What is the role of spironolactone (Mineralocorticoid Receptor Antagonist) in treating Heart Failure with mid-range Ejection Fraction (HFmrEF)?

Spironolactone for Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

Spironolactone should be considered for patients with HFmrEF (LVEF 41-49%) to reduce heart failure hospitalizations and cardiovascular mortality, particularly in those with elevated natriuretic peptides or recent heart failure hospitalization. 1

Evidence Base and Guideline Recommendations

The 2022 ACC/AHA/HFSA guidelines provide a Class 2b recommendation for spironolactone in HFmrEF, indicating it "may be considered" based on post-hoc analyses of trials that included patients in this ejection fraction range. 1 This recommendation stems primarily from subgroup analyses rather than dedicated HFmrEF trials:

• TOPCAT post-hoc analysis examined 520 patients with LVEF 44-49% and demonstrated that spironolactone reduced the composite endpoint of cardiovascular death, heart failure hospitalization, or resuscitated sudden death, driven mainly by cardiovascular mortality reduction. 1 However, this benefit was predominantly seen in patients enrolled in North and South America, not in the Russia/Georgia cohort where medication adherence was questionable. 1

• Real-world registry data from Japan showed that among 457 HFmrEF patients, spironolactone use at discharge was associated with a 37% reduction in the composite of all-cause death or heart failure rehospitalization (adjusted HR 0.63,95% CI 0.44-0.90). 2

• Chinese observational data demonstrated that spironolactone (both 25 mg and 50 mg daily) significantly reduced death and heart failure rehospitalization compared to no treatment (21.3% vs 34.5%, p=0.014), with no additional benefit from higher dosing. 3

Patient Selection Criteria

Spironolactone is most appropriate for HFmrEF patients who meet the following criteria: 1

• LVEF 41-49% on echocardiography
• Symptomatic heart failure (NYHA Class II-IV)
• Elevated BNP/NT-proBNP levels or heart failure hospitalization within the past year
• eGFR >30 mL/min/1.73m² and creatinine <2.5 mg/dL
• Serum potassium <5.0 mEq/L at baseline

Spironolactone is particularly favored in HFmrEF patients with poorly controlled hypertension, given its established role in blood pressure management. 1

Dosing Strategy

Start with 12.5-25 mg daily and titrate to a maximum of 25-50 mg daily based on tolerance. 4, 5 The evidence does not support routine use of doses exceeding 50 mg daily:

• In TOPCAT, patients actually received lower average doses than the target 45 mg/day (median 22.5 mg/day in the spironolactone group), particularly among elderly patients, those with renal dysfunction, and those with baseline potassium >4.5 mmol/L. 5

• Lower doses (≈20-25 mg/day) maintained efficacy without significant heterogeneity across high-risk subgroups, suggesting that dose reduction to manage side effects is preferable to discontinuation. 5

• Chinese data showed no difference in outcomes between 25 mg and 50 mg daily dosing. 3

Monitoring Requirements

Implement intensive monitoring to prevent hyperkalemia and renal dysfunction: 1, 4

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

If potassium rises >5.5 mEq/L, reduce the spironolactone dose or discontinue—do not simply add potassium binders as a first-line strategy. 4 In TOPCAT, hyperkalemia occurred in 18.7% of spironolactone patients versus 9.1% on placebo, but with frequent monitoring, serious adverse events requiring dialysis were not significantly increased. 6

Critical Caveats and Safety Considerations

Spironolactone discontinuation is associated with worse outcomes—in TOPCAT, 25.4% of patients discontinued spironolactone in the first year (versus 18.3% on placebo), and discontinuation was associated with a two to fourfold higher risk of subsequent cardiovascular events. 5 This underscores the importance of dose reduction rather than complete cessation when side effects occur.

The evidence for spironolactone in HFmrEF is weaker than for HFrEF, where the RALES trial demonstrated a definitive 30% mortality reduction (RR 0.70,95% CI 0.60-0.82). 7 For HFmrEF, the data comes from subgroup analyses and observational studies rather than dedicated randomized trials. 1

Regional variation in trial results raises concerns about generalizability—the TOPCAT trial showed marked geographic heterogeneity, with benefit seen only in the Americas cohort, likely due to poor medication adherence in Russia/Georgia. 1 This emphasizes the importance of ensuring actual medication adherence in clinical practice.

Gynecomastia or breast pain occurs in approximately 10% of men treated with spironolactone, which may limit long-term adherence. 7 Using the lowest effective dose (12.5-25 mg daily) can minimize this antiandrogenic effect. 4

Comparison to Other HFmrEF Therapies

SGLT2 inhibitors have stronger evidence in HFmrEF and carry a Class 2a recommendation (versus Class 2b for spironolactone). 1 The EMPEROR-Preserved trial included 1,983 patients with LVEF 41-49% and showed consistent benefit across this ejection fraction range without the hyperkalemia risk associated with spironolactone. 1

Beta-blockers, ACE inhibitors/ARBs, and ARNIs also have Class 2b recommendations for HFmrEF based on similar post-hoc analyses of HFrEF trials. 1 The choice among these agents should be guided by comorbidities, with spironolactone particularly useful when hypertension control is suboptimal.

Practical Implementation Algorithm

1. Confirm HFmrEF diagnosis with LVEF 41-49% and symptomatic heart failure
2. Verify eligibility: eGFR >30 mL/min, creatinine <2.5 mg/dL, potassium <5.0 mEq/L
3. Prioritize SGLT2 inhibitor first if not already prescribed (stronger evidence)
4. Initiate spironolactone 12.5-25 mg daily if additional therapy needed, particularly if hypertension present
5. Monitor potassium/creatinine at 3 days, 1 week, monthly × 3, then quarterly
6. Titrate to 25-50 mg daily if tolerated and potassium remains <5.0 mEq/L
7. If potassium >5.5 mEq/L or creatinine rises significantly, reduce dose by 50% rather than discontinuing
8. Reassess LVEF periodically to determine if patient has transitioned to HFrEF (where spironolactone has Class I indication) or HFpEF 1