Age and Ageing Advance Access originally published online on September 19, 2007
Age and Ageing 2007 36(6):625-627; doi:10.1093/ageing/afm117
Copyright © The Author 2007. Published by Oxford University Press on behalf of the British Geriatrics Society.
Cholinesterase inhibitors in dementia: yes, no, or maybe?
Afina W. Lemstra*,
Edo Richard and
Willem A. van Gool
Academic Medical Centre, Department of Neurology, PO Box 22660, 1100 DD Amsterdam, The Netherlands
Address correspondence to: Afina W. Lemstra. Tel: +31-20-5663842; Fax: +31-20-6971438. Email: a.w.lemstra{at}amc.uva.nl
Keywords: cholinesterase inhibitors, dementia, cholinergic system, pharmaceutical industries
 |
Introduction
|
|---|
Often it is not for the benefit of patients, when a clinical
issue is debated in public domain. Currently, patients with
dementia who are considered for treatment with one of the cholinesterase
inhibitors are in danger of being crushed between clinical opinion
leaders, national guidelines, pharmaceutical companies and politicians.
After a review of the cost effectiveness of cholinesterase inhibitors
for Alzheimer's disease (AD), the UK National Institute of Clinical
Excellence recently recommended that these drugs should be used
only in patients with a score for cognitive impairment within
a specific range [
1]. Patients' organisations orchestrated street
protests, two companies started a judicial review of the process
leading to this recommendation and an American politician contended
that restrictive guidelines ultimately hinder development and
innovation in biomedical research. Where does that leave patients
with dementia? Is there an alternative for the power play of
solicitors and politicians? We believe that conscientious analysis
of all available data should offer a rational solution for this
escalating conflict. More so because it concerns essentially
a clinical issue that is to be solved by clinical reasoning
rather than by a vigorous legal battle.
|
Do patients with dementia benefit from cholinesterase inhibitor therapy?
|
|---|
Some 10 years ago, the worldwide licensing of cholinesterase
inhibitors (CEIs) has brought a little hope on the previously
dim scene of treatment of dementia. Several meta-analyses of
CEIs like rivastigmine, donepezil and galantamine have documented
consistent treatment effects for patients with mild to moderate
AD [
2]. Treatment effects were measured with cognitive assessment
scales and scales for behavioural problems and activities of
daily living. Though statistically significant at the level
of groups consisting of hundreds of patients, the clinical relevance
of these treatment effects remains questionable, especially
for each and every individual patient using a CEI. This is clearly
illustrated by a long term study of donepezil, that indeed reproduced
the short term and small improvements in cognition and activities
in daily living in AD, but failed to show any reduction in the
rate of institutionalisation or progress of disability after
2 years of treatment [
3].
The randomised clinical trials that served the licensing of CEIs have been subject to various criticism such as the high drop out rates that were observed in almost all studies, the way data on dropouts were handled and the fact that masking of treatment allocation may have been hampered because of frequently occurring side-effects. Also the relatively small differences in average scores at the group level are the subject of the heated controversy surrounding the CEIs. Some argue that these drugs hardly offer any benefit at all, whereas others are convinced that withholding this small benefit from any patient is to be considered as unethical. Because of the rising temperature of this debate, the simple fact tends to be ignored that some patients may have substantial benefit from these drugs, whereas others may not benefit at all.
Depending on the exact criterion that is used for labelling individual ‘responders’, 10–20% of Alzheimer patients using a CEI satisfy this criterion, whereas the same holds 5–15% of patients using placebo [4]. The latter illustrates that the responder criteria proposed so far are not too restrictive at all. Thus, most probably about only 5–15% of patients with AD truly benefit from the consequences of cholinesterase inhibition, and the remainder of so-called responders may benefit from non-specific factors that are associated both with drug as well as placebo treatment. In dementia with Lewy bodies and Parkinsons’ disease, the percentage of true responders may be somewhat higher [5, 6]. These drugs are by no means miracle drugs, but they appear to be not completely worthless either. CEIs simply are effective in some patients and not in others, a fact that is common wisdom for many other drugs used in other fields of medicine. Acknowledging this self evident fact by all parties involved could be the beginning of a solution.
|
Defining patients who will benefit from cholinesterase inhibitor therapy
|
|---|
Clinical symptoms of confusion, disorientation or frank dementia
can be elicited by different functional impairments. With a
somewhat circular line of reasoning, patients with clinical
symptoms that respond well to CEI therapy, can be considered
to have suffered from a cholinergic deficiency before starting
treatment (Figure
1). On the basis of data on the effects of
anticholinergic drugs, case studies of patients receiving CEI
therapy and on experimental work relevant to the functional
ramifications of cholinergic neurotransmission, we have speculated
on the clinical characteristics of such a ‘cholinergic
deficiency syndrome’ (CDS) [
7]. Treatment with anticholinergic
drugs can cause restlessness, some excitement, confusion, and
at higher doses impaired consciousness, perceptual distortions,
memory deficits, anxiety, illusions and most frequently visual
hallucinations may develop. Interestingly, administration of
the CEI tetrahydroaminoacridine, currently better known as tacrine,
has been reported in the past to reverse this neuropsychiatric
syndrome within minutes [
8].
Several exploratory studies have been undertaken in attempts
to define characteristics of responders to CEIs and some study
results are consistent with the clinical syndrome delineated
above. In an early retrospective study, Mega
et al. already
pointed out that a pre-treatment behavioural profile can help
to predict response to donepezil [
9]. Others coined disease
severity, fluctuating cognition, a diagnosis of Lewy body dementia
(LBD) or PDD, and older age as possible predictors of beneficial
therapeutic response in retrospective studies [
10–14].
Post hoc analyses of trial data of AD and LBD patients proposed
that patients with visual hallucinations and specific behavioural
symptoms such as apathy and anxiety are more likely to respond
to CEI treatment [
15–17].
Unfortunately, large-scale post hoc analyses of baseline characteristics that define responders to CEIs have never been performed on the thousands of patients who provided the data that are on file with pharmaceutical industries (Table 1). Such analyses, even if they were exploratory in nature could very well provide a first in delineation of the clinical profile of patients who benefit most from cholinomimetic therapy. The validity of the resulting predictor profile could be investigated in subsequent cohort studies and even might apply to open label treatment. Such studies could document whether or not the benefits of CEI treatment in patients defined according to that profile outweigh the side-effects with a greater margin of profit than in unselected patients or in patients who do not have the characteristics of the CDS.
|
Access to Trial Data in the Interest of Future Patients
|
|---|
Such a strategy may eventually lead to a more satisfactory approach
to CEI treatment than the present NICE proposal that advocates
use of a rather arbitrarily defined range of scores on the Mini
Mental Status Examination for selecting patients for CEI therapy.
It may also reconcile those who fear a nihilistic therapeutic
approach towards patients with dementia and those who contend
that the indiscriminate use of CEIs subjects many patients to
disturbing side-effects without offering any benefit. Till date
there is hardly any data that provides a solid basis for selective
use of CEIs. Instead of endless debates, protest manifestations
or legal procedures this issue should be high on the agenda
of dementia research, starting with a sound analysis of data
that already have been collected in the past. Therefore, it
is very unfortunate that despite many requests by independent
researchers, none of the manufacturers of the various CEI preparations
has consented to
post hoc analyses on trial data as a first
step. In some cases companies refused with reference to protection
of patents. However, patients who in the past agreed to participate
in clinical trials of cholinesterase inhibitors, as well as
caregivers supporting this decision and facilitating the actual
participation of patients did so in the belief that it would
contribute to the advancement of science and the improvement
of therapeutic care for patients with dementia. Most likely
the informed consent form that they signed did not specify that
access to the trial data would be strictly limited to employees
of the pharmaceutical company involved. Protection of any patent
or other interests of the pharmaceutical companies had most
probably not a high priority for these trial participants. Failure
to provide access to data that were generated with the generous
help of patients with dementia and their caregivers not only
violates their trust, but also hinders more rational use of
CEIs by future patients.
|
Key points
|
|---|
- Cholinesterase inhibitors showed limited but consistent therapeutic effects in randomised clinical trials
- Defining clinical characteristics of true responders could help to select patients who will really benefit from these drugs
- On the basis of the cholinergic hypothesis such a predictive clinical profile will probably include attentional deficits and neuropsychiatric features
- Selective use of cholinesterase inhibitors could prevent unnecessary exposure to disturbing side effects
- Drug companies should release their data for independent post hoc analyses to find valid predictors for response to treatment with CEIs in patients with dementia
|
Conflict of interest
|
|---|
AWL & ER none declared; WAvG has been invited by NICE to
act as an expert witness in the judicial procedure (no fee involved).
|
References
|
|---|
- 2006) http://www.nice.org.uk/CG035 Ref Type: Electronic Citation.
- Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev (2006) 1:CD005593.[Medline]
- Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet (2004) 363:2105–15.[CrossRef][Web of Science][Medline]
- Committee for Proprietary Medicinal products. European public assessments report of rivastigmine. (2002) http://www.eudra.org/emea.html Ref Type: Electronic Citation.
- McKeith I, Del ST, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet (2000) 356:2031–6.[CrossRef][Web of Science][Medline]
- Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med (2004) 351:2509–18.[Abstract/Free Full Text]
- Lemstra AW, Eikelenboom P, van Gool WA. The cholinergic deficiency syndrome and its therapeutic implications. Gerontology (2003) 49:55–60.[CrossRef][Web of Science][Medline]
- Itil T, Fink M. Anticholinergic drug-induced delirium: experimental modification, quantitative EEG and behavioral correlations. J Nerv Ment Dis (1966) 143:492–507.[Web of Science][Medline]
- Mega MS, Masterman DM, O'Connor SM, et al. The spectrum of behavioral responses to cholinesterase inhibitor therapy in Alzheimer disease. Arch Neurol (1999) 56:1388–93.[Abstract/Free Full Text]
- Pakrasi S, Mukaetova-Ladinska EB, McKeith IG, et al. Clinical predictors of response to acetyl cholinesterase inhibitors: experience from routine clinical use in Newcastle. Int J Geriatr Psychiatry (2003) 18:879–86.[CrossRef][Web of Science][Medline]
- Farlow MR, Small GW, Quarg P, et al. Efficacy of rivastigmine in Alzheimer's disease patients with rapid disease progression: results of a meta-analysis. Dement Geriatr Cogn Disord (2005) 20:192–7.[CrossRef][Web of Science][Medline]
- Connelly PJ, Prentice NP, Fowler KG. Predicting the outcome of cholinesterase inhibitor treatment in Alzheimer's disease. J Neurol Neurosurg Psychiatr (2005) 76:320–4.[Abstract/Free Full Text]
- Van der Putt R, Dineen C, Janes D, et al. Effectiveness of acetylcholinesterase inhibitors: diagnosis and severity as predictors of response in routine practice. Int J Geriatr Psychiatry (2006) 21:755–60.[CrossRef][Web of Science][Medline]
- Onofrj M, Thomas A, Iacono D, et al. The effects of a cholinesterase inhibitor are prominent in patients with fluctuating cognition: a part 3 study of the main mechanism of cholinesterase inhibitors in dementia. Clin Neuropharmacol (2003) 26:239–51.[CrossRef][Web of Science][Medline]
- McKeith IG, Wesnes KA, Perry E, et al. Hallucinations predict attentional improvements with rivastigmine in dementia with lewy bodies. Dement Geriatr Cogn Disord (2004) 18:94–100.[CrossRef][Web of Science][Medline]
- Herrmann N, Rabheru K, Wang J, et al. Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials. Am J Geriatr Psychiatry (2005) 13:527–34.[CrossRef][Web of Science][Medline]
- Burn D, Emre M, McKeith I, et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson's disease. Mov Disord (2006) 21:1899–907.[CrossRef][Web of Science][Medline]
Received 30 May 2007; accepted in revised form 20 July 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
Top
Introduction
Do patients with dementia...