What is ARNI
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ARNI — Angiotensin Receptor-Neprilysin Inhibitor
ARNI stands for Angiotensin Receptor-Neprilysin Inhibitor. It is a drug class that combines two distinct mechanisms in a single agent. The only approved ARNI is sacubitril/valsartan (brand name: Entresto).
Components
| Component | Mechanism |
|---|---|
| Valsartan | Angiotensin II receptor blocker (ARB) — blocks the RAAS system |
| Sacubitril | Neprilysin inhibitor — prevents the breakdown of natriuretic peptides (BNP, ANP), bradykinin, and other vasoactive peptides |
How It Works
Neprilysin is an endopeptidase that breaks down natriuretic peptides, bradykinin, and other peptides. By inhibiting neprilysin, sacubitril raises levels of these peptides, producing:
- Vasodilation
- Natriuresis and diuresis (sodium/water excretion)
- Reduced cardiac remodeling and fibrosis
- Blood pressure lowering
The ARB component (valsartan) is co-administered because neprilysin inhibition alone would also increase angiotensin II levels (another neprilysin substrate), causing vasoconstriction — the ARB counteracts this.
Bradykinin, also a neprilysin substrate, is thought to contribute to the cardioprotective effects of the drug through NO generation, prostacyclin release, and protection against ischemia-reperfusion injury.
Primary Indication: Heart Failure with Reduced EF (HFrEF)
The landmark PARADIGM-HF trial compared sacubitril/valsartan to enalapril in HFrEF patients and showed:
- 20% reduction in the risk of HF hospitalization or cardiovascular death versus enalapril
This established sacubitril/valsartan as a cornerstone of HFrEF management, now recommended over ACE inhibitors or ARBs alone in eligible patients.
Use in HFpEF (Preserved EF)
The PARAGON-HF trial tested sacubitril/valsartan vs. valsartan in HFpEF (LVEF ≥45%). It narrowly missed statistical significance for the primary outcome (RR 0.87; 95% CI 0.75–1.01; P = 0.06), but subgroup analyses suggested benefit in:
- Women
- Patients with LVEF below the median (~57%)
- Those with recent HF hospitalization
Use in Hypertension
ARNIs also effectively lower blood pressure over 24 hours and are an emerging therapy for hypertension, especially in patients with concurrent heart failure.
Key Safety Points
- Do NOT combine with ACE inhibitors — increased risk of angioedema (ACE inhibitors already raise bradykinin; neprilysin inhibition adds further)
- A 36-hour washout after stopping an ACE inhibitor is required before starting an ARNI
- Monitor renal function and potassium
Sources: Fuster and Hurst's The Heart, 15th Ed. | Goodman & Gilman's Pharmacological Basis of Therapeutics | Comprehensive Clinical Nephrology, 7th Ed.
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