Clinical Question: Are cholinesterase inhibitors effective in patients with Alzheimer’s disease?

Setting: Various (meta-analysis)

Study Design: Meta-analysis (randomized controlled trials)

Synopsis: Three medications for Alzheimer’s disease work by inhibiting cholinesterase: donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). The authors of this meta-analysis combined the results of 22 randomized controlled trials evaluating the drugs’ effects on clinical outcomes. The research was identified by searching three databases for studies in any language. Three researchers independently selected studies on the basis of predetermined criteria. Many of the studies were of poor quality; the most common problem was that the results were not analyzed by intention to treat, which can inflate the evidence of benefit. Most studies evaluated patients using the Alzheimer’s Disease Assessment Scale-Cognitive subscale, which uses scores ranging from zero (no impairment) to 70 (very severe impairment). For all three medications, the differences between the treatment and placebo groups were 1.5 to 3.9 points. In 12 trials, effectiveness also was measured using the Clinician’s Interview-Based Impression of Change; the scores were not significantly different between treatment and placebo groups. One study used a measure of cognitive decline and showed an average of five months’ delay with donepezil compared with placebo before a clinically evident functional decline was noted.

Bottom Line: The evidence supporting the effectiveness of cholinesterase inhibitors is based on exceedingly small effects found in poorly analyzed studies. Studies of Alzheimer’s drugs need to be scrutinized carefully for methodologic errors that inflate the appearance of benefit. (Level of Evidence: 1a)