What is the recommended use and dosage of Spironolactone (aldosterone antagonist) in patients with resistant hypertension or heart failure?

Spironolactone in Resistant Hypertension and Heart Failure

For resistant hypertension, add low-dose spironolactone (25 mg once daily) to existing therapy after reinforcing lifestyle measures, particularly sodium restriction, as this is the recommended first-line add-on treatment. 1

Resistant Hypertension

Indications and Positioning

• Spironolactone is the preferred add-on agent when blood pressure remains uncontrolled despite optimal doses of at least three first-line antihypertensive medications (typically including a RAS blocker, calcium channel blocker, and thiazide diuretic). 1
• This recommendation is based on superior blood pressure reduction compared to other fourth-line agents, with average reductions of approximately 22/10 mmHg documented in clinical trials. 2, 3

Dosing for Resistant Hypertension

• Starting dose: 25 mg once daily 1, 4
• Target dose: 25-100 mg daily, though doses above 100 mg generally provide no additional blood pressure benefit 4
• Titrate at two-week intervals if needed 4
• Most patients achieve adequate control with 25-50 mg daily 2

Alternative Agents if Spironolactone Fails or Is Not Tolerated

• Eplerenone (alternative mineralocorticoid receptor antagonist with lower risk of gynecomastia) 1
• Amiloride (potassium-sparing diuretic) 1
• Higher-dose thiazide/thiazide-like diuretic or loop diuretic 1
• Beta-blocker (bisoprolol) if not already prescribed 1
• Alpha-blocker (doxazosin) 1

Heart Failure

Indications by Heart Failure Type

• HFrEF (reduced ejection fraction): Spironolactone is recommended as part of foundational therapy alongside ACE inhibitors/ARBs/ARNi, beta-blockers, and SGLT2 inhibitors to improve survival and reduce hospitalizations. 1
• HFmrEF (mildly reduced ejection fraction): Mineralocorticoid receptor antagonists are recommended for symptomatic patients. 1
• HFpEF (preserved ejection fraction): MRAs may be considered to reduce heart failure hospitalizations in patients with blood pressure above target. 1
• Spironolactone is indicated as second-line therapy after ACE inhibitors and beta-blockers, particularly for NYHA class III-IV heart failure. 1

Dosing for Heart Failure

• Starting dose: 25 mg once daily (or every other day in patients at higher risk for hyperkalemia) 1, 5, 4
• Target dose: 25-50 mg once daily 1, 5, 4
• For eGFR 30-50 mL/min/1.73 m²: Consider initiating at 25 mg every other day due to hyperkalemia risk 4
• For eGFR >50 mL/min/1.73 m² and potassium ≤5.0 mEq/L: Start at 25 mg daily, may increase to 50 mg daily if tolerated 4
• Patients tolerating 25 mg daily may have dose increased to 50 mg daily as clinically indicated; those developing hyperkalemia on 25 mg daily may be reduced to 25 mg every other day 4

Clinical Benefits in Heart Failure

• The RALES study demonstrated that spironolactone reduces mortality by 30%, reduces cardiac hospitalizations by 30%, and improves NYHA functional class when added to standard therapy. 1, 4
• Benefits include improved survival, reduced hospital admissions, and symptom improvement within weeks to months. 1, 5

Monitoring Protocol

Initial Monitoring (Critical for Safety)

• Baseline: Check serum potassium, creatinine, and eGFR before initiation 1, 5
• Early monitoring: Check at 1,4,8, and 12 weeks after starting therapy 1, 5
• Long-term monitoring: Check at 6,9, and 12 months, then every 6 months thereafter 1, 5
• After dose changes: More frequent monitoring recommended, with checks 4-6 days after initiation and 1 week after dose increases 5

Hyperkalemia Management Algorithm

• Potassium 5.0-5.5 mmol/L: Reduce spironolactone dose by 50% 5
• Potassium 5.5-6.0 mmol/L: Reduce dose to 25 mg every other day and monitor closely 1, 5
• Potassium ≥5.5 mmol/L: Stop spironolactone 5
• Potassium >6.0 mmol/L: Discontinue immediately and seek specialist advice 1

Renal Function Monitoring

• Creatinine >221 µmol/L (>2.5 mg/dL): Reduce dose to 25 mg every other day and monitor closely 1, 5
• Recheck potassium and renal function within 24-48 hours if severe hyperkalemia develops 6

Critical Drug Interactions and Contraindications

High-Risk Combinations Requiring Caution

• ACE inhibitors and ARBs (monitor potassium closely when combined) 1, 5
• Other potassium-sparing diuretics (amiloride, triamterene) 1, 5
• Potassium supplements (including KCl) 1, 5
• NSAIDs (increase hyperkalemia and nephrotoxicity risk; avoid over-the-counter ibuprofen) 1, 5
• "Low salt" substitutes with high potassium content 1, 5

When to Hold Temporarily

• Episodes of diarrhea or vomiting (instruct patients to stop and contact physician) 1, 5
• Dehydration or when loop diuretic therapy is interrupted 6

Common Pitfalls and How to Avoid Them

Pitfall 1: Inadequate Monitoring Leading to Severe Hyperkalemia

• Solution: Adhere strictly to the monitoring schedule, especially in the first 12 weeks and after any dose adjustment. 1, 5
• Hyperkalemia >6.0 mmol/L increases risk of cardiac arrhythmias and sudden death. 6

Pitfall 2: Failing to Discontinue with Severe Hyperkalemia

• Solution: Discontinue immediately (not just hold) when potassium exceeds 6.0 mmol/L and obtain ECG to assess for hyperkalemia-related changes. 6

Pitfall 3: Restarting Too Soon or at Too High a Dose

• Solution: When restarting after hyperkalemia, use lower dose (12.5 mg daily or every other day) and monitor potassium within 3-7 days. 6

Pitfall 4: Ignoring Renal Function

• Solution: Avoid initiation if eGFR <30 mL/min/1.73 m² without specialist guidance; use every-other-day dosing for eGFR 30-50. 4

Pitfall 5: Not Counseling Patients on Dietary Potassium

• Solution: Instruct patients to avoid high-potassium foods, supplements, and salt substitutes. 6

Patient Counseling Points

Expected Benefits

• Treatment improves symptoms, prevents worsening of heart failure, increases survival, and lowers blood pressure. 1, 5
• Symptom improvement typically occurs within weeks to months. 1, 5

Safety Instructions

• Avoid NSAIDs not prescribed by physician (especially over-the-counter products). 1, 5
• Temporarily stop during diarrhea/vomiting and contact physician. 1, 5
• Monitor for signs of hyperkalemia: weakness, fatigue, paresthesias. 5

Side Effects to Anticipate

• Male patients may develop breast discomfort or gynecomastia (consider switching to eplerenone if this occurs). 1
• Hyperkalemia is the major concern, though uncommon at recommended doses with proper monitoring. 1, 5

Special Populations

Cirrhosis with Edema

• Initiate therapy in hospital setting and titrate slowly. 4
• Starting dose: 100 mg daily (range 25-200 mg), administered for at least 5 days before increasing. 4

Primary Hyperaldosteronism

• Dose range: 100-400 mg daily for surgical preparation or long-term maintenance if surgery unsuitable. 4