title: Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF.
abstract: BACKGROUND
  The age at which heart failure develops varies widely between countries and drug tolerance and outcomes also vary by age. We have examined the efficacy and safety of LCZ696 according to age in the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF).
  
  
  METHODS
  In PARADIGM-HF, 8399 patients aged 18-96 years and in New York Heart Association functional class II-IV with an LVEF ≤40% were randomized to either enalapril or LCZ696. We examined the pre-specified efficacy and safety outcomes according to age category (years): <55 (n = 1624), 55-64 (n = 2655), 65-74 (n = 2557), and ≥75 (n = 1563).
  
  
  RESULTS
  The rate (per 100 patient-years) of the primary outcome of cardiovascular (CV) death or heart failure hospitalization (HFH) increased from 13.4 to 14.8 across the age categories. The LCZ696:enalapril hazard ratio (HR) was <1.0 in all categories (P for interaction between age category and treatment = 0.94) with an overall HR of 0.80 (0.73, 0.87), P < 0.001. The findings for HFH were similar for CV and all-cause mortality and the age category by treatment interactions were not significant. The pre-specified safety outcomes of hypotension, renal impairment and hyperkalaemia increased in both treatment groups with age, although the differences between treatment (more hypotension but less renal impairment and hyperkalaemia with LCZ696) were consistent across age categories.
  
  
  CONCLUSIONS
  LCZ696 was more beneficial than enalapril across the spectrum of age in PARADIGM-HF with a favourable benefit-risk profile in all age groups.
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
authors.forename: Pardeep S
authors.initials: PS
authors.lastname: Jhund
authors.affiliation: Department of Medicine, Sahlgrenska University Hospital/Östra Hospital, Göteborg, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Fu
authors.affiliation: Fundación Cardiovascular de Aguascalientes A.C., México.
authors.forename: Edmundo
authors.initials: E
authors.lastname: Bayram
authors.affiliation: Department of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chen-Huan
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department and Clinic of Cardiology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Negrusz-Kawecka
authors.affiliation: Dr. Arvo Rosenthal LLC, Estonia.
authors.forename: Arvo
authors.initials: A
authors.lastname: Rosenthal
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Akshay S
authors.initials: AS
authors.lastname: Desai
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Lefkowitz
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Adel R
authors.initials: AR
authors.lastname: Rizkala
authors.affiliation: Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Canada.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Rouleau
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Shi
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.affiliation: Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK john.mcmurray@glasgow.ac.uk.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000613:Aminobutyrates / Q000008:administration & dosage* / Q000009:adverse effects; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D001713:Biphenyl Compounds; D002423:Cause of Death; D004338:Drug Combinations; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D000068756:Valsartan; D055815:Young Adult
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Age; Angiotensin; Heart failure; Neprilysin; Receptors