What is the first-line treatment with a mineralocorticoid receptor antagonist (MRA) for patients who may benefit from it?

First-Line Mineralocorticoid Receptor Antagonist Treatment

For patients who may benefit from mineralocorticoid receptor antagonist (MRA) therapy, spironolactone at an initial dose of 25 mg once daily is the first-line MRA treatment, with dose titration to 50 mg daily after one month if tolerated. 1

Patient Populations That Benefit from MRA Therapy

MRAs are indicated for the following patient populations:

1. Heart Failure with Reduced Ejection Fraction (HFrEF):

   • Patients with NYHA class II-IV symptoms and LVEF ≤40% 1
   • Should be added to standard therapy including ACE inhibitor/ARB and beta-blocker 1

2. Resistant Hypertension:

   • Patients not meeting blood pressure targets on three classes of antihypertensive medications (including a diuretic) 1
   • Added to existing treatment with ACE inhibitor/ARB, thiazide-like diuretic, and dihydropyridine calcium channel blocker 1

3. Diabetic Kidney Disease:

   • Patients with type 2 diabetes, eGFR ≥25 ml/min/1.73 m², normal serum potassium, and albuminuria (ACR ≥30 mg/g) 1

Dosing and Titration Protocol

Spironolactone (First-Line MRA)

• Starting dose: 25 mg once daily 1
• Target dose: 50 mg once daily after 4 weeks if serum potassium <5.0 mEq/L 1, 2
• Dose adjustment: For patients with eGFR 31-49 mL/min/1.73 m², reduce dose by half 1

Eplerenone (Alternative MRA)

• Starting dose: 25 mg once daily 1, 2
• Target dose: 50 mg once daily after 4 weeks if serum potassium <5.0 mEq/L 2
• When to use: Consider as an alternative if spironolactone is not tolerated due to sexual side effects 3

Monitoring Protocol

1. Initial monitoring:

   • Check serum potassium and renal function within 1-2 weeks after initiation 1
   • Then at 4 weeks after initiation or dose change 1

2. Long-term monitoring:

   • Every 6 months once stable 1
   • More frequent testing for clinical instability 1

3. Discontinuation criteria:

   • Serum potassium cannot be maintained at <5.5 mEq/L despite mitigation measures 1
   • Creatinine increases by more than 30% 1

Clinical Pearls and Caveats

• Hyperkalemia risk: Adding an MRA to ACE inhibitor or ARB therapy increases hyperkalemia risk, requiring careful monitoring 1
• Contraindications: Avoid in patients with eGFR <30 mL/min/1.73 m² or serum potassium ≥5.0 mEq/L 1
• Combination therapy: Never combine MRAs with both ACE inhibitors and ARBs 1
• Resistant hypertension: Spironolactone is particularly effective for resistant hypertension at doses between 25-50 mg/day 3
• Medication adherence: Consider barriers to adherence such as cost and side effects when prescribing MRAs 1

Comparative Efficacy

• Spironolactone demonstrated 30% RRR in mortality in severe HF (RALES trial) 1
• Eplerenone showed 37% RRR in cardiovascular death or HF hospitalization in mild HF (EMPHASIS-HF trial) 1
• Newer non-steroidal MRAs (e.g., finerenone) are in development with potentially improved selectivity and reduced side effect profiles 4, 5

MRAs provide high economic value in patients with HFrEF and NYHA class II-IV symptoms 1, making them a cost-effective therapeutic option when clinically indicated.