What is Angiotensin Receptor-Neprilysin Inhibitor (ARNI)?

Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

ARNI is a novel therapeutic class that combines an angiotensin receptor blocker (ARB) with a neprilysin inhibitor, designed to simultaneously block the renin-angiotensin system while enhancing beneficial natriuretic peptide pathways to reduce morbidity and mortality in heart failure patients. 1, 2

Mechanism of Action

ARNIs work through a dual mechanism:

1. Neprilysin Inhibition:

   • Sacubitril (prodrug) is metabolized to LBQ657, which inhibits neprilysin (neutral endopeptidase)
   • This prevents degradation of beneficial peptides including natriuretic peptides, bradykinin, and adrenomedullin
   • Results in vasodilation, natriuresis, and anti-fibrotic effects

2. Angiotensin Receptor Blockade:

   • Valsartan blocks the angiotensin II type-1 (AT1) receptor
   • Prevents the harmful effects of angiotensin II (vasoconstriction, sodium retention, cardiac remodeling)
   • Inhibits angiotensin II-dependent aldosterone release 3

Clinical Applications

ARNIs are primarily indicated for:

• Heart Failure with Reduced Ejection Fraction (HFrEF):

  • Recommended for patients with LVEF ≤40% and NYHA class II-III symptoms 1
  • Can be used as initial therapy or as replacement for ACEi/ARB 2
  • Reduces cardiovascular death and heart failure hospitalization by 20% compared to ACEi 1

• Pediatric Heart Failure:

  • Indicated for symptomatic heart failure with systemic left ventricular systolic dysfunction in children aged one year and older 3

• Emerging Applications (under investigation):

  • Hypertension
  • Heart failure with preserved ejection fraction (HFpEF)
  • Post-myocardial infarction with reduced LVEF
  • Chronic kidney disease 4, 5

Available Formulation

The only currently approved ARNI is sacubitril/valsartan (Entresto):

• Available in three dosage strengths:

  • 24/26 mg (sacubitril/valsartan)
  • 49/51 mg
  • 97/103 mg 2, 3

• The target dose is 97/103 mg twice daily 2

Important Considerations

Contraindications

• Absolute contraindications:
  • Concomitant use with ACE inhibitors (requires 36-hour washout period) 1, 2
  • History of angioedema with ACEi or ARB
  • Pregnancy or planned pregnancy
  • Severe hepatic impairment 2, 3

Adverse Effects

• Hypotension (more common than with ACEi)
• Renal dysfunction
• Hyperkalemia
• Angioedema (comparable incidence to ACEi)
• Cough (less common than with ACEi) 2, 3

Monitoring Requirements

• Blood pressure
• Renal function
• Serum potassium
• Signs of angioedema 2

Practical Prescribing Points

• Initiation:

  • Must wait 36 hours after last ACE inhibitor dose before starting ARNI 1, 2
  • No washout period needed when switching from ARB 2
  • Starting dose is typically 49/51 mg twice daily
  • Lower starting dose (24/26 mg twice daily) for patients with severe renal impairment or moderate hepatic impairment 2

• Titration:

  • Titrate to target dose of 97/103 mg twice daily as tolerated
  • Titration interval of 2-4 weeks recommended 2

Evidence Base

The primary evidence for ARNI comes from the PARADIGM-HF trial, which demonstrated:

• 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril
• Benefits seen consistently across subgroups
• Reduction in both cardiovascular mortality and heart failure hospitalizations 1, 2

Common Pitfalls to Avoid

• Failure to observe ACEi washout period - can lead to potentially life-threatening angioedema 1, 2
• Inadequate blood pressure monitoring - may result in symptomatic hypotension
• Delayed initiation in eligible patients - guidelines support early initiation for optimal outcomes 2
• Concomitant use with ACEi - strictly contraindicated due to increased risk of angioedema 1
• Suboptimal dosing - aim for target dose when tolerated for maximum benefit 1

ARNIs represent a significant advancement in heart failure therapy by simultaneously addressing multiple pathophysiological pathways involved in heart failure progression.