What is the role of spironolactone (aldosterone antagonist) in the management of Heart Failure with preserved Ejection Fraction (HFpEF)?

Spironolactone for HFpEF

Spironolactone may be considered in carefully selected HFpEF patients primarily to reduce heart failure hospitalizations, though it does not reduce mortality, and requires strict patient selection criteria and intensive monitoring for hyperkalemia and renal dysfunction. 1

Recommendation Strength and Evidence Base

The 2022 ACC/AHA/HFSA guidelines assign spironolactone a Class IIb recommendation (Level B-R evidence) for HFpEF, meaning it "might be considered" but is not strongly recommended. 1 This modest recommendation stems from the TOPCAT trial, which showed:

• No significant reduction in the primary composite endpoint of death, aborted cardiac death, and HF hospitalization (HR 0.89, not statistically significant) 1
• Modest reduction in HF hospitalizations (HR 0.83) 1
• Significant regional variation that undermined confidence in the overall results 1

Critical Nuance from TOPCAT Regional Analysis

A post-hoc analysis revealed profound geographic differences that fundamentally altered interpretation of the trial. In the Americas cohort, spironolactone showed clear benefit (HR 0.83 for the primary endpoint), while in Russia/Georgia there was no benefit (HR 1.10). 1 Notably, patients from Russia/Georgia had non-detectable levels of spironolactone metabolites despite being in the active treatment arm, suggesting non-adherence or incorrect enrollment. 1 This finding strengthens the case for spironolactone use in appropriately selected patients.

Patient Selection Criteria

Only use spironolactone in HFpEF patients who meet ALL of the following criteria: 1, 2

• EF ≥45%
• Elevated BNP levels OR HF hospitalization within the past year
• eGFR >30 mL/min/1.73 m²
• Serum creatinine <2.5 mg/dL in men or <2.0 mg/dL in women
• Serum potassium <5.0 mEq/L
• Symptomatic HF despite standard therapy

Additional Considerations for Patient Selection

Post-hoc analyses suggest spironolactone efficacy may be greatest at the lower end of the LVEF spectrum within the HFpEF range (closer to 45% than 65%). 1 Patients with elevated BNP levels appear to derive more benefit. 1

Avoid spironolactone in patients with: 3

• Advanced chronic kidney disease (eGFR <30 mL/min) unless extremely close laboratory surveillance is possible
• Baseline hyperkalemia
• Concurrent use of ACE inhibitor + ARB (triple RAAS blockade dramatically increases hyperkalemia risk) 4

Dosing Protocol

Initial dose: 12.5-25 mg once daily 1, 2

Target dose: 25-50 mg once daily 1, 2

Titration strategy: Start at 25 mg daily, then consider up-titration to 50 mg daily after 4-8 weeks if potassium remains <5.5 mEq/L and creatinine is stable or improving. 4

Mandatory Monitoring Protocol

The risk of hyperkalemia and worsening renal function necessitates intensive monitoring, particularly in real-world practice where hyperkalemia rates reach 24-36% compared to 2-5% in trials. 4

Monitoring schedule: 2, 4

• Baseline: Potassium, creatinine, eGFR
• Early intensive phase: At 3 days, 1 week, then 1,4,8, and 12 weeks
• Maintenance phase: At 6,9, and 12 months, then every 6 months thereafter

Dose Adjustment Algorithm Based on Laboratory Values

If potassium 5.5-6.0 mEq/L: 2, 4

• Reduce dose to 25 mg every other day
• Recheck potassium within 3-7 days
• Review concomitant medications (NSAIDs, ACE inhibitors, ARBs)

If potassium >6.0 mEq/L:

• Discontinue spironolactone immediately
• Treat hyperkalemia per standard protocols
• May cautiously retry at lower dose once potassium <5.0 mEq/L

If creatinine rises to >220 μmol/L (2.5 mg/dL): 4

• Reduce dose to 25 mg on alternate days
• Recheck within 1 week

If creatinine rises to >310 μmol/L (3.5 mg/dL): 4

• Discontinue spironolactone completely

If creatinine is decreasing or stable: 4

• No dose adjustment needed
• Continue current dose and monitoring schedule

Safety Considerations and Common Pitfalls

Hyperkalemia risk is amplified by: 4, 3

• Declining renal function (risk increases substantially with eGFR <45 mL/min)
• Concurrent ACE inhibitor or ARB use, especially at higher doses
• NSAID or COX-2 inhibitor use
• Elderly patients with low muscle mass (creatinine underestimates renal dysfunction)
• Dehydration, diarrhea, or vomiting

Gynecomastia or breast pain occurs in approximately 10% of men. 2 Consider switching to eplerenone if this becomes problematic, though eplerenone is more expensive.

Critical Patient Education Points

Instruct patients to temporarily stop spironolactone and contact their physician during: 2, 4

• Episodes of diarrhea or vomiting
• Dehydration
• When loop diuretics are interrupted
• Acute illness requiring hospitalization

Advise patients to avoid: 4

• NSAIDs and COX-2 inhibitors
• Salt substitutes containing potassium
• Excessive dietary potassium intake

Clinical Context and Limitations

Unlike HFrEF where spironolactone provides clear mortality benefit, in HFpEF the benefit is limited to reducing hospitalizations without mortality reduction. 1 This more modest benefit must be weighed against the real risks of hyperkalemia and worsening renal function, particularly in elderly patients with multiple comorbidities.

Research shows that even when spironolactone causes worsening renal function in HFpEF patients, those with spironolactone-associated WRF had lower cardiovascular mortality compared to placebo-associated WRF, suggesting the drug provides benefit even in the presence of renal function decline. 5 However, this does not negate the need for careful monitoring and dose adjustment.

The absolute risk for adverse events requiring drug discontinuation is amplified in patients with lower baseline eGFR, suggesting heightened intolerance with declining renal function. 3 Use spironolactone in advanced CKD only when extremely close laboratory surveillance is feasible.

Practical Algorithm for Decision-Making

1. Confirm HFpEF diagnosis with EF ≥45% and symptomatic HF
2. Check eligibility labs: eGFR, creatinine, potassium, BNP
3. If ALL criteria met (see Patient Selection Criteria above): Consider spironolactone 25 mg daily
4. If ANY criterion not met: Do not initiate spironolactone; optimize other HFpEF therapies (diuretics, blood pressure control, treatment of comorbidities)
5. Implement intensive monitoring protocol as outlined above
6. Adjust dose based on laboratory algorithm
7. Educate patient on when to temporarily discontinue and avoid potassium-rich foods/supplements