Elsevier

The Lancet

Volume 367, Issue 9516, 1–7 April 2006, Pages 1057-1065
The Lancet

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Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study

https://doi.org/10.1016/S0140-6736(06)68350-5Get rights and content

Summary

Background

The cholinesterase inhibitor donepezil is used to treat mild-to-moderate Alzheimer's disease. Its efficacy in severe dementia has not been assessed and is controversial. Our aim was to ascertain the effectiveness of donepezil in patients with severe Alzheimer's disease, by focusing primarily on cognition and activities of daily living.

Methods

We did a 6-month, double-blind, parallel-group, placebo-controlled study in 248 patients with severe Alzheimer's disease (mini mental state examination score 1–10) who were living in assisted care nursing homes ran by trained staff in Sweden. We assigned patients oral donepezil (5 mg per day for 30 days then up to 10 mg per day thereafter, n=128) or matched placebo (n=120). Our primary endpoints were change from baseline to month 6 in the severe impairment battery (SIB) and modified Alzheimer's Disease Cooperative Study activities of daily living inventory for severe Alzheimer's disease (ADCS-ADL-severe). We analysed outcomes for patients with data at baseline and at one or more other timepoints (modified intent-to-treat population) with last observation carried forward used to replace missing data.

Findings

95 patients assigned donepezil and 99 patients assigned placebo completed the study. Patients treated with donepezil improved more in SIB scores and declined less in ADCS-ADL-severe scores at 6 months after initiation of treatment compared with baseline than did controls (least squares [LS] mean difference, 5·7, 95% CI 1·5–9·8; p=0·008, and 1·7, 0·2–3·2; p=0·03, respectively). The incidence of adverse events was comparable between groups (donepezil 82% [n=105] vs placebo 76% [n=91]), with most being transient and mild or moderate in severity. More patients discontinued treatment because of adverse events in the donepezil group (n=20) than in the placebo group (n=8).

Interpretation

Donepezil improves cognition and preserves function in individuals with severe Alzheimer's disease who live in nursing homes.

Introduction

Individuals with Alzheimer's disease eventually develop severe dementia and as a result become further cognitively impaired. As their health deteriorates they become less able to communicate and less mobile, develop apraxia, agnosia, and neuropsychiatric symptoms, and need increasing amounts of nursing care. About 20% of patients with Alzheimer's disease have severe dementia.1 The cholinesterase inhibitors donepezil, galantamine, and rivastigmine stabilise or slow down progress in mild-to-moderate disease,2, 3, 4 but do not prevent eventual development of severe disease. Some specialists and treatment guidelines5 recommend discontinuation of cholinesterase inhibitors once a patient reaches this stage.

Results of studies of donepezil that have included patients with severe Alzheimer's disease are not consistent, since improvement in some variables (global function and cognition) but not all (behaviour and function) were noted in patients living in nursing homes,6 whereas there was effective management of cognitive, functional, and behavioural symptoms in those living in the community.7 Co-administration of the N-methyl-D-aspartate receptor antagonist memantine with donepezil further slows cognitive and functional deterioration in patients with moderate-to-severe Alzheimer's disease.8 As a monotherapy, memantine has positive effects on global function and cognition in individuals with moderate-to-severe Alzheimer's disease9 and on global function in severe Alzheimer's disease.10 Our aim was to assess the effect of donepezil on cognition and activities of daily living in patients with severe Alzheimer's disease living in nursing homes ran by trained staff.

Section snippets

Patients

Between October, 2002, and October, 2004, we did a double-blind, parallel-group, placebo-controlled study in patients living in 50 assisted-care facilities (nursing homes run by trained staff) in Sweden. Our inclusion criteria were age 50 years or older, ability to walk alone or with help, a mini mental state examination (MMSE)11 score of 1–10, and a functional assessment staging (FAST) rating of stage 5 (requires assistance in choosing proper clothing) to 7c (non-ambulatory—unable to walk

Results

Of the 334 patients screened, we randomised and treated 248 (figure 1). There were no notable differences between the groups with respect to their demographic or psychometric characteristics at baseline (table 1). 95 patients assigned donepezil and 99 controls completed the study. The median duration of treatment with donepezil was 176 days (range 2–231) and with placebo 180 days (5–218). Mean daily doses of donepezil and placebo for the safety population were 8·2 mg (SD 1·5) and 8·4 mg (1·2),

Discussion

Our findings indicate that donepezil can improve cognition and preserves function in patients with severe Alzheimer's disease. The data presented lend support to the neurobiological premise that cholinergic deficits in the brain of people with severe Alzheimer's disease can be, at least in part, alleviated by cholinesterase inhibitors.22 Our patients had not received cholinergic inhibitor therapy for 3 months before study entry and for the most part had a limited exposure to such agents during

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