Is Entresto (sacubitril/valsartan) contraindicated in Heart Failure with preserved Ejection Fraction (HFpEF)?

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

Entresto (sacubitril/valsartan) is not contraindicated in Heart Failure with Preserved Ejection Fraction (HFpEF) and can be beneficial in reducing heart failure hospitalizations in selected patients with HFpEF, particularly those with ejection fraction in the lower range of preservation (45-57%).

Evidence for Entresto in HFpEF

• The 2022 AHA/ACC/HFSA Heart Failure Guidelines indicate that sacubitril/valsartan was studied in the PARAGON-HF trial for HFpEF patients (LVEF ≥45%), but 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, pre-specified subgroup analyses showed a benefit of sacubitril/valsartan compared with valsartan 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 2022 meta-analysis of randomized controlled trials found that sacubitril/valsartan reduced the risk of hospitalization for heart failure (OR: 0.78; 95% CI: 0.70-0.88; p<0.0001) and the incidence of worsening renal function (RR: 0.79, p=0.002) in HFpEF patients 2

FDA Approval Status and Guidelines

• In February 2021, the FDA approved sacubitril/valsartan for selected patients with HFpEF based largely on the PARAGON-HF trial, despite not meeting its primary endpoint 1

• The American College of Cardiology recommends sacubitril/valsartan as part of guideline-directed medical therapy for HFpEF management, particularly for patients who remain symptomatic despite other therapies 3

Patient Selection and Considerations

• Sacubitril/valsartan should be considered particularly for HFpEF patients with:

  • Ejection fraction in the lower range of preservation (EF 45-57%) 1, 3
  • Female sex 1
  • Patients who remain symptomatic despite other therapies 3

• Monitor for potential adverse effects:

  • Increased incidence of hypotension (RR: 1.44; p<0.00001) 2
  • Higher risk of angioedema (RR: 2.66; p<0.04) 2
  • No significant difference in hyperkalemia risk compared to valsartan 2

Practical Implementation

• Start with lower doses (24/26 mg twice daily) in patients with:

  • Severe renal impairment 3
  • Moderate hepatic impairment 3
  • Elderly patients (≥75 years) 3

• A 36-hour washout period is mandatory when transitioning from ACE inhibitors to sacubitril/valsartan to avoid angioedema 3

• Consider reducing diuretic doses in non-congested patients when initiating sacubitril/valsartan due to enhanced natriuresis 3

• Monitor renal function and electrolytes within 1-2 weeks after initiation and with each dose increase 3

Treatment Algorithm for HFpEF

1. First-line therapy: Risk factor management (hypertension, diabetes, obesity, atrial fibrillation) and symptom control with diuretics 3

2. Consider SGLT2 inhibitors (dapagliflozin, empagliflozin) which have shown significant benefits in HFpEF 3, 1

3. Consider mineralocorticoid receptor antagonists (spironolactone) for selected HFpEF patients with elevated natriuretic peptides or recent hospitalization 3

4. Consider sacubitril/valsartan for patients who remain symptomatic despite other therapies, particularly those with ejection fraction in the lower range of preservation (EF 45-57%) 1, 3

In conclusion, while Entresto is not contraindicated in HFpEF, its benefits are most pronounced in specific subgroups, particularly those with LVEF in the lower range of preservation and women. Careful patient selection and monitoring are essential to maximize benefits while minimizing risks.