What is the mechanism and clinical use of sacubitril/valsartan?

• A. It blocks beta-adrenergic receptors to reduce heart rate.
• B. It acts as a diuretic to reduce volume overload in HFpEF.
• C. RAAS blockade alone improves remodeling; neprilysin inhibition has no role.
• D. Neprilysin inhibition increases natriuretic peptides; ARB provides RAAS blockade; improves remodeling and outcomes in HFrEF.

Answer: (D)

This medication works by a dual mechanism: inhibiting neprilysin to raise levels of natriuretic peptides, and blocking the angiotensin II receptor to suppress RAAS effects. Neprilysin inhibition increases natriuretic peptides such as ANP and BNP, which promote vasodilation, natriuresis, diuresis, and anti-fibrotic remodeling in the heart and vessels. The ARB component (valsartan) blocks the angiotensin II type 1 receptor, reducing vasoconstriction, aldosterone release, sodium retention, and adverse structural remodeling. Together, these actions decrease both preload and afterload and improve cardiac remodeling, leading to better outcomes in heart failure with reduced ejection fraction (HFrEF). Landmark trials in HFrEF show reduced mortality and fewer heart failure hospitalizations with this combination, making it preferred over RAAS blockade alone due to the added benefit from enhanced natriuretic peptide signaling. It’s primarily proven in HFrEF rather than HFpEF, and its use centers on replacing another RAAS blocker in eligible patients to achieve better remodeling and survival outcomes.