Concomitant Use of Cholinesterase Inhibitors, Memantine May be Confounded with Outcomes in Alzheimer Clinical Trials


In clinical trials, differences in the use of cholinesterase inhibitors and memantine between treatment and placebo groups may lead to the conclusion that a treatment is effective when it is not, or vice versa.

Dr Richard Kennedy

Richard Kennedy MD, PhD, University of Alabama Birmingham

Richard Kennedy MD, PhD

A meta-analysis revealed that participants receiving cholinesterase inhibitors (ChEIs) or memantine had 1.4 points per year difference on the Alzheimer Disease Assessment Scale-cognitive (ADAS-Cog) subscale compared to those receiving neither medication, producing potentially confounding outcomes that a treatment is effective when it is not, or vice versa, a significant difference that’s roughly the same size as the expected effect of new therapeutic drugs investigated in clinical trials.

Clinical trials of new therapies for Alzheimer disease allow participants to continue receiving ChEIS and memantine—2 FDA-approved therapies for dementia due to Alzheimer—during the trial if the dose remains stable, however, it’s not known whether participants receiving these medications differ significantly from those not receiving these medications and if such differences affect trial outcome.

“The use of concomitant medications must specifically be account 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,” said Richard Kennedy, MD, PhD, University of Alabama at Birmingham, one of the study authors.

Participants were drawn from a meta-database consisting of 18 studies from the Alzheimer Disease Cooperative Study and Alzheimer Neuroimaging Initiative (ADNI), representing clinical trials and observational studies in dementia due to Alzheimer disease, mild cognitive impairment due to Alzheimer disease and normal participants. Analyses were restricted to 10 studies—9 randomized clinical trials and 1 observational ADNI study—and examined a total of 2714 participants; study characteristics included a mean age of 75 years, 58% were female and 9% racial/ethnic minorities. In the study population, there were 906 (33.4%) participants receiving ChEIs, 143 (5.3%) receiving memantine, 923 (34%) receiving both and 742 (27.3%) receiving neither.

The analysis estimated the annual rate of decline on the ADAS-Cog subscale utilizing linear-mixed effects models, comparing rates for participants receiving ChEIs and memantine, alone and combined, with those not receiving either medication through random-effects meta-analysis.

Participants receiving ChEIs or memantine were associated with significantly greater and faster annual rate of decline on the ADAS-Cog than those receiving neither medication (1.4 points/y; 95% CI, 0.1—2.7). Restricting the analysis to randomized clinical trials yielded a slightly faster rate of decline of 1.5 points per year (95% CI, 0.1–2.8).

Subanalyses of those receiving only ChEIs versus those receiving neither ChEIs nor memantine showed a faster rate of decline in those receiving only ChEIS of 0.9 points/y, although this wasn’t statistically significant (95% CI, -0.6 to 2.3), while subanalyses of those receiving memantine with or without ChEIs was faster than those receiving ChEIS only or receiving neither medication by 2.0 points/y (95% CI, 1.3—2.7).

The researchers caution that these findings are a bit more concerning for clinical trials than observation studies, as the rate of decline for receiving ChEIS, memantine or both (1.41 points/y for either medication compared to receiving neither, or 1.97 points/y when receiving or not receiving memantine) could offset an effect of a successful therapeutic intervention. Depending on the concomitant medication use among groups, the rates of decline could lead to inaccurate conclusions that a therapeutic intervention is effective.

The research has shown that participants receiving concomitant medications for dementia due to Alzheimer show faster rate of decline which can exceed the effect of trial interventions. The use of concomitant medications, particularly memantine added to ChEIs, should be accounted for in clinical trial design and analysis of data.


Kennedy R, Cutter G, Fowler M, et al. Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical Trials. JAMA Open. 2018;1(7):e184080. doi: 10.1001/jamanetworkopen.2018.4080.

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