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Drugs for Alzheimer's Disease
Three acetylcholinesterase inhibitors (AChE-I) are licensed for Alzheimer's
Disease (AD) in Canada: donepezil (Aricept), rivastigmine (Exelon), and
galantamine (Reminyl). In 2004 memantine (Ebixa), a neuro-receptor antagonist,
was conditionally approved.
What treatment outcomes are important to patients and
Relevant goals for community-living patients with dementia include:
- avoiding or delaying institutionalization;
- preserving activities of daily living (ADL) and cognitive functions such
as reading and writing, ability to hold conversations, enjoy TV, radio, or
- improving the patient and caregiver(s)' quality of life;
- avoiding adverse drug effects, hospitalization, and extra costs or
What does AChE-I treatment achieve?
Results of double blind RCTs
Donepezil - One trial measured
AD2000 trial: This randomized controlled trial (RCT) of donepezil vs.
placebo studied clinically suspected mild to moderate AD in 565 patients:
donepezil (n=282), placebo (n=283); median age 75, baseline median Mini Mental
Status Exam (MMSE) score 19 (30-pt scale).1 292
patients completed 60 weeks, and 111 completed 114 weeks of treatment, making
this the longest RCT for AD. The authors reported: “Donepezil did not reduce
the relative risk of entering institutional care: RR 0.97 [95% CI 0.72-1.30;
p=0.8] nor the combined risk of progression of disability or
institutionalization: RR 0.96 [95% CI 0.74-1.24; p=0.7]. No significant
differences were seen between donepezil and placebo in behavioural and
psychological symptoms, carer psychopathology, formal care costs, unpaid
caregiver time, adverse events or deaths, or between 5 mg/d and 10 mg/d doses of
Eleven additional published trials provide evidence that donepezil 5-10
mg/d improves test scores assessing cognition and clinical impressions over 3-12
months, versus placebo:
- mean difference in MMSE of ~ 1 point (30-pt scale);
- 2-3 point mean difference in the Alzheimer's Disease Assessment Scale,
cognitive subscale (ADAS-Cog), a 70-pt scale;
- mean difference of ~ 0.5 on a 7-pt scale, a clinical observer's
interview-based impression of change with caregiver input (CIBIC+), where a
1-pt change represents minimal improvement.2-12
Cholinergic effects such as diarrhea [absolute risk increase (ARI)=12%;
number needed to harm (NNH)=8] and nausea [ARI=5%, NNH=20] are the most frequent
adverse effects.7 Meta-analysis of 9 RCTs
reporting serious adverse events (SAE) indicates a trend to increased SAE with
donepezil 10 mg/d: 150/1345 (11.2%) vs. placebo 123/1317 (9.3%), RR 1.22
Rivastigmine and Galantamine
Similar magnitude of effect on scores
Rivastigmine: 5 published 3-6 month placebo controlled RCTs of
rivastigmine 6-12 mg/d in mild to moderate AD found changes similar to those
observed with donepezil.13-17 In a meta-analysis
- mean ADAS-cog differed by ≤ 2.1
- Progressive Disability Scale differed by ≤
2.2 points (100-pt scale);
- CIBIC+ “improved” in ≤ 7% of
Nausea [ARI=17%, NNH=6] and vomiting [ARI=14%, NNH=7] were the most frequent
adverse effects, and 1/6 to 1/5 of patients lost > 7% of body weight.
Galantamine: 5 published 6-12 month RCTs found that galantamine at
16-24 mg/d changed ADAS-cog by ~ 3.4 points.19-23
However, galantamine led to more withdrawals due to adverse effects [ARI=7.5%,
NNH=13] and caused cholinergic adverse effects in up to 20% of patients (e.g.
NNH=5 for nausea at 24 mg/d).
What do trial results mean for patients?
The clinical relevance of this degree of difference on cognitive, ADL and
clinical impression scales has not been established. In AD2000, a mean 0.8-pt
improvement in MMSE was observed but disability and institutionalization were
unaffected.1 A metaanalysis of 16 RCTs
summarized findings for AChE-I vs. placebo:
- 9% more patients experience improvement on CIBIC+ or a similar scale
[number needed to treat (NNT)=12];
- 8% more patients experience adverse effects [NNH=12].24
AChE-I trial reports tend to exaggerate beneficial effects and underestimate
adverse effects. This is due to incomplete follow-up and the bias introduced by
more early withdrawals from the active-treatment groups in a progressively
deteriorating disease. A systematic review concludes that, “Because of flawed
methods and small clinical benefits, the scientific basis for recommendations of
cholinesterase inhibitors for the treatment of Alzheimer's disease is
Is one AChE-I better for AD?
No double-blind RCT compares donepezil, galantamine or rivastigmine with one
another. Three open label or partially blinded trials each claim that the
sponsor's drug did better than the comparator.26-28
New evidence about prevention of AD
Mild cognitive impairment may precede diagnosis of AD. In a recent trial
involving patients with mild cognitive impairment, progression to AD occurred in
16% of patients per year.29 Placebo (n=259) was
compared with donepezil 10 mg/d (n=253) or vitamin E 2000 IU/d (n=257) in
patients whose baseline mean MMSE was 27 and average age was 73. Over 3 years,
neither active treatment prevented progression to AD. Donepezil caused more
adverse effects, including diarrhea [ARI=10.1%, NNH=10], muscle cramps [ARI=14.4%,
NNH=7], insomnia [ARI=8.9%, NNH=11], nausea [ARI=6.5%, NNH=15], and abnormal
dreams [ARI=5.2%, NNH=19]. Mortality did not differ between groups. Total
serious adverse events were not reported.
Two large unpublished RCTs of galantamine 8-12 mg b.i.d. (combined n=2057) also
found no effect on progression to AD, nor on a modified test of cognition at 1
or 2 years. However, combined analysis showed higher mortality in the
galantamine groups (galantamine = 13/1026, placebo = 2/1022; hazard ratio = 4.86
[1.76-13.4],30 prompting a Health Canada safety
Can AChE-I therapy be discontinued?
The AD2000 trial observed at least 167 patients who discontinued donepezil or
placebo under doubleblinded conditions. There was no evidence of adverse effects
from treatment discontinuation.1
Memantine is licensed for moderate to severe AD. Two double blind RCTs
(n=252; n=340) compared memantine 20 mg/d with placebo over a 24-28 week period.31,32
In a third RCT (n=403) in patients already taking donepezil, addition of
memantine 20 mg/d was compared with placebo.33
None of these trials reports a difference in mortality, serious morbidity,
time-to-institutionalization, or clinically significant functional advantages.
Mean CIBIC+ scores did not differ31 or improved
by 0.25-0.3 points32,33 with memantine use (1-pt
difference = minimal improvement). A 100-point Severe Impairment Battery (SIB)
scale assessing cognitive performance differed by 6.1 points (p<0.001) in one
placebo-controlled trial,31 but was unaffected
in a second larger trial.32 With memantine +
donepezil vs. donepezil alone, although a significant difference in SIB scores
was reported, the two treatment arms differed more at baseline (by 2 points)
than at study termination (by 1.4 points).33 ADL
was unaffected or differed by 1.4 or 2.1 points out of a possible 54 points.31-33
Memantine did not increase the rate of withdrawals in total or due to adverse
Drugs for Alzheimer's disease
|ERRATUM: Due to a typographical
error in the original published version of this Letter the daily dose
and cost for galantamine and rivastigmine were incorrect (inversed).
This error was corrected in the table above. For the record, the
original published version of this Letter can be found at
- Donepezil has not been demonstrated to improve outcomes of importance
to patients and caregivers (e.g. institutionalization or disability).
Rivastigmine and galantamine have not been studied for these outcomes.
- AChE-I cause gastrointestinal, muscular, and other adverse effects and
likely increase serious adverse events.
- There is no evidence that stopping AChE-I treatment is harmful.
- In advanced AD, memantine has not been demonstrated to improve outcomes
of importance to patients and caregivers.
Therapeutics Letter was submitted for
review to 50
experts and primary care
physicians in order to correct any inaccuracies and to ensure that the
information is concise and relevant to clinicians.
- Courtney C, Farrell D, Gray R, et al.
for the AD 2000 Collaborative Group. Long-term donepezil treatment in 565
patients with Alzheimer's disease (AD2000): randomized double-blind trial.
Lancet 2004; 363:2105-2115.
- Rogers SL, Friedhoff LT. The
efficacy and safety of donepezil in patients with Alzheimer's disease:
results of a US Multicentre, Randomized, Double-Blind, Placebo-Controlled
Trial. Dementia 1996; 7:293-303.
- Rogers SL, Farlow MR, Doody RS, et
al. A 24-week, double-blind, placebo-controlled trial of donepezil in
patients with Alzheimer's disease. Neurology 1998; 50:136-145.
- Rogers SL, Doody, RS, Mohs RC,
Friedhoff LT. Donepezil improves cognition and global function in
Alzheimer disease: a 15-week, double-blind, placebo-controlled study.
Arch Intern Med 1998; 158:1021-1031.
- Burns A, Rossor M, Hecker J, et al.
The effects of donepezil in Alzheimer's disease - results from a
multinational trial. Dement Geriatr Cogn Disord 1999; 10:237-244.
- Greenberg SM, Tennis MK, Brown LB, et
al. Donepezil therapy in clinical practice: a randomized crossover study.
Arch Neurol 2000; 57:94-99.
- Mohs RC, Doody RS, Morris JC, et al.
for the Donepezil “312” Study Group. A 1-year, placebocontrolled
preservation of function survival study of donepezil in AD patients.
[erratum appears in Neurology 2001; 57:1942]. Neurology 2001; 57:481-488.
- Winblad B, Engedal K, Soininen H, et
al. for the Donepezil Nordic Study Group. A1-year, randomized,
placebo-controlled study of donepezil in patients with mild to moderate AD.
Neurology 2001; 57:489-495.
- Feldman H, Gauthier S, Hecker J, et
al. for the Donepezil MSAD Study Investigators Group. A 24-week,
randomized, double-blind study of donepezil in moderate to severe
Alzheimer's disease. Neurology 2001; 57:613-620.
- Tariot PN, Cummings JL, Katz IR, et
al. A randomized, double-blind, placebo-controlled study of the efficacy
and safety of donepezil in patients with Alzheimer's disease in the nursing
home setting. J Am Geriatr Soc 2001; 49:1590-1599.
- Homma A, Takeda M, Imai Y, et al.
Clinical efficacy and safety of donepezil on cognitive and global function
in patients with Alzheimer's disease. A 24-week, multi center, double-blind,
placebo-controlled study in Japan. E2020 Study Group. Dement Geriatr
Cogn Disord 2000; 11:299-313.
- Seltzer B, Zolnouni P, Nunez M, et
al. for the Donepezil “402” Study Group. Efficacy of Donepezil in
Early-Stage Alzheimer Disease: a randomized placebo-controlled trial.
[erratum appears in Arch Neurol 2005; 62: 825]. Arch Neurol 2004;
- Agid Y, Dubois B, Anand R, Gharabawi
G. Efficacy and tolerability of rivastigmine in patients with dementia of
the Alzheimer type. Curr Ther Res Clin Exp 1998; 59:837-845.
- Anand R, Gharabawi G, Enz A.
Efficacy and safety results of the early phase studies with Exelon(TM)
(ENA-713) in Alzheimer's disease: An overview. J Drug Dev Clin Pract
- Corey-Bloom J, Anand R, Veach J. A
randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine
tartrate), a new acetylcholinesterase inhibitor, in patients with mild to
moderately severe Alzheimer's disease. Int J Geriatr Psychopharmacol
- Forette F, Anand R, Gharabawi G. A
phase II study in patients with Alzheimer's disease to assess the
preliminary efficacy and maximum tolerated dose of rivastigmine (ExelonTM).
Eur J Neurol 1999; 6:423-429.
- Rosler M, Anand R, Cicin-Sain A, et
al. Efficacy and safety of rivastigmine in patients with Alzheimer's
disease: International randomised controlled trial. Br Med J 1999;
- Birks J, Grimley Evans J, Iakovidou
V, Tsolaki M. Rivastigmine for Alzheimer's disease. The Cochrane
Database of Systematic Reviews 2000, Issue 4. Art. No.:CD001191.
- Wilcock GK, Lilienfeld S, Gaens E.
Efficacy and safety of galantamine in patients with mild to moderate
Alzheimer's disease: multicentre randomised controlled trial. Galantamine
International-1 Study Group. Br Med J 2000; 321:1445-1449.
- Raskind MA, Peskind ER, Wessel T,
Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial
with a 6-month extension. The Galantamine USA-1 Study Group. Neurology
- Tariot PN, Solomon PR, Morris JC, et
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The Galantamine USA-10 Study Group. Neurology 2000; 54:2269-2276.
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- Lanctot KL, Hermann N, Yau KK, et al.
Efficacy and safety of cholinesterase inhibitors for Alzheimer's disease:
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Comparative trials of AChE-I:
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et al. A multinational, randomised, 12-week, comparative study of
donepezil and rivastigmine in patients with mild to moderate Alzheimer's
disease. Int J Clin Pract 2002; 56:441-446.
- Jones RW. Soininen H. Hager K, et al.
A multinational, randomised, 12-week study comparing the effects of
donepezil and galantamine in patients with mild to moderate Alzheimer's
disease. Int J Geriatr Psychiatry 2004; 19:58-67.
- Wilcock G, Howe I, Coles H, et al.
for the GAL-GBR-2 Study Group. A long-term comparison of galantamine and
donepezil in the treatment of Alzheimer's disease. Drugs Aging 2003;
Minimal Cognitive Impairment:
- Peterson RC, Thomas RG, Grundman M,
et al. for the Alzheimer's Disease Cooperative Study Group. Vitamin E and
donepezil for the treatment of mild cognitive impairment. N Engl J Med
- Johnson & Johnson. Synopsis.
GAL-INT-11, GAL-INT-18, and GAL-COG-302 (Interim Analysis). Accessed
August 4, 2005 at
- Reisberg B, Doody R, Stoffler A, et
al. for the Memantine Study Group. Memantine in moderate-to-severe
Alzheimer's disease. N Engl J Med 2003; 348:1333-41.
- Forest Laboratories Clinical Trial
Registry. Study No. MEM-MD-01. A Randomized, Double-Blind,
Placebo-Controlled Evaluation of the Safety and Efficacy of Memantine in
Patients with Moderate to Severe Dementia of the Alzheimer's Type
(unpublished, accessed July 4, 2005 at
- Tariot PN, Farlow MR, Grossberg GT,
et al. for the Memantine Study Group. Memantine treatment in patients
with moderate to severe Alzheimer disease already receiving donepezil: a
randomized controlled trial. JAMA 2004; 291:317-324.
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