Is sacubitril/valsartan (Entresto) recommended for a patient with heart failure and left‑ventricular ejection fraction greater than 40%?

Entresto in Heart Failure with EF Greater Than 40%

Entresto (sacubitril/valsartan) may be considered for patients with heart failure and ejection fraction greater than 40%, but only in highly selected populations—specifically women and those with LVEF in the 45-57% range—while SGLT2 inhibitors remain the preferred first-line disease-modifying therapy for HFpEF.

Evidence Base and Guideline Recommendations

The 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. Despite this neutral primary outcome, the FDA approved sacubitril/valsartan for selected HFpEF patients in February 2021 based on prespecified subgroup analyses 2.

Who Benefits Most

Prespecified subgroup analyses revealed two populations with significant benefit:

• Women with HFpEF showed substantial benefit (rate ratio 0.73; 95% CI 0.59-0.90), primarily through reduction in heart failure hospitalizations 1, 2
• Patients with LVEF 45-57% (below the median) demonstrated benefit (rate ratio 0.78; 95% CI 0.64-0.95) compared to those with higher LVEF 1, 2

The 2022 AHA/ACC/HFSA guidelines assign sacubitril/valsartan a Class 2b recommendation for HFpEF, indicating it "may be considered" for selected patients, particularly those with LVEF on the lower end of the spectrum and in women 2.

Treatment Algorithm for HF with EF >40%

First-Line Therapy (Class 2a)

SGLT2 inhibitors (dapagliflozin or empagliflozin) should be initiated first as the cornerstone disease-modifying therapy for HFpEF 3. Dapagliflozin reduced worsening HF and cardiovascular death (HR 0.82; 95% CI 0.73-0.92) in the DELIVER trial, while empagliflozin reduced hospitalization for HF and cardiovascular death (HR 0.79; 95% CI 0.69-0.90) in EMPEROR-PRESERVED 3.

Second-Line Considerations

If patients remain symptomatic despite SGLT2 inhibitor therapy:

• Consider spironolactone (Class 2b), particularly if LVEF is in the lower preserved range (40-50%) 3. The TOPCAT trial showed spironolactone reduced heart failure hospitalizations (HR 0.83; 95% CI 0.69-0.99) 3

• Consider sacubitril/valsartan (Class 2b) specifically for:

  • Female patients 2
  • LVEF 45-57% 2
  • Elevated natriuretic peptides 2
  • Symptomatic disease despite SGLT2 inhibitor therapy 2

Symptom Management

Loop diuretics remain essential for managing congestion and relieving orthopnea/paroxysmal nocturnal dyspnea, titrated to the lowest effective dose 3.

Practical Implementation When Using Sacubitril/Valsartan in EF >40%

Dosing Strategy

• Initial dose: 24/26 mg twice daily for most HFpEF patients, especially those with borderline blood pressure, severe renal impairment (eGFR <30 mL/min/1.73m²), moderate hepatic impairment, or age ≥75 years 4, 2
• Titration: Double dose every 2-4 weeks as tolerated, targeting 97/103 mg twice daily 4
• Washout period: Mandatory 36-hour washout when transitioning from ACE inhibitors to avoid angioedema; no washout needed from ARBs 4, 2

Monitoring Requirements

• Blood pressure within 1-2 weeks after initiation and with each dose increase 2
• Renal function and serum potassium within 1-2 weeks after initiation and dose changes 4
• Consider reducing diuretic doses in non-congested patients due to enhanced natriuresis 2

Critical Distinctions from HFrEF

The evidence for sacubitril/valsartan is fundamentally different between HFrEF and HFpEF:

• In HFrEF (EF ≤40%), sacubitril/valsartan has a Class 1 recommendation with proven 20% reduction in cardiovascular death and HF hospitalization compared to enalapril 4, 5
• In HFpEF (EF ≥45%), sacubitril/valsartan has only a Class 2b recommendation with benefits limited to specific subgroups and no proven mortality reduction 1, 2

Common Pitfalls to Avoid

• Do not treat HFpEF patients the same as HFrEF patients—the response to therapies differs significantly between these populations 3
• Do not prioritize sacubitril/valsartan over SGLT2 inhibitors in HFpEF, as SGLT2 inhibitors have stronger evidence (Class 2a vs Class 2b) 2
• Do not use sacubitril/valsartan as first-line therapy in HFpEF without first optimizing SGLT2 inhibitors and managing comorbidities 3, 2
• Avoid excessive concern about asymptomatic hypotension—this should not prevent initiation or titration, as benefits occur regardless of baseline blood pressure 4
• Do not overlook the importance of managing comorbidities (hypertension, diabetes, obesity, atrial fibrillation), which significantly impact HFpEF outcomes 3

The Bottom Line

For patients with EF >40%, prioritize SGLT2 inhibitors first, then consider sacubitril/valsartan only if the patient is female or has LVEF 45-57% and remains symptomatic despite optimal therapy 3, 2. The evidence supporting sacubitril/valsartan in this population is substantially weaker than in HFrEF, and most patients will derive greater benefit from SGLT2 inhibitors as the foundation of disease-modifying therapy 3, 2.