What is the role of eplerenone in treating hypertension and heart failure, particularly in patients with hyperkalemia who cannot tolerate Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs)?

Role of Eplerenone in Treating Hypertension and Heart Failure

Eplerenone is recommended as a mineralocorticoid receptor antagonist (MRA) for patients with heart failure with reduced ejection fraction (HFrEF) and can be used in hypertension, particularly when patients cannot tolerate ACE inhibitors or ARBs due to hyperkalemia, though close monitoring of potassium levels is essential. 1, 2

Indications for Eplerenone

Heart Failure

• Recommended for patients with HFrEF and NYHA class II to IV symptoms to reduce morbidity and mortality when eGFR is >30 mL/min/1.73 m² and serum potassium is <5.0 mEq/L 1
• Particularly beneficial after myocardial infarction with left ventricular dysfunction (LVEF ≤40%) 1, 2
• Shown to reduce mortality by approximately 15% in post-MI patients with heart failure in the EPHESUS trial 1, 3
• May be considered in heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%) 1

Hypertension

• Indicated for treatment of hypertension, either alone or in combination with other antihypertensive agents 2
• Reduces systolic blood pressure by approximately 9.21 mmHg and diastolic blood pressure by 4.18 mmHg compared to placebo 4
• Effective dose range for hypertension is 50-200 mg/day, with no significant additional benefit at higher doses 4

Advantages in Patients with Hyperkalemia

• Eplerenone can be used when ACE inhibitors or ARBs cannot be tolerated, though it still requires careful potassium monitoring 1
• More selective for mineralocorticoid receptors than spironolactone, resulting in fewer sex hormone-related side effects (gynecomastia, breast pain, menstrual irregularities) 1, 5, 6
• May be particularly beneficial in patients with hypertension and heart failure, as the improvement in relative risk was greater in patients with a history of hypertension 1

Dosing and Monitoring

Initial Dosing

• Heart failure: Start with 25 mg once daily 1
• Hypertension: Start with 25 mg once daily, may increase to 50 mg daily if needed 2

Monitoring Requirements

• Check renal function and electrolytes (particularly potassium) before starting treatment 1
• Monitor at 1 and 4 weeks after starting/increasing dose, then at 8 and 12 weeks, 6,9, and 12 months, and 4-monthly thereafter 1
• If potassium rises above 5.5 mmol/L or creatinine rises to >221 μmol/L (2.5 mg/dL), halve the dose and monitor closely 1
• If potassium rises to >6.0 mmol/L or creatinine to >310 μmol/L (3.5 mg/dL), stop eplerenone immediately 1

Contraindications and Cautions

Contraindications

• Serum potassium >5.0 mmol/L before initiation 1
• Severe renal dysfunction (creatinine >2.5 mg/dL in men or >2.0 mg/dL in women; eGFR <30 mL/min/1.73 m²) 1
• Concomitant use of strong CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, etc.) 1, 2

Drug Interactions

• Increased risk of hyperkalemia when used with ACE inhibitors or ARBs, requiring close monitoring 2
• Avoid triple combination of ACE inhibitor, ARB, and MRA due to high risk of hyperkalemia 1
• Caution with NSAIDs, which may reduce antihypertensive effect and increase risk of hyperkalemia 1, 2
• Avoid potassium supplements and potassium-sparing diuretics 1

Clinical Algorithm for Use in Patients with Hyperkalemia

1. For patients with hyperkalemia who cannot tolerate ACE inhibitors/ARBs:

   • Confirm hyperkalemia is related to ACE inhibitors/ARBs (K+ >5.0 mmol/L) 1
   • Assess renal function (eGFR should be >30 mL/min/1.73 m²) 1
   • If suitable, initiate eplerenone at 25 mg daily 1
   • Monitor potassium and renal function at 1 week and 4 weeks 1

2. For patients with heart failure:

   • Ensure patient is on optimal heart failure therapy including beta-blockers 1
   • Add eplerenone if LVEF ≤40% and NYHA class II-IV symptoms 1
   • Monitor closely for hyperkalemia, especially if diabetes or renal impairment is present 2

3. For patients with hypertension:

   • Start with 25 mg once daily 2
   • May increase to 50 mg daily if blood pressure response is inadequate 2
   • Consider combination with thiazide diuretics if needed for better blood pressure control and to mitigate hyperkalemia risk 1

Common Pitfalls and Caveats

• Risk of serious hyperkalemia is higher in clinical practice than in clinical trials 1
• Patients with diabetes or proteinuria have increased risk of hyperkalemia (18% vs 13% in diabetics; 16% vs 11% in proteinuria) 2
• Avoid in patients taking potassium supplements or salt substitutes high in potassium 1
• Dehydration, diarrhea, or vomiting can increase risk of hyperkalemia and renal dysfunction; patients should be advised to temporarily stop eplerenone if these occur 1
• Despite its selectivity, eplerenone has not been proven superior to spironolactone in overall efficacy 6

By following these guidelines and monitoring protocols, eplerenone can be safely and effectively used in patients with hypertension and heart failure, including those who cannot tolerate ACE inhibitors or ARBs due to hyperkalemia.