What is the evidence of mortality benefit with spironolactone and dapagliflozin in patients with Congestive Heart Failure (CHF)?

From the Guidelines

Spironolactone and dapagliflozin both demonstrate significant mortality benefits in heart failure patients, with spironolactone reducing mortality by approximately 30% in patients with severe heart failure with reduced ejection fraction (HFrEF) and dapagliflozin reducing cardiovascular death and heart failure hospitalizations by 26% in patients with HFrEF, regardless of diabetes status. The evidence for spironolactone comes from the RALES trial, which showed a relative risk reduction (RRR) in death of 30% and an RRR in hospital admission for worsening HF of 35% within an average of 2 years of starting treatment 1. The benefits of dapagliflozin are supported by the 2024 ESC guidelines, which recommend an SGLT2 inhibitor (dapagliflozin or empagliflozin) for CCS patients with HFrEF to reduce the risk of HF hospitalization and death, and also for patients with Heart Failure with mildly reduced Ejection Fraction (HFmrEF) or HFpEF to reduce the risk of HF hospitalization or cardiovascular death 1. Key points to consider when prescribing these medications include:

• Monitoring potassium levels closely, especially in patients with renal impairment, and being aware of potential gynecomastia when prescribing spironolactone
• Counseling patients about genital mycotic infections, and temporarily discontinuing dapagliflozin during acute illness to prevent euglycemic diabetic ketoacidosis
• Using these medications as part of a comprehensive treatment plan, including ACE-I, beta-blockers, and diuretics, to reduce the risk of HF hospitalization and death. The mortality benefits of these medications are thought to occur through different mechanisms, with spironolactone blocking aldosterone receptors, reducing fibrosis and sodium retention, and dapagliflozin likely working through multiple pathways including improved cardiac energetics, reduced preload and afterload, and cardiorenal protective effects.

From the FDA Drug Label

The Randomized Spironolactone Evaluation Study was a placebo controlled, double-blind study of the effect of spironolactone on mortality in patients with highly symptomatic heart failure and reduced ejection fraction ... Compared to placebo, spironolactone reduced the risk of death by 30% (p< 0. 001; 95% confidence interval 18% to 40%). Dapagliflozin reduced the incidence of the composite endpoint of CV death or hospitalization for heart failure [HR 0.71 (95% CI 0.55,0.92), p=0.0089] and all-cause mortality [HR 0.69 (95% CI 0.53,0.88), p=0. 0035].

The evidence of mortality benefit with spironolactone in CHF patients is a 30% reduction in the risk of death compared to placebo, as shown in the Randomized Spironolactone Evaluation Study 2. The evidence of mortality benefit with dapagliflozin in CHF patients is a 31% reduction in the risk of CV death or hospitalization for heart failure and a 31% reduction in all-cause mortality, as shown in the DAPA-CKD trial 3 and supported by the DAPA-HF trial. Key points:

• Spironolactone reduces mortality in CHF patients with reduced ejection fraction.
• Dapagliflozin reduces CV death, hospitalization for heart failure, and all-cause mortality in CHF patients.
• Both spironolactone and dapagliflozin have been shown to have a mortality benefit in CHF patients, but the studies were conducted separately and the combination of both drugs was not directly evaluated.

From the Research

Mortality Benefit with Spironolactone in CHF Patients

• The addition of spironolactone to standard therapy can reduce the risk of both morbidity and mortality in patients with severe heart failure 4.
• Spironolactone use in patients with congestive heart failure (CHF) has resulted in side effects and complications, but appropriate use and close follow-up by a dedicated HF team can minimize the risk for adverse events and complications 5.
• Spironolactone reduces morbidity and mortality in patients with heart failure (HF) with reduced ejection fraction (EF) and decreases hospitalizations in HF with preserved EF 6.

Safety and Tolerability of Spironolactone in CHF Patients with CKD

• Spironolactone may be safe to initiate in hospitalized patients with HF and chronic kidney disease (CKD), but appropriateness of therapy must be assessed upon admission to the hospital 6.
• The use of spironolactone in CKD patients with CHF has shown improvement in predictors of cardiovascular mortality, but reduction in glomerular filtration rate and hyperkalemia are potential adverse effects 7.
• Hyperkalemia risk associated with combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure is much stronger in real-life practice than observed in clinical trials 8.

Dapagliflozin in CHF Patients

• There is no direct evidence provided regarding the mortality benefit of dapagliflozin in CHF patients in the given studies.