Donepezil is somewhat effective for Alzheimer's, probably better than galantamine
BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.328.7431.0-g (Published 09 January 2004) Cite this as: BMJ 2004;328:0-g
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Dear Sirs,
POEM section: Review of a published article Efficacy and Safety of
Cholinesterase Inhibitors in Alzheimer’s disease: a meta-analysis
(Lanctot et al CMAJ 2003; 169:557-64)
I refer to the brief review of the meta-analysis by Lanctot et al [1]
in the POEM section of the BMJ: 2004; 328 - 7431, which attempted to
summarise the efficacy and safety of cholinesterase inhibitors in the
treatment of Alzheimer’s disease (AD).
I wish to point out several shortfalls in the analyses discussed and
draw attention to newer data, all of which strongly influence the validity
of the conclusions.
Your review fails to recognize that the Lanctot et al analyses
include data obtained using sub-therapeutic and high non-recommended doses
from early studies in the development of these drugs (particularly
galantamine, see below) across a wide range of treatment periods (12 weeks
to 1 year). Therefore, the heterogeneity reported by the authors is not
surprising. The effects on safety of different treatments, doses and
titration schedules were not adequately explored. Focusing on recommended
maintenance doses at common time-points would produce the reliable and
clinically relevant analyses desired.
The authors (and your review) failed to appreciate that in AD, in
which untreated patients deteriorate progressively over time, maintenance
of the status quo (eg after 6 months treatment) is a treatment success.
The improvement exhibited by a substantial proportion of patients,
especially in the short term, is a welcome bonus. Therefore definitions of
‘global’ and ‘cognitive’ response criteria should realistically be based
on ‘improvement or no change’ at a time point (say 5-6 months) after
starting treatment when response to therapy can satisfactorily be
assessed.
The conclusions of the meta-analysis regarding NNT to achieve a
response are therefore out of line with generally accepted criteria.
Choice of realistic definitions for response would produce much lower NNT
efficacy values.
More generally, given the importance of cognition to AD, and the
relatively smaller inter-rater variation, we suggest that more weight be
given to findings with the ADAS-Cog parameter.
Your reference to the relative safety profiles of donepezil and
galantamine does not reflect galantamine’s product labeling and its
recommended clinical use. The clinical development of galantamine evolved
from high doses (32mg) and fast (weekly) titration [2,3,5,6] to lower
doses (16 & 24mg) with a slower (monthly) titration schedule to
improve the benefit/risk of treatment [4]. Yet Lanctot et al incorporated
data from these earlier ‘off-label’ trials in their analyses - with
associated higher discontinuation rates, which distort overall rates.
Safety data from a galantamine trial consistent with product labeling [4]
show discontinuation rates due to adverse events similar to placebo [7].
A recent head-to-head comparative trial [8] has confirmed the similar
safety profile of galantamine to donepezil.
The POEM article was clearly out of date in stating, in the ‘Bottom
line’, that head-to-head trials are lacking. The 12-month randomized,
parallel group comparison of galantamine and donepezil, mentioned above,
involving 182 patients was published four months ago [8].
The Wilcock et al study [8], the first and only long-term head-to-
head comparison of two active treatments in Alzheimer’s disease,
demonstrated the benefits of galantamine treatment over 12 months in
multiple domains affected by AD. Advantages on cognition, as measured by
the widely used parameters, MMSE and ADAS-cog/11, were found for
galantamine compared with donepezil at time points over 12 months in the
total population (baseline MMSE scores of 9-18) as well as in patients
with baseline scores of 12-18. These study findings confirm previous
safety and tolerability results for galantamine and demonstrate
equivalence with donepezil.
Randomised studies for extended treatment periods, incorporating
licensed doses and escalation regimens, are surely more reliable and
worthy of comment than the above meta-analysis reported in the BMJ, with
its shortcomings detailed above?
We suggest that the BMJ review this head-to-head, comparative study.
Overall the BMJ review missed an opportunity to add to existing
knowledge in this area [7,9] and hence to improve the therapy currently
provided for these unfortunate patients.
Yours faithfully,
Dr Ian Howe
Medical Director
Shire Pharmaceuticals Limited
References:
1. Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM,
Einarson TR. Efficacy and safety of cholinesterase inhibitors in
Alzheimer’s disease: a meta-analysis. CMAJ 2003; 169: 557-64
2. Raskind MA, Peskind PR, Wessel T, Yuan W. Galantamine in AD: A 6-
month randomised, placebo-controlled trial with a 6-month extension. The
galantamine USA-1 study group. Neurology 2000; 54: 2261-8
3. Wilcock G, Lilienfeld S, Gaens E. Efficacy and safety of
galantamine in patients with mild to moderate Alzheimer’s disease: a mult-
centre randomised controlled trial. Galantamine International-1 Study
Group, BMJ 2000; 321: 1445-9.
4. Tariot PN, Solomon PR, Morris JC, Kershaw P. A 5-month,
randomised, placebo-controlled trial of galantamine in AD. The
Galantamine USA-10 study group, Neurology 2000; 54: 2269-76.
5. Wilkinson D, Murray J. Galantamine: a randomised, double-blind,
dose comparison in patients with Alzheimer’s disease. International
Journal of Geriatric Psychiatry 2001; 16: 852-7.
6. Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects
of a flexible galantamine dose in Alzheimer’s disease: a randomised,
controlled trial. J Neurol Neurosurg Psychiatry 2001; 71: 589-95.
7. Olin J, Schneider L. Galantamine for Alzheimer’s disease. In:
The Cochrane Library, Issue 4, 2001, Oxford: Update software.
8. Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, Bullock
R and members of the GAL-GBR-2 Study Group. A long-term comparison of
galantamine and donepezil in the treatment of Alzheimer’s disease. Drugs
Aging; 20: 777-89.
9. Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K,
Waugh N. Clinical and cost-effectiveness of donepezil, rivastigmine and
galantamine for Alzheimer’s disease. Int J Technol Assess Health Care
2002; 18: 497-507.
Competing interests:
Ian Howe is an employee of Shire Pharmaceuticals Ltd, the UK licence holder for Reminyl (galantamine)
Competing interests: No competing interests
Dear Editor,
A recent POEM* [1] article stating that donepezil is more effective
and a bit better tolerated than galantamine unfortunately reflects
shortcomings in the original paper they summarize [2] that we have
highlighted with a letter to the editor.
First, the analyses for galantamine failed to exclude data for sub-
therapeutic or higher than recommended doses. The clinical development of
galantamine evolved away from high doses (32mg) and weekly titration [3-6]
to lower dosing (16 & 24mg) with monthly titration with improved risk-
benefit of treatment [7]. Lanctot et al. [2] combined data from early
trials with those from the later trial, and thus presented discontinuation
rates that incorrectly appear higher than those for donepezil. Safety data
from a trial consistent with product labeling [7] show excess
discontinuation due to adverse events similar to placebo (16mg -0.2%,
95%CI -4.6, 4.1; 24mg 2.6% 95% CI -2.2, 7.4). The similar safety profile
of galantamine to donepezil has also been confirmed in a recent
comparative trial [8].
Second, the inter-study comparison of results for global clinical
measures is problematic since the semi-structured processes used to obtain
these results means that the domains and questions covered vary between
raters and individual subjects [9]. Furthermore individual rater’s
relative weighting of changes in different domains for their overall
clinical judgment of change also vary. In addition to the inter-rater
reliability issues for individual global measures, further variation
between different global clinical measures (GGIC, CIBIC, CIBIC+) also
makes inter-study comparison problematic [9]. In the context of a
progressively degenerative disease, the widely varying durations of the
trials included (3-12 months) and the narrow focus on improvement in
Lanctot et al’s analyses are also questionable.
More generally, given the importance of cognition to AD, and the
relatively smaller inter-rater variation, more weight should be given to
findings on cognitive measures. For example, the data from separate
Cochrane reviews (6 month last observation carried forward analyses) [10,
11] show that the treatment effect for galantamine versus placebo on ADAS-
Cog (16mg weighted mean difference -3.1 95%CI -4.1, -2.1; 24mg -3.3 95% CI
-3.9, -2.7) is at least as good as those for donepezil (5mg -1.9 95% CI -
2.6, -1.1; 10mg -2.9 95% CI -3.7, -2.2). Direct evidence from a 12-month
trial comparing galantamine with donepezil found that although most
measures were equivalent, a greater proportion of patients treated with
galantamine were maintained at or above baseline on MMSE [8].
An important outcome of the regulatory process is that a recommended
dosing regimen with proven risk-benefit is identified and it is upon this
basis that recommendations to clinicians should be based rather than on
data from earlier development trials.
References:
1. POEM* Donepezil is somewhat effective for Alzheimer’s probably
better than galantamine. BMJ 2004; 328, page number?
2. Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM,
Einarson TR. Efficacy and safety of cholinesterase inhibitors in
Alzheimer’s disease: a meta-analysis. CMAJ 2003; 169: 557-564
3. Raskind MA, Peskind PR, Wessel T, Yuan W. Galantamine in AD: A 6-
month randomised, placebo-controlled trial with a 6-month extension. The
galantamine USA-1 study group. Neurology 2000; 54: 2261-8
4. Wilcock G, Lilienfeld S, and Gaens E. Efficacy and safety of
galantamine in patients with mild to moderate Alzheimer’s disease: a mult-
centre randomised controlled trial. Galantamine International-1 Study
Group, BMJ 2000; 321: 1445-9.
5. Wilkinson D, Murray J. Galantamine: a randomised, double-blind,
dose comparison in patients with Alzheimer’s disease. International
Journal of Geriatric Psychiatry 2001; 16:852-857.
6. Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of
a flexible galantamine dose in Alzheimer’s disease: a randomised,
controlled trial. J Neurol Neurosurg Psychiatry 2001; 71:589-595.
7. Tariot PN, Solomon PR, Morris JC, Kershaw P. A 5-month,
randomised, placebo-controlled trial of galantamine in AD. The Galantamine
USA-10 study group, Neurology 2000; 54:2269-76.
8. Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, Bullock
R and members of the GAL-GBR-2 Study Group. A long-term comparison of
galantamine and donepezil in the treatment of Alzheimer’s disease. Drugs
Aging; 20:777-789.
9. Schneider L. CIBIC+: what, why and how? Alzheimer Insights; June
1997: 2-8
10. Olin J, Schneider L. Galantamine for Alzheimer’s disease. In: The
Cochrane Library, Issue 4, 2001, Oxford: Update software.
11. Birks JS, Melzer D, and Beppu H. Donepezil for Mild and
Moderate Alzheimer’s disease. In: The Cochrane Library, Issue 3, 2001,
Oxford: Update software.
Competing interests:
Shane Kavanagh, Luc Truyen and Patricia Kabathova are employees of Johnson & Johnson.
Reminyl (galantamine) was developed by Johnson & Johnson Pharmaceutical Research and Development under a co-development and licensing agreement with UK-based Shire Pharmaceuticals Group plc. Reminyl is marketed by Shire and Janssen-Cilag in the UK
Competing interests: No competing interests
A Cochrane Review indicates that extract of Ginkgo biloba may also be
effective in the treatment of Alzheimer's dementia. {Ref. 1.} It has
several advantages:
1. It is well tolerated (no more adverse effects than placebo)
2. It is available over the counter.
3. The cost is low (£6 a month from a leading supermarket compared to
£70 to £100 for donepezil).
4. It probably works through a different mechanism to donepezil and
therefore may work in combination with it.
http://www.update-software.com/abstracts/ab003120.htm
Ref. 1. Birks J, Grimley Evans J, Van Dongen M. Ginkgo Biloba for
Cognitive Impairment and Dementia (Cochrane Review). In: The Cochrane
Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd.
Competing interests:
None declared
Competing interests: No competing interests
Shortfalls in analysis of original paper
Dear Sirs,
POEM section: Review of a published article Efficacy and Safety of
Cholinesterase Inhibitors in Alzheimer’s disease: a meta-analysis (Lanctot
et al CMAJ 2003; 169:557-64)
I refer to the brief review of the meta-analysis by Lanctot et al [1]
in the POEM section of the BMJ: 2004; 328 - 7431, which attempted to
summarise the efficacy and safety of cholinesterase inhibitors in the
treatment of Alzheimer’s disease (AD).
I wish to point out several shortfalls in the analyses discussed and
draw attention to newer data, all of which strongly influence the validity
of the conclusions.
Your review fails to recognize that the Lanctot et al analyses
include data obtained using sub-therapeutic and high non-recommended doses
from early studies in the development of these drugs (particularly
galantamine, see below) across a wide range of treatment periods (12 weeks
to 1 year). Therefore, the heterogeneity reported by the authors is not
surprising. The effects on safety of different treatments, doses and
titration schedules were not adequately explored. Focusing on recommended
maintenance doses at common time-points would produce the reliable and
clinically relevant analyses desired.
The authors (and your review) failed to appreciate that in AD, in
which untreated patients deteriorate progressively over time, maintenance
of the status quo (eg after 6 months treatment) is a treatment success.
The improvement exhibited by a substantial proportion of patients,
especially in the short term, is a welcome bonus. Therefore definitions of
‘global’ and ‘cognitive’ response criteria should realistically be based
on ‘improvement or no change’ at a time point (say 5-6 months) after
starting treatment when response to therapy can satisfactorily be
assessed.
The conclusions of the meta-analysis regarding NNT to achieve a
response are therefore out of line with generally accepted criteria.
Choice of realistic definitions for response would produce much lower NNT
efficacy values.
More generally, given the importance of cognition to AD, and the
relatively smaller inter-rater variation, we suggest that more weight be
given to findings with the ADAS-Cog parameter.
Your reference to the relative safety profiles of donepezil and
galantamine does not reflect galantamine’s product labeling and its
recommended clinical use. The clinical development of galantamine evolved
from high doses (32mg) and fast (weekly) titration [2,3,5,6] to lower
doses (16 & 24mg) with a slower (monthly) titration schedule to
improve the benefit/risk of treatment [4]. Yet Lanctot et al incorporated
data from these earlier ‘off-label’ trials in their analyses - with
associated higher discontinuation rates, which distort overall rates.
Safety data from a galantamine trial consistent with product labeling [4]
show discontinuation rates due to adverse events similar to placebo [7]. A
recent head-to-head comparative trial [8] has confirmed the similar safety
profile of galantamine to donepezil.
The POEM article was clearly out of date in stating, in the ‘Bottom
line’, that head-to-head trials are lacking. The 12-month randomized,
parallel group comparison of galantamine and donepezil, mentioned above,
involving 182 patients was published six months ago [8].
The Wilcock et al study [8], the first and only long-term head-to-
head comparison of two active treatments in Alzheimer’s disease,
demonstrated the benefits of galantamine treatment over 12 months in
multiple domains affected by AD. Advantages on cognition, as measured by
the widely used parameters, MMSE and ADAS-cog/11, were found for
galantamine compared with donepezil at time points over 12 months in the
total population (baseline MMSE scores of 9-18) as well as in patients
with baseline scores of 12-18. These study findings confirm previous
safety and tolerability results for galantamine and demonstrate
equivalence with donepezil.
Randomised studies for extended treatment periods, incorporating
licensed doses and escalation regimens, are surely more reliable and
worthy of comment than the above meta-analysis reported in the BMJ, with
its shortcomings detailed above?
We suggest that the BMJ review this head-to-head, comparative study.
Overall the BMJ review missed an opportunity to add to existing
knowledge in this area [7-9] and hence to improve the therapy currently
provided for these unfortunate patients.
Yours faithfully,
Dr Ian Howe
Medical Director
Shire Pharmaceuticals Limited
References:
1. Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM,
Einarson TR. Efficacy and safety of cholinesterase inhibitors in
Alzheimer’s disease: a meta-analysis. CMAJ 2003; 169: 557-64
2. Raskind MA, Peskind PR, Wessel T, Yuan W. Galantamine in AD: A 6-
month randomised, placebo-controlled trial with a 6-month extension. The
galantamine USA-1 study group. Neurology 2000; 54: 2261-8
3. Wilcock G, Lilienfeld S, Gaens E. Efficacy and safety of
galantamine in patients with mild to moderate Alzheimer’s disease: a mult-
centre randomised controlled trial. Galantamine International-1 Study
Group, BMJ 2000; 321: 1445-9.
4. Tariot PN, Solomon PR, Morris JC, Kershaw P. A 5-month,
randomised, placebo-controlled trial of galantamine in AD. The Galantamine
USA-10 study group, Neurology 2000; 54: 2269-76.
5. Wilkinson D, Murray J. Galantamine: a randomised, double-blind,
dose comparison in patients with Alzheimer’s disease. International
Journal of Geriatric Psychiatry 2001; 16: 852-7.
6. Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of
a flexible galantamine dose in Alzheimer’s disease: a randomised,
controlled trial. J Neurol Neurosurg Psychiatry 2001; 71: 589-95.
7. Olin J, Schneider L. Galantamine for Alzheimer’s disease. In: The
Cochrane Library, Issue 4, 2001, Oxford: Update software.
8. Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, Bullock
R and members of the GAL-GBR-2 Study Group. A long-term comparison of
galantamine and donepezil in the treatment of Alzheimer’s disease. Drugs
Aging 2003; 20: 777-89.
9. Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K,
Waugh N. Clinical and cost-effectiveness of donepezil, rivastigmine and
galantamine for Alzheimer’s disease. Int J Technol Assess Health Care
2002; 18: 497-507.
Competing interests:
Ian Howe is an employee of Shire Pharmaceuticals Ltd, the UK licence holder for Reminyl (galantamine)
Competing interests: No competing interests