Is sacubitril + valsartan (angiotensin receptor-neprilysin inhibitor) effective for treating heart failure with preserved ejection fraction (HFpEF) with an ejection fraction of 55%?

Sacubitril/Valsartan for Heart Failure with Preserved Ejection Fraction (EF 55%)

Sacubitril/valsartan can be considered for patients with HFpEF and an ejection fraction of 55%, particularly if the patient is female or has recently been hospitalized for heart failure, though SGLT2 inhibitors remain the preferred first-line disease-modifying therapy. 1, 2

Evidence from PARAGON-HF Trial

The pivotal PARAGON-HF trial evaluated sacubitril/valsartan in 4,822 patients with HFpEF (LVEF ≥45%) and 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 However, prespecified subgroup analyses revealed important treatment effects:

• Patients with LVEF 45-57% (below the median) showed significant benefit with rate ratio 0.78 (95% CI 0.64-0.95), suggesting greater efficacy in the lower preserved range. 1, 2
• Women demonstrated substantial benefit with rate ratio 0.73 (95% CI 0.59-0.90), indicating sex-specific treatment response. 1, 2
• Heart failure hospitalizations showed a trend toward reduction (rate ratio 0.85; 95% CI 0.72-1.00; p=0.056). 1

Recent Pooled Analysis Data

A 2023 pooled analysis of PARAGLIDE-HF and PARAGON-HF (5,262 patients total) demonstrated that sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death compared to valsartan (rate ratio 0.86; 95% CI 0.75-0.98; p=0.027). 3 Treatment benefits were substantially larger in patients with LVEF ≤60% (rate ratio 0.78; 95% CI 0.66-0.91) compared to those with LVEF >60% (rate ratio 1.09; 95% CI 0.86-1.40). 3

Current Guideline Recommendations

The 2022 AHA/ACC/HFSA guidelines assign sacubitril/valsartan a Class 2b recommendation (may be considered) for HFpEF, indicating it is a reasonable option but not first-line therapy. 1, 2 The FDA approved sacubitril/valsartan for selected HFpEF patients in February 2021, acknowledging that "benefits are most clearly evident in patients with left ventricular ejection fraction below normal." 4, 5

Treatment Algorithm for HFpEF with EF 55%

First-line therapy:

• SGLT2 inhibitors (dapagliflozin or empagliflozin) should be initiated first, as they have Class 2a recommendations and demonstrated significant reductions in heart failure hospitalizations and cardiovascular death in DELIVER and EMPEROR-PRESERVED trials. 2
• Loop diuretics for symptom management if congestion is present. 2

Second-line considerations:

• Sacubitril/valsartan can be added if the patient remains symptomatic despite SGLT2 inhibitor therapy, particularly if: 2, 4
  • Female sex (stronger evidence of benefit)
  • Recent heart failure hospitalization
  • LVEF in the 45-57% range (though 55% falls in this range)

Third-line options:

• Mineralocorticoid receptor antagonists (spironolactone) may be considered, particularly for patients with LVEF closer to 45-50%. 2

Practical Implementation

Dosing strategy:

• Start with 24/26 mg twice daily if transitioning from an ACE inhibitor or ARB, or if the patient is elderly (≥75 years), has severe renal impairment, or moderate hepatic impairment. 4, 6
• Start with 49/51 mg twice daily if previously on high-dose ACE inhibitors. 6
• Titrate dose every 2-4 weeks to target dose of 97/103 mg twice daily as tolerated. 4, 6

Critical safety considerations:

• Mandatory 36-hour washout period when transitioning from ACE inhibitors to avoid angioedema. 4, 6
• No washout required when switching from ARBs. 6
• Monitor blood pressure closely, as hypotension is more common with sacubitril/valsartan than valsartan alone. 1
• Monitor renal function and potassium within 1-2 weeks after initiation and with each dose increase. 4

Additional Benefits

Sacubitril/valsartan demonstrated favorable effects on:

• Renal outcomes: 40% reduction in renal composite endpoint (≥50% decline in eGFR, end-stage renal disease, or renal death) in pooled analysis (HR 0.60; 95% CI 0.44-0.83; p=0.002). 3
• NT-proBNP reduction: 19% greater reduction compared to valsartan at 16 weeks (95% CI 14-23%; p<0.001), with consistent effects across sex and LVEF subgroups. 7
• Cardiac remodeling: Significant improvement in global circumferential strain (Δ4.42%, 95% CI 0.67-8.17, p=0.021) in the PARAMOUNT trial. 8

Common Pitfalls to Avoid

• Do not use sacubitril/valsartan as first-line therapy in HFpEF when SGLT2 inhibitors have stronger evidence and higher guideline recommendations. 2
• Avoid treating all HFpEF patients identically to those with HFrEF, as treatment responses differ significantly between these populations. 2
• Do not overlook comorbidity management (hypertension, diabetes, obesity, atrial fibrillation), which significantly impacts outcomes in HFpEF. 2
• Avoid excessive diuresis when initiating sacubitril/valsartan due to enhanced natriuresis, which may lead to hypotension and worsening renal function. 4, 6