What is the recommended treatment for patients with heart failure with reduced ejection fraction using Mineralocorticoid Receptor Antagonists (MRAs)?

Mineralocorticoid Receptor Antagonists for Heart Failure with Reduced Ejection Fraction

Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are recommended for all symptomatic patients with HFrEF and LVEF ≤35% despite treatment with an ACE inhibitor and beta-blocker, providing at least 20% mortality reduction and reducing sudden cardiac death. 1, 2

Indications and Patient Selection

Start MRAs in all symptomatic HFrEF patients (NYHA Class II-IV) with LVEF ≤35% who remain symptomatic despite ACE inhibitor/ARB and beta-blocker therapy. 1, 2

• MRAs are part of the foundational quadruple therapy that should be initiated as soon as possible after HFrEF diagnosis, alongside SGLT2 inhibitors, beta-blockers, and ARNI/ACE inhibitor/ARB 2
• The FDA specifically approves eplerenone for improving survival in stable patients with symptomatic HFrEF after acute myocardial infarction 3
• MRAs reduce both mortality and heart failure hospitalizations, with greater efficacy in HFrEF (hazard ratio 0.66) compared to HFmrEF/HFpEF (hazard ratio 0.87) 4

Dosing Strategy

Initiate eplerenone at 25 mg once daily and titrate to the target dose of 50 mg once daily within 4 weeks as tolerated. 3

• For spironolactone, start at 12.5-25 mg once daily and titrate to 25-50 mg once daily based on potassium levels and renal function 1, 2
• MRAs have minimal blood pressure effects, making them ideal for early initiation even in patients with borderline low blood pressure 2
• Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 2

Contraindications and Safety Thresholds

Do not initiate MRAs if serum potassium >5.0 mmol/L, creatinine clearance ≤30 mL/min, or in patients taking strong CYP3A inhibitors. 1, 3

• Absolute contraindications per FDA labeling include serum potassium >5.5 mEq/L at initiation and creatinine clearance ≤30 mL/min 3
• For hypertension indication only (not HFrEF), additional contraindications include type 2 diabetes with microalbuminuria, serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females, and concomitant potassium supplements 3
• Exercise caution in patients with impaired renal function and those with serum potassium levels >5.0 mmol/L 1

Monitoring Requirements

Check serum potassium and renal function before starting MRAs, at 1 week, 1 month, then every 3 months during the first year, and every 6 months thereafter. 1, 2

• Measure serum potassium before starting eplerenone and periodically thereafter per FDA guidance 3
• The risk of hyperkalaemia doubles with MRA use (odds ratio 2.27), but serious hyperkalaemia (potassium >6.0 mmol/L) remains low at 2.9% versus 1.4% with placebo 4
• MRAs actually reduce the risk of hypokalaemia by half (7% vs 14% with placebo), which is beneficial given the arrhythmogenic potential of low potassium 4

Dose Adjustments Based on Potassium Levels

If potassium rises to 5.5-5.9 mEq/L, reduce the MRA dose by 50%; if potassium ≥6.0 mEq/L, discontinue the MRA and restart at a lower dose once potassium normalizes. 2, 3

• For eplerenone specifically, dose adjustments are required based on potassium levels per FDA labeling 3
• Regular monitoring according to clinical status is essential to safely maintain therapy 1

Drug Interactions

When using moderate CYP3A inhibitors (verapamil, erythromycin, fluconazole) with eplerenone in post-MI HFrEF patients, do not exceed 25 mg once daily. 3

• Strong CYP3A inhibitors (ketoconazole, itraconazole, ritonavir) are absolute contraindications to eplerenone use 3
• Never combine ACE inhibitor + ARB + MRA (triple RAS blockade) due to increased risk of renal dysfunction and hyperkalemia 2, 5

Choice Between Spironolactone and Eplerenone

Both spironolactone and eplerenone are equally effective for reducing mortality and heart failure hospitalizations in HFrEF, but eplerenone has fewer hormonal side effects and better treatment adherence. 6, 7

• In a nationwide cohort study, there were no differences in clinical outcomes between eplerenone and spironolactone (HR 1.02 for composite outcome) 7
• Treatment withdrawal occurred in 34% with eplerenone versus 53% with spironolactone, suggesting better tolerability of eplerenone 7
• Spironolactone is less selective and can cause gynecomastia, breast tenderness, and menstrual irregularities due to binding to androgen and progesterone receptors 1
• Daily doses >25 mg at 12 months were achieved in 37% of eplerenone patients versus only 12% of spironolactone patients, indicating better dose optimization with eplerenone 7

Common Pitfalls to Avoid

Do not permanently discontinue MRAs for modest creatinine increases (<30% from baseline) if the patient is clinically stable, and do not withhold MRAs solely for asymptomatic low blood pressure with adequate perfusion. 2, 8

• Accepting suboptimal doses is a common error—always attempt to reach target doses of 50 mg daily for eplerenone or 25-50 mg daily for spironolactone 2
• Delaying initiation of MRAs as part of quadruple therapy leads to worse outcomes—start early alongside other guideline-directed medical therapies 2
• Inadequate monitoring of potassium and renal function increases risk of serious adverse events 2
• Stopping medications for laboratory abnormalities alone without clinical deterioration is inappropriate 8