What is the recommended use and dosing of Sacubitril (Angiotensin Receptor-Neprilysin Inhibitor) Valsartan for patients with Heart Failure with reduced Ejection Fraction (HFrEF)?

Sacubitril/Valsartan Use in Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan is strongly recommended as a replacement for ACE inhibitors or ARBs in patients with heart failure with reduced ejection fraction (HFrEF) to reduce the risk of heart failure hospitalization and cardiovascular death. 1

Indications and Patient Selection

• Primary indication: HFrEF (LVEF ≤35%) patients who remain symptomatic despite optimal medical therapy
• Patient criteria:
  • NYHA class II-IV symptoms
  • Already on stable doses of ACE inhibitor/ARB
  • Systolic blood pressure ≥100 mmHg
  • eGFR ≥30 mL/min/1.73m²
  • Serum potassium <5.0 mEq/L

Dosing Protocol

Adult HFrEF Patients:

1. Starting dose: 49/51 mg orally twice daily
2. Titration: Double the dose after 2-4 weeks
3. Target maintenance dose: 97/103 mg twice daily, as tolerated 2

Dose Adjustments:

• Severe renal impairment (eGFR <30 mL/min/1.73m²): Start at half the recommended dose (24/26 mg twice daily) 2
• Hypotension risk: Consider lower starting dose in patients with SBP 100-110 mmHg
• Elderly patients: No specific dose adjustment required, but monitor closely

Administration Guidelines

1. Washout period: Must allow 36-hour washout period when switching from ACE inhibitor to sacubitril/valsartan 2
2. Monitoring: Check renal function, electrolytes, and blood pressure:
   • At baseline
   • 1-2 weeks after initiation
   • 1-2 weeks after each dose increase
   • Every 3-6 months during maintenance therapy

Clinical Benefits

• 20-25% reduction in cardiovascular mortality and heart failure hospitalizations compared to ACE inhibitors 1
• Improvement in NYHA functional class in approximately 37.5% of patients 3
• Improvement in left ventricular ejection fraction (≥5% improvement in 56.3% of patients) 3
• Reduction in NT-proBNP levels (≥30% reduction in 39.7% of patients) 3

Potential Adverse Effects

• Hypotension (most common reason for intolerance, occurring in 12% of patients during follow-up) 3, 4
• Renal dysfunction (monitor creatinine)
• Hyperkalemia (occurs in approximately 2.6% of patients) 3
• Angioedema (rare but serious)

Risk Factors for Intolerance

Patients with 4 or more of the following factors have nearly 50% probability of intolerance 4:

• Lower mean arterial pressure
• Lower serum chloride
• Presence of ICD/CRT device
• Moderate or greater mitral regurgitation
• Non-use of ACE inhibitor/ARB at screening
• Insulin use
• Advanced heart failure (NYHA class IV)

Special Populations

Advanced Heart Failure:

• Higher intolerance rates (approximately 18%) 4
• Start with lower doses and titrate more cautiously
• Monitor closely for hypotension

End-Stage Kidney Disease:

• Can improve left ventricular systolic and diastolic function in HFrEF patients with ESKD 5
• Monitor potassium levels closely, though significant hyperkalemia is uncommon

Algorithm for Implementation

1. Identify eligible patients: HFrEF (LVEF ≤35%), symptomatic despite optimal therapy
2. Assess contraindications:
   • Current ACE inhibitor use (requires 36-hour washout)
   • History of angioedema
   • SBP <100 mmHg
   • eGFR <30 mL/min/1.73m² (requires dose adjustment)
   • K+ >5.0 mEq/L
3. Initiate therapy:
   • Standard patients: 49/51 mg twice daily
   • Severe renal impairment: 24/26 mg twice daily
4. Monitor and titrate:
   • Check BP, renal function, and electrolytes at 1-2 weeks
   • If tolerated, increase to target dose of 97/103 mg twice daily
   • Continue monitoring every 3-6 months

Common Pitfalls and Caveats

• Failure to observe ACE inhibitor washout period: Must wait 36 hours after last ACE inhibitor dose before starting sacubitril/valsartan to avoid angioedema risk
• Inadequate BP monitoring: Hypotension is the most common adverse effect
• Inappropriate patient selection: Patients with very low baseline BP (<100 mmHg) or advanced kidney disease require careful consideration
• Failure to discontinue ACE inhibitor: Concurrent use with ACE inhibitors is contraindicated
• Inadequate follow-up: Regular monitoring of renal function and electrolytes is essential

By following this structured approach to sacubitril/valsartan therapy in HFrEF patients, clinicians can optimize outcomes while minimizing adverse effects in this high-risk population.