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Letters

Drug therapy for Alzheimer's disease

Shane Kavanagh and Patricia Kabathova
CMAJ April 27, 2004 170 (9) 1371-1372; DOI: https://doi.org/10.1503/cmaj.1031912
Shane Kavanagh
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Patricia Kabathova
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We would like to highlight several shortcomings in the meta-analysis of cholinesterase inhibitors in Alzheimer's disease presented by Krista Lanctôt and associates1 and to clarify information on the risk–benefit ratio for galantamine.

First, some of the data used in the meta-analysis were obtained with subtherapeutic or higher-than-recommended doses, and treatment duration varied widely (12 weeks to 1 year). Consequently, the heterogeneity reported by Lanctôt and associates1 is unsurprising. Focusing on data obtained with recommended maintenance doses for common treatment durations would yield more reliable and clinically relevant information.

Second, the use of global clinical measures for examining patient change is problematic because of the processes used to obtain these results (usually semistructured interviews): with this method, the domains covered and specific questions used may vary from one subject to another. Furthermore, the relative contribution of changes in different domains to the overall clinical judgement about change from baseline values varies between clinicians. Inter-rater reliability and differences between the 2 assessment scales used in the study by Lanctôt and associates are also of concern.2 Given the degenerative nature of Alzheimer's disease, limiting the definition of treatment success to improvement may be too restrictive. Rather, an overall positive response encompasses not only an increase in the number of patients showing improvement, but also a reduction in the number showing (greater) deterioration, especially over the longer term. For example, longer-term clinical trials of galantamine (5 to 6 months) have shown statistically significant benefit of 16-mg and 24-mg doses over placebo.3,4,5 More generally, given the importance of cognition to Alzheimer's disease and the relatively smaller inter-rater variation in this measure, we suggest that more weight be given to findings for the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-Cog).

The data presented on the safety of galantamine do not reflect product labelling and recommended use in clinical settings. The clinical development of this drug has involved an evolution away from high doses (32 mg) and fast (weekly) titration3,4,6,7 toward lower dosing (16 and 24 mg) with a slower (monthly) titration schedule.5 By combining data from early and later trials, Lanctôt and associates1 determined discontinuation rates that incorrectly appear higher than those for donepezil or rivastigmine. Safety data from a trial in which dosing was consistent with product labelling5 showed discontinuation rates due to adverse events similar to placebo (odds ratio [OR] for 16-mg dose 0.97, 95% confidence interval [CI] 0.51 to 1.86; OR for 24-mg dose 1.46, 95% CI 0.80 to 2.64).8 The similarity in safety profiles of galantamine and donepezil was confirmed in a recent comparative trial.9

Shane Kavanagh Johnson & Johnson Pharmaceutical Services Beerse, Belgium Patricia Kabathova Johnson & Johnson Pharmaceutical Services Raritan, NJ

Footnotes

  • Competing interests: The authors are employed within Johnson & Johnson Pharmaceutical Services. Reminyl, a brand of galantamine, was developed by the research and development arm of Johnson & Johnson and is marketed around the world by various operating companies of Johnson & Johnson.

References

  1. 1.↵
    Lanctôt KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003;169(6):557-64.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    Schneider L. CIBIC+: What, why and how? Alzheimer Insights 1997;Jun:2-8.
  3. 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.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    Wilcock G, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: a multi-centre randomised controlled trial. Galantamine International-1 Study Group. BMJ 2000;321:1445-9.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    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.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    Wilkinson D, Murray J. Galantamine: a randomised, double-blind, dose comparison in patients with Alzheimer's disease. Int J Geriatr Psychiatry 2001;16:852-7.
    OpenUrlCrossRefPubMed
  7. 7.↵
    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.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    Olin J, Schneider L. Galantamine for Alzheimer's disease [Cochrane review]. In: The Cochrane Library; Issue 4, 2001. Oxford: Update Software.
  9. 9.↵
    Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, et al. A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease. Drugs Aging 2003;20:777-89.
    OpenUrlCrossRefPubMed
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Canadian Medical Association Journal: 170 (9)
CMAJ
Vol. 170, Issue 9
27 Apr 2004
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Drug therapy for Alzheimer's disease
Shane Kavanagh, Patricia Kabathova
CMAJ Apr 2004, 170 (9) 1371-1372; DOI: 10.1503/cmaj.1031912

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Drug therapy for Alzheimer's disease
Shane Kavanagh, Patricia Kabathova
CMAJ Apr 2004, 170 (9) 1371-1372; DOI: 10.1503/cmaj.1031912
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