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.

→ Heart Failure Module

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

→ Heart Failure Module

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