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Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomized double-blind trial

Background: Previous studies have found that donepezil treatment produces small improvements in cognitive function in patients with Alzheimer’s disease (AD), but these effects may not persist over prolonged periods. Also, these benefits may not translate into functional and behavioral improvements and decreased caregiver burden.

Objective: This trial sought to determine if treatment with donepezil positively affects non-cognitive symptoms of AD. It also examined the effect of several patient characteristics including age, comorbidity, and the presence/absence of vascular dementia on the patients’ responses to the study medication. In addition, the authors evaluated the long-term efficacy and optimal dose of the medication.

Methods: To be included in this double-blind trial, patients had to meet the following criteria: DSM-IV diagnosis of AD with or without vascular dementia, not receiving a cholinesterase inhibitor, living in the community, helped by a regular caregiver, and no contraindications to donepezil. Five hundred sixty-five patients were randomized to receive either donepezil 5 mg daily or placebo in a 12-week run-in period. Subsequently, 486 patients were randomized to receive donepezil 5 mg daily, donepezil 10 mg daily, or placebo for 48 weeks (Phase 1). Patients completing Phase 1 were given the option to continue treatment for another 48 weeks (Phase 2) after a 6-week washout period. Patients opting for this and following phases received the same treatment regimen that they were given during the first phase. Two more 48-week treatment periods were carried out after Phase 2. Each of these last two phases was preceded by a 4-week washout period. One hundred five patients began donepezil treatment for Phase 2, and 89 patients received placebo. Thirty-one patients were administered the treatment medication in Phase 3, and 20 subjects received placebo. One subject was given donepezil in Phase 4, and 3 patients received placebo. Primary outcome measures were progression of disability and placement into institutional care. Secondary outcomes included presence and severity of psychological and behavioral symptoms, cognition, functional disability, progression to severe cognitive disability, death from AD, compliance, and safety in terms of serious adverse effects. The authors calculated more than a 90% power to detect at p<0.05 a six-month delay in institutionalization. The study had the same power to detect an effect size of 0.3 SD on the secondary outcome measures at any one timepoint and more than 95% power at p<0.01 to detect an effect averaging 0.3 SD with all timepoints. Data were handled according to the intent-to-treat approach.

Results: Five hundred eleven, 293, 111, and 20 subjects completed the 12-week run-in period, Phase 1, Phase 2, and Phase 3, respectively. Results were pooled for both donepezil groups, and the data were reported together unless otherwise noted. Rates of institutionalization (9% vs. 14% at 1 year, p=0.15; 42% vs. 44% at 3 years, p=0.4) of the treatment group compared with the control group were not statistically significant. However, progression of disability scores (Bristol Activities of Daily Living Scale [BADLS] scores) were an average of 1.0 points (0.5-1.6, p=0.0004) higher in the donepezil group at all timepoints after 12 weeks. Compared to placebo, donepezil treatment led to statistically significant improvements in cognitive ability (0.8 points higher on the mini-mental status examination, 95% CI 0.5-1.2, p<0.0001). No statistically significant differences were found between the treatment and control groups for any of the other secondary outcome measures, and no significant differences were noted between the two donepezil groups. The authors conclude that small benefits for cognition exist with donepezil treatment, but these improvements do not lead to a decrease in institutionalization, slowing of the progression of disability, or changes in any of the other outcome measures to a clinically significant extent. Also, they state that one cannot distinguish donepezil responders from non-responders on the basis of any of the characteristics that were assessed, and money spent on cholinesterase inhibitor therapy may be better spent in other areas.

Strengths: The local nursing coordinators making the assessments were trained in the use of the scales used to measure outcomes. Training should help these clinicians to appropriately and more uniformly assess the study’s participants. Also, the authors analyzed 11 patient characteristics and their possible effect on response to donepezil in an effort to determine which patients might benefit most from donepezil treatment. However, due to multiple analyses between groups, any findings may be unreliable.

Weaknesses: No washout period was allowed after the 12-week run-in period, and, as a result, some of the patients that received donepezil during the run-in period then placebo during the treatment phase may have had carry-over effects into the first treatment period. Also, no statistical analysis is shown for the comparison of the group characteristics at baseline. Therefore, it cannot be determined if any statistically significant differences actually existed between the groups. In addition, patients were allowed to receive any other treatments deemed appropriate by their individual physicians while participating in this trial, and variability of these treatments could affect patient scores for outcome measures and subsequently the study’s findings. Furthermore, as mentioned above, the data for both donepezil groups were combined. No analysis was performed between placebo and the individual doses of donepezil. Perhaps significant differences could be found between the 10 mg dose and placebo.

Conclusion: Several factors, as mentioned above, could affect the findings of this trial. Therefore, further studies may be necessary to reinforce this study’s results. Response to the medication may vary, but some patients will see beneficial effects, though possibly minimal, from donepezil. Because therapeutic options for AD are limited, donepezil is a definite option for patients looking for any improvement.

Michael Grimes, PharmD. Candidate