title: Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction.
abstract: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials.
  
  
  
  In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with 'broad' and 'narrow' preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33-1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75-1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF.
  
  
  
  We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cannon
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: Pardeep S
authors.initials: PS
authors.lastname: Jhund
authors.affiliation: Rigshospitalet Copenhagen University Hospital, Copenhagen.
authors.forename: Søren L
authors.initials: SL
authors.lastname: Kristensen
authors.affiliation: Rigshospitalet Copenhagen University Hospital, Copenhagen.
authors.forename: Lars
authors.initials: L
authors.lastname: Køber
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: Chen
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Gong
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Lefkowitz
authors.affiliation: Institut de Cardiologie, 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: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London.
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: Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
mesh_terms: D000368:Aged; D000613:Aminobutyrates / Q000627:therapeutic use*; D000647:Amnesia / Q000453:epidemiology; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D003221:Confusion / Q000453:epidemiology; D003693:Delirium / Q000453:epidemiology; D003704:Dementia / Q000453:epidemiology*; D006970:Disorders of Excessive Somnolence / Q000453:epidemiology; D004338:Drug Combinations; D004656:Enalapril / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors; D016016:Proportional Hazards Models; D013318:Stroke Volume; D013777:Tetrazoles / Q000627:therapeutic use*; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: ARNI; Dementia; Heart failure; Neprilysin inhibition