Is spironolactone (mineralocorticoid receptor antagonist) a suitable treatment option for a patient with heart failure with mid-range ejection fraction (HFmrEF)?

Spironolactone for Heart Failure with Mid-Range Ejection Fraction (HFmrEF)

Spironolactone may be considered for patients with HFmrEF (LVEF 41-49%), particularly those with ejection fractions at the lower end of this spectrum (41-45%), elevated natriuretic peptides, or recent heart failure hospitalization, though the evidence is weaker than for HFrEF and SGLT2 inhibitors should be prioritized first. 1

Strength of Recommendation

The ACC/AHA/HFSA guidelines provide only a Class 2b recommendation for spironolactone in HFmrEF, meaning it "may be considered" but is not a standard therapy. 1 This contrasts sharply with the Class I recommendation for HFrEF (LVEF ≤35-40%), where spironolactone reduces mortality by 30% and heart failure hospitalizations by 35%. 2

SGLT2 inhibitors carry stronger evidence (Class 2a recommendation) in HFmrEF and should be prioritized if not already prescribed. 1

Evidence Base and Efficacy

The evidence supporting spironolactone in HFmrEF comes primarily from post-hoc analyses rather than dedicated prospective trials:

• Post-hoc analysis of TOPCAT examined 520 patients with LVEF 44-49% and demonstrated reduction in the composite endpoint of cardiovascular death, heart failure hospitalization, or resuscitated sudden death, driven mainly by cardiovascular mortality reduction. 1

• Real-world registry data from Japan (457 HFmrEF patients) showed spironolactone use at discharge was associated with a 37% reduction in the composite of all-cause death or HF rehospitalization (adjusted HR 0.63,95% CI 0.44-0.90, p=0.010). 3

• Chinese observational study (279 HFmrEF patients) demonstrated significantly lower death and HF-rehospitalization rates with spironolactone compared to untreated patients (21.3% vs 34.5%, p=0.014). 4

• Post-hoc analyses suggest efficacy is greatest at the lower end of the LVEF spectrum, meaning patients with LVEF 41-45% are more likely to benefit than those with LVEF 46-49%. 5, 2

Patient Selection Criteria

Only initiate spironolactone in HFmrEF patients who meet ALL of the following criteria: 1

• Symptomatic heart failure (NYHA Class II-IV) 1
• Elevated BNP/NT-proBNP levels or heart failure hospitalization within the past year 1
• eGFR >30 mL/min/1.73m² and creatinine <2.5 mg/dL 1
• Serum potassium <5.0 mEq/L at baseline 1
• Already on optimal doses of ACE inhibitor/ARB and beta-blocker 2

Dosing Strategy

• Start with 12.5-25 mg once daily 2, 1
• Titrate to target dose of 25-50 mg once daily after 4-8 weeks if tolerated and potassium remains <5.0 mEq/L 2, 1
• For patients intolerant of 25 mg daily, reduce to 25 mg every other day 2
• Maximum recommended dose is 50 mg daily 2
• Chinese data showed no additional benefit from 50 mg versus 25 mg daily dosing 4

Critical Monitoring Protocol to Prevent Life-Threatening Hyperkalemia

Intensive monitoring is mandatory: 1

• Check potassium and creatinine within 3 days of initiation 2, 1
• Recheck at 1 week 2, 1
• Then monthly for 3 months 2, 1
• Then every 3 months thereafter during stable therapy 2, 1

Hyperkalemia management algorithm: 2

• Potassium 5.0-5.5 mEq/L: Continue current dose with close monitoring
• Potassium >5.5 mEq/L: Halve the spironolactone dose and recheck within 3 days
• Potassium >6.0 mEq/L: Stop spironolactone immediately

Common Pitfalls and Caveats

• Do not combine spironolactone with other potassium-sparing diuretics (amiloride, triamterene) as hyperkalemia risk increases dramatically 2, 6

• Hyperkalemia risk is particularly elevated when combined with ACE inhibitors/ARBs, which is the typical clinical scenario in HFmrEF 6

• Gynecomastia occurs in approximately 10% of men on spironolactone; consider switching to eplerenone if this occurs 2

• Many HFmrEF patients have underlying renal dysfunction, requiring extra vigilance with potassium and creatinine monitoring 6

• The benefit observed in TOPCAT was driven entirely by the Americas cohort, with no benefit in Russia-Georgia where medication adherence was questionable 2, 1

Clinical Decision Algorithm

For a patient with HFmrEF, follow this sequence:

1. First, ensure SGLT2 inhibitor is prescribed (stronger evidence, Class 2a) 1
2. Consider spironolactone if:
   • LVEF is 41-45% (lower end of HFmrEF spectrum) 5, 2
   • Elevated natriuretic peptides or recent HF hospitalization 1
   • Potassium <5.0 mEq/L and creatinine <2.5 mg/dL 1
   • Already on ACE inhibitor/ARB and beta-blocker 2
3. Do NOT use spironolactone if:
   • Potassium ≥5.0 mEq/L or creatinine ≥2.5 mg/dL 1
   • eGFR ≤30 mL/min/1.73m² 1
   • Patient cannot comply with intensive monitoring 1