Acetylcholinesterase inhibitors for Alzheimer’s disease

The development of effective treatments for Alzheimer’s disease has been vigorously pursued over the past few decades. Most recent developments have focused on drugs which inhibit acetylcholinesterase and thus increase the availability of acetylcholine within the brain. In this week’s issue a pivotal clinical trial of rivastigmine shows, on average, modest benefits for older people with Alzheimer’s disease in cognition, clinical global assessment, and quality of life (as assessed by a carer) (p 633).¹ What does this add to the evidence for these cholinergic treatments?

The evidence to date is that treatments based on the cholinergic hypothesis are essentially symptomatic. No substantial data support the hypothesis that these medications modify the disease—that is, delay its progression. The first drug in this class to show a beneficial effect was tacrine. An early report of dramatic clinical response² was not confirmed, and documented hepatotoxicity³ severely curtailed its use. More recently developed drugs in this class have not, however, been troubled by this side effect.

A systematic review of tacrine did not find convincing evidence for improvement in behavioural disturbance or overall clinical condition,⁴ although some improvement was seen in the cognitive decline score on the Alzheimer’s disease assessment scale (ADAS-Cog), a common method for assessing cognition in this type of trial. A later systematic review using individual patient data supplied by the original investigators allowed more studies to be included, revealing benefits for both cognition and global clinical impression.⁵ This highlights the need to extract good quality data from all relevant studies if meta-analyses are to be meaningful. The size of the effect of differences for the cognitive outcome as measured by the ADAS-Cog was 2.1 points (95% confidence interval 1.4 to 2.8) for tacrine versus placebo over a treatment period of 12 weeks. The odds ratio for any improvement (minimal to marked) on the clinical global impression of change scale for the active group relative to placebo was 1.6 (1.2 to 2.1).

A systematic review of donepezil showed a significant improvement of 2.6 points (1.8 to 3.5) on the ADAS-Cog scale and an odds ratio of 2.4 (1.6 to 3.4) for clinical global impression for the lower dose of 5 mg/day versus placebo, for a treatment duration of 12-24 weeks.⁶ There was no evidence of improvement with donepezil on a patient rated quality of life scale, but decreased memory and lack of insight make such ratings problematic in patients with Alzheimer’s disease. In this week’s study of rivastigmine at the higher dose category the difference in changes on the ADAS-Cog after 26 weeks of treatment was 2.6 points (1.0 to 4.1) for the observed cases analysis but only 1.6 points (0.4 to 2.9) on the more conservative intention to treat analysis.¹ The odds ratio for showing any improvement on clinical global assessment was 2.4 (1.6 to 3.8) on the observed cases analysis. At the higher dose of rivastigmine, however, there were more withdrawals than on placebo and they appeared to be associated with cholinergic side effects including nausea, vomiting, diarrhoea, and abdominal pain.

What is the clinician to make of these modest improvements associated with acetylcholinesterase inhibitors in people with Alzheimer’s disease? Firstly the effect is modest but may be more prominent in some patients than others. Secondly, trials to date have focused on patients with mild to moderate disease. There is little evidence that these medications work in patients with either incipient dementia or advanced disease. Thirdly, concerns have been raised about how these modest increases in cognition and global impression translate into clinical effects that can be used in a total care package for people with dementia.⁷ In this week’s study there is at least some evidence of a modest improvement in carer rated quality of life, but an average change of 2.8 points in a scale with a mean disability score of 54 points does not appear dramatic. Future trials will benefit from the deliberations of the international working group on harmonisation of dementia drug guidelines,⁸ but at this stage pharmacoeconomic analysis of dementia drugs is in its infancy. Delays to institutionalisation or extreme dependency, as measured in another study,⁹ may be more appropriate end points for this type of analysis.

Clearly, the selection of patients and costs of these treatments raise complex issues. Those clinicians who elect to treat patients with these drugs are likely to pursue cautious therapeutic trials in highly selected patients. Clearly too, these symptomatic treatments for Alzheimer’s disease necessitate comprehensive assessment of people with Alzheimer’s disease and their carers. These assessment facilities may be as costly as the medications themselves but have the potential to provide better access to services and general support for people with dementia and their carers.

Papers p 633