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Concomitant use of dementia drugs may speed-up decline in Alzheimer’s disease

Clinical trial participants receiving concomitant medications for dementia due to Alzheimer’s disease — particularly memantine added to cholinesterase inhibitors —showed faster rate of cognitive decline, according to data published in JAMA Network Open.

“Clinical trials of new therapies for [Alzheimer’s disease] typically allow participants to continue receiving [cholinesterase inhibitors] and memantine during the trial if the dose remains stable,” Richard E. Kennedy, MD, PhD, from the University of Alabama at Birmingham, and colleagues wrote. “Thus, it is critical to know whether participants receiving these concomitant medications differ significantly from those not receiving these medications, particularly if such differences may affect trial outcome.”

According to the researchers, findings from prior observational studies suggest that participants experience greater rate of cognitive decline when they continue receiving concomitant medications, including cholinesterase inhibitors and memantine. The current study examined whether concomitant use of cholinesterase inhibitors or memantine affects cognitive outcomes in Alzheimer’s disease clinical trials.

Researchers conducted a meta-analysis of studies with data on cholinesterase inhibitors and memantine use that included assessment of specified outcome measures to estimate the annual rate of decline on the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) using linear mixed-effects models. Using random-effects meta-analysis, they also compared rates for participants receiving cholinesterase inhibitors and memantine, alone and combined, with those not receiving either medication.

Analysis included 10 studies encompassing 2,714 participants (mean age, 75 years). Overall, 906 participants (33.4%) received cholinesterase inhibitors, 143 received memantine, 923 received both and 742 received neither.

Results from the meta-analysis showed that those receiving cholinesterase inhibitors or memantine were significantly more likely to experience a faster annual rate of cognitive decline on the ADAS-cog than those receiving neither medication (1.4 points per year; 95% CI, 0.1-2.7). Kennedy and colleagues found no clear trend that the rate of cognitive decline varied over time.

Subanalyses showed that patients receiving cholinesterase inhibitors demonstrated a faster rate of decline (0.9 points per year; 95% CI, –0.6 to 2.3) than those receiving neither medication. However, subanalyses that compared participants receiving memantine with or without cholinesterase inhibitors to those receiving cholinesterase inhibitors alone or neither showed a significantly faster rate of decline in patients receiving memantine (2 points per year; 95% CI, 1.3-2.7), according to the findings.

“We have shown that participants receiving concomitant medications for dementia due to [Alzheimer’s disease] (particularly memantine added to [cholinesterase inhibitors]) show faster rate of decline that can exceed the effect of trial interventions,” the researchers 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.” – by Savannah Demko

Disclosure: Kennedy reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.