For an older female patient with heart‑failure with preserved ejection fraction (LVEF ≥ 45%, NYHA class II‑III, recent HF hospitalization or elevated natriuretic peptides), how is sacubitril/valsartan (Entresto) indicated, initiated, titrated, and monitored?

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

Sacubitril/valsartan carries a Class 2b recommendation for HFpEF, meaning it "may be considered" in selected patients—specifically women and those with LVEF 45–57%—but it is NOT first-line therapy and did not meet its primary endpoint in the pivotal PARAGON-HF trial. 1, 2

Evidence Base and Guideline Recommendations

The 2022 AHA/ACC/HFSA guidelines assign sacubitril/valsartan a Class 2b recommendation (Level of Evidence: B-R) for HFpEF, which is substantially weaker than its Class I recommendation for HFrEF. 1, 2 This distinction is critical: in the PARAGON-HF trial of 4,822 patients with LVEF ≥45%, sacubitril/valsartan versus valsartan failed to achieve statistical significance for the primary composite endpoint of cardiovascular death or total HF hospitalizations (rate ratio 0.87; 95% CI 0.75–1.01; p=0.06). 1

Subgroup Benefits That Drive the Indication

Despite the neutral overall result, two prespecified subgroups showed significant benefit that form the basis for selective use: 1, 2

• Women: Rate ratio 0.73 (95% CI 0.59–0.90), driven primarily by reduction in HF hospitalizations 1, 2
• LVEF 45–57% (below the trial median): Rate ratio 0.78 (95% CI 0.64–0.95) 1

There was no mortality benefit in the overall population (HR 0.97 for all-cause mortality, HR 0.95 for CV death). 1 The signal of benefit was entirely in HF hospitalizations (rate ratio 0.85; 95% CI 0.72–1.00; p=0.056). 1

Patient Selection Criteria

Eligibility thresholds for initiating sacubitril/valsartan in HFpEF include: 2

Criterion	Threshold
LVEF	≥45% (preferably 45–57%)
NYHA class	II–III
Natriuretic peptides	Elevated (or HF hospitalization within 9 months)
eGFR	≥30 mL/min/1.73 m²
Serum potassium	≤5.2 mmol/L
Systolic BP	≥100 mm Hg (preferred)

Prioritize female patients and those with LVEF closer to 45–50%, as these subgroups derive the greatest benefit. 1, 2, 3 Sacubitril/valsartan should be considered after SGLT2 inhibitors (which have a stronger Class 2a recommendation for HFpEF) and in patients who remain symptomatic despite optimal management of comorbidities. 2, 3

Initiation and Dosing Algorithm

Switching from ACE Inhibitor or ARB

Mandatory 36-hour washout is required when transitioning from an ACE inhibitor to avoid angioedema (Class I recommendation, strong evidence). 4, 2 No washout is needed when switching from an ARB. 4

Starting dose: 4, 2

• Standard patients: 49/51 mg twice daily (if previously on high-dose ACE inhibitor or ARB)
• High-risk patients: 24/26 mg twice daily if:
  • Severe renal impairment (eGFR <30 mL/min/1.73 m²)
  • Moderate hepatic impairment (Child-Pugh B)
  • Age ≥75 years
  • Systolic BP 100–110 mm Hg

Titration Schedule

Double the dose every 2–4 weeks as tolerated, targeting 97/103 mg twice daily for maximum benefit. 4, 2 This target dose was used in PARAGON-HF and provides the greatest reduction in HF hospitalizations. 4

Monitoring Parameters

Essential monitoring at baseline, 1–2 weeks after initiation, and with each dose increase: 4, 2

• Blood pressure: Watch for symptomatic hypotension (most common adverse effect in older adults; pinteraction = 0.026 for age-related hypotension risk) 5
• Renal function: Serum creatinine and eGFR (sacubitril/valsartan actually favored better renal outcomes than valsartan in PARAGON-HF) 1
• Serum potassium: Particularly when combined with MRAs; hold if K⁺ >5.2 mmol/L 2
• Volume status: Consider reducing diuretic dose in non-congested patients due to enhanced natriuresis 4, 2

Management of Adverse Effects

Hypotension (the most common barrier to titration): 4, 2

• Asymptomatic hypotension is NOT a reason to withhold or reduce dose—benefits are maintained even with systolic BP <110 mm Hg 4, 2
• Symptomatic hypotension: First reduce diuretic dose if patient is euvolemic; if persistent, temporarily reduce sacubitril/valsartan dose then re-titrate (40% of patients who required temporary dose reduction were successfully restored to target) 4

Hyperkalemia: 2

• Mild elevation (<0.5 mg/dL creatinine increase) is acceptable and does not require dose adjustment 4
• If K⁺ >5.5 mmol/L, hold dose and recheck; consider reducing or holding MRA if co-prescribed 2

Angioedema: 4, 2

• Occurs more frequently than with ACE inhibitors alone
• History of angioedema with prior ACE inhibitor/ARB is a precaution (not absolute contraindication) but requires careful counseling 4

Contraindications

Absolute contraindications: 4, 2

• Concomitant ACE inhibitor use (requires 36-hour washout)
• History of angioedema with sacubitril/valsartan
• Pregnancy or lactation
• Severe hepatic impairment (Child-Pugh C)

Treatment Algorithm for HFpEF

First-line disease-modifying therapy: SGLT2 inhibitors (dapagliflozin or empagliflozin) have a Class 2a recommendation and should be initiated first. 2, 3 They reduce the composite of worsening HF and CV death by 18–21% (DELIVER and EMPEROR-PRESERVED trials). 3

Second-line considerations for patients who remain symptomatic: 2, 3

1. Spironolactone 12.5–25 mg daily (Class 2b) if LVEF 40–50%
2. Sacubitril/valsartan (Class 2b) if female or LVEF 45–57%

Symptom management: Loop diuretics at the lowest effective dose for congestion. 3

Common Pitfalls to Avoid

• Do not treat HFpEF the same as HFrEF: Sacubitril/valsartan has a much weaker evidence base in HFpEF (Class 2b vs. Class I). 2, 3
• Do not initiate sacubitril/valsartan before SGLT2 inhibitors in most HFpEF patients—SGLT2 inhibitors have stronger evidence and a Class 2a recommendation. 2, 3
• Do not permanently discontinue for asymptomatic hypotension—temporary dose reduction with subsequent re-titration is preferred. 4
• Do not overlook the 36-hour ACE inhibitor washout—this is a Class I safety requirement to prevent angioedema. 4, 2
• Do not use in patients with LVEF >60%—there is no evidence of benefit in this population. 1, 2

Special Populations

Elderly patients (≥75 years): 5

• Start with 24/26 mg twice daily
• Higher risk of hypotension (pinteraction = 0.026) but treatment benefits are retained
• Monitor BP closely during titration

Chronic kidney disease: 2

• Requires eGFR ≥30 mL/min/1.73 m² for initiation
• Sacubitril/valsartan showed better renal outcomes than valsartan in PARAGON-HF (lower incidence of composite renal decline) 1

Peritoneal dialysis patients: 6

• Small observational study (n=21) showed safety and efficacy with 50–100 mg twice daily
• NT-proBNP decreased significantly (p=0.002) with no adverse drug reactions
• Consider in ESKD patients with HFpEF, though data are limited