MADRID – Donepezil appears to decrease the risk of death among patients with severe Alzheimer's disease by about 50% but may be dangerous for patients with vascular dementia, Dr. Lon Schneider said at the 10th International Conference on Alzheimer's Disease and Related Disorders.
“The unexpected benefit of donepezil means we should be looking at this drug more carefully for those with severe Alzheimer's,” said Dr. Schneider, professor of psychiatry, neurology, and gerontology at the University of Southern California, Los Angeles. “The magnitude of this effect implies that for every 41 such patients treated with donepezil, 1 death could be prevented.”
Conversely, he said, statistical variability among the vascular dementia trials indicates a potential for an increased risk of death as high as three times among vascular dementia patients taking the drug, which should alert physicians to be more cautious when prescribing it in that population.
Both risk analyses emerged as part of an ongoing Cochrane database review of mortality associated with the use of drugs approved for Alzheimer's disease.
The study was sparked by reports of increased death among patients with mild cognitive impairment taking galantamine (an almost fivefold increased risk compared with placebo), and by a recent phase III clinical trial of donepezil as a possible treatment for vascular dementia. In the phase III trial, there were 11 deaths in the active group, but none in the placebo group.
The review found no evidence of an overall increased risk of death for any of the cholinesterase inhibitors or memantine. The differences emerged only when the researchers stratified the results by disease type or severity. The four trials of donepezil in moderate to severe Alzheimer's showed a decreased risk of death in active patients compared with placebo. Two of the three trials of donepezil in vascular dementia showed an increased risk of death, while one showed a decreased risk.
“We can speculate that patients with vascular dementia have underlying cardiovascular disease which donepezil and other cholinesterase inhibitors may adversely affect,” Dr. Schneider said in an interview. “In patients with severe Alzheimer's who have the most severe cholinergic deficits, the drug may have beneficial effects on parasympathetic function, or may so substantially improve their levels of attention that they can be better cared for.”
Donepezil is not approved for vascular dementia or severe Alzheimer's, but Eisai Inc. has submitted a supplemental new drug application for use in severe Alzheimer's.
The conference was presented by the Alzheimer's Association.