title: Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck.
abstract: OBJECTIVE
  Heart failure remains a leading cause of morbidity and mortality worldwide. Advanced therapies have prolonged survival in patients with advanced heart failure, but pharmacotherapeutic optimization remains the mainstay of treatment. It has been over 10 years since the last mortality-reducing medication has been approved by the Food and Drug Administration. This article reviews the background, current knowledge and data supporting the use of sacubitril/valsartan (Entresto(®) ), the newly FDA-approved medication that dually inhibits angiotensin and neprilysin, in the treatment of heart failure.
  
  
  METHODS
  A literature search was performed (January 1980 to August 2015) using PubMed and the search terms were as follows: neprilysin inhibitor, heart failure, endopeptidase, natriuretic peptides, angiotensin, omapatrilat, LCZ696, valsartan and sacubitril. Peer-reviewed, published clinical trials, review articles, relevant treatment guidelines and prescribing information documents were identified and reviewed for relevance. Additionally, reference citations from publications identified were reviewed.
  
  
  CONCLUSIONS
  The inhibition of endopeptidases has been an area of extensive study for the treatment of heart failure. Previously published literature with the endopeptidase inhibitor omapatrilat failed to demonstrate a sufficient balance between clinical efficacy and safety to justify its approval. Omapatrilat blocked three pathways that break down bradykinin, leading to high rates of angioedema. Sacubitril, on the other hand, is metabolized to a form that is highly selective for neprilysin without possessing activity for the other two peptidases, ACE and APP. The combination of sacubitril with valsartan in a single formulation offers the benefit of concurrent blockade of the renin angiotensin aldosterone system and the inhibition of neprilysin while minimizing angioedema risk. When compared to ACE inhibitor therapy in systolic heart failure patients, sacubitril/valsartan demonstrated reductions in all-cause mortality and hospitalization due to heart failure while maintaining a similar safety profile.
  
  
  CONCLUSIONS
  A formulation that contains both sacubitril and valsartan was manufactured and approved by the FDA in July 2015 for the reduction of mortality and hospitalization in systolic heart failure patients. The new medication offers a potentially superior alternative to ACE inhibitor therapy in the management of systolic heart failure. The effects of treatment with sacubitril/valsartan in the setting of diastolic heart failure are currently under investigation in clinical trials.
authors.affiliation: Department of Pharmacy, Indiana University Health Methodist Hospital, Indianapolis, IN, USA.|Department of Pharmacy Practice, Butler University College of Pharmacy and Health Sciences, Indianapolis, IN, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Ansara
authors.affiliation: Department of Pharmacy, Loyola University Medical Center, Maywood, IL, USA.|Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Kolanczyk
authors.affiliation: Department of Pharmacy Practice, Butler University College of Pharmacy and Health Sciences, Indianapolis, IN, USA.|Pulmonary Rehabilitation and Transitional Care, Indiana University Health, Indianapolis, IN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Koehler
mesh_terms: D000613:Aminobutyrates / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000809:Angiotensins / Q000037:antagonists & inhibitors; D001713:Biphenyl Compounds; D004338:Drug Combinations; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000627:therapeutic use*; D000068756:Valsartan / Q000627:therapeutic use*
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D000809:Angiotensins; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: LCZ696; angiotensin; endopeptidase; heart failure; natriuretic peptides; neprilysin inhibitor; omapatrilat; sacubitril; valsartan