Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2018 Nov 2;1(7):e184080.
doi: 10.1001/jamanetworkopen.2018.4080.

Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical Trials: A Meta-analysis

Richard E Kennedy  1 , Gary R Cutter  1 , Mackenzie E Fowler  1 , Lon S Schneider  2
Affiliations
Meta-Analysis

Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical Trials: A Meta-analysis

Richard E Kennedy et al. JAMA Netw Open. .

Abstract

Importance: Clinical trials in Alzheimer disease (AD) generally allow participants to continue receiving concomitant medications, including cholinesterase inhibitors (ChEIs) and memantine, if the dose is stable. Previous analysis of observational studies indicates such individuals experience greater rate of decline on cognitive testing than those not receiving such medications.

Objective: To investigate whether concomitant use of ChEIs or memantine is associated with cognitive outcomes in AD clinical trials.

Data sources: Meta-database of 18 studies from the Alzheimer Disease Cooperative Study and Alzheimer Disease Neuroimaging Initiative.

Study selection: All studies with data on ChEI and memantine use that included assessment of specified outcome measures.

Data extraction and synthesis: The analysis estimated annual rate of decline on the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) using linear mixed-effects models, and compared rates for participants receiving ChEIs and memantine, alone and combined, with participants not receiving either medication using random-effects meta-analysis.

Main outcomes and measures: Annual rate of change on the ADAS-cog.

Results: Across 10 studies, of 2714 participants, the mean (SD) age was 75.0 (8.2) years, 58% were female, and 9% were racial/ethnic minorities. There were 906 participants (33.4%) receiving ChEIs, 143 (5.3%) receiving memantine, 923 (34.0%) receiving both, and 742 (27.3%) receiving neither. Meta-analysis showed those receiving ChEIs or memantine were associated with significantly greater annual rate of decline on the ADAS-cog than those receiving neither medication (1.4 points/y; 95% CI, 0.1-2.7).

Conclusions and relevance: Similar to observational studies, many participants in AD clinical trials receiving ChEIs or memantine experience greater cognitive decline. This difference is nearly as large as the hypothesized effect sizes of the treatments investigated in the trials. Concomitant use of ChEIs or memantine may be confounded with outcomes on the ADAS-cog and should be considered in design of clinical trials of potential therapeutic agents for AD. Post hoc analyses stratifying by ChEIs or memantine must be interpreted cautiously given the potential for confounding.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Cutter reported receiving personal fees from Merck; participated on data and safety monitoring boards for AMO Pharmaceuticals, Biolinerx, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva pharmaceuticals, the National Heart, Lung, and Blood Institute (protocol review committee), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obstetric-Fetal Pharmacology Research Unit oversight committee) outside the submitted work; has participated on data consulting or advisory boards for Atara Biotherapeutics, Axon, Biogen, Biotherapeutics, Argenix, Brainstorm Cell Therapeutics, Charleston Labs Inc, Click Therapeutics, Genzyme, Genentech, GW Pharma, Klein-Buendel Inc, Medimmune, Medday, Novartis, Roche, Scifluor, Somahlution, Teva Pharmaceuticals, TG Therapeutics, and the University of Texas at Houston; and is employed by the University of Alabama at Birmingham and president of Pythagoras, Inc, a private consulting company located in Birmingham, Alabama. Dr Schneider reported receiving personal fees from AC Immune, Avraham, Boehringer Ingelheim, Cognition, Neurim, Tau Rx, and vTv; participated on data and safety monitoring boards for Eli Lilly, Genentech, and Merck; participated on an adjudication committee for Takeda; received grants from Biogen, Roche, and Tau Rx outside the submitted work; served as a steering committee member of the Alzheimer’s Disease Cooperative Study at the University of California, San Diego, and participated in most of the studies included in this analysis; and in the distant past was a consultant to Pfizer and Forest Laboratories, who were marketers of donepezil and memantine. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Percentage of Study Participants Receiving ChEIs (With or Without Memantine) and Memantine (With or Without ChEIs), Grouped by Year of Study Initiation
ADNI indicates Alzheimer Neuroimaging Initiative; ChEIs, cholinesterase inhibitors; DHA, docosahexaenoic acid; ES, estrogen; HC, homocysteine; HU, huperzine; LL, lipid lowering; NS, nonsteroidal; PR, prednisone; SL, selegiline; and VN, valproate neuroprotection.
Figure 2.
Figure 2.. Rates of Decline for Participants Receiving ChEIs, Memantine, or Both Compared With Rates of Decline for Participants Receiving Neither Medication
Rates of decline for individual studies were combined using random-effects meta-analysis. Vertical reference line indicates no difference between participants receiving medication and participants not receiving medication; size of squares is proportional to the weight of the study in the analysis. AD indicates Alzheimer disease; ADAS-cog, Alzheimer Disease Assessment Scale–cognitive subscale; ADNI, Alzheimer Neuroimaging Initiative; ChEIs, cholinesterase inhibitors; DHA, docosahexaenoic acid; ES, estrogen; HC, homocysteine; HU, huperzine; LL, lipid lowering; NS, nonsteroidal; PR, prednisone; SL, selegiline; and VN, valproate neuroprotection.
See this image and copyright information in PMC

References

    1. Schneider LS, Insel PS, Weiner MW; Alzheimer’s Disease Neuroimaging Initiative . Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer’s Disease Neuroimaging Initiative. Arch Neurol. 2011;68(1):-. doi:10.1001/archneurol.2010.343 - DOI - PMC - PubMed
    1. Petersen RC, Aisen PS, Beckett LA, et al. . Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010;74(3):201-209. doi:10.1212/WNL.0b013e3181cb3e25 - DOI - PMC - PubMed
    1. Mohs RC, Knopman D, Petersen RC, et al. . Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer’s Disease Assessment scale that broaden its scope: the Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S13-S21. doi:10.1097/00002093-199700112-00003 - DOI - PubMed
    1. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412-2414. doi:10.1212/WNL.43.11.2412-a - DOI - PubMed
    1. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. doi:10.1016/0022-3956(75)90026-6 - DOI - PubMed

Publication types

MeSH terms