BY LIZETTE BORRELI
The concomitant use of medications for dementia due to Alzheimer's disease (AD), specifically memantine to cholinesterase inhibitors (ChEIs), was associated with a faster rate of cognitive decline in patients participating in AD clinical trials, according to a meta-analysis published online on November 2 in JAMA Network Open.
Participants who received ChEIs or memantine had 1.4 points per year difference on the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) compared to those who received neither medication.
"This difference is nearly as large as the hypothesized effect sizes of the treatments investigated in the trials," the researchers, led by Richard Kennedy, MD, PhD, University of Alabama at Birmingham, wrote. "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."
"While some may argue that these results demonstrate that ChEIs and memantine are ineffective in long-term treatment for dementia due to AD, it must be borne in mind that there are other possible explanations for our findings," the authors wrote. "In particular, the use of concomitant medications may represent confounding by indication, in which patients who are perceived as doing worse by their treating physician are the patients who were started on concomitant medications. This confounding by indication does not appear to be due to worse cognitive status, as individuals receiving concomitant medications had lower scores on the ADAS-cog at baseline, but may be related to other factors (such as participants' subjective sense of worsening cognition) that predict more rapid cognitive decline."
Differences in the use of cholinesterase inhibitors and memantine between treatment and placebo groups of clinical trials may lead to the conclusion that a treatment is effective when it is not, or vice versa, they said.
For the study, the team reviewed data from 10 studies that took place between 1997 and 2011, including a total of 2,714 participants (mean age, 75 years; 58 percent women; 9 percent racial/ethnic minorities).
Overall, 906 participants (33.4 percent) received ChEIs, 143 (5.3 percent) received memantine, 923 (34 percent) received both, and 742 (27.3 percent) received neither medication.
The meta-analysis showed participants on ChEIs or memantine or both had a significantly faster annual rate of cognitive decline on the ADAS-cog (1.4 points/year; 95% CI, 0.1 to 2.7).
It's unclear whether low ADAS-cog scores are due to the effect of concomitant medications on the course of disease, or prescribing practices that encourage beginning medications earlier instead of later on in the disease course, the study authors wrote.
Study limitations included the inability to determine why participants were or were not started on concomitant medications. This hindered the researchers' ability to fully address the "potential issue of confounding by indication.". Moreover, the sample size included generally highly educated individuals only with only a small percentage of racial/ethnic minorities, so the finding may not be generalizable.
The National Institutes of Health provided funding for the study. Dr. Kennedy reported no relevant financial disclosures. A complete list of other authors' relevant financial disclosures are provided in the study.
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Kennedy RE, Cutter GR, Fowler ME, et al. Association of concomitant use of cholinesterase inhibitors or memantine with cognitive decline in Alzheimer clinical trials: A meta-analysis. JAMA Netw Open 2018; Epub 2018 Nov 2.