title: Effects of Sacubitril/Valsartan (LCZ696) on Natriuresis, Diuresis, Blood Pressures, and NT-proBNP in Salt-Sensitive Hypertension.
abstract: Salt-sensitive hypertension (SSH) is characterized by impaired sodium excretion and subnormal vasodilatory response to salt loading. Sacubitril/valsartan (LCZ696) was hypothesized to increase natriuresis and diuresis and result in superior blood pressure control compared with valsartan in Asian patients with SSH. In this randomized, double-blind, crossover study, 72 patients with SSH received sacubitril/valsartan 400 mg and valsartan 320 mg once daily for 4 weeks each. SSH was diagnosed if the mean arterial pressure increased by ≥10% when patients switched from low (50 mmol/d) to high (320 mmol/d) sodium diet. The primary outcome was cumulative 6- and 24-hour sodium excretion after first dose administration. Compared with valsartan, sacubitril/valsartan was associated with a significant increase in natriuresis (adjusted treatment difference: 24.5 mmol/6 hours, 50.3 mmol/24 hours, both P<0.001) and diuresis (adjusted treatment difference: 291.2 mL/6 hours, P<0.001; 356.4 mL/24 hours, P=0.002) on day 1, but not on day 28, and greater reductions in office and ambulatory blood pressure on day 28. Despite morning dosing of both drugs, ambulatory blood pressure reductions were more pronounced at nighttime than at daytime or the 24-hour average. Compared with valsartan, sacubitril/valsartan significantly reduced N-terminal pro B-type natriuretic peptide levels on day 28 (adjusted treatment difference: -20%; P=0.001). Sacubitril/valsartan and valsartan were safe and well tolerated with no significant changes in body weight or serum sodium and potassium levels with either treatments. In conclusion, sacubitril/valsartan compared with valsartan was associated with short-term increases in natriuresis and diuresis, superior office and ambulatory blood pressure control, and significantly reduced N-terminal pro B-type natriuretic peptide levels in Asian patients with SSH.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01681576.
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Tzung-Dau
authors.initials: TD
authors.lastname: Wang
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Ru-San
authors.initials: RS
authors.lastname: Tan
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Ihm
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Moo-Yong
authors.initials: MY
authors.lastname: Rhee
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Brian
authors.initials: B
authors.lastname: Tomlinson
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Parasar
authors.initials: P
authors.lastname: Pal
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hirschhorn
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Prescott
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.).
authors.forename: Markus
authors.initials: M
authors.lastname: Hinder
authors.affiliation: From the Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan (T.-D.W.); National Heart Centre, Department of Cardiology, Singapore (R.-S.T.); Seoul National University Hospital, Department of Internal Medicine, South Korea (H.-Y.L.); The Catholic University of Korea Bucheon, St Mary's Hospital, Department of Cardiology, Bucheon-si, Gyeonggi-do, South Korea (S.-H.I.); Dongguk University Ilsan Hospital, Cardiovascular Center, Goyang-si, Gyeonggi-do, South Korea (M.-Y.R.); The Chinese University of Hong Kong, Department of Medicine & Therapeutics, Shatin, NT (B.T.); Novartis Healthcare Private Limited, Biostatistical Sciences, Hyderabad, India (P.P.); Novartis Institutes for Biomedical Research, Translational Medicine, Beijing, China (F.Y.); Novartis Institutes for Biomedical Research, Inc, Translational Medicine, Cambridge, MA (E.H.); Novartis Pharmaceuticals Corporation, Global Clinical Development, East Hannover, NJ (M.F.P.); and Novartis Pharma AG, Translational Medicine, Basel, Switzerland (M.H., T.H.L.). thomas.langenickel@novartis.com tdwang@ntu.edu.tw.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Langenickel
mesh_terms: D000613:Aminobutyrates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004231:Diuresis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects*; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D013777:Tetrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013997:Time Factors; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D010446:Peptide Fragments; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: LCZ696; blood pressure; diuresis; natriuresis; salt-sensitive hypertension