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 and enhance beneficial natriuretic peptide pathways, significantly reducing morbidity and mortality in heart failure patients with reduced ejection fraction. 1

Mechanism of Action

ARNIs work through a dual mechanism:

1. Neprilysin inhibition: Sacubitril (prodrug) is metabolized to LBQ657, which inhibits neprilysin, an endopeptidase that degrades various peptides including:

   • Natriuretic peptides
   • Bradykinin
   • Adrenomedullin
   • Substance P
   • Angiotensin I and II
   • Endothelin 2, 3

2. Angiotensin receptor blockade: Valsartan blocks the angiotensin II type-1 (AT1) receptor, inhibiting the effects of angiotensin II and reducing aldosterone release 3

This combination results in:

• Increased levels of beneficial vasodilatory peptides
• Natriuresis and diuresis
• Reduced vasoconstriction
• Decreased cardiac remodeling 4

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
• Pediatric heart failure: Approved for symptomatic heart failure with systemic left ventricular systolic dysfunction in patients aged one year and older 3

Evidence Base

The landmark PARADIGM-HF trial demonstrated:

• 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril
• Reduced cardiovascular mortality
• Decreased heart failure hospitalizations 1

Additionally, ARNIs have shown:

• Improved left ventricular ejection fraction
• Decreased BNP levels
• Slowed eGFR decline compared to ARBs alone 2, 5

Dosing and Administration

• Starting dose: 49/51 mg twice daily (24/26 mg twice daily for patients with severe renal impairment or moderate hepatic impairment)
• Target dose: 97/103 mg twice daily
• Titration interval: 2-4 weeks 1, 3

Important Precautions

• Contraindicated with ACE inhibitors: Requires a 36-hour washout period due to increased risk of angioedema 1
• Other contraindications:
  • History of angioedema with ACEi or ARB
  • Pregnancy or planned pregnancy
  • Severe hepatic impairment 1, 3

Monitoring Requirements

Regular assessment of:

• Blood pressure (hypotension is common)
• Renal function
• Serum potassium
• Signs of angioedema 1

Clinical Pearls and Pitfalls

• Initiation timing: Can be started before hospital discharge in HFrEF patients without contraindications 1
• Switching from ACEi/ARB: Chronic HFrEF patients should be switched from ACEi/ARB to ARNi if they tolerate the former 1
• Common pitfall: Failure to observe the ACEi washout period, which can lead to angioedema 1
• Paradoxical effect: Despite slowing eGFR decline, ARNIs may increase albuminuria, possibly due to preferential vasodilation of the afferent arteriole 2

Special Populations

• Renal impairment: No dose adjustment for mild to moderate impairment; half starting dose for severe impairment (eGFR <30 mL/min/1.73 m²) 3
• Hepatic impairment: No adjustment for mild impairment; half starting dose for moderate impairment; not recommended for severe impairment 3

ARNIs represent a significant advancement in heart failure therapy, offering mortality and morbidity benefits beyond traditional renin-angiotensin system inhibitors by leveraging the beneficial effects of natriuretic peptides.