title: Efficacy and safety of sacubitril/valsartan (LCZ696) in Japanese patients with chronic heart failure and reduced ejection fraction: Rationale for and design of the randomized, double-blind PARALLEL-HF study.
abstract: BACKGROUND
  The prognosis of heart failure patients with reduced ejection fraction (HFrEF) in Japan remains poor, although there is growing evidence for increasing use of evidence-based pharmacotherapies in Japanese real-world HF registries. Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor shown to reduce mortality and morbidity in the recently completed largest outcome trial in patients with HFrEF (PARADIGM-HF trial). The prospectively designed phase III PARALLEL-HF (Prospective comparison of ARNI with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) study aims to assess the clinical efficacy and safety of LCZ696 in Japanese HFrEF patients, and show similar improvements in clinical outcomes as the PARADIGM-HF study enabling the registration of LCZ696 in Japan.
  
  
  METHODS
  This is a multicenter, randomized, double-blind, parallel-group, active controlled study of 220 Japanese HFrEF patients. Eligibility criteria include a diagnosis of chronic HF (New York Heart Association Class II-IV) and reduced ejection fraction (left ventricular ejection fraction ≤35%) and increased plasma concentrations of natriuretic peptides [N-terminal pro B-type natriuretic peptide (NT-proBNP) ≥600pg/mL, or NT-proBNP ≥400pg/mL for those who had a hospitalization for HF within the last 12 months] at the screening visit. The study consists of three phases: (i) screening, (ii) single-blind active LCZ696 run-in, and (iii) double-blind randomized treatment. Patients tolerating LCZ696 50mg bid during the treatment run-in are randomized (1:1) to receive LCZ696 100mg bid or enalapril 5mg bid for 4 weeks followed by up-titration to target doses of LCZ696 200mg bid or enalapril 10mg bid in a double-blind manner. The primary outcome is the composite of cardiovascular death or HF hospitalization and the study is an event-driven trial.
  
  
  CONCLUSIONS
  The design of the PARALLEL-HF study is aligned with the PARADIGM-HF study and aims to assess the efficacy and safety of LCZ696 in Japanese HFrEF patients.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University, Fukuoka, Japan. Electronic address: htsutsui@cardiol.med.kyushu-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.affiliation: Cardiovascular Division, Jichi Medical University, Saitama Medical Center, Saitama, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Momomura
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Molecular Medicine and Therapeutics, Tottori University, Yonago, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Novartis Pharma K.K., Tokyo, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ohishi
authors.affiliation: Novartis Pharma K.K., Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Okino
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Weinong
authors.initials: W
authors.lastname: Guo
mesh_terms: D000613:Aminobutyrates / Q000009:adverse effects / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People; D001713:Biphenyl Compounds; D002908:Chronic Disease; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D012107:Research Design; D016037:Single-Blind Method; D013318:Stroke Volume / Q000187:drug effects; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D000068756:Valsartan; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D010446:Peptide Fragments; D013777:Tetrazoles; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Heart failure with reduced ejection fraction; Japanese; LCZ696; Neprilysin; Sacubitril/valsartan