Authors: Destiny F. Chau, MD and Jorge Guerrero, MD - Arkansas Children’s Hospital /University of Arkansas for Medical Sciences, Little Rock, AR
A 9 y/o female child with a history of an extracardiac fenestrated Fontan presents for tonsillectomy and adenoidectomy. A recent cardiac catheterization demonstrated a Fontan pressure of 19 mmHg. Home medications include aspirin and sacubitril/valsartan. Which class of medication does sacubitril belong to?
Sacubitril is a neprilysin inhibitor, which is a naturally occurring endopeptidase enzyme that degrades neuropeptides that are known to contribute to the pathophysiology of heart failure. Chronic heart failure is associated with elevated neprilysin levels and faster clearance of neuropeptides.
Heart failure results in the activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone system leading to increased levels of renin, angiotensin II, aldosterone, and anti-diuretic hormone. The end result is increased vascular tone and blood pressure, which are compensatory mechanisms to increase organ perfusion. However, this activation impairs the function of endogenous neuropeptides such as atrial natriuretic peptide and B-type natriuretic peptide, bradykinin, and adrenomedullin. These peptides cause vasodilation, natriuresis, diuresis, and counteract the abnormal sympathetic response implicated in maladaptive vascular and cardiac remodeling.
The inhibition of neprilysin prevents the degradation of endogenous neuropeptides leading to an increased concentration of bradykinin, natriuretic peptides, adrenomedullin and angiotensin II. Therefore, a neprilysin inhibitor is paired with an angiotensin receptor blocker (ARB) to mitigate the effects of elevated angiotensin II levels. This class of drug, termed an ARNI (angiotensin receptor neprilysin inhibitor), received FDA approval in 2015 for the treatment of symptomatic heart failure with reduced ejection fraction. Patients must demonstrate tolerability to an angiotensin-converting enzyme inhibitor (ACEI) or ARB before starting sacubitril/valsartan.
Angiotensin II effects can reduced by using an ACEI. However, the combination of both a neprilysin inhibitor and an ACEI was found to cause significant angioedema due to the fact that both drugs increase bradykinin levels thus worsening angioedema. Therefore, the combination of an ACEI and ARNI should be avoided. Coadministration of a neprilysin inhibitor within 36 hours of an ACEI is contraindicated.
In a prospective, randomized trial by McMurray et al. (widely known as PARADIGM-HF - Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) of adult patients with symptomatic heart failure and reduced ejection fraction, the use of sacubitril/valsartan demonstrated increased efficacy in reducing morbidity and mortality versus standard treatment with enalapril. Adverse effects of sacubitril/valsartan included hypotension, hyperkalemia, renal failure, cough, and angioedema. Compared to enalapril, treatment with sacubitril/valsartan resulted in a higher incidence of hypotension and symptomatic hypotension but a lower risk of increased serum potassium and creatinine and lower risk of cough. Although not statistically significant, angioedema in the sacubitril/valsartan group was higher than in the enalapril group, with no reported cases of angioedema causing airway compromise.
According to the most recent 2022 AHA/ACC/HFSA guidelines (Heidenreich et al.), treatment with sacubitril/valsartan is a Class I recommendation for the management of symptomatic heart failure with reduced ejection fraction. Additionally, treatment with sacubitril/valsartan is a Class 2b recommendation for the management of heart failure with preserved ejection fraction. This drug is also known to enhance right sided ejection fraction and reduce pulmonary artery pressures independent of an improvement in left ventricular function. Sacubitril/valsartan use in pediatric patients is based upon data from the adult population. However, there are current ongoing studies in the pediatric population.
The effect of general anesthesia on the blood pressure of patients taking an ARNI is currently unknown. Given the presence of an ARB in this combination drug and the reports of a higher risk of hypotension with ARNI use as compared to enalapril, it is reasonable to deduce that ARNI use may also be associated with severe refractory hypotension under general anesthesia. Therefore, vigilance and preparation for severe hypotension in patients taking an ARNI whilst undergoing general anesthesia is warranted. As of yet, there are no guidelines on how to best manage perioperative ARNI use.
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