Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size.
OBJECTIVE
We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria.


METHODS
This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N=974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale and Clinician's Interview-Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method.


RESULTS
Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale (least-squares mean difference, -1.156; 95% CI, -1.98 to -0.33; P<0.01) but not on the Clinician's Interview-Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7%), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group.


CONCLUSIONS
Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.
Román
Gustavo C
GC
Alzheimer Center, Methodist Neurological Institute, 6560 Fannin Street, Suite 802, Houston, TX 77030, USA. GCRoman@tmhs.org
Salloway
Stephen
S
Black
Sandra E
SE
Royall
Donald R
DR
Decarli
Charles
C
Weiner
Michael W
MW
Moline
Margaret
M
Kumar
Dinesh
D
Schindler
Rachel
R
Posner
Holly
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003071:Cognition / Q000187:drug effects*; D015140:Dementia, Vascular / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging*; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D009929:Organ Size; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011859:Radiography
D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil
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