What are the criteria for sacubitril (Angiotensin Receptor-Neprilysin Inhibitor) valsartan (Angiotensin II Receptor Blocker) therapy in patients with heart failure with reduced ejection fraction (HFrEF)?

Criteria for Sacubitril/Valsartan Therapy in Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan is recommended as a replacement for an ACE inhibitor in ambulatory patients with heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal treatment with an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA). 1

Primary Indications

• Sacubitril/valsartan is FDA-approved to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction 2
• It is indicated for patients with NYHA functional class II-IV HFrEF according to FDA approval, though the ACC/AHA/HFSA guidelines specifically support its use in NYHA class II-III patients 1
• Sacubitril/valsartan should be used as a replacement for ACE inhibitors or ARBs in patients who remain symptomatic despite optimal medical therapy 1

Patient Selection Criteria

Required Criteria

• Confirmed diagnosis of heart failure with reduced ejection fraction 1, 2
• NYHA functional class II-III symptoms (class IV patients were minimally represented in clinical trials) 1
• Currently on stable doses of guideline-directed medical therapy including:
  • ACE inhibitor/ARB (ideally equivalent to at least enalapril 10 mg daily) 1
  • Beta-blocker at target or maximally tolerated dose 1
  • MRA (if indicated and tolerated) 1

Hemodynamic and Laboratory Parameters

• Systolic blood pressure >100 mmHg (caution with lower values) 1
• Estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m² 1
• Serum potassium <5.2 mmol/L 1

Contraindications

• Hypersensitivity to any component of sacubitril/valsartan 2
• History of angioedema related to previous ACE inhibitor or ARB therapy 2
• Concomitant use with ACE inhibitors (must wait 36 hours after last ACE inhibitor dose before initiating sacubitril/valsartan) 2
• Concomitant use with aliskiren in patients with diabetes 2
• Severe hepatic impairment 2

Dosing Considerations

• Starting dose: 49 mg/51 mg orally twice daily for most patients 2
• Target maintenance dose: 97 mg/103 mg orally twice daily 2
• Reduced starting dose (24 mg/26 mg twice daily) recommended for:
  • Patients with severe renal impairment (eGFR <30 ml/min/1.73m²) 2
  • Patients with moderate hepatic impairment 2
  • Patients not currently taking an ACE inhibitor or ARB 1
  • Patients with systolic blood pressure 100-110 mmHg 1

Monitoring Recommendations

• Blood pressure: Monitor for hypotension, especially during dose titration 2
• Renal function: Monitor serum creatinine, especially in patients with pre-existing renal impairment 2
• Serum potassium: Monitor for hyperkalemia, particularly in patients with renal impairment or taking potassium-sparing medications 2
• Signs/symptoms of angioedema: Facial swelling, airway compromise 2

Important Clinical Considerations

Evidence Gap

• The PARADIGM-HF trial primarily enrolled patients with NYHA class II (70.1%) and III (23.9%), with minimal representation of class IV patients (0.7%) 1
• Many real-world HFrEF patients may not meet the strict enrollment criteria of PARADIGM-HF but still have FDA approval for sacubitril/valsartan therapy 1
• Key groups with limited evidence include:
  • Patients with systolic BP ≤100 mmHg 1
  • Patients with eGFR ≤30 ml/min/1.73m² 1
  • NYHA class IV patients 1
  • Patients not previously taking ACE inhibitors/ARBs at target doses 1

Practical Implementation

• A 36-hour washout period is required when switching from an ACE inhibitor to sacubitril/valsartan to minimize angioedema risk 2
• No washout period is needed when switching from an ARB 2
• Dose titration should occur every 2-4 weeks as tolerated 2
• Temporary down-titration may be necessary to manage side effects before attempting to reach target dose 3

Potential Benefits and Risks

Benefits

• Reduced risk of cardiovascular death by approximately 20% compared to enalapril 1, 4
• Reduced hospitalizations for heart failure 1, 4
• Improved NYHA functional class in some patients 5, 4

Common Adverse Effects

• Hypotension (more common than with ACE inhibitors) 2, 4
• Hyperkalemia (though less common than with ACE inhibitors) 2, 4
• Renal dysfunction (though less common than with ACE inhibitors) 2, 4
• Cough (less common than with ACE inhibitors) 2, 4
• Angioedema (rare but serious) 2, 4

Real-World Implementation Challenges

• Despite guideline recommendations, many eligible patients do not receive sacubitril/valsartan therapy 6
• In real-world settings, approximately 59% of patients reach target dose 6
• Common reasons for discontinuation include gastrointestinal effects, elevated creatinine, malaise, and vertigo 6
• Female gender and higher NT-proBNP levels are associated with higher rates of medication discontinuation 6