Sacubitril/Valsartan is an Angiotensin Receptor–Neprilysin Inhibitor (ARNI).
It combines:
• Sacubitril – neprilysin inhibitor • Valsartan – angiotensin receptor blocker (ARB)
ARNI therapy is preferred over ACE inhibitors or ARBs in HFrEF.
Sacubitril:
• Inhibits neprilysin • Increases natriuretic peptides (ANP, BNP) • Promotes natriuresis • Promotes vasodilation • Reduces remodeling
Valsartan:
• Blocks AT1 receptor • Reduces angiotensin II effects • Decreases aldosterone • Reduces afterload
Net Effects:
• ↓ Afterload • ↓ Preload • ↓ Remodeling • ↓ Mortality • ↓ Hospitalization
ARNI enhances protective pathways while suppressing maladaptive RAAS activation.
PARADIGM-HF Trial:
• Reduced cardiovascular death • Reduced HF hospitalization • Superior to enalapril
ARNI is now preferred first-line RAAS therapy in HFrEF.
Alternative if not tolerated:
• ACE Inhibitor • ARB
• NYHA Class II–IV • Part of the Four Pillars of GDMT
Not indicated for HFpEF as core therapy.
Do NOT start ARNI within 36 hours of ACE inhibitor use.
Reason:
• Increased bradykinin levels • Increased risk of angioedema
Switching from ACE inhibitor requires 36-hour washout.
Switching from ARB does NOT require washout.
• Hypotension • Hyperkalemia • Increased creatinine • Angioedema (rare but serious)
Lower cough risk compared to ACE inhibitors.
Monitor:
• Blood pressure • Serum potassium • Renal function
Check labs within 1–2 weeks of initiation or dose increase.
• History of angioedema • Concomitant ACE inhibitor use • Pregnancy • Severe hypotension
Use caution in:
• Advanced renal dysfunction • Hyperkalemia
ACE Inhibitors: • Block angiotensin II production • Increase bradykinin • Cause cough
ARBs: • Block AT1 receptor • No bradykinin increase
ARNI: • Blocks AT1 receptor • Inhibits neprilysin • Enhances natriuretic peptides • Superior outcomes in HFrEF
✔ First-line RAAS therapy in HFrEF ✔ Superior to ACE inhibitors in reducing mortality ✔ Requires 36-hour ACE inhibitor washout ✔ Part of the Four Pillars of GDMT ✔ Monitor potassium and renal function
Related:
→ Heart Failure Module → ACE Inhibitors → ARBs → Return to Cardiovascular Modules