What is the impact of spironolactone on cardiac function?

Impact of Spironolactone on Cardiac Function

Spironolactone significantly improves cardiac function in patients with heart failure with reduced ejection fraction (HFrEF) by reducing mortality by 30%, decreasing heart failure hospitalizations, and improving left ventricular remodeling, while its benefits in heart failure with preserved ejection fraction (HFpEF) are more modest and primarily limited to reducing hospitalizations. 1, 2

Heart Failure with Reduced Ejection Fraction (HFrEF)

Mortality and Morbidity Benefits

• Spironolactone reduces all-cause mortality by 30% (relative risk 0.70, p<0.001) in patients with NYHA class III-IV heart failure and ejection fraction ≤35%. 1, 2

• The mortality benefit is attributed to both reduced death from progressive heart failure and reduced sudden cardiac death. 2

• Heart failure hospitalizations are reduced by 35% (relative risk 0.65, p<0.001) when spironolactone is added to standard therapy including ACE inhibitors and diuretics. 2

• Patients experience significant improvement in NYHA functional class symptoms. 3, 2

Mechanisms of Cardiac Improvement

Left Ventricular Remodeling:

• Spironolactone reduces left ventricular end-systolic volume (188 ml to 171 ml at 12 months, p=0.03) and improves ejection fraction (33% to 36%, p=0.02) through reverse remodeling. 4

• The drug reduces myocardial and vascular fibrosis by blocking aldosterone's profibrotic effects. 3

• Procollagen III N-terminal peptide (PIIINP), a marker of collagen turnover, decreases significantly (3.767 to 3.156 μg/ml, p<0.001), indicating reduced cardiac fibrosis. 5

Diastolic Function:

• Spironolactone improves restrictive mitral filling patterns, a marker of severe diastolic dysfunction, with 67% of patients showing improvement at 12 months (p=0.02). 4

• Mechanistic studies demonstrate improved measures of diastolic function in HFpEF patients through effects on cardiac remodeling. 3

Vascular and Endothelial Function:

• Acetylcholine-induced vasodilation improves significantly (p=0.044), indicating enhanced endothelial function. 5

• Vascular ACE activity decreases (p=0.006), contributing to improved vascular function. 5

Cardiac Biomarkers:

• B-type natriuretic peptide (BNP) decreases from 48.5 to 36.8 pg/ml (p=0.039) and NT-proBNP shows greater reductions compared to placebo (p=0.017), reflecting reduced cardiac wall stress and filling pressures. 5, 6

• High-sensitivity cardiac troponin I (hs-cTnI) levels show no significant change, suggesting spironolactone does not directly affect ongoing myocardial injury. 6

Electrophysiological Effects:

• QTc interval shortens from 473 ms to 455 ms (p=0.002) and QT dispersion decreases from 84.5 ms to 72.1 ms (p=0.037), potentially reducing arrhythmic risk. 5

Exercise Capacity:

• Peak oxygen consumption increases significantly in patients receiving 50 mg spironolactone daily (17.7 to 18.5 ml/kg/min, p=0.01), indicating improved functional capacity. 4

Heart Failure with Preserved Ejection Fraction (HFpEF)

Clinical Trial Evidence

• In the TOPCAT trial, spironolactone reduced heart failure hospitalizations (HR 0.83) but did not significantly reduce the composite endpoint of death, aborted cardiac death, and HF hospitalization (HR 0.89, not statistically significant). 3

• Post-hoc analysis of the Americas cohort showed efficacy (HR 0.83) with greater benefit at lower ejection fractions, while the Russia/Georgia cohort showed no benefit (HR 1.10) due to suspected non-adherence. 3

Current Recommendations for HFpEF

The 2022 ACC/AHA/HFSA guidelines give spironolactone a Class IIb recommendation (may be considered) for appropriately selected HFpEF patients to decrease hospitalizations. 3

Patient Selection Criteria:

• Ejection fraction ≥45% 3
• Elevated BNP levels or HF admission within 1 year 3
• eGFR >30 mL/min and creatinine <2.5 mg/dL 3
• Potassium <5.0 mEq/L 3

Dosing and Monitoring Protocol

Initiation and Titration

• Start at 25 mg once daily (or every other day in high-risk patients). 3

• Target dose is 25-50 mg once daily, with the mean effective dose in clinical trials being 26 mg daily. 3, 1

• Patients tolerating 25 mg daily at 8 weeks may increase to 50 mg daily if needed. 3, 1

Monitoring Schedule

Critical monitoring is required to prevent hyperkalemia and renal dysfunction:

• Check serum potassium and creatinine at 1,4,8, and 12 weeks, then at 6,9, and 12 months, then every 6 months thereafter. 3

Management of Hyperkalemia:

• If potassium rises to 5.5-6.0 mEq/L or creatinine rises to 221 μmol/L (2.5 mg/dL): reduce dose to 25 mg every other day and monitor closely. 3
• If potassium exceeds 6.0 mEq/L: seek specialist advice immediately. 3

Common Pitfalls and Safety Considerations

Drug Interactions

Avoid or use extreme caution with:

• ACE inhibitors, ARBs, and other potassium-sparing diuretics (risk of severe hyperkalemia) 3
• NSAIDs (increase hyperkalemia risk and nephrotoxicity) 3
• Potassium supplements and "low salt" substitutes with high potassium content 3

Adverse Effects

• Gynecomastia or breast pain occurs in 10% of men treated with spironolactone versus 1% with placebo (p<0.001). 3, 2

• Hyperkalemia risk is minimal when proper monitoring protocols are followed, though it was uncommon even in the RALES trial. 3, 2

• Patients should temporarily stop spironolactone during episodes of diarrhea or vomiting and contact their physician. 3

Clinical Context

• Spironolactone is indicated as second-line therapy after ACE inhibitors and beta-blockers in NYHA class III-IV heart failure. 3

• The drug should be used in conjunction with loop diuretics, ACE inhibitors, and beta-blockers for optimal benefit. 3, 1

• Benefits on symptoms appear within weeks to months of starting treatment. 3