How does Entresto (sacubitril/valsartan) cause vasoplegia?

Mechanism of Entresto (Sacubitril/Valsartan) Causing Vasoplegia

Entresto (sacubitril/valsartan) causes vasoplegia primarily through its potent vasodilatory effects, which result from the dual mechanism of neprilysin inhibition and angiotensin receptor blockade.

Dual Mechanism Contributing to Vasoplegia

1. Neprilysin Inhibition (Sacubitril)

• Sacubitril inhibits neprilysin (neutral endopeptidase; NEP), which is responsible for degrading various vasodilatory peptides 1
• This inhibition leads to increased levels of:
  • Natriuretic peptides (ANP, BNP)
  • Bradykinin
  • Adrenomedullin
  • Substance P
  • Other vasodilatory peptides 2, 1
• These peptides cause significant vasodilation throughout the vascular system

2. Angiotensin Receptor Blockade (Valsartan)

• Valsartan blocks the angiotensin II type-1 (AT1) receptor 1
• This blockade:
  • Prevents angiotensin II-mediated vasoconstriction
  • Reduces aldosterone release
  • Further contributes to vasodilation 2, 1

Clinical Evidence of Vasodilatory Effects

• Entresto is associated with more symptomatic hypotension than valsartan alone 2
• The FDA label specifically notes that hypotension is the most likely result of overdosage due to the blood pressure lowering effects 1
• Case reports have documented profound vasoplegia in heart transplant patients receiving sacubitril/valsartan, requiring treatment with methylene blue and high-dose vasopressors 3

Physiological Mechanisms

• Entresto causes preferential vasodilation of the afferent arteriole and relative vasoconstriction of the efferent arteriole 2
• The drug increases:
  • Urine ANP and cGMP
  • Plasma cGMP
  • Vasodilatory peptides 1
• Simultaneously decreases:
  • Plasma NT-proBNP
  • Aldosterone
  • Endothelin-1 (a potent vasoconstrictor) 1

Clinical Implications and Monitoring

• Blood pressure monitoring is essential when initiating or titrating Entresto 2, 4
• Starting at a lower dose is recommended in patients with:
  • Severe renal impairment (eGFR <30 mL/min/1.73 m²)
  • Moderate hepatic impairment 1
• Addition of other vasodilatory medications (e.g., sildenafil) can further enhance the blood pressure-lowering effect 1
• Patients should be educated about postural hypotension 2

Precautions to Avoid Severe Vasoplegia

• Consider withholding treatment in patients awaiting heart transplantation, particularly those with risk factors for vasoplegia 3
• Use with caution in patients with baseline hypotension (systolic BP <100 mmHg) 4
• Monitor for warning signs including:
  • Unexplained changes in blood pressure
  • New or worsening edema
  • Changes in heart rhythm
  • Increased fatigue 4

Entresto's potent vasodilatory effects, while beneficial for heart failure management, can lead to vasoplegia through the combined action of increased vasodilatory peptides (via neprilysin inhibition) and blocked angiotensin II-mediated vasoconstriction (via AT1 receptor blockade).