How is spironolactone used as adjunctive therapy in patients with chronic heart failure with reduced ejection fraction who are already receiving optimal guideline‑directed medical therapy?

How Spironolactone is Used in Heart Failure with Reduced Ejection Fraction

Spironolactone is a foundational medication for all symptomatic HFrEF patients (NYHA class II-IV) with LVEF ≤35%, started at 12.5-25 mg daily and titrated to a target of 50 mg daily, providing at least 20% mortality reduction and reducing sudden cardiac death when added to ACE inhibitors, beta-blockers, and diuretics. 1, 2

Patient Selection Criteria

Spironolactone is indicated for:

• Symptomatic heart failure patients with NYHA class II-IV symptoms 3
• Left ventricular ejection fraction ≤35% 1, 2
• Patients already receiving ACE inhibitors (or ARNIs) and beta-blockers as part of quadruple therapy 1

Critical exclusion criteria before initiation:

• Baseline serum creatinine >2.5 mg/dL or recent 25% increase 3
• Baseline serum potassium >5.0 mEq/L 3
• Estimated glomerular filtration rate <30 mL/min/1.73 m² 2

Dosing and Titration Protocol

Initial dosing:

• Start with 12.5-25 mg once daily 1, 3
• The mean daily dose in the landmark RALES trial was 26 mg, demonstrating that even modest doses provide substantial benefit 3

Uptitration strategy:

• Assess tolerance at 1-4 weeks; if intolerant, reduce to 25 mg every other day 3
• If tolerant at 8 weeks, increase to target dose of 50 mg daily 1, 3
• In real-world practice, 37% of patients receive <25 mg, 48% receive 25-50 mg, and only 15% receive ≥50 mg 4

Sequencing within quadruple therapy:

• Start spironolactone early alongside SGLT2 inhibitors, as both have minimal blood pressure effects 2
• This allows optimization before adding or uptitrating ARNI and beta-blockers, which lower blood pressure more substantially 2

Monitoring Requirements

Mandatory laboratory surveillance:

• Check serum potassium and creatinine every 4 weeks for the first 12 weeks 3
• Then every 3 months for the first year 3
• Then every 6 months thereafter 3
• More frequent monitoring (every 5-7 days) is required in patients with advanced chronic kidney disease until values stabilize 5

Acceptable laboratory changes during therapy:

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 2
• Hyperkalemia occurs in approximately 4.3% at first follow-up visit in real-world practice 4

Clinical Efficacy and Outcomes

Mortality benefit:

• Spironolactone reduces all-cause mortality by 30% (95% CI: 18-40%, p<0.001) in NYHA class III-IV patients 3
• The mortality reduction is at least 20% across multiple studies, with particular benefit in reducing sudden cardiac death 1, 2
• In real-world practice, 3-year mortality reduction was significant in patients with LVEF ≤26% (adjusted HR 0.79,95% CI 0.64-0.97, p=0.023) 4

Hospitalization benefit:

• Reduces hospitalization for cardiac causes by 30% (95% CI: 18-41%, p<0.001) 3
• Specifically reduces heart failure hospitalizations by 17% (HR 0.83,95% CI 0.69-0.99, p=0.04) 6

Subgroup considerations:

• The favorable effect appears similar for both genders and all age groups except patients younger than 55 3
• Benefit appears greater in patients with low baseline serum potassium levels 3
• Benefit is less pronounced in patients with ejection fractions <20% 3

Integration with Modern Quadruple Therapy

Spironolactone as part of the four-drug class approach:

• Mineralocorticoid receptor antagonists (MRAs) are one of four foundational medication classes, alongside beta-blockers, RAS inhibitors/ARNIs, and SGLT2 inhibitors 1
• All four classes should be initiated simultaneously as soon as possible after diagnosis 2
• The combination of all four classes reduces all-cause mortality by 61% (HR 0.39,95% CI 0.32-0.49) and provides approximately 5.3 additional life-years 2

Compatibility with sacubitril/valsartan (ARNI):

• Spironolactone can be safely combined with ARNI 2
• ARNI actually reduces the risk of hyperkalemia when combined with MRAs compared to ACE inhibitors plus MRAs 2
• Never combine ACE inhibitor + ARB + MRA due to extreme hyperkalemia risk 1, 2

Safety Profile and Adverse Effects

Common adverse effects:

• Painful gynecomastia develops in 10% of patients 1
• If gynecomastia occurs, consider switching to eplerenone, which has lower affinity for androgen and progesterone receptors 1
• Hyperkalemia occurred in 18.7% in TOPCAT versus 9.1% with placebo, but with frequent monitoring, serious adverse events were not significantly different 6

Critical safety considerations:

• Discontinuing spironolactone after hyperkalemia is associated with two- to fourfold higher risk of subsequent adverse events compared to continuing therapy 2
• If hyperkalemia develops, consider potassium binders like patiromer rather than discontinuing life-saving medications 2
• The combination of ARNI and spironolactone in CKD stage IV creates extreme hyperkalemia risk and requires nephrology co-management 5

Role in Heart Failure with Preserved Ejection Fraction

Limited indication in HFpEF:

• In appropriately selected HFpEF patients, spironolactone may be considered to lower hospitalizations for heart failure 1
• The TOPCAT trial showed no significant reduction in the primary composite outcome of cardiovascular death, aborted cardiac arrest, or hospitalization in HFpEF patients with LVEF ≥45% 6
• However, ejection fraction modified the treatment effect, with stronger benefits at the lower end of the LVEF spectrum (LVEF <50%: HR 0.72,95% CI 0.50-1.05) 7
• Spironolactone improved cardiac structure and function in HFpEF, reducing left atrial volume index by -1.1 ml/m², left ventricular mass index by -3.6 g/m², and E/e' ratio by -1.3 8

Common Pitfalls to Avoid

Do not:

• Delay initiation due to unfounded concerns about blood pressure—spironolactone has minimal BP effects 2
• Accept suboptimal doses without attempting forced-titration strategies used in landmark trials 1
• Discontinue for asymptomatic hyperkalemia without first attempting potassium binders 2
• Use spironolactone as monotherapy—it must be part of comprehensive quadruple therapy 1, 2
• Combine with both ACE inhibitor and ARB simultaneously 1, 2

Do:

• Start early alongside SGLT2 inhibitors before uptitrating blood pressure-lowering agents 2
• Monitor potassium and creatinine rigorously according to the RALES protocol 3
• Attempt uptitration to 50 mg daily in tolerant patients 1, 3
• Continue therapy even if modest hyperkalemia develops, using potassium binders if needed 2