From the Dementia Trialists' Collaboration, Cochrane Dementia Group, Department of Clinical Geratology, University of Oxford, Radcliffe Infirmary, Oxford, England (Dr Qizilbash); MPS Research Unit, University of Reading, England (Ms Whitehead); Systematic Reviews Training Unit, Institute of Child Health, London, England (Dr Higgins); Department of Care of the Elderly, Frenchay Hospital, Bristol, England (Dr Wilcock); Department of Psychiatry, University of Southern California School of Medicine, Los Angeles (Dr Schneider); and Department of Neurology, Indiana University School of Medicine, Indianapolis (Dr Farlow).
Objectives.— 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.
Data Sources.— The Cochrane Dementia Group registry of trials.
Study Selection.— 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.
Data Extraction.— Two reviewers independently selected trials for inclusion and individual
patient data were sought.
Data Synthesis.— 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, Whitehead A, Higgins J, Wilcock G, Schneider L, Farlow M, for the Dementia Trialists' Collaboration . Cholinesterase Inhibition for Alzheimer DiseaseA Meta-analysis of the Tacrine Trials. JAMA. 1998;280(20):1777-1782. doi:10.1001/jama.280.20.1777