What is the class indication for Spironolactone (Spiro) and Dapagliflozin (Dapa) in Heart Failure with Preserved Ejection Fraction (HFpEF)?

Class Indications for Spironolactone and Dapagliflozin in HFpEF

In HFpEF, dapagliflozin has a Class 2a indication while spironolactone has a Class 2b indication according to the 2022 AHA/ACC/HFSA guidelines, with dapagliflozin showing stronger evidence for reducing hospitalizations and cardiovascular mortality. 1, 2

SGLT2 Inhibitors (Dapagliflozin)

• Dapagliflozin has a Class 2a recommendation (Level of Evidence: B-R) in patients with HFpEF, indicating that it "can be beneficial in decreasing HF hospitalizations and cardiovascular mortality" 1
• The DELIVER trial demonstrated that dapagliflozin significantly reduced the primary composite endpoint of worsening heart failure and cardiovascular death (HR: 0.82; 95% CI: 0.73-0.92) in patients with HFpEF (LVEF >40%) 1
• Dapagliflozin showed a 23% reduction in heart failure hospitalizations (HR: 0.77; 95% CI: 0.67-0.89) in the DELIVER trial, making it particularly effective for reducing morbidity 1
• The FDA has approved dapagliflozin for HFpEF based on the DELIVER trial results, which showed consistent benefits regardless of baseline diuretic use or dosing 3, 4
• Dapagliflozin also improves health status and quality of life in HFpEF patients as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores 5

Mineralocorticoid Receptor Antagonists (Spironolactone)

• Spironolactone has a Class 2b recommendation (Level of Evidence: B-R) in HFpEF, indicating that it "may be considered to decrease hospitalizations, particularly among patients with LVEF on the lower end of this spectrum" 1
• The TOPCAT trial showed that spironolactone did not significantly reduce the primary composite outcome of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization in the overall population (HR: 0.89; 95% CI: 0.77-1.04) 1, 6
• However, spironolactone did reduce heart failure hospitalizations (HR: 0.83; 95% CI: 0.69-0.99) in the TOPCAT trial 1
• A significant regional variation was observed in TOPCAT, with benefits seen primarily in patients enrolled in North America (HR: 0.82; 95% CI: 0.69-0.98) but not in Russia/Georgia 1
• Spironolactone appears to be more effective in patients with LVEF in the lower range of preservation (closer to 45-50%) 1

Comparative Efficacy and Combination Therapy

• The American College of Cardiology recommends SGLT2 inhibitors (including dapagliflozin) as first-line disease-modifying therapy for most HFpEF patients due to stronger evidence for reducing cardiovascular outcomes 7, 2
• Recent evidence suggests that combining dapagliflozin with spironolactone may provide additional benefits in reducing NT-proBNP levels compared to dapagliflozin alone, though with increased risk of hyperkalemia and reduced eGFR 8
• When initiating therapy, the 2023 ACC expert consensus recommends starting with an SGLT2 inhibitor like dapagliflozin first, with consideration of adding spironolactone in selected patients, particularly those with LVEF closer to 45% 1

Clinical Considerations and Monitoring

• When prescribing spironolactone, careful monitoring of potassium, renal function, and diuretic dosing is essential to minimize the risk of hyperkalemia and worsening renal function 1
• Dapagliflozin has demonstrated safety and efficacy even in patients recently hospitalized for heart failure, making it suitable for initiation during or shortly after hospitalization 9
• Dapagliflozin may reduce the need for loop diuretics over time and attenuate the longitudinal increase in diuretic requirements seen in HFpEF patients 4

Common Pitfalls to Avoid

• Do not delay initiation of SGLT2 inhibitors like dapagliflozin in eligible HFpEF patients given their proven benefits on hospitalization and mortality 7, 2
• Avoid treating all HFpEF patients the same as those with reduced ejection fraction, as response to therapies differs significantly between these populations 1, 2
• Do not overlook the importance of managing comorbidities in HFpEF patients, including hypertension, diabetes, obesity, and atrial fibrillation, which can significantly impact outcomes 1, 7