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Therapeutics Letter, issue 56, April - August 2005

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 caregivers?

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 music;
• improving the patient and caregiver(s)' quality of life;
• avoiding adverse drug effects, hospitalization, and extra costs or doctor visits.

What does AChE-I treatment achieve?
Results of double blind RCTs

Donepezil - One trial measured institutionalization

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 donepezil.”

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 [0.97-1.52].^{TI, unpublished}

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 vs. placebo:

• mean ADAS-cog differed by ≤ 2.1 points;
• Progressive Disability Scale differed by ≤ 2.2 points (100-pt scale);
• CIBIC+ “improved” in ≤ 7% of patients.¹⁸

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 questionable.”²⁵

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 warning. See: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisoriesavis/public/reminyl_pa-ap_e.html

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

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 points^32,33 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 effects.

Drug costs

Drugs for Alzheimer's disease

Conclusions

• 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.

References

Donepezil trials

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Greenberg SM, Tennis MK, Brown LB, et al. Donepezil therapy in clinical practice: a randomized crossover study. Arch Neurol 2000; 57:94-99.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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; 61:1852-1856.

Rivastigmine trials:

13. 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.
14. 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 1996; 8:109-116.
15. 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 1998; 1:55-65.
16. 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 (Exelon^TM). Eur J Neurol 1999; 6:423-429.
17. 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; 318:633-640.
18. 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.

Galantamine trials:

19. 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.
20. 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 2000; 54:2261-2268.
21. Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology 2000; 54:2269-2276.
22. Rockwood K, Mintzer J, Truyen L, et al. Effects of a flexible galantamine dose in Alzheimer's disease: a randomized, controlled trial. J. Neurol Neurosurg Psychiatry 2001; 71:589-595.
23. Wilkinson D, Murray J. Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease. Int J Geriatr Psychiatry 2001; 16:852-857.

AChE-I Meta-analysis:

24. Lanctot KL, Hermann N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors for Alzheimer's disease: a meta-analysis. CMAJ 2003; 169:557-564.
25. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt H-P, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. Br Med J 2005; 331:321-327.

Comparative trials of AChE-I:

26. Wilkinson DG, Passmore AP, Bullock R, 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.
27. 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.
28. 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; 20:777-789.

Minimal Cognitive Impairment:

29. 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 2005; 352:2379-2388.
30. Johnson & Johnson. Synopsis. GAL-INT-11, GAL-INT-18, and GAL-COG-302 (Interim Analysis). Accessed August 4, 2005 at
    http://www.clinicalstudyresults.org/documents/companystudy_96_1.pdf
    http://www.clinicalstudyresults.org/documents/company-study_96_2.pdf
    http://www.clinicalstudyresults.org/documents/company-study_96_4.pdf

Memantine:

31. 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.
32. 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 http://www.forestclinicaltrials.com/CTR/CTRController/CTRCompletedListStudies)
33. 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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