02 Aug 2007

The acetyl cholinesterase inhibitor donepezil is one of only four FDA-approved drugs available for treating Alzheimer disease symptoms. Soon after its initial approval for mild to moderate AD in 1996, some physicians began prescribing the drug to patients with severe dementia, and the FDA finally approved that use last year. But despite FDA approval and the widespread use of donepezil in patients with severe dementia, the benefits of such treatment have remained somewhat questionable (see ARF related news story). Now, results of another randomized clinical trial of donepezil for severe AD seem to confirm earlier findings that while the drug helps with cognition and global function, it has no significant effect on activities of daily living.

Writing in the July 31 Neurology, Sandra Black, University of Toronto, and colleagues (including employees of the trial sponsors, Eisai and Pfizer), report the results of a 24-week randomized clinical trial. This trial, only the second to focus exclusively on donepezil for severe AD, enrolled community-dwelling rather than institutionalized patients. Primary endpoints for the trial were the Severe Impairment Battery (SIB) and the Clinician’s Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus). Secondary endpoints included the Mini Mental State Exam (MMSE) and the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev) and the Neuropsychiatric Inventory to assess behavior. Patients were allowed to have taken acetylcholinesterase inhibitors previously, but must have stopped at least 3 months before the trial began.

The results suggest that in patients with severe AD, donepezil helps with cognition and global function, but has little effect on activities of daily living or behavior, a major worry for caregivers because patients with severe AD experience episodes of irritability, anxiety, aggression and general emotional discomfort. Patients taking the drug scored higher in the SIB than those on placebo (higher scores are better). In fact, SIB scores increased above baseline in the drug group, reached a peak at 16 weeks, and then declined. At 24 weeks the scores were still above baseline. In contrast, SIB scores in the placebo group consistently declined. The CIBIC-Plus also favored patients in the drug group who were more likely to score as improved or unchanged and less likely to score as worsened. MMSE scores in the donepezil group increased slightly over the trial, while those in the placebo group were unchanged. The results were statistically significant.

Though the donepezil group scored slightly better in the ADCS-ADL-sev and slightly poorer in the NPI scale, over the course of the trial, those results did not reach statistical significance. All told, the results paint a very similar picture to those reported last year by Bengt Winblad and colleagues at the Karolinska Intitute, Stockholm (see ARF related news story). Interestingly, in their study of institutionalized patients, Winblad and colleagues did see a significant difference between placebo and donepezil groups in activities of daily living. In that case the decline in the placebo group was much greater, which may reflect the nature of the patient cohort—institutionalized patients are likely to have disease of greater severity than patients living in the community.

The authors acknowledge that treating severe AD patients is unlikely to reverse cognitive or functional decline. “However, maintenance or less than expected decline might be a worthwhile treatment goal because it may help to keep patients at home longer—something that patients and caregivers often desire and which delays the costs of institutionalization,” they write. In this regard it is unfortunate that the drug did not help with behavioral problems given that they are often the deciding factor in placing patients in institutional care.—Tom Fagan