Cholinesterase Inhibitor Discontinuation in Patients With Alzheimer's Disease: A Meta-Analysis of Randomized Controlled Trials

Objective: This meta-analysis examined the effects of cholinesterase inhibitor (ChEI) discontinuation in patients with Alzheimer’s disease (AD).

Data Sources: Electronic records up to March 2014 were searched from MEDLINE, Embase, PsycINFO, Cochrane Library, Allied and Complementary Medicine Database, and Cumulative Index to Nursing and Allied Health Literature. Search terms included Alzheimer’s disease and cholinesterase inhibitors, plus discontinuation or cessation or tapering or withdrawal. There were no language limits.

Study Selection: Randomized, double-blind, placebo-controlled studies investigating the effect of ChEI discontinuation on patients with AD according to standardized criteria (eg, National Institute of Neurologic and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association, DSM-IV) and presenting measurable results of neuropsychological testing were included.

Data Extraction: Demographics, setting, ChEI treatment length, discontinuation protocol, follow-up duration, study outcomes, and dropouts during the double-blind phase were extracted.

Results: Of 1,430 records returned, 18 were reviewed. Five ChEI discontinuation randomized controlled trials (N = 321 continued and N = 332 discontinued, following patients for 1.5-24 months) were analyzed. Discontinued patients demonstrated a significant worsening of cognition (standard mean Mini-Mental State Examination difference: −0.29 [95% CI, −0.45 to −0.13], N = 300 continued/307 discontinued, P < .001), a significant worsening of neuropsychiatric symptoms (standard mean Neuropsychiatric Inventory difference: −0.32 [−0.51 to −0.12], N = 199/211, P = .001), and significantly higher dropout rates (risk ratio [RR] = 1.33 [1.11-1.59], N = 321/332, P = .002) compared to those who continued. No difference in adverse events was observed (RR = 1.01 [0.85-1.20], N = 314/326, P = .92).

Conclusions: ChEI discontinuation may have negative effects on cognition and neuropsychiatric symptoms, a finding corroborated by a higher incidence of trial dropout.