Effectiveness of rivastigmine in Alzheimer's disease
BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7210.640a (Published 04 September 1999) Cite this as: BMJ 1999;319:640All rapid responses
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Editor - In a recent article on the cholinesterase inhibitor
rivastigmine in Alzheimer's disease (AD)1, clinical benefits were
reported for cognition and activities of daily living (ADL). We would like to present some additional evidence of improvements in AD observed with this agent. A retrospective analysis of patient records, collected from three different centres, has revealed that rivastigmine can provide clinically relevant benefits in certain behavioural and psychopathological abnormalities associated with this disease. All
patients included in the analysis were diagnosed with mild-to-moderately severe AD and administered rivastigmine for a minimum of 6 months (13% on 12 mg/day rivastigmine at endpoint). Benefits were observed with three different instruments used at separate
centres: the Neuropsychiatric Inventory2 (NPI), the Behavioural Pathology in Alzheimer's Disease rating scale3 (BEHAVE-AD) and the Mini Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia (MOUSEPAD)4. Responders and non-responders to treatment were identified. In all instruments specific behavioural
and psychopathological symptoms improved with rivastigmine therapy, particularly a resolution of apathy, hallucinations and activity disturbances. Cognition also improved significantly with rivastigmine treatment - assessed using the Mini-Mental State Examination (MMSE) (Table).
Although not complete, these naturalistic data provide additional
supportive evidence for the potential benefits of rivastigmine in AD.
However, no specific claims can be made as we recognise the limitations
of our analysis and that the results are not obtained from a controlled
clinical trial. There is evidence that certain behavioural or psychopathological symptoms will respond to cholinesterase inhibitors5 and it may be helpful if we could identify individuals who are likely to benefit prior to treatment. In our view, assessing behaviour is a clinically relevant measurement of efficacy for cholinesterase inhibitors that can help in the decision to continue treatment.
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Fraser Inglis, Consultant Geriatrician
Crosshouse Hospital,
Department of Medicine for the Elderly,
Level 5 East,
Kilmarnock,
Ayreshire KA2 OBE
Evelyn Russell, Consultant in Old Age Psychiatry
Department of Psychiatry,
Withington Hospital,
Nell Lane,
West Didsbury,
Manchester M20 8LR
Alasdair Sim, Consultant in Old Age Psychiatry
Udston Hospital,
Farm Road,
Hamilton,
Lanarkshire ML3 9LA
Sean Page, Clinical Nurse Specialist
Memory Clinic,
Department of Psychiatry,
Withington Hospital,
Nell Lane,
West Didsbury,
Manchester M20 8LR
Acknowledgement: We would like to thank Dr C.D. Andrews (Novartis, UK) for his statistical analysis.
Competing interests: The authors have conducted research on behalf of pharmaceutical companies, received remuneration for consultancy and
lecturing. None of the authors has affiliation with any one pharmaceutical company.
1. Rösler M et al. Efficacy and safety of rivastigmine in patients
with Alzheimer's disease: results of an international, 26 week,
multicentre, randomised, placebo-controlled trial. BMJ 1999; 318: 633-638.
2. Cummings JL et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308-2314.
3. Reisberg B et al. Behavioural symptoms in Alzheimer's disease:
phenomenology and treatment. J Clin Psychiatry 1987; 48: 9-15.
4. Allen NHP et al. Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia (MOUSEPAD). B J Psych 1996; 169:293-307.
5. Mega M et al. The spectrum of behavioural responses to cholinesterase inhibitor therapy in Alzheimer disease. Arch Neurol 1999; 56: 1388-1393.
Competing interests: No competing interests
EDITOR- Polymorphisms in the apolipoprotein E gene have been
associated with a diverse set of human disorders ranging from
atherosclerosis to Alzheimer's disease. In Alzheimer's disease, it has
been established that carriers of the ApoE4 allele are at increased risk
for developing the illness compared to the general population.1
Additionally, it appears that the ApoE4 allele acts as a modifier of the
age of onset. Individuals who carry the ApoE4 allele and are affected
with Alzheimer's disease tend to have an onset of the illness earlier than
non-carriers.1 While ApoE4 carrier status moderately increases the risk
for Alzheimer's disease, other genetic alterations are also known to
contribute to the aetiology of the illness. Mutations in the amyloid
precursor protein (APP), presenilin (PS) 1, and 2 genes significantly
increase the risk for the disease. Families, in which mutations in the
APP and PS genes are observed, are at high risk for the development of
early onset Alzheimer's disease. Most recently, a polymorphism in the
alpha2 macroglobulin gene has also been noted to increase the risk for
Alzheimer's disease.2
It has been suggested that the apolipoprotein status may predict the
cognitive response to cholinesterase inhibitor therapy in AD patients.3
We investigated this relationship in AD patients participating in clinical
trials with rivastigmine (Exelon®).
While inhibition of neuronal acetylcholinesterase has been shown to
have beneficial effects in patients with Alzheimer's disease, the
pathophysiological connection between the acetylcholine system and the
diverse genetic aetiologic factors for Alzheimer's disease remains
unknown. The beneficial response seen with treatment with cholinesterase
inhibitors including rivastigmine could suggest action of the
acetylcholine system in Alzheimer's disease in a pathway upstream,
downstream or parallel to the known aetiologic pathways.
Participants, methods, and results
We have investigated the segregation of the ApoE4 allele in Alzheimer's
disease patients treated with rivastigmine in prospective, randomised
double blind, multicentre, double blind, placebo controlled, parallel
group clinical trials. Response to rivastigmine was measured by the
Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-cog) and
the results have been published.4 In a total of 262 patients ranging in
age from 45-90 years of age with mild to moderately severe Alzheimer's
disease treated with rivastigmine, 49 showed improvement of >4 points
in the ADAS-cog. No significant association was observed between the
ApoE4 carrier status and response rate to rivastigmine as shown in the
table. Additional analyses for associations between homozygous or
heterozygous carriers for the ApoE3 or ApoE4 alleles similarly revealed no
significant association.
Comment
Clinical response to rivastigmine occurs in Alzheimer's disease patients
regardless of their ApoE genotype. These results are in agreement with
recent reports of non association of ApoE4 carrier status and treatment
response with acetylcholinesterase inhibitors.5 However, these results
contrast with an initial report of a negative correlation between tacrine
and ApoE4 carrier status.3 The reported negative response to tacrine
(Cognex®) in ApoE4 carriers may be due to a small number of individuals in
that study or it could point to individual differences between members of
the class of compounds. In conclusion, our genotype analysis of the ApoE
gene in Alzheimer's disease patients treated with rivastigmine suggests no
significant association between treatment response and ApoE4 carrier
status. These results suggest that an equal response rate is expected
between ApoE4 carriers and non-carriers.
Genotypes in the ApoE gene in Alzheimer's patients treated with rivastigmine in placebo controlled phase III trials ____________________________________________________ ApoE alleles ____________________________ */3 */4 (*=2 (*=2,3 or 3) or 4) 3/3 4/4 ____________________________________________________ Responders (49) 11 38 7 10 Non Responders (217) 75 142 68 36 ____________________________________________________ */3 vs. response (chi square=1.086 p=0.297) */4 vs. response (chi square=0.338 p=0.561) 3/3 vs. response (chi square=2.889 p=0.089) 4/4 vs. response (chi square=0.107 p=0.744)
Authors:
Mihael H. Polymeropoulos,
vice president,
Pharmacogenetics
Department, Novartis Pharmaceuticals Corporation, 59 Route 10, East
Hanover, NJ 07936
Kenneth W. Culver,
executive director,
Pharmacogenetics Department,
Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936
Fiona Crawford,
associate director,
Roskamp Institute, University of
South Florida, 3515 E. Fletcher Ave., Tampa, FL 33613
Michael Mullan,
director,
Roskamp Institute, University of South
Florida, 3515 E. Fletcher Ave., Tampa, FL 33613
Richard D. Hartman,
clinical research manager,
CNS Medical Affairs,
Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936
Ravi Anand,
executive director,
CNS Medical Affairs, Novartis
Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936
Correspondence to: mihael.polymeropoulos@pharma.novartis.com
References
1. Tanzi RE, Kovacs DM, Kim TW, Moir RD, Guenette SY, Wasco W. The gene
defects responsible for familial Alzheimer's disease. Neurobiol Dis
1996;3:159-68
2. Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RC, et al.
Alpha-2 macroglobulin is genetically associated with Alzheimer disease.
Nat Genet 1998;19:357-60
3. Farlow MR, Lahiri DK, Poirier J, Davignon J, Hui S. Apolipoprotein E
genotype and gender influence response to tacrine therapy. Neurology
1998;50:669-77.
4. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et
al. Efficacy and safety of rivastigmine in patients with Alzheimer's
disease: international randomised controlled trial. BMJ 1999;318:633-8
5. Poirier J, Delisle MC, Quirion R, Aubert I, Farlow M, Lahiri D, et al.
Apolipoprotein E4 allele as a predictor of cholinergic deficits and
treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A
1995;92:12260-4
Contributors: RDH and RA participated in the design and execution of
the study. FC and MM conducted the ApoE4 genotyping assays. MHP and KWC
performed the data analysis and were the primary writers of the
manuscript. MHP will act as the guarantor.
Funding: This study was supported by funding from Novartis
Pharmaceuticals Corporation
Competing interests: MHP, KWC, RDH, and RA are employees of Novartis.
Competing interests: Genotypes in the ApoE gene in Alzheimer's patients treated with rivastigmine in placebo controlled phase III trials____________________________________________________ ApoE alleles ____________________________ */3 */4 (*=2 (*=2,3 or 3) or 4) 3/3 4/4____________________________________________________Responders (49) 11 38 7 10Non Responders (217) 75 142 68 36____________________________________________________*/3 vs. response (chi square=1.086 p=0.297)*/4 vs. response (chi square=0.338 p=0.561)3/3 vs. response (chi square=2.889 p=0.089)4/4 vs. response (chi square=0.107 p=0.744)
BED BLOCKING AND CHOLINESTERASE INHIBITORS
EDITOR - The benefits of cholinesterase inhibitors and their place in
the management of patients with Alzheimer's disease is questioned by
Bentham et al.Their call is for support for AD 2000 and this indeed may
enhance our understanding of the benefits of these agents.
As a clinician involved in the day to day management of patients with
Alzheimer's disease I have been witness to the benefits that treatment can
offer individual patients and their families. Current practice centres
around patients usually still living at home with family support.
We know that throughout the country large numbers of NHS beds are
blocked by patients waiting for nursing home placement and undergoing
community care assessment. In my own experience a significant number of
the patients suffer from Alzheimer's disease.
It would be very interesting to see if patients with Alzheimer's
disease, blocking NHS beds could benefit from treatment with
cholinesterase inhibitor therpy and be successfully returned to live in
the community. This question could be addressed immediately and may
provide
further evidence of the benefits of these agents.
1. Bentham P, Gray R, Sellwood S, Raferty J. Effectiveness of
Rivastigmine in Alzheimer's disease. BMJ 1999;319:640.
Competing interests: No competing interests