What are the guidelines for the use of Mineralocorticoid Receptor Antagonists (MRAs) in heart failure?

Guidelines for Mineralocorticoid Receptor Antagonist Use in Heart Failure

MRAs (spironolactone or eplerenone) are strongly recommended for all symptomatic patients with HFrEF (LVEF ≤35-40%) who remain symptomatic despite ACE inhibitor/ARB and beta-blocker therapy, provided eGFR is >30 mL/min/1.73 m² and serum potassium is <5.0 mEq/L. 1

Indications by Heart Failure Type

Heart Failure with Reduced Ejection Fraction (HFrEF)

Class I Recommendation (Strongest Evidence):

• All patients with LVEF ≤35% and NYHA Class II-IV symptoms should receive an MRA in addition to ACE inhibitor/ARB/ARNI and beta-blocker therapy to reduce mortality and HF hospitalization 1
• For NYHA Class II patients specifically, they should have either a history of 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) 1
• Post-MI patients with LVEF ≤40% who develop HF symptoms or have diabetes mellitus should receive MRA therapy 1

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

Class IIb Recommendation (May Be Considered):

• In patients with LVEF 41-49% and current or previous symptomatic HF, MRAs may be considered to reduce HF hospitalization and cardiovascular mortality, particularly in those with LVEF on the lower end of this spectrum 1

Heart Failure with Preserved Ejection Fraction (HFpEF)

Class IIb Recommendation:

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

Absolute Contraindications

Do NOT prescribe MRAs if:

• Serum potassium ≥5.0 mEq/L at baseline 1
• eGFR ≤30 mL/min/1.73 m² 1
• Serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women 1
• Concomitant use of both ACE inhibitor AND ARB (triple RAAS blockade increases hyperkalemia risk) 1

Dosing Protocol

Initial Dosing:

• Start with spironolactone 25 mg daily OR eplerenone 25 mg daily 1, 2
• For patients with eGFR 31-49 mL/min/1.73 m², reduce starting dose by half (12.5 mg daily) 1

Titration:

• After 4 weeks, if potassium remains <5.0 mEq/L and renal function is stable, increase to spironolactone 50 mg daily OR eplerenone 50 mg daily 1, 2
• Target doses used in clinical trials: spironolactone 25-50 mg daily, eplerenone 50 mg daily 1

Mandatory Monitoring Protocol

Critical monitoring schedule to prevent life-threatening hyperkalemia:

Initial Phase:

• Check serum potassium and renal function at 1 week after initiation 1, 3
• Recheck at 4 weeks after initiation 1, 3
• Then at 8 weeks, 12 weeks 3

Maintenance Phase:

• Check at 6,9, and 12 months 3
• Subsequently every 4 months indefinitely 3
• More frequent monitoring required during clinical instability, dose changes, or addition of interacting medications 1

Management of Hyperkalemia

Potassium 5.0-5.5 mEq/L:

• Reduce MRA dose by 50% 3
• Recheck potassium within 3-7 days 1
• Review concomitant medications (NSAIDs, potassium supplements) 3
• Provide dietary counseling on low-potassium foods 4

Potassium 5.5-6.0 mEq/L:

• Discontinue or reduce MRA dose by half 1
• This threshold occurred in approximately 12% of patients in EMPHASIS-HF 1
• Identify and eliminate other causes (NSAIDs, potassium supplements, dietary sources) 3

Potassium >6.0 mEq/L:

• Immediately discontinue MRA 1, 3
• This represents life-threatening hyperkalemia requiring urgent management 1

Creatinine >3.5 mg/dL (310 μmol/L):

• Stop MRA immediately 3

Critical Clinical Pitfalls to Avoid

Common Errors:

• Do not prematurely discontinue MRAs for mild hyperkalemia (4.8-5.0 mEq/L) - even upper-normal potassium levels are associated with higher mortality risk, but this should not prevent appropriate MRA use 3
• Avoid NSAIDs in all HF patients on MRAs - they cause fluid retention, attenuate diuretic effects, and significantly increase hyperkalemia risk 3
• Do not combine ACE inhibitor + ARB + MRA (triple RAAS blockade) - this dramatically increases hyperkalemia and renal dysfunction risk 1
• Do not use in acute decompensated HF until patient is stabilized - initiate only after clinical stabilization 1

Underutilization Problem:

• Despite Class I recommendations, only 33% of eligible patients receive MRAs in real-world practice, representing a major treatment gap 1, 5
• The primary barrier is fear of hyperkalemia, but with proper monitoring protocols, risks are manageable 4, 5

Drug Selection Considerations

Both spironolactone and eplerenone are effective:

• Spironolactone is less selective and may cause gynecomastia in men (10-15% of patients) due to androgen receptor binding 1, 6
• Eplerenone is more selective for mineralocorticoid receptors with lower rates of hormonal side effects 6
• Both demonstrate equivalent mortality and morbidity benefits in their respective trials (RALES, EPHESUS, EMPHASIS-HF) 1, 6

Drug Interactions Requiring Dose Adjustment

Moderate CYP3A inhibitors (erythromycin, fluconazole, verapamil, saquinavir):

• Reduce eplerenone starting dose to 25 mg every other day 2
• Maximum dose should not exceed 25 mg daily 2

Strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir):

• Eplerenone is contraindicated 2

Evidence Base

The recommendation is supported by three landmark trials in HFrEF:

• RALES: spironolactone in NYHA Class III-IV reduced mortality by 30% 1
• EPHESUS: eplerenone post-MI with HF reduced mortality by 15% 1
• EMPHASIS-HF: eplerenone in NYHA Class II reduced cardiovascular death/HF hospitalization by 37% 1, 7

All trials excluded patients with potassium >5.0 mEq/L and significant renal impairment, establishing the safety parameters now used in guidelines 1