Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Dementia Trialists' Collaboration.
OBJECTIVE
To determine the effects of cholinesterase inhibition with tacrine hydrochloride for the symptoms of Alzheimer disease in terms of cognitive performance, clinical global impression, behavior, and functional autonomy.


METHODS
The Cochrane Dementia Group registry of trials.


METHODS
Unconfounded, randomized, double-blind, placebo-controlled trials in which tacrine had been given for more than 1 day and that were completed before January 1, 1996.


METHODS
Two reviewers independently selected trials for inclusion and individual patient data were sought.


RESULTS
Data were analyzed from 12 trials that included 1984 patients with Alzheimer disease. At 12 weeks, cognitive performance, as measured by the Mini-Mental State Examination (score range, 0-30), was better in patients receiving tacrine than in patients receiving placebo by 0.62 points (95% confidence interval [CI], 0.23-1.00; P=.002). Compared with similar untreated patients who would be expected to deteriorate by 0.50 to 1.00 points on the Mini-Mental State Examination during 12 weeks, the progress of patients receiving tacrine would be expected to range between an improvement of 0.12 and a deterioration of 0.38 points. The odds ratio for improvement on the Clinical Global Impression of Change scale (range, 1-7) for patients receiving tacrine compared with those receiving placebo was 1.58 (95% CI, 1.18-2.11; P=.002). The behavioral noncognitive subscale of the Alzheimer's Disease Assessment Scale (range, 0-50) showed a difference in favor of tacrine of 0.58 points (95% CI, 0.17-1.00; P= .006). Improvement on the Progressive Deterioration Scale, largely an index of functional activities, was not significant (0.75; 95% CI, -0.43 to 1.93; P=.21). Age, severity of dementia, and exposure to tacrine prior to randomization had no clear influence on the treatment effect. There was a nonsignificant trend toward increasing effect with increasing dose for cognitive function and the Clinical Global Impression of Change. For patients without prior exposure to tacrine, the odds of patients' withdrawing during the study while they were receiving tacrine compared with placebo was 3.63 (95% CI, 2.80- 4.71; P<.001). Eleven (95% CI, 7-31) patients would need to be treated to achieve any improvement on the Clinical Global Impression scale, and 42 (95% CI, 23-125) to achieve a moderate or marked improvement. One patient would be expected to withdraw for every 4 (95% CI, 3-5) patients treated.


CONCLUSIONS
Cholinesterase inhibition with tacrine appears to reduce deterioration in cognitive performance during the first 3 months and increase the odds of global clinical improvement. Effects observed on measures of behavioral disturbance were of questionable clinical significance, and functional autonomy was not significantly affected. The clinical relevance of the benefits of cholinesterase inhibition remains controversial, and long-term trials with clinically relevant end points are required.
Qizilbash
N
N
Department of Clinical Geratology, University of Oxford, Radcliffe Infirmary, England. nawab.qizilbash@geratology.ox.ac.uk
Whitehead
A
A
Higgins
J
J
Wilcock
G
G
Schneider
L
L
Farlow
M
M
D000544:Alzheimer Disease / Q000188:drug therapy*; D001519:Behavior; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D003071:Cognition; D006801:Humans; D008609:Mental Status Schedule; D009483:Neuropsychological Tests; D016032:Randomized Controlled Trials as Topic; D013619:Tacrine / Q000627:therapeutic use*
D002800:Cholinesterase Inhibitors; D013619:Tacrine