Examples of Angiotensin Receptor-Neprilysin Inhibitors (ARNi)
Sacubitril/valsartan is currently the only commercially available ARNi, representing a first-in-class medication that combines neprilysin inhibition with angiotensin receptor blockade in a single crystalline complex. 1, 2
The Single ARNi Agent
- Sacubitril/valsartan (formerly known as LCZ696) is the prototype and only approved ARNi for clinical use 3, 4, 2
- This medication consists of two molecular moieties in a single crystalline complex: the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril 2
- Available dosage strengths include 24/26 mg, 49/51 mg, and 97/103 mg (sacubitril/valsartan) tablets 5
Mechanism and Classification
- The European Society of Cardiology refers to sacubitril as a "neprilysin inhibitor" and the combination as an "angiotensin receptor neprilysin inhibitor" 1
- Sacubitril inhibits neprilysin, an endopeptidase that normally degrades beneficial vasoactive peptides including natriuretic peptides and adrenomedullin, leading to vasodilation 1
- Valsartan blocks the angiotensin II type-1 (AT1) receptor, preventing harmful effects including sodium and water retention, aldosterone release, and sympathetic activation 1
Clinical Evidence and Approval
- The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril 1, 3, 4
- Following PARADIGM-HF results, sacubitril/valsartan was approved by American and European regulatory authorities for treatment of heart failure with reduced ejection fraction 4
- The American College of Cardiology recommends sacubitril/valsartan as a Class I indication for patients with HFrEF (LVEF <40%) and NYHA class II-III symptoms 6
Historical Context of ARNi Development
- Earlier neprilysin inhibitors including ecadotril, candoxatril, and omapatrilat were tested but discontinued due to lack of efficacy or side effects 2
- Sacubitril/valsartan succeeded where previous neprilysin inhibitors failed by combining neprilysin inhibition with angiotensin receptor blockade rather than ACE inhibition 3, 2
Nomenclature in Clinical Practice
- In guideline-directed medical therapy frameworks, ARNi is abbreviated as "ARNI" to distinguish it from other renin-angiotensin system (RAS) inhibitors 7
- The medication is positioned as part of "quadruple therapy" for HFrEF alongside beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors 6
- ARNi is preferred over ACE inhibitors or ARBs as first-line renin-angiotensin system inhibition in eligible HFrEF patients 6