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20th March 2012
In a relatively small (n=295) randomised controlled trial of moderate-to-severe Alzheimer’s disease, continuing donepezil resulted in slower cognitive decline over 12 months than stopping donepezil. However, there was no clinically important improvement in activities of daily living. Switching to or adding memantine provided no advantages over continuing donepezil.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Action
Healthcare professionals should follow NICE guidance (TA 217) on prescribing cholinesterase inhibitors or memantine for Alzheimer’s disease. Donepezil, galantamine and rivastigmine are recommended as options for mild-to-moderate Alzheimer’s disease. Memantine is recommended as an option only for people with moderate Alzheimer’s disease who are intolerant of or have a contraindication to cholinesterase inhibitors, or those with severe Alzheimer’s disease. Treatment should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional or behavioural symptoms.
Where donepezil is continued, its clinical benefit should be reassessed on a regular basis. The results of this study may help prescribers assess the risks and benefits of treatment, when stopping donepezil and/or introducing memantine is being considered. Note that donepezil is not currently licensed for treatment of severe Alzheimer’s disease, and NICE does not specifically recommend its use for this severity.
What is the background to this?
Evidence for the efficacy of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) comes largely from clinical trials in mild-to-moderate dementia. There is insufficient evidence to differentiate between them in terms of clinical effectiveness. Evidence for memantine comes mainly from studies in moderate-to-severe Alzheimer’s disease. There is little evidence to help people decide whether or not to continue cholinesterase inhibitors in moderate-to-severe Alzheimer’s disease — regardless of whether or not memantine is prescribed.
What does this study claim?
This study investigated whether or not patients with moderate-to-severe Alzheimer’s disease, who were being considered for discontinuation of donepezil, would benefit from continued donepezil and/or starting memantine. .In all groups, mental ability declined, as assessed by the Standardized Mini-Mental State Examination (SMMSE), on average from scores of approximately 9 at the start of the study to 3–6 after 52 weeks.
Continuing donepezil over 12 months resulted in a statistically significant reduction in the decline of cognitive function in people with moderate-to-severe Alzheimer’s disease compared with discontinuation. The score on the SMMSE was 1.9 points higher (95% confidence interval [CI] 1.3 to 2.5) in patients continuing donepezil. This mean difference reached the pre-specified threshold for clinical importance (1.4 points). Donepezil was also associated with a statistically significantly lower Bristol Activities of Daily Living Scale (BADLS) score, i.e. less impairment. However, this mean difference (3.0 points, 95% CI 1.8 to 4.3) did not reach the pre-specified threshold for clinical importance (threshold 3.5 points).
Statistically significant differences in SMMSE or BADLS scores, suggesting less of a decline in cognitive and functional status, were seen between patients who received memantine and those that received ‘memantine placebo’. However, the benefits of adding memantine to donepezil over continuing donepezil or switching to memantine were not considered clinically important.
So what?
This study suggests that for patients living in the community with moderate-to-severe Alzheimer’s disease, continuing donepezil is effective in reducing the rate of cognitive decline compared with discontinuation. None of the drug treatments arrested the decline in cognition or functional status. The benefit achieved with donepezil and/or memantine was on average small in comparison with the overall decline in scores seen in patients generally. For example, in patients who continued donepezil, the improvement in cognitive function score (1.9 SMMSE points) relative to those who discontinued donepezil, was only about a third of the reduction in score (5.8 points) in those who discontinued donepezil and received placebo memantine.
According to NICE guidance, treatment with cholinesterase inhibitors should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional or behavioural symptoms. For patients who are gaining benefits from donepezil, this study provides some limited evidence to support its continuation rather than discontinuing it or switching to memantine in people with moderate-to-severe disease.
It is not possible to predict individual response, and some patients will gain more benefit than others from continuing donepezil. However, subgroup analysis according to severity suggests the possibility that benefit may have been greater and only clinically important for people with moderate (SMMSE scores 10–13) rather than severe dementia (SMMSE scores 5–9). Note that donepezil is not currently licensed for treatment of severe Alzheimer’s disease, and NICE does not specifically recommend its use for this severity. We also do not know if the benefits seen with donepezil in this study apply to other cholinesterase inhibitors (galantamine and rivastigmine).
Interpretation of results is limited by a number of factors. The study had difficulty in recruitment and fell short of its target numbers, thus reducing its statistical power to identify statistical significance. Of the 295 patients entering the study and randomised into one of the four treatment groups, only 218 completed follow-up and only 172 were eligible for per protocol analysis. The study was restricted to people living in the community and may not necessarily apply to the large number of people with moderate-to-severe Alzheimer’s disease who are living in residential or nursing homes.
Study details
Howard R, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. New Engl J Med 2012;366:893–903
Design: Double-blind, placebo-controlled, randomised controlled trial
Patients: 295 community-dwelling UK patients (planned sample size 430) with probable moderate or severe Alzheimer’s disease (SMMSE scores 5–13) who were already receiving donepezil for at least 3 months (10 mg for at least 6 weeks). Patients were only included if a change of drug treatment was being considered (i.e. stopping donepezil and/or introducing memantine).
Intervention and comparison: Patients were randomised into four groups to receive different combinations of active drugs and placebos. The groups received the following treatment plans for 52 weeks:
- continue on donepezil and begin taking a memantine placebo
- discontinue donepezil and begin taking a donepezil placebo alongside a memantine placebo
- discontinue donepezil and begin taking memantine alongside a donepezil placebo
- continue on donepezil and begin taking memantine.
The co-primary efficacy outcomes were SMMSE scores and BADLS scores. Clinically important differences between groups were specified as 1.4 and 3.5 points respectively. The primary analyses compared the differences in the groups of patients who received donepezil or memantine placebos.
Outcomes and results:
In all groups, mental ability declined as assessed by the SMMSE, on average from scores of approximately 9 at the start of the study to 3–6 after 52 weeks. Scores on the BADLS test of daily living increased from around 26–29 at the start of the study to 34–42 after 52 weeks.
Patients who continued donepezil scored on average 1.9 points higher (95% CI 1.3 to 2.5; p < 0.001) on the SMMSE compared with those who discontinued donepezil.
Patients who continued donepezil scored on average 3.0 points lower (95% CI 1.8 to 4.3, p < 0.001) on the BADLS compared with those who discontinued donepezil.
Although it may have been a chance finding, subgroup analysis suggested that the severity of dementia at enrolment influenced the effect of donepezil on cognitive function, with larger benefits seen in patients with moderate disease. The average difference in SMMSE scores between patients who continued donepezil and those who discontinued donepezil was 2.6 points (95% CI 1.5 to 3.7) in patients with an initial score of 10–13 and 1.3 points (95% CI 0.2 to 2.4)in patients with an initial score of 5–9.
Patients who received memantine had an SMMSE score on average 1.2 points higher (95% CI 0.6 to 1.8, p < 0.001) and a BADLS score that was 1.5 points lower (95% CI 0.3 to 2.8, p = 0.02) compared with those who received memantine placebo.
Patients who received memantine in addition to donepezil had an SMMSE score on average 0.8 points higher (95% CI –0.1 to 1.6, p < 0.07) and a BADLS score that was 0.5 points lower (95% CI –2.2 to 1.2, p = 0.57) compared with those who received placebo. In both cases the differences were not statistically significantly different.
Secondary outcomes included measures of behavioural and psychological symptoms, patient health-related quality of life and caregiver health status. No clinically important differences were seen between groups for these measures.
There was no evidence that serious adverse events or death differed between treatment groups (p < 0.77).
Sponsorship:
Funded by the Medical Research Council and the Alzheimer’s Society.
More information on dementia can be found within the CNS and mental health NPC e-learning materials and on NHS Evidence
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