What is the indication for Entresto (sacubitril/valsartan)?

Entresto (Sacubitril/Valsartan) Indication

Entresto (sacubitril/valsartan) is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure with reduced ejection fraction (HFrEF), and is recommended as a replacement for an ACE inhibitor in ambulatory patients who remain symptomatic despite optimal treatment with an ACE-I, beta-blocker, and MRA. 1, 2

Primary Indications

According to the FDA label and clinical guidelines:

• Adult Heart Failure:

  • To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure 1
  • Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal 1
  • Specifically recommended for patients with HFrEF who remain symptomatic despite optimal treatment with an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA) 2

• Pediatric Heart Failure:

  • For treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older 1
  • Reduces NT-proBNP and is expected to improve cardiovascular outcomes 1

Patient Selection Algorithm

1. Confirm HFrEF diagnosis:

   • LVEF ≤35% documented by echocardiography 2
   • Symptomatic heart failure (NYHA Class II-IV) 2

2. Verify current treatment:

   • Patient should be on optimal medical therapy including:
     • ACE inhibitor or ARB at target doses
     • Beta-blocker at maximally tolerated dose
     • MRA if appropriate 2

3. Assess for contraindications:

   • History of angioedema related to previous ACE inhibitor or ARB therapy
   • Concomitant use with ACE inhibitors (must wait 36 hours after last ACE inhibitor dose)
   • Concomitant use with aliskiren in patients with diabetes
   • Severe hepatic impairment 1

4. Check baseline parameters:

   • Systolic blood pressure (should be >100 mmHg)
   • Renal function (use with caution in severe renal impairment)
   • Serum potassium (monitor for hyperkalemia) 2, 1

Dosing Considerations

• Starting dose:

  • Standard: 49 mg/51 mg twice daily
  • Reduced to 24 mg/26 mg twice daily for:
    • Patients not currently taking an ACE inhibitor or ARB
    • Patients previously taking low doses of these agents
    • Patients with severe renal impairment
    • Patients with moderate hepatic impairment 1

• Target dose: 97 mg/103 mg twice daily, with dose adjustments every 2-4 weeks as tolerated 1

Clinical Pearls and Caveats

• Timing of initiation: Must discontinue ACE inhibitor at least 36 hours before initiating sacubitril/valsartan to reduce risk of angioedema 1

• Monitoring: Regular assessment of:

  • Blood pressure (risk of hypotension)
  • Renal function
  • Serum potassium 1

• Pregnancy warning: Discontinue when pregnancy is detected due to fetal toxicity risk 1

• Common adverse effects: Hypotension, hyperkalemia, cough, dizziness, and renal failure 1

• Drug interactions:

  • Avoid concomitant use with aliskiren in patients with eGFR <60
  • Use caution with potassium-sparing diuretics (increased hyperkalemia risk)
  • Monitor for interactions with NSAIDs (increased renal impairment risk)
  • Increased risk of lithium toxicity when used together 1

• Real-world eligibility: Studies suggest approximately 38% of HFrEF patients may be eligible for sacubitril/valsartan when GDMT is appropriately achieved 3

• Efficacy regardless of HF duration: Evidence shows benefits in biomarkers, health status, and cardiac remodeling regardless of how long patients have had heart failure 4

Entresto represents a significant advancement in heart failure therapy, offering mortality and morbidity benefits beyond traditional ACE inhibitor therapy for properly selected patients with HFrEF.