Donepezil

Black S, Roman GC, Geldmacher DS, et al; Donepezil 307 Vascular Dementia Study Group. Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial Stroke 2003; 34:2323-2332.

* BACKGROUND

Donepezil provides some benefits in cognition, global function, and activities of daily living for patients with mild to moderate dementia from Alzheimer disease. There has been no conclusive evidence of similar beneficial effects of cholinergic agents in vascular dementia.

* POPULATION STUDIED

The researchers studied an international group of men and women (n=603), average age 74 years, with Mini-Mental State Examination (MMSE) scores between 10 and 26 (out of a possible 30) and radiographic abnormalities consistent with cerebrovascular disease. Patients were classified as having probable vascular dementia (70%) or possible (30%) vascular dementia according to criteria of the National Institute of Neurologic Disorders and Stroke.

Patients were excluded if they had neuro-degenerative disorders, Alzheimer dementia, new strokes, psychiatric disorders including major depression, or other serious medical conditions.

* STUDY DESIGN AND VALIDITY

This was a 24-week, double-blind, randomized (masked allocation) study. Patients received single daily doses of donepezil (5 or 10 mg) or matching placebo. Researchers performed psychometric evaluations, physical and neurological examinations, laboratory determinations, and measurements of vital signs at screening, baseline, and (together with checks for medication compliance and adverse events) at weeks 6, 12, 18, and 24.

The groups were similar in baseline characteristics. Researchers analyzed the subjects in the groups to which they were assigned (intention-to-treat analysis). A total of 79% of patients completed the entire study; dropout rates and reasons for doing so were equal in the placebo and 5-mg groups, but increased in the 10-mg group due to larger numbers of adverse events. Most of the patients were from the US and Canada, with a smaller proportion from other countries. The results are likely generalizable to primary care practice. (Level of evidence: 2b)

* OUTCOMES MEASURED

The primary efficacy outcome measured was cognition as assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinician's Interview-Based Impression of Change-Plus version (CIBIC-plus). Secondary efficacy endpoints were based on the MMSE, the Sum of the Boxes of the Clinical Dementia Rating (CDRSB), and the Alzheimer's Disease Functional Assessment and Change Scale (ADFACS).

* RESULTS

While the donepezil-treated groups showed statistically significant improvement as measured by the ADAS-cog (2 points improvement vs no change in placebo group), as many patients got worse as got better as measured by the CIBIC-plus. MMSEs improved by 1.04 [+ or -] 0.21 (P<.05) and 1.49 [+ or -] 20 (P<.001) points in the 5- and 10-mg groups, respectively, compared with 0.39 [+ or -] 0.23 in the placebo group. Activities of daily living did not deteriorate as much in the treatment groups--0.64 [+ or -] 0.36 (P<.05) for the 5-mg group and 0.53 [+ or -] 0.38 (P<.05) for the 10-mg group, compared with 1.44 [+ or -] 0.42 for placebo.

Adverse events were similar to placebo in the 5-mg group (22%) but double in the 10-mg group (44%). The most common side effects included nausea, diarrhea cramps, anorexia, vomiting, headache, and abnormal dreams.

* PRACTICE RECOMMENDATIONS

Donepezil (Aricept--a potent acetylcholinesterase inhibitor) had small effects on mentation for patients with mild to moderate vascular dementia as measured by validated instruments of cognition.

Donepezil's side effects are similar to placebo at 5 mg but double at 10 mg, with no improvement in the patient's cognition. Even though this medication was minimally effective, there are no other highly effective medical treatments for vascular dementia. Therefore, if a patient chooses a trial of donepezil, the lower, 5-mg dose should be offered.

The medication's effect is likely a class effect and not an individual drug effect; therefore, rivastigmine (Exelon) and galantamine(Reminyl) are 2 other acetylcholinesterase inhibitors that should also be considered. Cost is similar for all 3 drugs at about $130.00 per month.

Kenneth H. Johnson, DO, Family Practice Residency Program, Eastern Maine Medical Center Bangor Maine. E-mail: Kjohnson@ernh.org.

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