Donepezil: improved cognitive scores in CADASIL

Issue: April 2008

The off-label use of donepezil did not improve cognitive ability scores in patients with an early onset form of cardiovascular dementia, study results indicated.

Researchers from several sites in Europe and the United States examined the effects of donepezil (Aricept; Eisai, Pfizer), a drug used to treat Alzheimer’s disease, on the progression of a type of vascular dementia called cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Martin Dichgans, MD, professor of neurology at the University of Muenchen, Germany, presented the results at the 2008 International Stroke Conference in New Orleans.

Primary endpoint missed

Donepezil in Subcortical Vascular Cognitive Impairment: a Randomized Double Blind Trial in CADASIL included 168 patients. In one group, patients were randomly assigned to 10 mg of donepezil each day (n=86). Patients in a second group were randomly assigned to placebo (n=82). The researchers observed no statistically significant differences between donepezil and placebo regarding the primary study endpoint, defined as change from baseline in the score on Vascular-Alzheimer’s Disease Assessment Scale-cognitive subscale at 18 weeks.

Although the researchers observed no significant effects on the primary endpoint, they found a significant correlation between donepezil administration and several other secondary executive function tests. The cognitive tests included evaluations of time spent to complete certain tasks, color and word tests and an interview. Discontinuation of the medication due to adverse events occurred at a slightly higher rate in the donepezil group (11.6%) than in the placebo group (8.5%).

“The adverse events were more frequent in the donepezil group than in the placebo group,” Dichgans said. “They corresponded to the known spectrum of adverse events associated with cholinesterase inhibitors.”

Study limitations

In an editorial that accompanied the study’s simultaneous ahead-of-print publication in The Lancet Neurology, Lon S. Schneider, MD, of the University of Southern California Keck School of medicine, said that the study population might not have been the sample the researchers hoped they had garnered.

“Half of the outcomes measured, including the Vascular-Alzheimer’s Disease Assessment Scale-cognitive subscale (V-ADAS-cog), the [Mini-mental State Examination], clinical dementia rating (CDR) sum of boxes and activities of daily living scale, were more appropriate for patients with mild-to-moderate dementia who have orientation, memory and comprehension deficits,” Schneider wrote.

In concluding his editorial, Schneider said, “Dichgans and colleagues showed the feasibility of multicenter trials with patients with CADASIL and the therapeutic potential of cholinesterase inhibitors. In future trials, the sample selection should be reconsidered to define better the cognitive impairment syndrome to be treated, choose outcomes that reflect the deficits to be treated and identify the individual patients who benefit from treatment.”

“Donepezil had no treatment effect on the primary endpoint in this population of CADASIL patients who had cognitive impairment, although the clinical relevance of the noted improvements in certain executive functions is currently unknown,” Dichgans said. “We believe this trial has important implications for the design of future vascular dementia trials, and our results emphasize the need for focusing on etiological subgroups that further illustrate the need of using dedicated neuropsychological tests.” – by Eric Raible

Donepezil in Subcortical Vascular Cognitive Impairment

For more information:

Dichgans M. Alzheimer’s drug does not improve the cognitive ability score in hereditary vascular dementia. Session XIII. Presented at: the International Stroke Conference; Feb. 20-22, 2008; New Orleans.
Schneider LS. Does donepezil improve executive function in patients with CADASIL? Lancet Neurology. 2008;doi:10.1016/S1474-4422(08)70047-4.