title: Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.
abstract: Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
authors.affiliation: From Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. scott.hubers@Vanderbilt.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Hubers
authors.affiliation: From Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000613:Aminobutyrates / Q000008:administration & dosage / Q000191:economics / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000799:Angioedema / Q000139:chemically induced; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000378:metabolism / Q000627:therapeutic use; D001920:Bradykinin / Q000378:metabolism; D000075202:Contraindications; D004338:Drug Combinations; D016527:Drug Costs; D004357:Drug Synergism; D004656:Enalapril / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced; D006973:Hypertension / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects; D015337:Multicenter Studies as Topic; D045265:Natriuretic Peptides / Q000502:physiology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011446:Prospective Studies; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013318:Stroke Volume / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage / Q000191:economics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013841:Thiazepines / Q000009:adverse effects / Q000627:therapeutic use*; D000068756:Valsartan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C000609743:LBQ657; D045265:Natriuretic Peptides; D011355:Prodrugs; D011725:Pyridines; D013777:Tetrazoles; D013841:Thiazepines; C106266:omapatrilat; D004656:Enalapril; D000068756:Valsartan; D015260:Neprilysin; D001920:Bradykinin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: heart failure; natriuretic peptides; pharmacology; prescription drugs