Is Eplerenone (eplerenone) contraindicated in a patient with diastolic dysfunction, likely heart failure with preserved ejection fraction (HFpEF), iron deficiency, low stroke volume index, and mild bilateral pitting edema?

Eplerenone is NOT Contraindicated in This Patient with HFpEF

Eplerenone is appropriate and potentially beneficial for this patient with diastolic dysfunction and likely HFpEF, provided renal function and potassium levels are acceptable. The presence of iron deficiency, low stroke volume index, and mild edema do not constitute contraindications to eplerenone use.

Key Clinical Context

Your patient presents with:

• Preserved ejection fraction (55-60%) with diastolic dysfunction suggesting HFpEF
• Low stroke volume index (34 ml/m²) indicating reduced cardiac output despite preserved EF
• Mild bilateral pitting edema suggesting volume overload
• Iron deficiency (ferritin 27) which is common in HF and should be addressed separately

Evidence Supporting Eplerenone Use in HFpEF

Limited but Emerging Evidence

• While mineralocorticoid receptor antagonists (MRAs) have proven mortality benefit in HFrEF with LVEF ≤35-40%, the evidence in HFpEF is less robust but shows promise 1, 2.
• Spironolactone has demonstrated reduction in heart failure hospitalizations and improvement in diastolic function in HFpEF patients, though mortality benefit remains unproven 3.
• The EMPHASIS-HF trial with eplerenone focused on HFrEF patients (LVEF ≤30-35%), not HFpEF, showing 37% reduction in cardiovascular death or HF hospitalization 1, 4.

Specific Considerations for Your Patient

• The mild edema and diastolic dysfunction suggest volume overload and potential benefit from MRA therapy 3.
• Eplerenone may improve diastolic function and reduce myocardial fibrosis, which are key pathophysiologic features in HFpEF 3.
• The low stroke volume index despite preserved EF suggests impaired ventricular filling, a target for MRA therapy 3.

Absolute Contraindications to Check

Before prescribing eplerenone, verify the following are NOT present 1, 2, 5:

• Serum potassium >5.0 mEq/L (absolute contraindication)
• Serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women 5
• eGFR <30 mL/min/1.73m² (absolute contraindication) 2
• Concomitant use of potassium supplements or potassium-sparing diuretics 1
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) 5

Dosing Protocol for HFpEF

Initiation Strategy

• Start with eplerenone 25 mg once daily (lower than the 50-100 mg used for primary aldosteronism) 2, 5.
• This is the standard starting dose for heart failure, appropriate for your patient's clinical scenario 1, 2.

Titration Approach

• Target dose is 50 mg daily, which can be achieved after 4 weeks if tolerated 1, 2.
• Unlike primary aldosteronism, HFpEF does not typically require doses exceeding 50 mg daily 5.

Mandatory Monitoring Protocol

Initial Phase (Critical)

• Check potassium and creatinine within 3 days of starting eplerenone 1, 2, 5.
• Recheck at 7 days after initiation 1, 5.
• Monthly monitoring for the first 3 months 1, 2, 5.
• Every 3 months thereafter 2, 5.

Response to Abnormal Values

• If potassium 5.0-5.4 mEq/L: Continue current dose and monitor closely 1.
• If potassium 5.5-5.9 mEq/L: Reduce dose by 50% or switch to alternate-day dosing 1, 5.
• If potassium ≥6.0 mEq/L: Discontinue eplerenone immediately; can restart when potassium <5.5 mEq/L 1, 5.
• If creatinine increases significantly: Reduce dose or discontinue 1.

Critical Drug Interactions to Avoid

• Do NOT combine with ACEi + ARB simultaneously (triple RAAS blockade increases hyperkalemia risk dramatically) 2.
• NSAIDs and COX-2 inhibitors should be avoided as they impair potassium excretion and reduce eplerenone efficacy 1.
• If patient is on ACEi or ARB: This is acceptable and expected, but increases hyperkalemia risk requiring vigilant monitoring 1, 4.

Addressing the Iron Deficiency

• The ferritin of 27 ng/mL represents true iron deficiency (threshold <100 ng/mL in HF, or <300 ng/mL with transferrin saturation <20%) 2.
• Iron deficiency is NOT a contraindication to eplerenone; these are separate issues requiring concurrent management.
• Consider intravenous iron replacement (ferric carboxymaltose or iron sucrose) as oral iron is poorly absorbed in HF 2.
• Iron repletion may improve symptoms, exercise capacity, and quality of life independent of eplerenone effects 2.

Managing the Edema

• The mild bilateral pitting edema indicates volume overload requiring diuretic therapy 1.
• Loop diuretics (furosemide or torsemide) are appropriate for symptom management 1.
• Eplerenone provides additional diuretic effect through aldosterone blockade, which may help reduce loop diuretic requirements over time 2.
• Monitor for excessive diuresis when combining eplerenone with loop diuretics, particularly in the first weeks 2.

Common Pitfalls to Avoid

Hyperkalemia Risk Factors in Your Patient

• Renal function is the most critical determinant of hyperkalemia risk; ensure eGFR >30 mL/min before starting 1, 2.
• Concomitant ACEi/ARB therapy (likely present) increases risk but is not a contraindication—just requires closer monitoring 1, 4.
• Dehydration from aggressive diuresis can precipitate acute kidney injury and hyperkalemia 1.

Monitoring Failures

• The most common serious error is inadequate potassium monitoring in the first month, when hyperkalemia risk is highest 1.
• Population-based studies show hyperkalemia rates of 13-24% with spironolactone in real-world practice (vs. 2% in trials), primarily due to inadequate monitoring 1.
• Do not rely on serum creatinine alone in elderly patients; calculate eGFR or creatinine clearance as creatinine underestimates renal dysfunction in low muscle mass 1.

Expected Clinical Benefits

Timeline for Benefit

• Significant reduction in cardiovascular events can be observed as early as 26 days after initiation in HFrEF patients 6.
• Symptom improvement (reduced edema, improved exercise tolerance) may occur within 2-4 weeks 3.
• Diastolic function improvement and reverse remodeling occur over 3-6 months 3.

Realistic Expectations for HFpEF

• Eplerenone is more likely to reduce HF hospitalizations than mortality in HFpEF (unlike the proven mortality benefit in HFrEF) 3.
• Improvement in quality of life and functional capacity are reasonable treatment goals 3.
• The low stroke volume index may improve with better volume management and reduced myocardial fibrosis 3.

Alternative Consideration: Spironolactone

• Spironolactone has more HFpEF-specific data than eplerenone, showing reduction in HF hospitalizations and improvement in diastolic function 3.
• Spironolactone is less expensive but has higher rates of gynecomastia, breast pain, and sexual dysfunction due to non-selective receptor binding 7.
• Starting dose for spironolactone is 12.5-25 mg daily, with target of 25-50 mg daily 1, 8.
• If cost is not a barrier, eplerenone is preferred due to better tolerability 7.