Donepezil for dementia due to Alzheimer's disease

Jacqueline Birks, Richard J Harvey
2006 The Cochrane library  
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
more » ... 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). ■ No difference in institutionalisation (RR=0.97 † , 95% CI 0.72-1.3) over 114 weeks. This conflicts with a previous drug company-sponsored trial indicating a significant delay in nursing home placement of about 21 months. 5 However, the sponsored trial was a non-randomised, open-label study with large potential for selection bias. The survival curves for AD2000 seem to indicate some gap at one year (Fig. 1), a potential 2-3 month delay in institutionalisation. This is consistent with many studies showing a 2-3 month delay in symptomatic progression, however this is not sustained and the overall rates at two years are similar. ■ No difference in progression to disability (RR=1.02, 95% CI 0.72-1.45) over 114 weeks. ■ There was a statistical difference in the functional score (as measured on the Bristol activities of daily living scale, BADLS) of about 1 point, out of a total of 60. Like the statistical difference in the mini-mental state examination, this difference was present by 24 weeks, but there was no further divergence (or convergence) of the curves with continued treatment. Neither of these score differences met previous, externally set criteria for clinical significance. ■ There was no difference in behavioural and psychological symptoms as measured by the neuropsychiatric inventory. * CI confidence interval † RR relative risk Knowledge about new drugs is usually limited to the experience of the carefully selected patients who participated in the clinical trials. A drug which satisfies short-term criteria of safety and efficacy may be less effective in the long term. The editorial by John Attia and Peter Schofield suggests that any benefits of donepezil may not be sustained, while Jeffrey Post and Mark Kelly say that cardiovascular diseasemay be emerging as a long-term adverse effect of antiretroviral therapy. To improve our knowledge of drug safety it is important to report adverse events, particularly to new drugs. Kerri Mackay explains what happens to your reports of adverse reactions. Amiodarone is a drug with many possible adverse reactions. Terry Campbell therefore advises on how to minimise the risk of serious adverse effects.
doi:10.1002/14651858.cd001190.pub2 pmid:16437430 fatcat:6nd7e2ebfnaudcb3ja3bl46my4