When should Entresto (sacubitril/valsartan) be started in a patient with impaired left ventricular function, specifically a left ventricular ejection fraction (LVEF) of 35-40% and symptoms of heart failure, despite optimal treatment with Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists?

When to Start Entresto (Sacubitril/Valsartan)

Start Entresto immediately in patients with LVEF ≤40% who remain symptomatic (NYHA class II-III) despite at least 3 months of optimal therapy with ACE inhibitors or ARBs, beta-blockers, and mineralocorticoid receptor antagonists. 1

Specific Eligibility Criteria

Your patient with LVEF 35-40% and persistent heart failure symptoms meets the criteria for Entresto initiation based on the following:

Required Prerequisites

• LVEF ≤40% documented on echocardiography or other cardiac imaging 1
• Minimum 3 months of ACE inhibitor or ARB therapy at guideline-directed doses 1
• Persistent symptoms (NYHA class II or III) despite optimal medical therapy 1
• Concurrent therapy with beta-blockers and mineralocorticoid receptor antagonists already established 1

Timing Considerations

• Outpatient setting: Initiate within a 12-month period when seen in clinic 1
• Inpatient setting: Can be prescribed at hospital discharge for heart failure hospitalization 1
• ACE inhibitor washout: Must discontinue ACE inhibitors for 36 hours before starting Entresto to avoid angioedema risk 2

Dosing Algorithm

Initial Dose Selection

• Standard starting dose: 49 mg/51 mg twice daily for most patients 2
• Reduced starting dose (24 mg/26 mg twice daily) required for: 2
  • Patients not currently on ACE inhibitor/ARB or on low doses
  • Severe renal impairment (eGFR <30 mL/min)
  • Moderate hepatic impairment

Titration Schedule

• Uptitrate every 2-4 weeks to target maintenance dose of 97 mg/103 mg twice daily 2
• Target at least 50% of maximum dose (49 mg/51 mg twice daily minimum) for optimal benefit 1
• Monitor blood pressure, renal function, and potassium 1-2 weeks after each dose increase 3

Evidence Supporting Early Initiation

The rationale for starting Entresto in your patient is compelling:

Mortality and Morbidity Benefits

• 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril 1
• 6.8% mortality at 6 months with sacubitril/valsartan versus 34% with conventional ACE inhibitor/ARB therapy 4
• 4.5% heart failure hospitalization rate versus 59% with conventional therapy 4
• Benefits are consistent across subgroups regardless of age, sex, etiology, or comorbidities 5

Mechanism of Superiority

Entresto provides dual neurohormonal blockade through neprilysin inhibition (sacubitril) and angiotensin II receptor blockade (valsartan), offering superior reverse cardiac remodeling compared to ACE inhibitors or ARBs alone 5, 6

Safety Monitoring Requirements

Contraindications to Verify Before Starting

• No history of angioedema with previous ACE inhibitor or ARB 2
• Not currently on ACE inhibitor (must have 36-hour washout) 2
• No concomitant aliskiren use if patient has diabetes 2
• No severe hepatic impairment 2

Monitoring Parameters

• Hypotension: Most common adverse effect (15.9% incidence); systolic BP <100 mmHg requires dose adjustment 4
• Hyperkalemia: Monitor potassium levels, especially with concurrent MRA use 2
• Renal function: Check creatinine and eGFR at baseline and after dose changes 3
• Angioedema: Rare but serious; higher risk in patients with prior ACE inhibitor-related angioedema 2

Common Pitfalls to Avoid

Critical Errors

• Starting Entresto without ACE inhibitor washout: Increases angioedema risk substantially 2
• Using Entresto with ACE inhibitors concurrently: Absolutely contraindicated 2
• Inadequate uptitration: Stopping at low doses negates mortality benefit; must reach at least 50% of target dose 1
• Premature discontinuation for mild hypotension: Asymptomatic BP drops often resolve; only adjust if symptomatic 4

Optimization Strategy

• Reduce diuretics temporarily 24 hours before initiation if patient is euvolemic to minimize hypotension risk 3
• Avoid NSAIDs: They interfere with efficacy and increase renal impairment risk 3
• Avoid potassium-sparing diuretics during initiation beyond the MRA already prescribed 3

Current Guideline Position

The 2020 ACC/AHA guidelines establish Entresto as preferred over ACE inhibitors/ARBs for symptomatic HFrEF patients, not merely as an alternative 1. The FDA label confirms "benefits are most clearly evident in patients with left ventricular ejection fraction below normal," which includes your patient's LVEF of 35-40% 2, 6.

Recent evidence supports Entresto as first-line therapy rather than requiring failure of ACE inhibitor/ARB therapy first, though the 3-month ACE inhibitor/ARB trial remains the formal guideline recommendation 5.