title: Discontinuation, Efficacy, and Safety of Cholinesterase Inhibitors for Alzheimer's Disease: a Meta-Analysis and Meta-Regression of 43 Randomized Clinical Trials Enrolling 16 106 Patients.
abstract: We investigated the effect of cholinesterase inhibitors on all-cause discontinuation, efficacy and safety, and the effects of study design-, intervention-, and patient-related covariates on the risk-benefit of cholinesterase inhibitors for Alzheimer's disease.
  
  
  
  A systematic review and meta-analysis of randomized placebo-controlled clinical trials comparing cholinesterase inhibitors and placebo was performed. The effect of covariates on study outcomes was analysed by means of meta-regression using a Bayesian framework.
  
  
  
  Forty-three randomized placebo-controlled clinical trials involving 16106 patients were included. All-cause discontinuation was higher with cholinesterase inhibitors (OR = 1.66), as was discontinuation due to adverse events (OR=1.75). Cholinesterase inhibitors improved cognitive function (standardized mean difference = 0.38), global symptomatology (standardized mean difference=0.28) and functional capacity (standardized mean difference=0.16) but not neuropsychiatric symptoms. Rivastigmine was associated with a poorer outcome on all-cause discontinuation (Diff OR = 1.66) and donepezil with a higher efficacy on global change (Diff standardized mean difference = 0.41). The proportion of patients with serious adverse events decreased with age (Diff OR = -0.09). Mortality was lower with cholinesterase inhibitors than with placebo (OR = 0.65).
  
  
  
  While cholinesterase inhibitors show a poor risk-benefit relationship as indicated by mild symptom improvement and a higher than placebo all-cause discontinuation, a reduction of mortality was suggested. Intervention- and patient-related factors modify the effect of cholinesterase inhibitors in patients with Alzheimer's disease.
authors.affiliation: TransLab Research Group, and Department of Medical Sciences, University of Girona, Spain; Research Group on Statistics, Econometrics and Health, University of Girona, Spain; CIBER of Epidemiology and Public Health, Spain; Girona Biomedical Research Institute, Salt, Spain.
authors.forename: Lídia
authors.initials: L
authors.lastname: Blanco-Silvente
authors.affiliation: TransLab Research Group, and Department of Medical Sciences, University of Girona, Spain; Research Group on Statistics, Econometrics and Health, University of Girona, Spain; CIBER of Epidemiology and Public Health, Spain; Girona Biomedical Research Institute, Salt, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Castells
authors.affiliation: TransLab Research Group, and Department of Medical Sciences, University of Girona, Spain; Research Group on Statistics, Econometrics and Health, University of Girona, Spain; CIBER of Epidemiology and Public Health, Spain; Girona Biomedical Research Institute, Salt, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Saez
authors.affiliation: TransLab Research Group, and Department of Medical Sciences, University of Girona, Spain; Research Group on Statistics, Econometrics and Health, University of Girona, Spain; CIBER of Epidemiology and Public Health, Spain; Girona Biomedical Research Institute, Salt, Spain.
authors.forename: Maria Antònia
authors.initials: MA
authors.lastname: Barceló
authors.affiliation: TransLab Research Group, and Department of Medical Sciences, University of Girona, Spain; Research Group on Statistics, Econometrics and Health, University of Girona, Spain; CIBER of Epidemiology and Public Health, Spain; Girona Biomedical Research Institute, Salt, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Garre-Olmo
authors.affiliation: TransLab Research Group, and Department of Medical Sciences, University of Girona, Spain; Research Group on Statistics, Econometrics and Health, University of Girona, Spain; CIBER of Epidemiology and Public Health, Spain; Girona Biomedical Research Institute, Salt, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Vilalta-Franch
authors.affiliation: TransLab Research Group, and Department of Medical Sciences, University of Girona, Spain; Research Group on Statistics, Econometrics and Health, University of Girona, Spain; CIBER of Epidemiology and Public Health, Spain; Girona Biomedical Research Institute, Salt, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Capellà
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000401:mortality; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D006801:Humans; D017063:Outcome Assessment, Health Care; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors
keywords: Alzheimer’s disease; Bayesian meta-analysis; cholinesterase inhibitor; discontinuation; efficacy