"Is Long-Term Treatment With Cholinesterase Inhibitors Justified?: Presented at AAT"
By Chris Berrie
GENEVA, SWITZERLAND -- April 21, 2006 -- Although there does not appear to be any major evidence of negative effects from long-term treatment with the cholinesterase inhibitors (ChEIs) in patients with mild-to-moderate dementia, there remain a number of problems inherent in the making of the decision to use these agents, according to a presentation here on April 20[th at the 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT).
Several studies of relatively short study duration have supported the use of ChEIs in patients with mild AD, said Roy Jones, MD, FRCP, director, Research Institute for the Care of the Elderly, and professor of clinical gerontology, University of Bath, Bath, United Kingdom. He cited placebo-controlled research in patients with Mini-Mental State Examination (MMSE) score of 24 by Seltzer and colleagues (Arch Neurol. 2004), which showed an improvement in cognition with donepezil compared with placebo.
In studies of more advanced disease, Dr. Jones cited a study by Feldman et al., which enrolled patients with a mean MMSE of 11.7, and showed significant benefit with donepezil over 24 weeks (Feldman et al. Neurology. 2001).
For longer-term benefits, he then discussed the 1-year data from Mohs et al. (Neurology. 2001) that included patient decline in functioning, where the probability of survival while maintaining functional ability at 48 weeks was 51% for patients on donepezil and 35% for those on placebo. Dr. Jones also stressed the importance of this sort of data. "Obviously, as a clinician, we are much more concerned about what patients are able to do and how they can function in everyday life," he said.
In addition, a long-term study (8 years) showed that use of ChEIs can significantly delay nursing home admission in patients with AD compared with those who had never used ChEIs (Lopez et al. J Neurol Neurosurg Psychiatry. 2002), Dr. Jones said.
He then discussed changes in mean score changes from baseline over 6 months on the AD Assessment Scale cognitive subscale (ADAS-cog) in a study that evaluated galantamine against placebo (Raskind et al. Arch Neurol, 2004). The researchers calculated the placebo decline over the year, and then using the Sterney equation (Am J Psychiat. 1994), they calculated the placebo decline to 3 years. Although Dr. Jones said this study used a "slightly artificial system", the results do give a "rough idea" of the benefits of galantamine as compared with placebo.
Further to this, 3-year follow-up data that considered mean MMSE scores were published recently (Winblad et al. Dement Geriatr Cogn Disord. 2006). As well as supporting the earlier galantamine study, these data with donepezil show a further important aspect of this longer-term ChEI treatment of patients with AD, Dr. Jones said. Although placebo subjects who were moved over onto donepezil at the end of the planned 1-year trial also achieved improvements in MMSE scores, they never caught up with the improvements seen among subjects who were on donepezil throughout the trial and follow-up period. "This suggests that introducing the drug early is actually quite an important concept," Dr. Jones stressed.
He then moved on more specifically to benefits of ChEIs in preventing progression of AD symptoms, as defined originally by Feldman et al. in Clinical diagnosis and Management of AD, 1st edition (1998). Dr. Jones indicated, "What I am trying to raise here is the fact that as we go through the course of Alzheimer's disease, clearly what we are interested in is changes."
Thus, with mild AD, the interest is mainly in the memory problems and the more complex activities of daily living (ADLs), like driving and cooking, he said. Then in moving on to severe AD, the more basic ADLs need to be considered. This should thus be reflected in the specific items of interest followed, he explained. "And this is something that we need to be aware of when we are designing trials," he added.
Finally, he moved on to what is still considered by many as a difficult decision -- "when should stopping treatment with ChEIs be considered?" In terms of possible troublesome patient tolerability to the drug, as this generally occurs early on in treatment, this is not specifically related to longer-term treatment, while for the development of relevant comorbidities, Dr. Jones said that he has not seen this to be a major issue with patents on ChEIs.
However, if the patient is considered to have severe dementia, he said, he noted that these drugs are only licensed for use in patients with mild-to-moderate dementia. Thus, this remains a difficult issue that raises several problems. First, how do you define severe dementia? Second, if the drug treatment is discontinued or the dose reduced, about 40% of patients will actually need to restart the treatment, Dr. Jones said. Indeed, previous trials have indicated that patients with AD who have been taking ChEIs for relatively short periods of time have also chosen to continue on these drugs, if give the option.
Dr. Jones stressed that although there remain no hard and fast rules, "In all cases, if you are considering stopping these drugs, as I do, this decision should only be made after discussions with both patients and family."
The round-table meeting was titled "Controversies in Cholinergic Therapy for Mild Cognitive Impairment and Alzheimer's Disease." The meeting's chair was Jeffrey Cummings, MD, professor of neurology and director, Alzheimer's Disease Research Centre, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, United States.
Eisai Europe Ltd. and Pfizer Inc. sponsored this meeting. Dr. Jones also acknowledges the receipt of grants/ research support from Axonyx, Eisai, Lundbeck, Myriad, Pfizer, Servier, and Shire; he is also a consultant for Eisai, Lundbeck, Pfizer, and Shire, and is a member of the speakers' bureau for Eisai, Lundbeck, Mertz, and Pfizer.
[Presentation title: Is Long-Term Treatment With Cholinesterase Inhibitors Justified? Combined Abstract 19]
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