PracticeUpdate Neurology February 2019

EDITOR’S PICKS 9

Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Clinical Trials of Alzheimer’s Disease JAMA Network Open

Take-home message • This study explored whether the concomitant use of cholinesterase inhibitors (ChEIs) and memantine among participants in clinical trials of Alzheimer’s disease impacted the trials’ cognitive outcomes. The researchers conducted a meta-analysis of 18 studies and estimated an annual rate of decline on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). Their analysis showed that study participants who received ChEls and/or memantine had a significantly greater annual rate of decline than participants receiving neither medication. Those taking memantine, with or without ChEIs, experienced a faster rate of decline than those taking only ChEIs or taking nei- ther medication. Notably, in later studies, just about all of the participants were taking ChEIs at study entry, and the majority were also taking memantine. • The concomitant use of medications for Alzheimer’s dis- ease among trial participants is associated with a rate of cognitive decline that can exceed the hypothesized effect of the interventions being investigated in a given clinical trial, and, unless that use is accounted for in trial design and in interpretation of trial results, it may be confounded with outcomes on the ADAS-cog. Moshe Ornstein MD

COMMENT By Irene Mace Hamrick MD, FAAFP, AGSF T his study examined nine randomized clinical trials and one observational study, with a total of 2714 participants with Alzheimer’s dementia (AD), who were enrolled in studies of new AD medications. In these studies, most patients were allowed to continue on their previous stable-dose demen- tia medications, and one-third was taking acetylcholinesterase inhibitors (AchEI), 5.4% memantine, one-third both, and 27.4% were taking neither. The ADAS-cog, a 70-point scale was the primary outcome, and showed a 1.5-point worsening of cogni- tion with the concomitant use of AchEI, and a 2-point worsening with the use of memantine compared with patients who were on neither. Although a 2-point difference is often used to define a significant therapeutic effect in AD clinical trials, one study showed that a 10% difference (7 points) is needed to for a clin- ically meaningful difference. 1 These medications have shown a statistical difference, leading to FDA approval, but very rarely have I seen clinical improve- ment in my patients. More recent studies support my clinical experience, and one Bayesian network meta-analysis of 142 studies, after an exhaustive review of the literature, demon- strated that cognitive enhancers in general have minimal effects on cognition. 2 The current study adds to our knowledge that more (demen- tia medicine) is not better. We should monitor our patients started on these dementia medications for side effects, includ- ing bradycardia, diarrhea, and weight loss. I usually stop these medications after a trial of 3 to 6 months and monitor for wors- ening of cognition. Rarely do my patients’ families or I see worsening, and then I restart them, monitoring for improvement. What may be equally important, is to stop medications that contribute to dementia, an effect that seems to be cumulative throughout life: benzodiazepines and anticholinergic meds. 3,4 References 1. Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease. Am Fam Physician 2011;83(12):1403-1412. 2. Tricco AC, Ashoor HM, Soobiah C, et al. Comparative effectiveness and safety of cognitive enhancers for treating Alzheimer’s disease: systematic review and network metaanalysis. J Am Geriatr Soc 2018;66(1):170-178. 3. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ 2014;349:g5205. 4. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 2015;175(3):401-407.

Dr. Hamrick is Associate Professor of Clinical Health Sciences in the Department of Family Medicine, University of Wisconsin, and Director of Geriatrics Services, Department of Family Medicine at the University of Wisconsin in Madison, Wisconsin.

Association of Concomitant Use of Cholinesterase Inhibitors or Meman- tine With Cognitive Decline in Alzheimer Clinical Trials: A Meta-Analysis. JAMA Netw Open 2018 Nov 02;1(7)e184080, RE Kennedy, GR Cutter, ME Fowler, LS Schneider www.practiceupdate.com/c/75573

VOL. 4 • NO. 1 • 2019