Toxicity

There are no known overdose reports of eplerenone, but the most likely manifestations of overdose would be hypotension or hyperkalemia.  Researchers have not observed any lethality in overdose studies in mice, rats, or dogs, but dogs demonstrated emesis, salivations, and tremors at a concentration 41 times the human therapeutic concentration of eplerenone. These progressed to sedation and convulsions at higher exposures.  

Should toxicity occur, eplerenone binds extensively to charcoal but is not removable by hemodialysis. There is no specific antidote to eplerenone; thus, supportive treatment for hypotension or hyperkalemia would be necessary. Eplerenone is not dialyzable.

Enhancing Healthcare Team Outcomes

Over two decades of experience have demonstrated the effect of aldosterone antagonists on survival and hospitalizations in heart failure patients with reduced ejection fraction. Therefore, one of the chief duties of the interprofessional healthcare team is to ensure that such patients receive aldosterone antagonists, including eplerenone, when appropriate, as part of guideline-directed medical therapy. Pharmacists should review the dose, check for drug interactions, and provide patient education. Specialty trained nurses such are cardiology nurses monitor patients, provide education, and report status changes to the team. These examples of interprofessional interaction and collaboration should lead to more effective use of eplerenone. [Level 5]

As regards safety, regular lab monitoring is of paramount importance for patients taking eplerenone. Following the release of the RALES trial, hospitalizations and deaths secondary to serious hyperkalemia significantly increased.[14] Researchers postulated this to be due to the increased use of spironolactone without the close lab monitoring utilized during the clinical trial. Since patients with heart failure are often co-managed by primary care clinicians and specialists, it is easy to become siloed and assume the other clinician is monitoring therapy. When used for patients who have experienced gynecomastia on spironolactone, the patient requires monitoring to resolve this adverse effect.

Finally, though eplerenone is now generic, it is more expensive than spironolactone.