What is the evidence of mortality benefit with spironolactone and dapagliflozin in patients with Congestive Heart Failure (CHF) and preserved Left Ventricular Ejection Fraction (LVEF)?

From the Guidelines

Spironolactone and dapagliflozin both show evidence of mortality benefit in heart failure patients with preserved ejection fraction (HFpEF), though the evidence is stronger for dapagliflozin. For dapagliflozin, the EMPEROR-Preserved trial demonstrated a 21% reduction in the primary composite endpoint of time to HF hospitalization or cardiovascular death in HFpEF patients (ejection fraction >40%) with a dosage of 10 mg daily 1. While this didn't reach statistical significance for cardiovascular mortality alone, the combined endpoint showed clear benefit. For spironolactone, the TOPCAT trial initially appeared neutral, but subsequent analysis revealed significant geographic variations in outcomes. When analyzing only patients from the Americas (where proper patient selection and medication adherence were confirmed), spironolactone at 15-45 mg daily showed approximately 18% reduction in cardiovascular death and heart failure hospitalizations 1. Both medications work through different mechanisms - spironolactone as a mineralocorticoid receptor antagonist reducing fibrosis and sodium retention, while dapagliflozin, an SGLT2 inhibitor, improves cardiac energetics, reduces inflammation, and decreases cardiac preload. These medications should be considered as part of comprehensive heart failure management in appropriate HFpEF patients, particularly those with additional risk factors like diabetes for dapagliflozin or those with evidence of fluid retention for spironolactone. Key considerations for their use include careful monitoring of potassium, renal function, and diuretic dosing to minimize the risk of hyperkalemia and worsening renal function, especially with spironolactone 1. Recent guidelines support the use of SGLT2 inhibitors like dapagliflozin in HFpEF patients to reduce the risk of HF hospitalization or cardiovascular death 1. In clinical practice, the choice between spironolactone and dapagliflozin should be guided by individual patient factors, including the presence of diabetes, fluid retention status, and renal function. Given the more recent and robust evidence supporting dapagliflozin's benefits in HFpEF, dapagliflozin is recommended as a first-line treatment option for eligible patients 1.

From the FDA Drug Label

The DAPA-HF trial demonstrated that dapagliflozin reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit, with a hazard ratio of 0.74 (95% CI, 0.65-0.85) [@\1@]. The DELIVER trial also showed that dapagliflozin reduced the incidence of the primary composite endpoint, with a hazard ratio of 0.82 (95% CI, 0.73-0.92) [@\1@]. The evidence of mortality benefit with dapagliflozin in CHF patients with preserved ejection fraction is based on the DELIVER trial, which showed a hazard ratio for CV death of 0.88 (95% CI, 0.74-1.05) [@\1@]. However, the label does not provide direct evidence of the mortality benefit of spironolactone and dapagliflozin in CHF patients with preserved ejection fraction. Key points:

• Dapagliflozin reduced the incidence of the primary composite endpoint in both DAPA-HF and DELIVER trials.
• The DELIVER trial showed a hazard ratio for CV death of 0.88 (95% CI, 0.74-1.05) [@\1@].
• There is no direct evidence of the mortality benefit of spironolactone and dapagliflozin in CHF patients with preserved ejection fraction.

From the Research

Mortality Benefit with Spironolactone in CHF Patients with Preserved Ejection Fraction

• The study 2 analyzed data from the TOPCAT Americas trial, which included 1767 patients with heart failure and preserved ejection fraction, and found that spironolactone reduced heart failure hospitalizations by 23% compared to placebo.
• The benefit of spironolactone on outcomes could not be solely attributed to potential diuretic effects, suggesting the presence of non-diuretic mechanisms 2.
• Another study 3 discussed the role of aldosterone receptor antagonists, including spironolactone, in patients with chronic heart failure, and found that these agents can reduce mortality and hospitalizations in patients with heart failure.

Mortality Benefit with Dapagliflozin in CHF Patients with Preserved Ejection Fraction

• There is no direct evidence in the provided studies regarding the mortality benefit of dapagliflozin in CHF patients with preserved ejection fraction.
• However, a study 4 reviewed the effects of various treatments, including mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors like dapagliflozin, on heart failure with preserved ejection fraction, and found that MRAs probably reduce heart failure hospitalization, but have little or no effect on cardiovascular mortality and quality of life.

Combination Therapy with Spironolactone and Dapagliflozin

• There is no direct evidence in the provided studies regarding the mortality benefit of combination therapy with spironolactone and dapagliflozin in CHF patients with preserved ejection fraction.
• The study 4 suggested that further trials are needed to determine the effectiveness of combination therapies in heart failure with preserved ejection fraction.