Spironolactone Dosing for Heart Failure with Reduced Ejection Fraction
For patients with heart failure and reduced ejection fraction (≤35%), initiate spironolactone at 25 mg once daily if serum potassium is ≤5.0 mEq/L and eGFR >50 mL/min/1.73m², with a target dose of 25-50 mg once daily. 1, 2, 3
Initial Dose Selection
Standard initiation:
- Start with 25 mg once daily for patients with eGFR >50 mL/min/1.73m² and potassium ≤5.0 mEq/L 1, 2, 3
- This dose is supported by the landmark RALES trial, which demonstrated a 30% reduction in mortality using 25-50 mg daily in NYHA class III-IV patients 4, 5
Modified initiation for high-risk patients:
- Consider 12.5 mg once daily in patients with severe heart failure (NYHA class III-IV) who are at higher risk for hyperkalemia 2
- Use 25 mg every other day for patients with eGFR 30-49 mL/min/1.73m² to minimize hyperkalemia risk 1, 3
- Elderly patients (≥75 years) often require lower doses due to increased hyperkalemia risk 6, 7
Target Dose and Titration
Target dosing:
- Aim for 25-50 mg once daily as the evidence-based target dose 4, 3, 1
- Patients tolerating 25 mg once daily may have their dose increased to 50 mg once daily as clinically indicated 1
- Titration should occur at 8 weeks if tolerated, after checking renal function and potassium 5
Important caveat: The RALES trial used doses of 25-50 mg daily, and doses of 12.5-25 mg have been shown to effectively block aldosterone while minimizing hyperkalemia risk 8. Even lower doses (median ~20 mg/day) in high-risk subgroups maintained efficacy without significant heterogeneity in outcomes 7.
Patient Selection Criteria
Mandatory prerequisites before initiation:
- LVEF ≤35% 4, 5
- NYHA functional class III-IV symptoms (or class II with elevated risk features) 4, 5
- Already receiving optimal doses of ACE inhibitor (or ARB) and beta-blocker 2, 5
- Baseline potassium <5.0 mmol/L 2, 3
- Baseline creatinine <2.5 mg/dL (221 μmol/L) 4, 2
Monitoring Protocol
Critical safety monitoring schedule:
- Check potassium and creatinine before initiation 5
- Recheck at 1 week after starting 2, 3
- Recheck at 4 weeks 2, 3
- Continue monitoring at 8 and 12 weeks, then every 3-6 months 3, 5
- After dose increases, recheck within 2-3 days and again at 7 days 3
Dose adjustment algorithm for hyperkalemia:
- Potassium 5.0-5.5 mmol/L: Reduce dose by 50% (e.g., from 25 mg daily to 25 mg every other day) 4, 3, 1
- Potassium 5.5-6.0 mmol/L: Reduce dose by 50% 3
- Potassium >5.5 mmol/L or >6.0 mmol/L: Stop spironolactone immediately 4, 2, 3
- Creatinine increase >50% from baseline or >3 mg/dL: Consider stopping or reducing dose 4
Common Pitfalls and Safety Considerations
Hyperkalemia risk factors:
- Renal impairment is the strongest predictor—hyperkalemia occurred in 6 of 9 patients with baseline creatinine >150 μmol/L versus 1 of 9 without renal impairment 6
- Concomitant use of ACE inhibitors other than captopril, higher ACE inhibitor doses, and baseline elevated creatinine or potassium increase risk 8
- Avoid concomitant potassium supplements, potassium-sparing diuretics, NSAIDs, and high-potassium salt substitutes 3, 5
Other adverse effects:
- Gynecomastia occurs in approximately 10% of men taking spironolactone 4, 5
- Consider switching to eplerenone if breast discomfort develops 4
Discontinuation rates:
- Approximately 25% of patients discontinue spironolactone within the first year, compared to 18% on placebo 7
- Discontinuation is associated with a 2-4 fold higher risk of subsequent cardiovascular events 7
- In patients unable to tolerate target doses, a low-dose strategy (12.5-20 mg daily) should be preferred to stopping treatment entirely 7
Clinical Benefits
The mortality benefit is substantial:
- 30% relative risk reduction in all-cause mortality in NYHA class III-IV patients 4, 5
- 11.4% absolute risk reduction after 2 years, translating to a number needed to treat of 9 to prevent one death 4, 5
- 35% reduction in heart failure hospitalizations 4, 5
- Benefits are additional to those gained with ACE inhibitors and beta-blockers 4