Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials.
OBJECTIVE
Pharmacological treatment of Alzheimer's disease focuses on correcting the cholinergic deficiency in the central nervous system with cholinesterase inhibitors. Three cholinesterase inhibitors are currently recommended: donepezil, rivastigmine, and galantamine. This review assessed the scientific evidence for the recommendation of these agents.


METHODS
The terms "donepezil", "rivastigmine", and "galantamine", limited by "randomized-controlled-trials" were searched in Medline (1989-November 2004), Embase (1989-November 2004), and the Cochrane Database of Systematic Reviews without restriction for language.


METHODS
All published, double blind, randomised controlled trials examining efficacy on the basis of clinical outcomes, in which treatment with donepezil, rivastigmine, or galantamine was compared with placebo in patients with Alzheimer's disease, were included. Each study was assessed independently, following a predefined checklist of criteria of methodological quality.


RESULTS
22 trials met the inclusion criteria. Follow-up ranged from six weeks to three years. 12 of 14 studies measuring the cognitive outcome by means of the 70 point Alzheimer's disease assessment scale--cognitive subscale showed differences ranging from 1.5 points to 3.9 points in favour of the respective cholinesterase inhibitors. Benefits were also reported from all 12 trials that used the clinician's interview based impression of change scale with input from caregivers. Methodological assessment of all studies found considerable flaws--for example, multiple testing without correction for multiplicity or exclusion of patients after randomisation.


CONCLUSIONS
Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable.
Kaduszkiewicz
Hanna
H
Department of Primary Medical Care, Center of Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. kaduszki@uke.uni-hamburg.de
Zimmermann
Thomas
T
Beck-Bornholdt
Hans-Peter
HP
van den Bussche
Hendrik
H
D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D000077265:Donepezil; D005702:Galantamine / Q000627:therapeutic use*; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D048448:Phenylcarbamates / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000592:standards; D000068836:Rivastigmine; D016896:Treatment Outcome
D002800:Cholinesterase Inhibitors; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D005702:Galantamine; D000077265:Donepezil; D000068836:Rivastigmine