Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical Trials: A Meta-analysis.
Level 3 - non-randomized controlled study
Meta-analysis of non-randomized, observational comparisons (concomitant medication use vs non-use) within clinical trial datasets.
PubMed 30646339 · doi:10.1001/jamanetworkopen.2018.4080
What was done
Researchers analyzed data from a meta-database of 18 studies from the Alzheimer Disease Cooperative Study (ADCS) and Alzheimer Disease Neuroimaging Initiative (ADNI). They analyzed 10 studies with available data on concomitant cholinesterase inhibitor (ChEI) and memantine use and cognitive outcome measures. Annual rate of decline on the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) was estimated using linear mixed-effects models, and random-effects meta-analysis compared participants receiving ChEIs and memantine (alone or combined) with those receiving neither.
What was found
Across 10 studies comprising 2,714 participants (mean age 75.0 years, 58% female, 9% racial/ethnic minorities): - 906 (33.4%) received ChEIs alone - 143 (5.3%) received memantine alone - 923 (34.0%) received both - 742 (27.3%) received neither Meta-analysis demonstrated that participants receiving ChEIs or memantine had a significantly greater annual rate of decline on the ADAS-cog than those receiving neither medication (1.4 points/year; 95% CI, 0.1-2.7).
Why it matters
The difference in decline rate (1.4 points/year) is comparable in magnitude to the hypothesized effect sizes of novel treatments investigated in clinical trials. This suggests substantial confounding by indication, meaning concomitant medication use can bias trial outcomes and post hoc subgroup stratifications if not properly accounted for in trial design.
Limits
Medication exposure was non-randomized and observational, creating substantial risk of confounding by indication. Only 10 of the 18 studies in the meta-database had sufficient data for inclusion. Racial and ethnic minority representation was low (9%).
Cited by
- context A meta-analysis published in a JAMA journal by Dr. Richard Kennedy found that Alzheimer's patients taking cholinesterase inhibitor drugs experienced more rapid cognitive decline compared to matched non-users.