What now for Alzheimer's disease? An epidemiological evaluation of the AD2000 trial
- John Attia, Peter Schofield
- Aust Prescr 2005;28:134-5
- 1 December 2005
- DOI: 10.18773/austprescr.2005.100
In recent years, acetylcholinesterase inhibitors have been approved for the treatment of Alzheimer's disease. This has been mainly on the strength of many randomised placebo-controlled trials showing a statistically significant improvement in cognitive, functional and behavioural scores mainly at 12 and 24 weeks.123 The questions now are whether this statistical difference translates into a clinically meaningful difference and whether treatment is cost-effective. The AD2000 trial4 sheds light on this question.
This placebo-controlled trial of donepezil was not sponsored by a drug company. The trial has many strengths as it:
The drawbacks of the trial were that recruitment was slower and smaller than planned (566 versus 3000 patients). It had a complex design (multiple treatment phases and washout periods) and a large withdrawal rate. This makes a true intention-to-treat analysis difficult, however, the overall effect of these factors is to bias away from the null, that is to overstate the effect size. With this caveat in mind, the results show:
So what can we say in summary? This trial once again highlights the importance of independent trials that enrol a representative patient population. Previous work shows that industry-sponsored studies tend to have more favourable results than non-industry studies.67 This may be a consequence of inclusion and exclusion criteria that are very tightly defined and implemented. After the initial wave of favourable, mainly company-sponsored, results using cognitive and behavioural scales, AD2000 suggests that these changes in scores do not translate into clinically important or cost-effective changes. It is also evident that most of the relative improvement in scores occurs in the first six months. Prolonged use does not continue to improve scores, although it is unclear whether this is needed to maintain the benefit or if stopping will accelerate the patient's decline.
Dr Schofield has received honoraria from Pfizer for lectures and consultancy.
While this article was under review, another study looking at the effect of donepezil and vitamin E on cognitive impairment was published with three-year outcomes (Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-88). The results of this study are very similar to those of the AD2000 trial, that is, although there may be some mild protective effect at one year, this is not sustained at longer time points.</
Associate Professor, Clinical Epidemiology, Centre for Clinical Epidemiology and Biostatistics, University of Newcastle
Clinical Director, Neuropsychiatry Service, Hunter Area Health and Conjoint Associate Professor of Psychiatry, University of Newcastle, Newcastle, New South Wales