What now for Alzheimer's disease? An epidemiological evaluation of the AD2000 trial

Abstract

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 placebocontrolled trials showing a statistically significant improvement in cognitive, functional and behavioural scores mainly at 12 and 24 weeks. 1,2,3 The questions now are whether this statistical difference translates into a clinically meaningful difference and whether treatment is cost-effective. The AD2000 trial 4 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:■ is the only trial to look at end points beyond one year ■ focuses primarily on clinical end points such as time to institutionalisation or progression to disability ■ includes measures of caregiver burden (as a secondary outcome)■ enrolled a broader spectrum of patients than those typically included in trials sponsored by drug companies.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:■ A difference in the 30-point mini-mental state examination of 0.8 points (95% CI 0.5-1.2*) between the treatment and placebo groups at two years. This is about half the treatment effect previously seen at one year in other trials (1.8 points, 95% CI 0.5-3.2). Amiodarone is a drug with many possible adverse reactions.Terry Campbell therefore advises on how to minimise the risk of serious adverse effects.