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[O4–03–05]: CONCOMITANT USE OF CHOLINESTERASE INHIBITORS OR MEMANTINE IS ASSOCIATED WITH COGNITIVE DECLINE IN ALZHEIMER's CLINICAL TRIALS
Author(s) -
Kennedy Richard E.,
Cutter Gary R.,
Schneider Lon S.
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.434
Subject(s) - memantine , galantamine , donepezil , concomitant , rivastigmine , cognitive decline , observational study , dementia , medicine , clinical trial , alzheimer's disease , psychology , randomized controlled trial , pharmacology , disease
Background:Clinical trials in Alzheimer’s disease generally allow subjects to continue taking concomitant medications, including cholinesterase inhibitors (ChEIs) and memantine, if the dose is stable. Previous analysis of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) observational study indicates that such individuals experience greater rate of decline on cognitive testing than those not taking such medications. However, it is not known whether use of ChEIs/memantinewould affect results of clinical trials. Methods: We used a metadatabase of 18 ADCS studies and ADNI to examine rates of decline for subjects taking ChEIs/memantine. We included 8 studies with data on the ADAS-cog and concomitant medications, with a total of 2,290 subjects with AD. We estimated the annual rate of decline using linear mixed effects models, and compared rates for subjects taking ChEIs/memantine to subjects not taking either medication using random effects meta-analysis. Results: Across the 8 studies, 40.4% of subjects were taking ChEIs (donepezil, rivastigmine, or galantamine), 2.3% were taking memantine, 42.4% were taking both, and 14.8% were taking neither. Meta-analysis showed those taking ChEIs/memantine had a significantly greater annual rate of decline on the ADAS-cog (2.16 points/year, 95% CI [1.066, 3.262]), with 3 of the 8 individual trials showing significant differences. Conclusions:Similar to observational studies, subjects in many AD clinical trials taking ChEIs/memantine experience a greater rate of decline on the ADAS-cog. This difference is often comparable to the hypothesized effect size of the treatment being investigated in the trial. Concomitant use of ChEIs/memantine may be confounded with outcomes on the ADAS-cog and should be considered in the design of clinical trials of potential therapeutic agents for AD. Post-hoc analyses stratifying by ChEIs/memantine must be interpreted cautiously given the potential for confounding.