How to Give Spironolactone
Indications for Starting Spironolactone
Spironolactone should be initiated in patients with heart failure who have LVEF ≤35-40%, NYHA class III-IV symptoms, and are already on optimal doses of ACE inhibitor (or ARB) plus beta-blocker, provided serum potassium is ≤5.0 mEq/L and creatinine clearance is >30 mL/min/1.73m². 1
Heart Failure Indications:
- LVEF ≤35-40% with moderate to severe symptoms (NYHA class III-IV) 1
- Already receiving optimal doses of beta-blocker AND ACE inhibitor (or ARB, but NOT both ACE inhibitor AND ARB together) 1
- Post-MI patients with LVEF ≤40% who develop heart failure or have diabetes, starting 3-14 days after acute MI 1, 2
Hypertension Indications:
- Resistant hypertension at doses of 25-100 mg daily 3
- Note: Doses >100 mg/day generally provide no additional blood pressure reduction 3
Pre-Treatment Requirements (Mandatory Checks)
Before prescribing spironolactone, verify ALL of the following 1:
- Serum potassium ≤5.0 mEq/L (do not start if >5.0 mEq/L)
- Serum creatinine ≤2.5 mg/dL (220 μmol/L) or estimated GFR >30 mL/min/1.73m² 1
- Patient is NOT taking both ACE inhibitor AND ARB simultaneously (triple combination with spironolactone causes excessive hyperkalemia risk) 2
- Discontinue all potassium supplements immediately when starting spironolactone 1, 4
Starting Dose and Titration Protocol
Initial Dose:
Start with spironolactone 25 mg once daily (or 12.5 mg once daily in elderly patients, those with eGFR 30-50 mL/min/1.73m², or baseline creatinine 1.6-2.5 mg/dL) 1, 2
- For post-MI patients: Start 25 mg once daily, 3-14 days after MI 2
- Alternative agent: Eplerenone 25 mg once daily (fewer anti-androgenic side effects like gynecomastia) 1, 2
Dose Titration:
- Check potassium and creatinine at 3 days and 1 week after starting 1, 2
- If tolerated and potassium remains ≤5.0 mEq/L, consider increasing to 50 mg once daily after 4-8 weeks 1, 2
- Recheck potassium and creatinine 1 week and 4 weeks after each dose increase 1
- Target dose: 25-50 mg once daily (doses >25 mg rarely needed and increase hyperkalemia risk) 1, 5, 6
Monitoring Schedule (Critical for Safety)
Intensive Early Monitoring:
- Days 3-7: Check potassium and creatinine 1, 2
- Week 1: Recheck potassium and creatinine 1
- Week 4: Recheck potassium and creatinine 1
Maintenance Monitoring:
- Months 1,2,3: Check potassium and creatinine monthly 1, 2
- After 3 months: Check every 3-6 months 1, 2
- Any dose change of spironolactone, ACE inhibitor, or ARB triggers a new monitoring cycle 4
Real-world hyperkalemia rates far exceed clinical trial rates, particularly in elderly patients and those with renal dysfunction, making intensive monitoring non-negotiable. 2, 5
Managing Adverse Effects
Hyperkalemia Management:
- Potassium 5.5-5.9 mEq/L: Reduce spironolactone dose by 50% (e.g., 25 mg every other day) and monitor closely 1
- Potassium ≥6.0 mEq/L: Stop spironolactone immediately and monitor blood chemistry closely; specific treatment of hyperkalemia may be needed 1
- Never restart potassium supplements unless documented hypokalemia occurs 4
Worsening Renal Function:
- Creatinine rises to 2.5-3.5 mg/dL (220-310 μmol/L): Reduce spironolactone dose by 50% and monitor closely 1
- Creatinine >3.5 mg/dL (>310 μmol/L): Stop spironolactone immediately 1
Gynecomastia/Breast Tenderness:
- Switch from spironolactone to eplerenone (10% incidence with spironolactone vs. rare with eplerenone) 1
High-Risk Populations Requiring Extra Caution
The following patients have substantially increased hyperkalemia risk and require more intensive monitoring or specialist referral 1, 5:
- Age ≥75 years (mean age in hyperkalemia case series: 74 years) 5
- Baseline creatinine >1.6 mg/dL or eGFR <50 mL/min/1.73m² 1, 5
- Diabetes mellitus (especially insulin-requiring) 1, 5
- Concomitant use of NSAIDs, COX-2 inhibitors, or other nephrotoxic drugs 1
- Higher doses of ACE inhibitors (captopril ≥75 mg daily, enalapril or lisinopril ≥10 mg daily) 1
- Risk factors for dehydration or acute illness 5
In a real-world case series of 25 patients admitted with life-threatening hyperkalemia (mean potassium 7.7 mEq/L) on combined ACE inhibitor and spironolactone therapy, 2 patients died, 2 required resuscitation, 17 needed hemodialysis, and mean hospitalization was 12 days. 5
Absolute Contraindications
Do not prescribe spironolactone if ANY of the following are present 1, 2:
- Baseline serum potassium >5.0 mEq/L
- Serum creatinine >2.5 mg/dL or eGFR <30 mL/min/1.73m²
- Concomitant use of both ACE inhibitor AND ARB
- Inability to ensure close laboratory monitoring
- Anuria or acute renal failure
Patient Counseling Points
- Avoid high-potassium foods (bananas, oranges, tomatoes, salt substitutes containing potassium)
- Avoid NSAIDs and COX-2 inhibitors (ibuprofen, naproxen, celecoxib)
- Report immediately: Severe weakness, irregular heartbeat, nausea, or muscle cramps (signs of hyperkalemia)
- Seek emergency care for: Diarrhea, vomiting, or dehydration (can precipitate acute renal failure and hyperkalemia) 1
- Expect symptom improvement within weeks to months 1
Special Considerations
Lower Than Target Doses:
If patients cannot tolerate 25-50 mg daily due to side effects, continuing spironolactone at lower doses (even 12.5 mg daily or 25 mg every other day) is preferable to stopping treatment entirely, as discontinuation is associated with 2-4 fold higher risk of subsequent cardiovascular events. 7
Advanced Heart Failure:
In highly selected NYHA class III-IV patients with persistent fluid overload despite standard therapy, doses of 50-200 mg daily may be necessary for natriuresis, but this requires specialist supervision and even more intensive monitoring. 8
Testosterone Therapy:
Spironolactone blocks androgen receptors and decreases testosterone production, rendering concurrent testosterone therapy ineffective. Discontinue spironolactone before initiating testosterone, allowing a 3-4 day washout period. 9