Alzheimer’s disease is a large and increasing public health problem. Because the cognitive deficits of the disease are thought to result from degeneration of cholinergic basal fore-brain neurons, therapy with cholinesterase inhibitors was developed to raise acetylcholine levels in the brain. Randomized controlled trials of three to 12 months of therapy in selected patients with mild to moderate Alzheimer’s disease have demonstrated small improvements in cognitive function. However, the effects on behavior and function have been inconsistent, and long-term benefits and effects on quality of life have not been established. The AD2000 Collaborative Group undertook a large multicenter trial of the long-term benefits of donepezil in Alzheimer’s disease.
The study included more than 500 patients referred to a memory clinic in the West Midlands region of England. All patients met the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., criteria for Alzheimer’s-related dementia, lived in the community, had a regular caretaker and no contraindications to donepezil, and were not already taking a cholinesterase inhibitor. During the initial 12 weeks of the study, 282 patients were randomly assigned to 5 mg donepezil per day, and 283 received an identical placebo. Of the 511 patients who completed this phase, 486 were re-randomized to receive 5 or 10 mg of donepezil daily (242 patients) or placebo (244 patients). After 48 weeks of treatment, all patients had a six-week washout phase during which no active anti-Alzheimer’s therapy was given. Patients were then free to continue their previous therapy for another 48 weeks. After a further four-week washout period, one more 48-week treatment period was offered. During the study, all other treatments were continued at the discretion of the patient’s usual physician. The primary endpoints were admission to institutional care and changes in scores on the Bristol Activities of Daily Living Scale (BADLS) of functional activity. Other outcomes included behavioral and psychologic symptoms or signs of dementia, cognitive function (as measureed by the Mini-Mental State Examination [MMSE]), psychologic well-being of the principal care-giver, death attributed to Alzheimer’s disease, adverse effects of therapy, and compliance with therapy. The study also included an economic evaluation to ascertain the cost-effectiveness of donepezil therapy.
The treatment groups remained well balanced throughout the study in terms of comorbidities, severity of dementia, medications, and other relevant variables. During the run-in period, significantly more patients allocated to donepezil dropped out compared with the control group (30 compared with 13). Three of the placebo and 17 of the donepezil patients attributed discontinuation to side effects. This trend continued after 13 weeks, with 7 percent of the donepezil group and 3 percent of the placebo group withdrawing from the study because of side effects.
The rates of institutionalization and progression of disability at one and three years were not significantly different in the treatment and placebo groups, and no significant differences could be detected in behavioral and psychologic symptoms. Over the first two years, treated patients scored an average of one point higher than control patients on the BADLS and 0.8 points higher on the MMSE, but the clinical significance of these differences is unclear, especially because of the greater dropout rate in the donepezil group. Serious adverse events were detected in 29 patients taking donepezil and 23 taking placebo. The number of deaths and the proportion of deaths attributed to dementia were comparable in the two groups. No significant differences were detected between the groups in caregiver psychopathology or health care costs.
The authors conclude that the small improvements in cognition and function detected over two years were not reflected in rates of institutionalization, disability, or benefits to caregivers. Donepezil was not a cost-effective therapy for Alzheimer’s dementia.
editor’s note: How could the results of this study influence care of older patients with Alzheimer’s disease and the advice physicians give to families? The task is to provide objective information and guidance without destroying hope. This study appears to contradict several previous studies and meta-analyses that indicated improvement in function and delay in institutionalization with cholinesterase-inhibitor therapy.1,2 Careful reading reveals that almost all published studies show small improvements (or delay in deterioration) in outcomes, despite differences in patient selection, study design, and outcome measures. The controversy concerns the implications of these benefits—do they make meaningful differences for patients and are they worth the human and financial costs? Particular care is needed in applying this British study to U.S. patients. The factors influencing the decision to institutionalize may be different between the two countries because of significant differences in health care systems, availability of community services, and societal expectations of the appropriate care of persons with dementia. All studies agree that there is a need for effective, safe, acceptable, and affordable therapies for dementing illnesses.—a.d.w.