Advances in Cardiovascular Pharmacotherapy. VI. Sacubitril-Valsartan, An Angiotensin Receptor-Neprilysin Inhibitor

Natriuretic peptides are endogenous hormones that are released in response to the mechanical stretch of cardiac myocytes or neurohormonal stimulation. These peptides cause vasodilation, natriuresis, and diuresis among other beneficial effects, indicating that they are potentially important therapeutic targets in patients with hypertension, heart failure (HF), or acute myocardial infarction (MI). Natriuretic peptides are metabolized by the nonselective metalloendopeptidase neprilysin, inhibition of which may augment their salutary actions. In this article, the authors review the biochemistry and physiology of natriuretic peptides and neprilysin; discuss the cardiovascular effects of neprilysin inhibitors with or without angiotensin-converting enzyme inhibitors; and describe the pharmacologic rationale for the combined use of the neprilysin inhibitor sacubitril and the angiotensin II type 1 receptor blocker valsartan. The major clinical trials comparing the use of sacubitril-valsartan with valsartan alone in patients with HF with reduced ejection fraction (HFrEF) are reviewed in detail. These studies established sacubitril-valsartan as one of the four cornerstones of contemporary medical therapy for HFrEF. We also review the clinical trials indicating that sacubitril-valsartan has efficacy in patients with HF with preserved ejection fraction and discuss the trials evaluating the benefits of treatment with the angiotensin receptor-neprilysin inhibitor in MI, congenital heart disease, left ventricular dysfunction resulting from cancer chemotherapy, advanced HF before heart transplantation with or without mechanical circulatory support, and left ventricular hypertrophy resulting from hypertension. Finally, the authors comment on the potential anesthetic implications of sacubitril-valsartan.