Objective: The objective of these analyses was to evaluate the safety and tolerability of the acetylcholinesterase inhibitor, donepezil (5 or 10 mg/day), versus placebo in vascular dementia (VaD) patients.
Background: VaD is the second most common form of dementia after Alzheimer's disease (AD). Studies indicate that, similar to AD patients, VaD patients may benefit from treatment with donepezil. VaD is frequently observed following stroke and these patients also exhibit high rates of cardiovascular disease, therefore a good tolerability profile is particularly desirable for VaD therapies.
Design: Combined analyses of safety and tolerability data from two 24-week, randomized, double-blind, placebo-controlled, parallel-group studies in patients with probable or possible VaD.
Materials and Methods: All patients had a diagnosis of VaD of >3 months’ duration (according to NINDS-AIREN criteria). Patients with a prior diagnosis of AD and subsequent cognitive impairment due to stroke or other cerebrovascular disease were excluded. Incidences of adverse events were compared across placebo and donepezil (5 or 10 mg/day) groups.
Results: 1219 VaD patients were enrolled in these two studies (donepezil 10 mg/day, n=421; donepezil 5 mg/day, n=406; placebo, n=392). A high proportion of patients (90%) had comorbid cardiovascular disease, including associated atherosclerosis (50%) and angina/myocardial infarction (29%). Almost all patients (99%) received concomitant medications, such as antithrombotics (83%), diuretics (31%), and calcium channel blockers (31%). The proportion of patients with AEs in each group were similar: donepezil 10 mg/day, 93%; donepezil 5 mg/day, 90%; and placebo, 88%. Withdrawals due to AEs were low: donepezil 10 mg/day, 19%; donepezil 5 mg/day, 11%; and placebo, 10%. Mortality rate (~1-2%) did not differ among treatment groups. The incidences of cardiovascular AEs were similar in donepezil- and placebo-treated VaD groups (reported by 20% of patients in both donepezil groups and in the placebo group). The incidences of cerebrovascular AEs were low, and were not significantly different in placebo- and donepezil treated VaD groups. Importantly, bradycardia (2% in each treatment group) and syncope (2-5%) did not differ significantly among treatment groups. The two most common AEs in donepezil-treated patients were diarrhea (donepezil 10 mg/day, 17%; donepezil 5 mg/day, 14%; and placebo, 10%) and nausea (donepezil 10 mg/day, 16%; donepezil 5 mg/day, 10%; and placebo, 7%). Most AEs were mild to moderate in intensity, and were considered unrelated to treatment in the majority of cases.
Conclusion: The most commonly reported AEs were generally related to the gastrointestinal system, and were consistent with donepezil’s cholinomimetic effect. These results demonstrate that despite high levels of cardiovascular and cerebrovascular disease, and the many concomitant medications taken by these VaD patients, donepezil was well tolerated and appears to be safe in this fragile population.
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