What is the role of spironolactone in the treatment of Heart Failure with Reduced Ejection Fraction (HFrEF)?

Spironolactone in Heart Failure with Reduced Ejection Fraction (HFrEF)

Spironolactone is a Class I, evidence-based therapy for all patients with symptomatic HFrEF (NYHA Class II-IV, LVEF ≤35-40%) who should receive it to reduce mortality by 30% and heart failure hospitalizations by 35%, provided potassium is <5.0 mEq/L and creatinine is <2.5 mg/dL. 1, 2

Core Evidence Base

The landmark RALES trial established spironolactone as life-saving therapy in severe HFrEF, demonstrating a 30% relative risk reduction in all-cause mortality (p<0.001) and a 35% reduction in heart failure hospitalizations in patients with NYHA Class III-IV symptoms and LVEF ≤35%. 1, 2 The absolute risk reduction in mortality was 11.4% after 2 years, translating to a number needed to treat of only 9 patients for 2 years to prevent one death. 1

The EMPHASIS-HF trial extended these benefits to milder disease (NYHA Class II, LVEF ≤30-35%), showing eplerenone reduced cardiovascular death or HF hospitalization by 37%, all-cause mortality by 24%, and HF hospitalizations by 42%. 1 These benefits were additive to ACE inhibitors and beta-blockers. 1

Patient Selection Criteria

Initiate spironolactone in patients meeting ALL of the following: 1, 2

• LVEF ≤35-40% (some guidelines use ≤35%, others ≤40%) 1
• NYHA Class II-IV symptoms (Class III-IV has strongest evidence) 1, 2
• Serum potassium <5.0 mEq/L at baseline 1, 2
• **Serum creatinine <2.5 mg/dL** or eGFR >30 mL/min/1.73m² 1, 2
• Already on ACE inhibitor/ARB and beta-blocker (standard background therapy) 1, 2

Dosing Strategy

Start with 12.5-25 mg once daily. 1, 3, 4 After 4-8 weeks, if tolerated and potassium remains <5.0 mEq/L, titrate to the target dose of 25-50 mg once daily. 1, 2 The mean dose in RALES was 26 mg daily, indicating many patients required dose adjustments. 2

For patients intolerant of 25 mg daily, reduce to 25 mg every other day. 2 The maximum recommended dose is 50 mg daily. 1, 3

Monitoring Requirements

Critical monitoring schedule to prevent life-threatening hyperkalemia: 1, 3

• Within 3 days of initiation: Check potassium and creatinine 3
• At 1 week: Recheck potassium and creatinine 3
• Monthly for 3 months: Continue frequent monitoring 3
• Every 3 months thereafter: During stable therapy 1, 3

Management of Hyperkalemia

Potassium 5.0-5.5 mEq/L: Continue current dose with close monitoring 1

Potassium >5.5 mEq/L: Halve the spironolactone dose and recheck within 3 days 1, 3

Potassium >6.0 mEq/L: Stop spironolactone immediately 1

The 2012 ESC guidelines established these thresholds, though a 2018 European Journal of Heart Failure editorial argued for revisiting these conservative cutoffs given newer potassium-binding agents. 1 However, current standard practice remains adherence to these safety thresholds. 1

Role in HFmrEF (LVEF 41-49%)

For HFmrEF, spironolactone receives a Class 2b recommendation ("may be considered"), particularly for patients with LVEF at the lower end of this spectrum (41-45%). 1, 4 Post-hoc analysis of TOPCAT showed that among 520 patients with LVEF 44-49%, spironolactone reduced the composite endpoint of cardiovascular death, HF hospitalization, or resuscitated sudden death, driven mainly by cardiovascular mortality reduction. 1, 4 This benefit was predominantly seen in patients enrolled in North and South America, not Russia/Georgia where medication adherence was questionable. 1, 4

SGLT2 inhibitors have stronger evidence (Class 2a) in HFmrEF and should be prioritized first. 1, 4 If spironolactone is used in HFmrEF, apply the same dosing (12.5-25 mg daily, titrate to 25-50 mg) and monitoring protocols as HFrEF. 4

Role in HFpEF (LVEF ≥50%)

Spironolactone is NOT routinely recommended for HFpEF. 1 The TOPCAT trial showed no significant reduction in the primary composite endpoint of cardiovascular death, HF hospitalization, or aborted cardiac arrest in patients with LVEF ≥45% (HR 0.89,95% CI 0.77-1.04, p=0.14). 1, 5 Only HF hospitalizations were reduced (HR 0.83, p=0.04). 1, 5

However, a 2016 post-hoc analysis demonstrated that spironolactone efficacy was greatest at the lower end of the LVEF spectrum, with potential benefit for LVEF <50% (HR 0.72) but not LVEF ≥60% (HR 0.97). 6 A 2024 real-world VA study showed spironolactone reduced all-cause death by 21% in HFpEF patients, though this was observational data. 7

Consider spironolactone in HFpEF only if: 1

• LVEF is at the lower end (45-50%)
• Poorly controlled hypertension is present
• Patient has elevated BNP/NT-proBNP or recent HF hospitalization

Common Pitfalls and Caveats

Hyperkalemia risk increases dramatically when combined with ACE inhibitors/ARBs, which nearly all HFrEF patients receive. 1, 3 After RALES publication, a population-based study showed increased hyperkalemia-associated morbidity and mortality from spironolactone use in real-world practice where monitoring was less rigorous than in trials. 1

Do not combine spironolactone with other potassium-sparing diuretics (amiloride, triamterene). 1 Loop diuretics are appropriate and were used in 100% of RALES patients. 2

Gynecomastia occurs in approximately 10% of men on spironolactone. 8 If this occurs, consider switching to eplerenone, which has less antiandrogenic effects. 1

For patients unable to swallow tablets, a liquid suspension formulation (CaroSpir®, 25 mg/5 mL) is FDA-approved and enables treatment in elderly or dysphagic patients. 9

Continue spironolactone during acute decompensation unless the patient is in shock or severely hypoperfused; dose reduction may be necessary but complete discontinuation should be avoided. 1