====== Sacubitril/Valsartan (ARNI) ======

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.

→ [[cardio:heart_failure:start|Heart Failure Module]]

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===== Mechanism of Action =====

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.

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===== Why ARNI > ACE Inhibitor =====

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:

• [[cardio:raas:acei|ACE Inhibitor]]
• [[cardio:raas:arb|ARB]]

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===== Indications =====

==== HFrEF (EF ≤40%) ★ ====

• NYHA Class II–IV
• Part of the Four Pillars of GDMT

→ [[cardio:heart_failure:start|Heart Failure Module]]

Not indicated for HFpEF as core therapy.

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===== ACE Inhibitor Washout Requirement =====

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.

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===== Adverse Effects =====

• Hypotension
• Hyperkalemia
• Increased creatinine
• Angioedema (rare but serious)

Lower cough risk compared to ACE inhibitors.

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===== Monitoring =====

Monitor:

• Blood pressure
• Serum potassium
• Renal function

Check labs within 1–2 weeks of initiation or dose increase.

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===== Contraindications =====

• History of angioedema
• Concomitant ACE inhibitor use
• Pregnancy
• Severe hypotension

Use caution in:

• Advanced renal dysfunction
• Hyperkalemia

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===== ARNI vs ACEi vs ARB =====

[[cardio:raas:acei|ACE Inhibitors]]:
• Block angiotensin II production
• Increase bradykinin
• Cause cough

[[cardio:raas:arb|ARBs]]:
• Block AT1 receptor
• No bradykinin increase

ARNI:
• Blocks AT1 receptor
• Inhibits neprilysin
• Enhances natriuretic peptides
• Superior outcomes in HFrEF

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===== Clinical Pearls =====

✔ 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  

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Related:

→ [[cardio:heart_failure:start|Heart Failure Module]]
→ [[cardio:raas:acei|ACE Inhibitors]]
→ [[cardio:raas:arb|ARBs]]
→ [[cardio:intro:start|Return to Cardiovascular Modules]]