Special Article
Metaanalysis of Randomized Trials of the Efficacy and Safety of Donepezil, Galantamine, and Rivastigmine for the Treatment of Alzheimer Disease

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The authors estimated the effects of each of the three commonly used drugs for Alzheimer disease (donepezil, galantamine, and rivastigmine) in terms of predefined clinical outcomes and trial completion rates, by dosing level, and described differences among them. Using both electronic and manual search strategies (January 1992 to July 2002), a metaanalysis examined the effect of the drugs on clinical outcomes and completion rates. Regression analyses compared the effect of dose on clinical outcomes and completion rates, using 10 donepezil, 6 galantamine, and 5 rivastigmine articles. All three drugs showed beneficial effects on cognitive tests, as compared with placebo. For donepezil and rivastigmine, larger doses were associated with larger effect. This was not the case with galantamine. The odds of clinical global improvement demonstrated superiority over placebo for each drug, with no dose effects noted. Dropout rates were greater with galantamine and rivastigmine. There was little difference in dropout rate for each drug at each dose-level, except with high-dose donepezil. This was accounted for by the high dropout rate in two 52-week studies using larger doses. In summary, all three drugs had similar cognitive efficacy, with donepezil and rivastigmine showing a dose effect across the dosing levels studied. However, both galantamine and rivastigmine were associated with a greater risk of trial dropout than placebo, especially at higher dosing levels.

Section snippets

Literature Review

There were five stages of searching: electronic searching of databases, direct contact with pharmaceutical companies, manual reviews of key journals and conference proceedings, manual searching of references in papers identified from electronic searching, and direct contact with authors by e-mail.

We searched MEDLINE; EMBASE; PsycINFO; the Cochrane Library Database (including the Cochrane Controlled Trials Register); International Pharmaceutical Abstracts; SIGLE (System for Information on Grey

RESULTS

Results of the literature search and the metaanalysis are presented separately.

DISCUSSION

The literature review proved effective. All of the papers used by the Cochrane Dementia Group in their metaanalyses were identified by our search strategy, although four articles were included in this study that were not in the Cochrane review.21, 22, 23, 29 The first three of these extra papers involved severe or nursing home-resident AD patients, and the final paper had also included subjects with vascular dementia.

The decision to not extract data for behavioral or neuropsychiatric efficacy

CONCLUSIONS

The aim of this study was, through a systematic review of the literature and metaanalysis, to describe the respective efficacy and safety of each of the three most commonly prescribed drugs in Alzheimer disease.

In essence, there is little to choose from in efficacy between donepezil and rivastigmine at high doses and galantamine at all doses in terms of change from baseline in the ADAS–Cog scale. It is interesting to note that our regression analysis demonstrated comparable efficacy across the

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    We thank Chris Frost at the London School of Hygiene and Tropical Medicine for his advice on regression techniques in metaanalysis.

    Dr. Ritchie is funded by a Health Services Research Fellowship Grant from the UK Medical Research Council. Dr. Ames has received consultancy fees, speaker's honoraria, and financial support to attend conferences from Pfizer/Eisai, Novartis, and Janssen-Cilag.

    Shire Pharmaceutical, Pfizer-Eisai, and Novartis all provided manuscripts and abstracts as part of the systematic review.

    Note: The following articles, cited below, were used in the metaanalysis: References 11 and 13–31.

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