When should a patient with chronic heart failure with reduced ejection fraction (HFrEF) and symptoms of heart failure (New York Heart Association (NYHA) class II-IV) be started on Entresto (sacubitril/valsartan)?

When to Start Entresto (Sacubitril/Valsartan) in Heart Failure

Start Entresto in patients with chronic HFrEF (LVEF ≤40%) who remain symptomatic (NYHA class II-IV) despite optimal treatment with an ACE inhibitor (or ARB) and beta-blocker, replacing the ACE inhibitor/ARB after a 36-hour washout period. 1

Patient Selection Criteria

Ejection Fraction Requirements:

• LVEF ≤40% is the FDA-approved threshold for initiating Entresto in adults with chronic heart failure 1
• Recent evidence supports use in patients with LVEF 40-60% (mildly reduced or preserved EF), particularly those with recent worsening HF events, though benefits are greatest when LVEF ≤60% 2

Symptomatic Status:

• Patients must be NYHA class II-IV despite current guideline-directed medical therapy 1
• The European Society of Cardiology recommends Entresto specifically for ambulatory patients who remain symptomatic after optimization of triple therapy (ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist) 3

Prerequisite Therapy:

• Patients should already be on stable doses of an ACE inhibitor or ARB plus a beta-blocker 3, 4
• The American College of Cardiology emphasizes attempting optimization of foundational therapies before switching to Entresto 5

Critical Timing and Washout Requirements

ACE Inhibitor Washout:

• You must allow a 36-hour washout period between stopping an ACE inhibitor and starting Entresto to avoid angioedema risk 1
• This washout is mandatory and non-negotiable due to the combined neprilysin and RAAS inhibition 1

No Washout Needed for ARBs:

• Patients can transition directly from an ARB to Entresto without a washout period, as both contain valsartan 4

Dosing Initiation Protocol

Starting Dose:

• Begin with 49/51 mg orally twice daily in adults 1
• For patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), start at half the usual dose (24/26 mg twice daily) 1

Titration Schedule:

• Double the dose every 2-4 weeks as tolerated 1
• Target maintenance dose is 97/103 mg twice daily 1

Benefits Across Disease Duration

Entresto works regardless of heart failure duration:

• Significant improvements in cardiac biomarkers (NT-proBNP, troponin T, ST2), health status, and reverse cardiac remodeling occur whether HF duration is <12 months or >60 months 6
• Absolute LVEF improvement ranges from 6.9% to 12.2% across all disease duration categories 6
• Do not delay initiation based on how long the patient has had heart failure 6

Special Populations

Recent Hospitalization:

• Pooled analysis of PARAGLIDE-HF and PARAGON-HF demonstrates that patients with recent worsening HF events (within 30 days of hospitalization) derive significant benefit, with a 22% reduction in total worsening HF events and cardiovascular death 2
• Treatment benefits become statistically significant by Day 9 after randomization 2

Renal Protection:

• Entresto reduces the composite renal endpoint (≥50% decline in eGFR, end-stage renal disease, or renal death) by 40% compared to valsartan alone in the pooled analysis 2

Common Pitfalls to Avoid

Never combine Entresto with an ACE inhibitor:

• Concomitant use is absolutely contraindicated due to severe angioedema risk 1
• The European Society of Cardiology warns against triple RAAS blockade (ACE inhibitor + ARB + MRA) due to life-threatening hyperkalemia and renal dysfunction 3

Monitor for hypotension:

• Symptomatic hypotension is more common with Entresto than with ACE inhibitors, though renal dysfunction, hyperkalemia, and cough are less common 4
• Check blood pressure, renal function, and electrolytes at baseline, 1-2 weeks after each dose adjustment, at 3 months, then every 6 months 3

Pregnancy contraindication:

• Entresto is absolutely contraindicated in pregnancy and must be discontinued immediately when pregnancy is detected 1

Clinical Outcomes

Mortality and Hospitalization:

• The PARADIGM-HF trial demonstrated that replacing enalapril with Entresto significantly reduces cardiovascular death, HF hospitalization, and all-cause mortality in HFrEF patients 4
• The effective rate is 94.87% with Entresto versus 76.92% with standard therapy, with significantly fewer cardiovascular events and worsening HF episodes 7

Quality of Life:

• Entresto significantly improves left ventricular diastolic function, 6-minute walk distance, and Minnesota Quality of Life scores compared to standard therapy 7