Sacubitril/Valsartan (Entresto): A Comprehensive Clinical and Pharmacological Monograph

Section 1: Pharmacological Profile and Mechanism of Action

1.1. Introduction to Angiotensin Receptor-Neprilysin Inhibition (ARNI)

Sacubitril/valsartan represents a seminal advancement in cardiovascular pharmacotherapy, establishing a novel therapeutic class known as Angiotensin Receptor-Neprilysin Inhibitors (ARNIs).[1] Marketed under the brand names Entresto and Entresto Sprinkle, it is a first-in-class agent formulated as a fixed-dose, supramolecular sodium salt complex containing two active moieties: the neprilysin inhibitor prodrug sacubitril and the angiotensin II receptor blocker (ARB) valsartan.[1] One complex of sacubitril/valsartan consists of six sacubitril anions, six valsartan dianions, 18 sodium cations, and 15 water molecules, yielding the molecular formula

C288​H330​N36​Na18​O48​⋅15H2​O.[2]

The development of the ARNI class was a direct and deliberate response to the limitations of prior attempts at neurohormonal modulation in heart failure. Specifically, the experience with omapatrilat, a vasopeptidase inhibitor that combined neprilysin inhibition with angiotensin-converting enzyme (ACE) inhibition, provided a critical lesson. While effective at lowering blood pressure, omapatrilat was associated with a prohibitively high incidence of angioedema.[4] This adverse effect was traced to the dual inhibition of two key enzymes responsible for bradykinin degradation: ACE and neprilysin.[2] The resulting excessive accumulation of bradykinin led to increased vascular permeability and angioedema. The ARNI class was intelligently designed to circumvent this issue by pairing the neprilysin inhibitor with an ARB instead of an ACE inhibitor. This strategic combination allows for potent blockade of the renin-angiotensin-aldosterone system (RAAS) without interfering with bradykinin metabolism to the same extent, thereby achieving a more favorable safe