What are examples of Mineralocorticoid Receptor Antagonists (MRAs) and their indications with dosing?

Mineralocorticoid Receptor Antagonists (MRAs): Examples and Indications with Dosing

Available MRA Medications

Two steroidal MRAs are approved and recommended for heart failure: spironolactone and eplerenone. 1 A newer non-steroidal MRA, finerenone, has recently been studied for heart failure with preserved ejection fraction. 2, 3

Primary Indications with Dosing

Heart Failure with Reduced Ejection Fraction (HFrEF)

MRAs are Class I, Level A recommended for all patients with HFrEF (LVEF ≤40%) and NYHA class II-IV symptoms to reduce morbidity and mortality. 1

Specific Dosing Regimens:

Spironolactone: 1

• Starting dose: 25 mg orally once daily
• Target dose: 50 mg orally once daily after 1 month
• Dose adjustment for renal impairment: For eGFR 31-49 mL/min/1.73 m², reduce dose by half (12.5 mg daily initially)

Eplerenone: 1, 4

• Starting dose: 25 mg orally once daily
• Target dose: 50 mg orally once daily, titrated within 4 weeks as tolerated
• Dose adjustment for renal impairment: For eGFR 31-49 mL/min/1.73 m², reduce dose by half

Post-Myocardial Infarction with LV Dysfunction

MRAs are recommended for patients following acute MI with LVEF ≤40% who develop heart failure symptoms or have diabetes. 1

Eplerenone dosing post-MI: 1, 4

• Initiate at 25 mg once daily
• Titrate to maximum 50 mg once daily within 4 weeks

Heart Failure with Preserved Ejection Fraction (HFpEF)

For HFpEF (LVEF ≥40%), MRAs reduce heart failure hospitalizations but not cardiovascular mortality. 2 The non-steroidal MRA finerenone has shown benefit in this population. 3

Absolute Contraindications

Do not initiate MRA therapy if: 1, 4

• Serum potassium >5.0 mEq/L at baseline
• eGFR ≤30 mL/min/1.73 m²
• Serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women (for hypertension indication)
• Concomitant use with strong CYP3A inhibitors

Critical Monitoring Protocol

Check serum potassium and renal function at these specific intervals: 1, 5

• 1 week after initiation or dose increase
• 4 weeks after initiation or dose increase
• At 8 and 12 weeks
• At 6,9, and 12 months
• Every 4 months thereafter

Dose Adjustment Algorithm Based on Potassium:

If potassium 5.5-6.0 mEq/L: 5

• Reduce MRA dose by 50%
• Recheck potassium within 3-7 days

If potassium >6.0 mEq/L: 5

• Immediately discontinue MRA
• Recheck potassium within 24-48 hours

If potassium >5.5 mEq/L cannot be maintained below this level: 1

• Discontinue MRA permanently to avoid life-threatening hyperkalemia

Common Pitfalls and How to Avoid Them

Underutilization remains the biggest problem—only 33% of eligible patients receive MRAs despite Class I recommendations. 1 This represents a critical treatment gap.

Sex-specific adverse effects differ between agents: 1

• Spironolactone causes gynecomastia more frequently in men, leading to higher discontinuation rates in males 1, 6
• Eplerenone causes more frequent early decline in eGFR in women 1
• Consider eplerenone in men concerned about gynecomastia

Treatment withdrawal is significantly higher with spironolactone (53%) versus eplerenone (34%) at 2 years. 6 This suggests eplerenone may have better long-term tolerability despite similar efficacy.

Do not discontinue beneficial MRA therapy prematurely for mild hyperkalemia (5.0-5.5 mEq/L). 5 Instead, reduce dose by 50% and optimize other medications that may contribute (NSAIDs, potassium supplements).

Avoid NSAIDs in all heart failure patients on MRAs—they cause fluid retention, attenuate diuretic effects, and increase hyperkalemia risk. 5

When using moderate CYP3A inhibitors (verapamil, erythromycin, fluconazole) with eplerenone: 4

• Do not exceed 25 mg once daily in post-MI HFrEF patients
• In hypertension, start at 25 mg once daily, maximum 25 mg twice daily

Clinical Efficacy Data

In HFrEF, MRAs provide: 1, 2

• 30% relative risk reduction in all-cause mortality
• 35% relative risk reduction in heart failure hospitalization
• Number needed to treat = 9 for 2 years to prevent one death

In HFmrEF/HFpEF, MRAs provide: 2

• 13% relative risk reduction in cardiovascular death or HF hospitalization
• 18% relative risk reduction in heart failure hospitalization
• No significant reduction in cardiovascular or all-cause mortality

MRAs are designated as "High Value" therapy by ACC/AHA guidelines for economic benefit. 1