What is the role of Entresto (sacubitril/valsartan) in treating chronic heart failure?

Role of Entresto (Sacubitril/Valsartan) in Treating Chronic Heart Failure

Entresto (sacubitril/valsartan) is strongly recommended as a first-line therapy to replace ACE inhibitors or ARBs in patients with heart failure with reduced ejection fraction (HFrEF) to reduce cardiovascular death and hospitalization risk. 1, 2

Indications and Benefits

• FDA-approved indications 2:

  • To reduce risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure
  • Benefits most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal
  • For treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older

• Clinical benefits:

  • 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril 1, 3
  • Similar benefits for both death and heart failure hospitalization components 1
  • 16% reduction in all-cause mortality 3
  • Improves left ventricular function with potential for LVEF improvement 4

Patient Selection

Recommended for:

• Patients with HFrEF (LVEF ≤40%) 1, 4
• NYHA functional class II-IV symptoms 1, 3
• Patients who remain symptomatic despite optimal ACE inhibitor or ARB therapy for at least 3 months 1
• Patients with systolic blood pressure >100 mmHg 4, 5

Contraindications:

• History of angioedema 2
• Severe renal impairment (eGFR <30 mL/min/1.73m²) 4
• Current use of ACE inhibitors (requires 36-hour washout period) 2
• Pregnancy (can harm or cause death to unborn baby) 2
• Concomitant use with aliskiren in patients with diabetes 2
• Systolic blood pressure ≤100 mmHg 5

Implementation in Practice

1. Initiation strategy:

   • For ACE inhibitor users: Discontinue ACE inhibitor for at least 36 hours before starting Entresto 2
   • For ARB users: Can be directly switched without washout period
   • Starting dose: 49/51 mg twice daily for most patients
   • Target dose: 97/103 mg twice daily 4

2. Monitoring:

   • Blood pressure (watch for symptomatic hypotension)
   • Renal function
   • Potassium levels
   • Heart failure symptoms

3. Real-world considerations:

   • Despite guideline recommendations, only about 38% of patients with HFrEF on optimized guideline-directed medical therapy may be eligible for sacubitril/valsartan in real-world practice 5
   • Main barriers to implementation include unfamiliarity with ARNIs, safety concerns, and reimbursement issues 6

Comprehensive Heart Failure Management

• Entresto should be part of a comprehensive heart failure management program 1
• Can be combined with other guideline-directed therapies:
  • Beta-blockers
  • Mineralocorticoid receptor antagonists (MRAs)
  • SGLT2 inhibitors
  • Device therapy (ICD, CRT) when indicated 4

Potential Mechanisms of Benefit

• Dual mechanism of action: neprilysin inhibition (sacubitril) and angiotensin receptor blockade (valsartan) 3
• Enhances natriuretic peptide system while suppressing RAAS 7
• May have antiarrhythmic properties that reduce risk of ventricular arrhythmias and sudden cardiac death 8
• Promotes diuresis, natriuresis, and vasodilation through increased natriuretic peptide levels 3

Common Side Effects and Management

• Symptomatic hypotension (most common side effect: 14% vs. 9.2% with enalapril) 4
• Angioedema (comparable incidence to enalapril) 1
• Less renal dysfunction, hyperkalemia, and cough compared to ACE inhibitors 7

Entresto represents a significant advancement in heart failure therapy with clear mortality and morbidity benefits. Its strong position in current guidelines reflects its importance in modern heart failure management.