The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease.
OBJECTIVE
To provide an update review of the best quality evidence for the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine for mild to moderately severe Alzheimer's disease (AD) and of memantine for moderately severe to severe AD.


METHODS
Electronic databases, experts in the field and manufacturer submissions to the National Institute for Health and Clinical Excellence (NICE).


METHODS
A systematic review of the literature and an economic evaluation were undertaken. The quality of included randomised controlled trials (RCTs) was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. An outline assessment of economic evaluations was undertaken using a standard checklist. The clinical and cost-effectiveness data were synthesised through a narrative review with full tabulation of the results of included studies. Where appropriate, meta-analysis of data was undertaken.


RESULTS
For mild to moderately severe AD, the results of the study suggested that all three treatments were beneficial when assessed using cognitive outcome measures. Global outcome measures were positive for donepezil and rivastigmine, but mixed for galantamine. Results for measures of function were mixed for donepezil and rivastigmine, but positive for galantamine. Behaviour and mood measures were mixed for donepezil and galantamine, but showed no benefit for rivastigmine. For memantine, two published RCTs were included; in one of these trials the participants were already being treated with donepezil. The results suggest that memantine is beneficial when assessed using functional and global measurements. The effect of memantine on cognitive and behaviour and mood outcomes is, however, less clear. Literature on the cost-effectiveness of donepezil, rivastigmine and galantamine was dominated by industry-sponsored studies, and studies varied in methods and results. Of the three UK studies, two report donepezil as not cost-effective, whereas a third study reports an additional cost (1996 pounds sterling) of between 1200 pounds sterling and 7000 pounds sterling per year in a non-severe AD health state (concerns over these estimates are raised, suggesting that they may underestimate the true cost-effectiveness of donepezil). Cost-effectiveness analysis undertaken in this review suggests that donepezil treatment has a cost per quality-adjusted life-year (QALY) in excess of 80,000 pounds sterling, with donepezil treatment reducing the mean time spent in full-time care (delays progression of AD) by 1.42-1.59 months (over a 5-year period). From four published cost-effectiveness studies, two UK studies report additional costs associated with rivastigmine treatment. Cost-effectiveness analysis undertaken in the current review suggests that rivastigmine treatment has a cost per QALY in excess of 57,000 pounds sterling, with rivastigmine treatment reducing the mean time spent in full-time care (delays progression) by 1.43-1.63 months (over a 5-year period). From five published cost-effectiveness studies, one UK study reports a cost per QALY of 8693 pounds sterling for 16-mg galantamine treatment and 10,051 pounds sterling for 24-mg galantamine treatment (concerns raised suggest that this may underestimate the true cost-effectiveness of galantamine). Cost-effectiveness analysis undertaken in the present review suggests that galantamine treatment has a cost per QALY in excess of 68,000 pounds sterling, with galantamine reducing the time spent in full-time care (delays progression) by 1.42-1.73 months (over a 5-year period). From two published cost-effectiveness studies, one reports analysis for the UK, finding that memantine treatment results in cost savings and benefits in terms of delaying disease progression (concerns raised suggest that this may underestimate the true cost-effectiveness of memantine). In the current review, the cost-effectiveness of memantine has not been modelled separately, but where alternative parameter inputs on the cost structure and utility values have been used in a reanalysis using the industry model, the cost-effectiveness is reported at between 37,000 pounds sterling and 52,000 pounds sterling per QALY, with this alternative analysis still based on what is regarded as an optimistic or favourable effectiveness profile for memantine.


CONCLUSIONS
Although results from the clinical effectiveness review suggest that these treatments may be beneficial, a number of issues need to be considered when assessing the results of the present review, such as the characteristics of the participants included in the individual trials, the outcome measures used, the length of study duration, the effects of attrition and the relationship between statistical significance and clinical significance. Many included trials were sponsored by industry. For donepezil, rivastigmine and galantamine, the cost savings associated with reducing the mean time spent in full-time care do not offset the cost of treatment sufficiently to bring estimated cost-effectiveness to levels generally considered acceptable by NHS policy makers. It is difficult to draw conclusions on the cost-effectiveness of memantine; it is suggested that further amendments to the potentially optimistic industry model (measure of effect) would offer higher cost per QALY estimates. Future research should include: information on the quality of the outcome measures used; development of quality of life instruments for patients and carers; studies assessing the effects of these interventions of durations longer than 12 months; comparisons of benefits between interventions; and research on the prediction of disease progression.
Loveman
E
E
Southampton Health Technology Assessments Centre, Wessex Institute for Health Research and Development, University of Southampton, UK.
Green
C
C
Kirby
J
J
Takeda
A
A
Picot
J
J
Payne
E
E
Clegg
A
A
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology; D003362:Cost-Benefit Analysis; D000077265:Donepezil; D015259:Dopamine Agents / Q000008:administration & dosage / Q000191:economics*; D019317:Evidence-Based Medicine; D005260:Female; D005702:Galantamine / Q000008:administration & dosage / Q000191:economics*; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000191:economics*; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000191:economics*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000191:economics*; D018697:Nootropic Agents / Q000008:administration & dosage / Q000191:economics*; D048448:Phenylcarbamates / Q000008:administration & dosage / Q000191:economics*; D010880:Piperidines / Q000008:administration & dosage / Q000191:economics*; D000068836:Rivastigmine; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology
D015259:Dopamine Agents; D007189:Indans; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D048448:Phenylcarbamates; D010880:Piperidines; D005702:Galantamine; D000077265:Donepezil; D000068836:Rivastigmine; D008559:Memantine