Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)
The only commercially available ARNI is sacubitril/valsartan (brand name Entresto), which combines the neprilysin inhibitor sacubitril with the angiotensin receptor blocker valsartan in a single tablet. 1, 2, 3
Available Formulations
Sacubitril/valsartan is available in three fixed-dose combination strengths 1, 2:
- 24 mg sacubitril / 26 mg valsartan (50 mg total)
- 49 mg sacubitril / 51 mg valsartan (100 mg total)
- 97 mg sacubitril / 103 mg valsartan (200 mg total)
The target dose proven effective in clinical trials was 97/103 mg twice daily, with the ARB component equivalent to valsartan 160 mg twice daily. 1
Mechanism of Action
Sacubitril/valsartan works through dual pathways: sacubitril inhibits neprilysin (which degrades natriuretic peptides), while valsartan blocks the angiotensin II type-1 receptor. 2 This combination increases beneficial natriuretic peptides while simultaneously blocking the harmful effects of angiotensin II. 1, 2
Historical Context: Failed ARNI Development
Omapatrilat, an earlier agent that combined ACE inhibition with neprilysin inhibition, was terminated from clinical development due to a 3-fold increased risk of angioedema compared to enalapril alone. 1, 4 This occurred because both ACE and neprilysin break down bradykinin—when both pathways are blocked simultaneously, bradykinin accumulates to dangerous levels, directly causing life-threatening angioedema. 1, 5 Black patients and smokers were at particularly elevated risk. 1, 5
Critical Safety Distinction
ARNIs must never be given concomitantly with ACE inhibitors or within 36 hours of the last ACE inhibitor dose. 1, 4, 5 This mandatory washout period allows bradykinin levels to normalize and prevents the same catastrophic angioedema risk that ended omapatrilat's development. 4, 5
Clinical Evidence
In the PARADIGM-HF trial, sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization by approximately 20% compared to enalapril in patients with heart failure with reduced ejection fraction (HFrEF). 1, 4, 5 This landmark trial established sacubitril/valsartan as superior to ACE inhibitors for symptomatic HFrEF. 6
Current Guideline Recommendations
The 2022 ACC/AHA/HFSA guidelines recommend sacubitril/valsartan as first-line therapy for patients with symptomatic HFrEF (NYHA class II-III) who can tolerate it, replacing ACE inhibitors or ARBs. 1, 4 This represents a Class I, Level A recommendation. 1
Common Pitfalls to Avoid
- Never prescribe sacubitril/valsartan to patients with any history of angioedema from any cause—this is an absolute contraindication (Class III: Harm). 1, 4, 7
- Do not use sacubitril/valsartan in pregnancy—it is contraindicated. 5
- Ensure the 36-hour washout when switching from ACE inhibitors—shorter intervals risk fatal angioedema. 1, 4, 5
- Monitor for hypotension during initiation and titration—sacubitril/valsartan commonly causes blood pressure lowering. 1, 8