Donepezil treatment in severe Alzheimer's disease: a pooled analysis of three clinical trials.
OBJECTIVE
Individual clinical trials have demonstrated benefits of donepezil in patients with severe Alzheimer's disease (AD). Data were pooled from three randomized, placebo-controlled trials of donepezil for severe AD to further evaluate treatment effects and overall tolerability/safety.


METHODS
Total scores and sub-scores were analyzed for measures of cognition, global function, function, and behavior. Additional analyses were performed to investigate (1) relationships between cognitive, functional, and behavioral changes, and (2) patterns of combined domain response.


RESULTS
Using pooled total scores, significant treatment differences at endpoint in favor of donepezil were observed for cognition, global function (both p < 0.0001), and function (p = 0.03), with an effect size (Cohen's d) of 0.51, 0.26, and 0.17, respectively. There was no significant treatment difference for behavior. However, donepezil-treated patients with stabilized/improved cognition tended to show significant improvements in function and behavior over placebo-treated patients. Patients treated with donepezil were 2-3 times more likely to achieve a combined domain response than placebo-treated patients (p < 0.0001). Adverse events were as expected for cholinergic therapy, and mortality rates were similar between the treatment groups.


CONCLUSIONS
These findings suggest measurable donepezil-mediated symptomatic benefits in cognition, global function, and daily living activities in patients with severe AD. The treatment effects support the importance of cholinesterase inhibition as a clinically relevant therapeutic option across the spectrum of AD.
Winblad
Bengt
B
Department of NVS, Karolinska Institutet Alzheimer Disease Research Center, Huddinge, Sweden. bengt.winblad@ki.se
Black
Sandra E
SE
Homma
Akira
A
Schwam
Elias M
EM
Moline
Margaret
M
Xu
Yikang
Y
Perdomo
Carlos A
CA
Swartz
Jina
J
Albert
Kenneth
K
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000077265:Donepezil; D005260:Female; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D010919:Placebos; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index; D016896:Treatment Outcome
D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D010919:Placebos; D000077265:Donepezil