Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial

Summary

Background

Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long?

Methods

565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models.

Findings

Cognition averaged 0·8 MMSE (mini-mental state examination) points better (95% Cl 0·5–1·2; p<0·0001) and functionality 1·0 BADLS points better (0·5–1·6; p<0·0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0·4) or progression of disability (58% vs 59% at 3 years; p=0·4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0·97 (95% Cl 0·72–1·30; p=0·8); the relative risk of progression of disability or entering institutional care was 0·96 (95% Cl 0·74–1·24; p=0·7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil.

Interpretation

Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than Cholinesterase inhibitors are needed for Alzheimer's disease.

Introduction

650 000 people have dementia in the UK, of whom 400 000 have Alzheimer's disease.¹ Annual costs of dementia care are estimated to be £6·1 billion (US$11 billion; at 1998/99 prices), with £3·3 billion direct spending on health and social services.²

Degeneration of cholinergic basal forebrain neurons innervating the cortex is believed to contribute substantially to cognitive deficits seen in Alzheimer's disease.³ This discovery triggered development of Cholinesterase inhibitors, which aim to raise acetylcholine levels in the brain by blocking the enzymes that metabolise this molecule. Donepezil was the first such drug to be licensed in the UK, in March 1997, followed by rivastigmine and galantamine.

Findings of randomised controlled trials have shown reliably that all three drugs produce similar small improvements on cognitive tests and global measures of change in selected patients with mild to moderate Alzheimer's disease over 3–12 months.4, 5, 6 Improvements in functionality and behaviour have been shown less reliably, and little information is available on the long-term effectiveness of Cholinesterase inhibitors or their usefulness in people with severe disease. Benefits in health-related quality of life have not been shown. Effectiveness in patients with an admixture of pathological findings remains unclear, but similar activity has been reported in vascular dementia⁷ and dementia with Lewy bodies.⁸

Cognitive improvements seem marginally higher with 10 mg donepezil than with 5 mg,⁴ although pharmacological studies predict little difference between doses.⁹ Cholinergically mediated gastrointestinal side-effects of Cholinesterase inhibitors are, however, clearly dose-dependent.¹⁰ Differential toxicity has led to large imbalances in the proportions of patients in active and placebo groups with missing outcome assessments in trials of Cholinesterase inhibitors,¹¹ which potentially introduces bias into effect-size calculations.⁴ To avoid bias, clinical trials must be randomised, double-blind, and the outcome of all patients analysed on an intention-to-treat basis.¹² If outcome data are missing, true intention-to-treat analyses cannot be undertaken.¹³

Alzheimer's disease is a complex multifaceted disorder and, for example, cognitive and functional decline may result from separate processes of disease progression.¹⁴ As a result, concern has been expressed that the small benefits seen on simple cognitive function tests (an average 3-point advantage over placebo on the 70-point ADAS-cog scale [see panel for list of definitions]) might not be associated with worthwhile clinical and social benefits, and insufficient objective clinical trial evidence is available to establish clinical usefulness and cost-effectiveness.15, 16, 17 Health-care purchasers have therefore questioned the value of cholinesterase inhibitors in the face of strong demand from clinicians and patients.¹⁸ The UK National Institute for Clinical Excellence (NICE) appraised cholinesterase inhibitors, recommending in 2001 that the drugs should be made available on the UK National Health Service (NHS) as one component of the management of people with mild to moderate Alzheimer's disease, with treatment continuing while there is clinical evidence of response.¹⁹ However, definition of response is difficult since assessment methods used in clinical trials and clinical practice have poor signal to noise ratios. Response to cholinesterase inhibitors is heterogeneous, with no reliable clinical or laboratory-based predictors available that would allow clinicians to focus treatment on patients with greater potential to derive worthwhile benefit.

By undertaking the AD2000 trial, we aimed to answer various questions that were highlighted by the NICE guidance. Does donepezil produce worthwhile improvements in non-cognitive and behavioural symptoms for typical patients with Alzheimer's disease? What is the optimal dose of donepezil? How long should treatment continue? Do clinical or genetic characteristics, or response to 12 weeks of treatment, predict which patients will benefit? The study included an integral health-economic assessment, and sought as complete as possible outcome ascertainment. A further aim of AD2000 was to establish whether aspirin—which is known to reduce the risk of stroke—might also produce moderate, but potentially worthwhile, benefits in Alzheimer's disease. The first results of the donepezil versus placebo comparisons are reported here. The aspirin results will be reported separately.