What is the most commonly used Angiotensin Receptor Neprilysin Inhibitor (ARNI) and its dosing for different stages of heart failure with reduced ejection fraction (HFrEF)?

ARNI Therapy for Heart Failure with Reduced Ejection Fraction

Most Commonly Used ARNI

Sacubitril/valsartan is the only ARNI currently approved and used in clinical practice for heart failure with reduced ejection fraction (HFrEF). 1, 2

Standard Dosing Regimen

Starting Dose

• Begin with 49/51 mg orally twice daily in most adult patients with HFrEF 1, 3, 2
• For patients with severe renal impairment or moderate hepatic impairment, reduce the starting dose to 24/26 mg twice daily 2

Target Maintenance Dose

• Titrate to 97/103 mg twice daily, which is the evidence-based target dose proven to reduce cardiovascular death and HF hospitalization 1, 3
• This target dose was used in the landmark PARADIGM-HF trial and demonstrated a 20% reduction in cardiovascular mortality compared to enalapril 1, 4, 5

Titration Schedule

• Double the dose every 2-4 weeks as tolerated by the patient 1, 3, 2
• Continue uptitration even if symptoms improve at lower doses, as clinical trial benefits were demonstrated at target doses 6

Dosing Across Heart Failure Stages

NYHA Class II-III (Mild to Moderate HF)

• Standard dosing applies: Start 49/51 mg twice daily, target 97/103 mg twice daily 1
• These patients must have elevated natriuretic peptides (BNP >150 pg/mL or NT-proBNP ≥600 pg/mL; OR BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with prior hospitalization in preceding 12 months) 1
• ARNI is preferred over ACE inhibitors/ARBs in this population to further reduce morbidity and mortality 6

NYHA Class IV (Advanced HF)

• Use caution with standard dosing in patients with very advanced HF, particularly those with baseline systolic blood pressure <100 mmHg 5
• Consider starting at the lower dose of 24/26 mg twice daily in hemodynamically unstable patients, though this dose was not tested in clinical trials 1
• Real-world data shows no significant outcome differences in patients with baseline SBP <100 mmHg compared to standard therapy 5

Asymptomatic HF (Stage B/C with minimal symptoms)

• Initiate early in the disease course regardless of symptom severity once HFrEF (LVEF ≤40%) is diagnosed 6
• Use standard starting dose of 49/51 mg twice daily 1, 3

Critical Safety Considerations

Mandatory Washout Period

• Wait 36 hours after discontinuing an ACE inhibitor before starting sacubitril/valsartan to avoid life-threatening angioedema 1, 3, 2
• No washout period is required when switching from an ARB 3
• Concomitant use with ACE inhibitors is absolutely contraindicated 1, 2

Monitoring Requirements

• Monitor blood pressure closely: Hypotension occurs in 14.0% of patients on ARNI versus 9.2% on ACE inhibitors 3
• Assess renal function and potassium before initiation and periodically thereafter 6
• Watch for angioedema, particularly during the first weeks after switching from an ACE inhibitor 1, 3

Special Populations

Renal Impairment

• Severe renal impairment: Start at 24/26 mg twice daily 2
• Real-world evidence demonstrates effectiveness even in advanced chronic kidney disease stages 5
• Avoid concomitant use with aliskiren if eGFR <60 mL/min 2

Hepatic Impairment

• Moderate hepatic impairment: Start at 24/26 mg twice daily 2
• Severe hepatic impairment: Use not recommended 2

Pediatric Patients (≥1 year old)

• Weight-based dosing: Start at 1.6 mg/kg twice daily, titrate to 3.1 mg/kg twice daily 2
• For patients ≥50 kg: Use adult dosing (49/51 mg → 97/103 mg twice daily) 2

Common Pitfalls to Avoid

• Do not delay initiation due to concerns about polypharmacy; start all four GDMT medication classes (ARNI/ACEi/ARB, beta-blockers, MRAs, SGLT2i) simultaneously at low doses 6
• Do not fail to uptitrate to target doses used in clinical trials, as benefits are dose-dependent 6
• Do not use lower doses indefinitely; gradual titration approaches maximize attainment of target doses 3
• Do not combine with ACE inhibitors under any circumstances due to angioedema risk 1, 2