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Cholinesterase Inhibition for Alzheimer Disease A Meta-analysis of the Tacrine Trials

Nawab Qizilbash, MRCP, DPhil; Anne Whitehead, MSc; Julian Higgins, PhD; Gordon Wilcock, FRCP, DM; Lon Schneider, MD; Martin Farlow, MD; for the Dementia Trialists' Collaboration
JAMA. 1998;280(20):1777-1782. doi:10.1001/jama.280.20.1777.
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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.

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Figure 1.—Change in Mini-Mental State Examination cognitive score for tacrine compared with placebo during 12 weeks. Results are based on standardized rates of change. The final dose is the average final daily dosage of all patients randomized to tacrine in each study.
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Figure 2.—Change in Mini-Mental State Examination cognitive score for tacrine relative to placebo at 6, 12, and 24 weeks for studies with fixed dosage regimens. Results are based on raw means at each time point. The dosage is that given at the time of the assessment.
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Figure 3.—Clinical Global Impression of Change. Odds of improvement on tacrine compared with placebo.
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Figure 4.—Change in Alzheimer's Disease Assessment Scale noncognitive score for tacrine compared with placebo during 12 weeks. Results are based on standardized rates of change.
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Figure 5.—Change in the Progressive Deterioration Scale scores for tacrine compared with placebo at 6, 12, and 24 weeks.



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