What is the role of Entresto (sacubitril/valsartan) in treating Heart Failure with preserved Ejection Fraction (HFpEF)?

Role of Entresto (Sacubitril/Valsartan) in Heart Failure with Preserved Ejection Fraction (HFpEF)

Sacubitril/valsartan (Entresto) may be considered for selected patients with HFpEF, particularly women and those with ejection fraction in the lower preserved range (45-57%), but it is not a first-line therapy for most HFpEF patients. 1, 2

Efficacy in HFpEF

• The PARAGON-HF trial, which evaluated sacubitril/valsartan in HFpEF patients (LVEF ≥45%), did not achieve a significant reduction in the primary composite endpoint of cardiovascular death or total heart failure hospitalizations (rate ratio 0.87; 95% CI 0.75-1.01; p=0.06) 1
• However, prespecified subgroup analyses showed potential benefit in:
  • Patients with LVEF below the median (45%-57%) (rate ratio 0.78; 95% CI 0.64-0.95) 1
  • Women (rate ratio 0.73; 95% CI 0.59-0.90) 1
• A recent meta-analysis found that sacubitril/valsartan substantially reduced heart failure hospitalization rates compared to ACEIs and ARBs (Relative Risk 0.78; 95% CI 0.65-0.85; p=0.001) 3

Current Guideline Recommendations

• Sacubitril/valsartan has a Class 2b recommendation for HFpEF in the 2022 AHA/ACC/HFSA guidelines, indicating it "may be considered" for selected patients 1
• The FDA approved sacubitril/valsartan for selected patients with HFpEF in February 2021, based largely on post-hoc analyses of the PARAGON-HF trial 1
• SGLT2 inhibitors (dapagliflozin, empagliflozin) have stronger evidence and higher recommendation (Class 2a) for HFpEF treatment 2

Patient Selection for Sacubitril/Valsartan in HFpEF

• Consider sacubitril/valsartan particularly for:
  • Patients with LVEF in the lower preserved range (closer to 45-50%) 1, 2
  • Female patients, who showed greater benefit in clinical trials 1, 2
  • Patients who remain symptomatic despite optimal therapy with other agents 2

Treatment Algorithm for HFpEF

1. First-line therapy: SGLT2 inhibitors (dapagliflozin or empagliflozin) due to stronger evidence from DELIVER and EMPEROR-PRESERVED trials 2
2. Symptom management: Loop diuretics at the lowest effective dose to manage fluid retention 2
3. Consider adding:
   • Mineralocorticoid receptor antagonists (spironolactone) - Class 2b recommendation 2
   • Sacubitril/valsartan - Class 2b recommendation, especially for women and those with LVEF 45-57% 1, 2

Monitoring and Side Effects

• Monitor for hypotension, which is the most common side effect of sacubitril/valsartan 4
• Assess renal function and electrolytes regularly, especially when combined with other heart failure medications 4
• Consider reducing diuretic doses in non-congested patients to mitigate hypotensive effects 4

Common Pitfalls to Avoid

• Treating all HFpEF patients the same as HFrEF patients - response to therapies differs significantly 2
• Overlooking the importance of SGLT2 inhibitors as first-line therapy for HFpEF 2
• Failing to optimize management of comorbidities (hypertension, diabetes, obesity, atrial fibrillation) 2
• Using sacubitril/valsartan as first-line therapy in HFpEF when stronger evidence supports SGLT2 inhibitors 2

Conclusion

While sacubitril/valsartan shows promise in reducing heart failure hospitalizations in selected HFpEF patients (particularly women and those with LVEF 45-57%), it did not meet its primary endpoint in the PARAGON-HF trial. SGLT2 inhibitors currently have stronger evidence and higher recommendation (Class 2a) for HFpEF treatment compared to sacubitril/valsartan (Class 2b).