What is the role of mineralocorticoid receptor antagonists, such as spironolactone (Spironolactone) and eplerenone (Eplerenone), in treating heart failure and resistant hypertension?

Mineralocorticoid Receptor Antagonists in Heart Failure and Resistant Hypertension

Mineralocorticoid receptor antagonists (spironolactone and eplerenone) are Class I, Level A therapies that reduce mortality by 30% and heart failure hospitalization by 35% in patients with HFrEF and should be prescribed to all symptomatic patients with LVEF ≤35% who remain symptomatic despite ACE inhibitor/ARB and beta-blocker therapy, provided potassium is <5.0 mEq/L and eGFR is >30 mL/min/1.73 m². 1, 2, 3

Primary Indications for MRA Therapy

Heart Failure with Reduced Ejection Fraction (HFrEF)

MRAs are indicated for all patients with LVEF ≤35% and NYHA Class II-IV symptoms to reduce morbidity and mortality. 1, 2, 3

• For NYHA Class II patients specifically, they must have either: cardiovascular hospitalization within the past 6-12 months OR elevated natriuretic peptides (BNP >250 pg/mL or NT-proBNP >500 pg/mL in men, >750 pg/mL in women) 3
• For NYHA Class III-IV patients, MRAs provide a 30% relative risk reduction in all-cause mortality with a number needed to treat of 9 for 2 years to prevent one death 2, 4
• Post-MI patients with LVEF ≤40% who develop HF symptoms or have diabetes mellitus should receive MRA therapy 2, 3

The evidence base includes three landmark trials: RALES (spironolactone in NYHA Class III-IV), EPHESUS (eplerenone post-MI with HF), and EMPHASIS-HF (eplerenone in NYHA Class II), all demonstrating significant mortality and morbidity reduction 1, 3

Resistant Hypertension

MRAs are indicated as add-on therapy for resistant hypertension when blood pressure remains uncontrolled on three or more antihypertensive agents including a diuretic. 1, 4, 5

• Spironolactone 25-50 mg daily is particularly effective in low-renin and salt-sensitive hypertension 5
• The combined use of spironolactone with adequate doses of a thiazide diuretic maximizes efficacy and reduces hyperkalemia risk 5
• Eplerenone is an appropriate alternative if spironolactone causes sexual side effects 5

Absolute Contraindications

Do NOT prescribe MRAs if any of the following are present: 1, 2, 3

• 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
• Concomitant use of both ACE inhibitor AND ARB (triple RAAS blockade)

These exclusion criteria were uniformly applied in all major clinical trials (RALES, EPHESUS, EMPHASIS-HF, TOPCAT) to prevent life-threatening hyperkalemia 1

Dosing Protocol

Start with spironolactone 25 mg daily OR eplerenone 25 mg daily. 2, 3, 4

• For patients with eGFR 31-49 mL/min/1.73 m², reduce starting dose by half (12.5 mg daily) 3
• Target doses: spironolactone 25-50 mg daily, eplerenone 50 mg daily 1, 2, 6
• Titrate eplerenone to 50 mg daily within 4 weeks if tolerated 6
• The mean daily dose in RALES was 26 mg, with dose adjustments based on tolerance 4

Mandatory Monitoring Protocol

Check serum potassium and renal function at the following intervals: 2, 3, 7

• 1 week after initiation
• 4 weeks after initiation
• 8 weeks and 12 weeks
• 6,9, and 12 months
• Every 4 months indefinitely thereafter

This intensive monitoring schedule is critical because hyperkalemia-associated morbidity and mortality increased following widespread spironolactone use after RALES publication 1

Management of Hyperkalemia During Treatment

Follow this algorithmic approach based on potassium levels: 1, 3, 7

Potassium 5.0-5.5 mEq/L

• Continue MRA at current dose with close monitoring 1, 7
• Some guidelines recommend reducing dose by 50% 7
• Recheck potassium within 1 week 7

Potassium 5.5-6.0 mEq/L

• Reduce MRA dose by 50% 1, 3, 7
• Discontinue all potassium supplements immediately 7
• Evaluate entire medication regimen for other contributors to hyperkalemia 7
• Recheck potassium within 1 week 7

Potassium >6.0 mEq/L

• Immediately discontinue MRA 1, 3, 7
• This represents a Class 3: Harm recommendation to avoid life-threatening hyperkalemia 7

Creatinine-Based Adjustments

• Hold MRA if creatinine rises to >3.5 mg/dL 7
• Halve dose if creatinine rises to >2.5 mg/dL 7
• Consider dose reduction or holding if eGFR falls to ≤30 mL/min/1.73 m² 7

Critical Clinical Pitfalls to Avoid

Do not prematurely discontinue MRAs for mild hyperkalemia (4.8-5.0 mEq/L). 3 Current guidelines suggest revisiting the traditional cutoffs, as observational data show worse outcomes with premature MRA discontinuation compared to clinical trials 1, 7

Avoid NSAIDs in all heart failure patients on MRAs. 3 NSAIDs increase hyperkalemia risk and worsen renal function, particularly when combined with RAAS inhibitors 1

Do not combine ACE inhibitor + ARB + MRA (triple RAAS blockade). 3 This combination substantially increases hyperkalemia risk without proven additional benefit 1

Temporarily hold MRAs during acute decompensation, diarrhea causing dehydration, or loop diuretic therapy interruption. 7 Re-institution should be attempted before hospital discharge 1

Spironolactone vs. Eplerenone: Practical Considerations

Both agents have equivalent efficacy for mortality and morbidity reduction in HFrEF, but differ in side effect profiles. 6, 8

• Spironolactone causes gynecomastia and sexual side effects more frequently in men due to anti-androgenic effects 1, 6
• Eplerenone is more mineralocorticoid receptor-specific with fewer sexual side effects but is less potent 6, 9
• Treatment withdrawal occurs in 34% with eplerenone vs. 53% with spironolactone, likely due to better tolerability 8
• Eplerenone is more commonly titrated to >25 mg daily (37% vs. 12% for spironolactone) 8
• Both agents carry equal hyperkalemia risk in clinical trials 6

Choose eplerenone if spironolactone causes gynecomastia, breast tenderness, or sexual dysfunction. 1, 5, 6

Special Populations

Heart Failure with Preserved Ejection Fraction (HFpEF)

MRAs may be considered in HFpEF to decrease risk of HF hospitalization, though evidence is weaker than for HFrEF. 1, 3

• The TOPCAT trial showed reduced HF hospitalization but no cardiovascular mortality benefit 1
• This represents a Class IIa recommendation compared to Class I for HFrEF 1

Sex-Related Differences

Women may achieve optimal benefit at half the guideline-recommended doses compared to men. 1 Spironolactone produces gynecomastia and hyperkalemia more frequently in men, while eplerenone induces more frequent early decline in eGFR in women 1

Post-Myocardial Infarction

MRAs are indicated for post-MI patients with LVEF ≤40% who develop HF symptoms or have diabetes mellitus. 2, 3 The EPHESUS trial demonstrated a 15% mortality reduction in this population 3