Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size

Abstract

Background and purpose: 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.

Figure 1

Decision tree for classifying patients as having possible vs probable VaD. CT indicates computed tomography; CVD, cardiovascular disease; and NINDS-AIREN, National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences.

Figure 2

Flowchart of patients excluded from the study and included patients randomized to active treatment with 5 mg/d donepezil or placebo. TIA indicates transient ischemic attack. *Patients might have >1 reason for screen failure, and some patients were screened more than once. ^†Twenty-five patients were excluded from the ITT population because they did not have a baseline assessment in addition to at least 1 postbaseline assessment for at least 1 of the primary efficacy variables. ^‡Eleven patients died during the study (all in the donepezil group).

Figure 3

Primary outcome measures in donepezil and placebo patients. A, V-ADAS-cog least-squares (LS) mean change from baseline; B, CIBIC-Plus overall change at end point. C, V-ADAS-cog LS mean change from baseline for patients with Scheltens’ score <2. D, V-ADAS-cog LS mean change from baseline for patients with Scheltens’ score ≥2. CMH indicates Cochran-Mantel-Haenszel; LOCF, last observation carried forward.