In Alzheimer Clinical Trials, Combination Therapy Tied to Quicker Cognitive Decline

November 9, 2018

By Will Boggs MD

NEW YORK—Concomitant use of cholinesterase inhibitors or memantine is associated with quicker cognitive decline in patients participating in Alzheimer clinical trials, according to a meta-analysis.

Patients with mild cognitive impairment due to Alzheimer disease (AD) in the observational Alzheimer Neuroimaging Initiative (ADNI) database who were receiving both cholinesterase inhibitors (ChEIs) and memantine had worse performance on various cognitive tests than those receiving only ChEIs.

It has been unclear whether such differences are also present in participants enrolling in clinical trials for AD, which typically allow participants to continue receiving stable doses of these medications.

Dr. Richard E. Kennedy of the University of Alabama at Birmingham and colleagues investigated whether concomitant use of ChEIs or memantine is associated with cognitive outcomes in AD clinical trials in a meta-analysis of 10 studies from the Alzheimer Disease Cooperative study and ADNI.

Among the 2,714 participants included in the analysis, 33.4% were receiving ChEIs, 5.3% were receiving memantine, 34.0% were receiving both and 27.3% were receiving neither. Patients receiving ChEIs or memantine were more likely to be in the placebo arm of trials.

Participants receiving ChEIs or memantine had lower (i.e., better) Alzheimer Disease Assessment Scale-cognitive (ADAS-cog) scores at baseline, but participants receiving both medications had more rapid cognitive decline over time than those not receiving these medications.

Patients receiving ChEIs only showed a non-significantly faster rate of decline than those receiving neither class of drugs, whereas participants receiving memantine with or without ChEIs showed a significantly faster rate of decline than those receiving ChEIs alone or neither medication, the researchers report in JAMA Network Open, online November 2.

"It is not clear if these lower scores represent an effect of concomitant medications on the course of the disease, or simply prescribing practices that begin medications earlier instead of later in the disease course," the researchers note.

Regardless of the reason, they conclude, "the use of concomitant medications must specifically be accounted for in the design and analysis of trial data to prevent erroneous conclusions that could result from imbalances in the rates of these medications among trial participants."

Dr. Rita Khoury from St. Louis University School of Medicine, in St. Louis, Missouri, who recently reviewed the progress in the pharmacotherapy of AD, told Reuters Health by email, "A major limitation of these findings is confounding by indication, by which subjects with a worse disease status at baseline or declining more rapidly before study enrollment are usually prescribed these medications early on in the course of the disease."

"Overall, this study raises the concern that concomitant use of AD symptomatic medication might neutralize any positive effect an investigational treatment for AD might have on cognition," said Dr. Khoury, who was not involved in the new research. "Enrolling subjects who are not taking any symptomatic therapy may be ideal, as controlling for concomitant medication use is not always optimal and might lead to erroneous findings, especially in post-hoc analyses."

Dr. Kennedy did not respond to a request for comments.


JAMA Network Open 2018.

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