What is the role of Entresto (sacubitril/valsartan) in the treatment of heart failure with preserved ejection fraction (HFpEF)?

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

Sacubitril/valsartan (Entresto) can be used in patients with HFpEF to reduce heart failure hospitalizations, but does not significantly improve mortality compared to other treatments. 1

Evidence and Efficacy

• The 2023 ACC Expert Consensus Decision Pathway recommends sacubitril/valsartan (ARNI) as part of guideline-directed medical therapy (GDMT) for HFpEF management, alongside SGLT2 inhibitors, mineralocorticoid receptor antagonists (MRAs), and ARBs 1

• In the PARAGON-HF trial, sacubitril/valsartan did not reach statistical significance for the primary composite outcome of total hospitalizations for heart failure and cardiovascular death compared to valsartan alone (rate ratio: 0.87; 95% CI: 0.75-1.01; p=0.06) 2

• However, sacubitril/valsartan did show a trend toward reducing heart failure hospitalizations (rate ratio: 0.85; 95% CI: 0.72-1.00) in HFpEF patients 2

• A meta-analysis demonstrated that sacubitril/valsartan significantly reduced hospitalization rates for heart failure in HFpEF patients compared to control groups (RR: 0.85; 95% CI: 0.79-0.93; p=0.0002) 3

Patient Selection and Subgroup Considerations

• Post-hoc analyses suggest potential heterogeneity in treatment response, with possible greater benefit in:

  • Patients with lower ejection fraction (closer to the mildly reduced range) 2
  • Female patients 2

• A pooled analysis of PARAGLIDE-HF and PARAGON-HF showed that sacubitril/valsartan reduced cardiovascular events particularly in patients with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared to those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021) 4

Treatment Algorithm for HFpEF

• First-line therapy for HFpEF should focus on risk factor management (hypertension, diabetes, obesity, atrial fibrillation) and symptom control with diuretics 1

• SGLT2 inhibitors (dapagliflozin, empagliflozin) have shown significant benefits in HFpEF and should be considered early in treatment 1

• Mineralocorticoid receptor antagonists (spironolactone) may be considered for selected HFpEF patients with elevated natriuretic peptides or recent hospitalization 1

• Sacubitril/valsartan can be considered for patients who remain symptomatic despite other therapies, particularly those with ejection fraction in the lower range of preservation (EF 40-60%) 1, 4

Safety Considerations

• Hypotension is a common side effect of sacubitril/valsartan, with meta-analyses showing increased risk of symptomatic hypotension (RR: 1.44; 95% CI: 1.25-1.66; p<0.00001) 3

• Monitor blood pressure closely during initiation and dose titration, particularly in patients with borderline blood pressure 1

• Sacubitril/valsartan was not associated with increased risk of renal function worsening or hyperkalemia in HFpEF patients 3

• A 36-hour washout period is mandatory when transitioning from ACE inhibitors to sacubitril/valsartan to avoid angioedema 5

Practical Implementation

• Start with lower doses (24/26 mg twice daily) in patients with severe renal impairment, moderate hepatic impairment, or elderly patients (≥75 years) 5

• Titrate dose gradually, doubling every 2-4 weeks as tolerated, aiming for the target dose of 97/103 mg twice daily if possible 5

• Consider reducing diuretic doses in non-congested patients when initiating sacubitril/valsartan due to enhanced natriuresis 5

• Monitor renal function and electrolytes within 1-2 weeks after initiation and with each dose increase 5

Common Pitfalls to Avoid

• Do not co-administer with ACE inhibitors - ensure the 36-hour washout period is strictly observed 5

• Do not discontinue therapy prematurely due to mild laboratory changes or asymptomatic hypotension 5

• Do not expect mortality benefits in HFpEF patients as seen in HFrEF - the primary benefit appears to be reduction in heart failure hospitalizations 2, 3