Sacubitril/valsartan is a new medication approved in 2015 for the treatment of New York Heart Association (NYHA) class II to IV heart failure with reduced ejection fraction. While the drug failed to meet the primary endpoint in patients with heart failure with preserved ejection fraction in the PARAGON-HF trial, improvements were noted in several secondary endpoints. Valsartan is an angiotensin receptor blocker and sacubitril is a neprilysin inhibitor. Neprilysin is an endopeptidase that degrades bradykinin, natriuretic peptides, and adrenomedullin. Neprilysin inhibition by sacubitril results in increased levels of vasoactive peptides, decreased vasoconstriction, sodium retention, and cardiovascular remodeling due to excessive neurohormonal stimulation in uncontrolled heart failure. Research has revealed that neprilysin inhibition may impact more than just cardiovascular targets. Neprilysin is an enzyme involved in the clearance of beta-amyloid peptides, proteins thought to contribute to development of Alzheimer dementia. Although pre-clinical and clinical studies have shown promising safety results, those studies have been heavily criticized for short monitoring time and targeted populations. In accordance with the requirements of the US Food and drug Administration (FDA), the ongoing Prospective Evaluation of Cognitive Function in Heart Failure: Efficacy and Safety of Entresto compared to Valsartan on Cognitive Function in Patients with Chronic Heart Failure and Preserved Ejection Fraction (PERSPECTIVE; NCT02884206) multicenter, randomized, double-blinded trial is assessing the long-term neurocognitive effects and safety of sacubitril/valsartan, and results are expected in early 2022.
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