Is Entresto Appropriate in HFpEF?
Entresto (sacubitril/valsartan) can be considered for selected patients with HFpEF, particularly those with ejection fraction in the lower range of preservation (45-57%), women, and those who remain symptomatic despite SGLT2 inhibitor therapy, though SGLT2 inhibitors should be prioritized as first-line therapy. 1
Evidence Base and FDA Approval
The PARAGON-HF trial studied sacubitril/valsartan in HFpEF patients (LVEF ≥45%) but did not achieve statistical significance for its 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 Despite this, the FDA approved sacubitril/valsartan for selected HFpEF patients based largely on this trial and subsequent subgroup analyses. 1
Guideline Recommendations and Treatment Hierarchy
The 2022 AHA/ACC/HFSA Heart Failure Guidelines assign sacubitril/valsartan a Class 2b recommendation for HFpEF, indicating it "may be considered" with moderate strength of evidence. 1 This is a weaker recommendation compared to SGLT2 inhibitors, which receive a Class 2a recommendation. 1
SGLT2 inhibitors (dapagliflozin, empagliflozin) should be prioritized over sacubitril/valsartan in most HFpEF patients as they have demonstrated more consistent benefits across the HFpEF spectrum. 1
Patient Selection Criteria: Who Benefits Most?
Patients with Lower-Range LVEF (45-57%)
Sacubitril/valsartan showed greater benefit in patients with LVEF in the lower range of preservation (45-57%), with a rate ratio of 0.78 (95% CI 0.64-0.95) compared to those with higher LVEF. 1 The most recent pooled analysis of PARAGLIDE-HF and PARAGON-HF confirmed that treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with LVEF >60% (RR 1.09; 95% CI 0.86-1.40). 2
Women with HFpEF
Women experienced significant benefit with sacubitril/valsartan, with a rate ratio of 0.73 (95% CI 0.59-0.90), primarily driven by reduction in HF hospitalizations. 1
Patients with Recent Worsening HF
The 2023 pooled analysis demonstrated that sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in participants with recent worsening HF (n=1088; RR 0.78; 95% CI 0.61-0.99; P=0.042). 2 Benefits emerged as early as Day 9 after randomization in the pooled analysis. 2
Clinical Algorithm for HFpEF Management
First-Line Therapy
- SGLT2 inhibitors (dapagliflozin or empagliflozin) should be initiated early as they have shown significant benefits in HFpEF. 1
- Risk factor management (hypertension, diabetes, obesity, atrial fibrillation) and symptom control with diuretics. 1
Second-Line Considerations
- Mineralocorticoid receptor antagonists (spironolactone) may be considered for selected patients with elevated natriuretic peptides or recent hospitalization. 1
Third-Line: When to Consider Sacubitril/Valsartan
Sacubitril/valsartan should be considered for patients who meet the following criteria: 1
- LVEF 45-57% (lower range of preservation)
- Female sex OR reduced kidney function
- Elevated natriuretic peptides
- Symptomatic disease despite SGLT2 inhibitor therapy
Practical Implementation
Dosing and Titration
Start with 24/26 mg twice daily in patients with severe renal impairment, moderate hepatic impairment, or elderly patients (≥75 years). 1 Titrate dose gradually, doubling every 2-4 weeks as tolerated, aiming for the target dose of 97/103 mg twice daily. 1
Safety Monitoring
- Monitor blood pressure closely during initiation and dose titration, particularly in patients with borderline blood pressure. 1
- A 36-hour washout period is mandatory when transitioning from ACE inhibitors to sacubitril/valsartan to avoid angioedema. 1
- Monitor renal function and electrolytes within 1-2 weeks after initiation and with each dose increase. 1
Additional Benefits: Renal Protection
Sacubitril/valsartan reduced the risk of worsening renal function (RR 0.79, p=0.002) in meta-analysis of HFpEF trials. 3 The 2023 pooled analysis showed lower rates of the renal composite endpoint (≥50% decline in eGFR, end-stage renal disease, or renal death) with HR 0.60 (95% CI 0.44-0.83; P=0.002). 2
Common Pitfalls and Safety Concerns
Adverse Effects to Monitor
Sacubitril/valsartan was associated with increased risk of symptomatic hypotension (RR 1.44; p<0.00001) and angioedema (RR 2.66; p<0.04) compared to valsartan. 3 Consider reducing diuretic doses in non-congested patients when initiating sacubitril/valsartan due to enhanced natriuresis. 1
No Mortality Benefit in HFpEF
Unlike in HFrEF, sacubitril/valsartan did not demonstrate significant reduction in all-cause mortality (OR 0.99,95% CI 0.84-1.15; p=0.86) or cardiovascular mortality (OR 0.95% CI 0.78-1.15; p=0.16) in HFpEF patients. 3 The primary benefit is reduction in heart failure hospitalizations (OR 0.78; 95% CI 0.70-0.88; p<0.0001). 3