title: Combined angiotensin receptor/neprilysin inhibitors: a review of the new paradigm in the management of chronic heart failure.
abstract: OBJECTIVE
  The aims of this article were to review the rationale behind the development of combined angiotensin receptor/neprilysin inhibitors (ARNIs) for the management of chronic heart failure (HF) and to review the major clinical trials of LCZ696, the first drug in this class, that have been conducted to date.
  
  
  METHODS
  A selected review was undertaken of publications examining the preclinical and clinical studies of drugs aimed at enhancing the activity of the endogenous natriuretic peptide system and their combination with inhibitors of the renin-angiotensin-aldosterone system, initially angiotensin-converting enzyme inhibitors (ACEIs) and more recently angiotensin II type 1 receptor blockers.
  
  
  RESULTS
  Selective neprilysin inhibitors are unlikely to be of benefit and may be associated with adverse effects when used in isolation in HF. Combining NIs with ACEIs is unsafe because of an unacceptably high prevalence of angioedema, which may be mediated by elevated levels of endogenous bradykinin. Combining a neprilysin inhibitor with an angiotensin II type 1 receptor blockers avoids the risk for angioedema. The ARNI LCZ696 was associated with greater reductions both mortality and morbidity compared with those with enalapril in a large-scale, Phase III clinical trial in patients with HF with reduced ejection fraction. Findings from a Phase II clinical trial suggested that LCZ696 may also be beneficial in HF with preserved ejection fraction, and a Phase III clinical trial of LCZ696 used for this indication is under way.
  
  
  CONCLUSIONS
  ARNIs have been described as a "game changer" by cardiologists. Based on findings from clinical trials conducted to date, there is an expectation that they will replace ACEIs as a building block of the pharmacologic treatment of chronic HF.
authors.affiliation: Heart Failure and Transplant Program, St. Vincent's Hospital, Sydney, Australia. Electronic address: peter.macdonald@svha.org.au.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Macdonald
mesh_terms: D000613:Aminobutyrates / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D002908:Chronic Disease; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000009:adverse effects / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000627:therapeutic use*; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004338:Drug Combinations; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: ARNI; angiotensin II receptor blockers; ejection fraction; heart failure; neprilysin inhibitors