Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease

K Rockwood, K Rockwood

Abstract

Background: Six cholinesterase inhibitors (ChEIs) have been tested in people with Alzheimer's disease, using methods currently required for regulatory approval. The clinical importance of their treatment effects is controversial.

Objective: To determine whether cholinesterase inhibition produces treatment effects in Alzheimer's disease that are large enough to be clinically detectable.

Methods: Overview analysis of published trials of ChEIs in which the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and a global clinical measure were primary outcomes. Two quantitative summary measures of the treatment effect (Cohen's d and the standardised response mean (SRM)) were calculated and presented as funnel plots. Observed cases analyses and intention to treat (ITT) with the last observation carried forward (LOCF) analyses were compared.

Results: The median Cohen's d effect sizes (ES) using ITT samples with LOCF for the ADAS-Cog were: low dose of a ChEI (n = 8 studies) median ES = 0.15, range = 0.03-0.22; medium dose (n = 13) median ES = 0.23, range = 0.12-0.29; high dose (n = 9) median ES = 0.28, range = 0.01-0.31. In general, the ES were larger when calculated as SRMs (for example, high dose ChEI studies, median SRM = 0.47; range = 0.30-0.63) and highest in the observed cases analyses (for example, high dose median SRM = 0.56, range = 0.35-0.78). Global clinical scales produced similar estimates of ES (for example, high dose ChEI, ITT/LOCF median Cohen's d = 0.29, range = 0.20-0.47).

Conclusions: ChEIs produce small-moderate effect sizes in clinical trials which are reproducible and demonstrate a dose response. Better descriptions of the patterns of treatment response are needed to guide individual patient decisions about the effectiveness of treatment, but group effects are evident and appear large enough to be clinically detectable.

References

    1. Dement Geriatr Cogn Disord. 2003;15(1):26-33
    1. Lancet. 2002 Apr 13;359(9314):1283-90
    1. Am Heart J. 2003 Jan;145(1):109-17
    1. JAMA. 2003 Jan 8;289(2):210-6
    1. Arthritis Rheum. 2003 Feb;48(2):313-8
    1. N Engl J Med. 2003 Apr 3;348(14):1333-41
    1. J Am Geriatr Soc. 2003 May;51(5):657-64
    1. Neurology. 2003 Aug 26;61(4):479-86
    1. Lancet Neurol. 2003 Oct;2(10):630-3
    1. J Psychiatr Res. 1975 Nov;12(3):189-98
    1. Am J Psychiatry. 1984 Nov;141(11):1356-64
    1. N Engl J Med. 1992 Oct 29;327(18):1253-9
    1. JAMA. 1994 Apr 6;271(13):985-91
    1. Neurology. 1994 Jul;44(7):1215-20
    1. Neurology. 1994 Dec;44(12):2315-21
    1. Alzheimer Dis Assoc Disord. 1996 Fall;10(3):124-31
    1. Dementia. 1996 Nov-Dec;7(6):293-303
    1. Neurology. 1996 Dec;47(6):1389-95
    1. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S22-32
    1. JAMA. 1997 Oct 22-29;278(16):1327-32
    1. Neurology. 1998 Jan;50(1):136-45
    1. Arch Intern Med. 1998 May 11;158(9):1021-31
    1. Neurology. 1998 May;50(5):1214-21
    1. Neurology. 1998 May;50(5):1222-30
    1. JAMA. 1998 Nov 25;280(20):1777-82
    1. J Gerontol A Biol Sci Med Sci. 1999 Feb;54(2):M65-9
    1. BMJ. 1999 Mar 6;318(7184):633-8
    1. J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):137-47
    1. Neurology. 1999 Apr 12;52(6):1146-52
    1. JAMA. 1999 Apr 21;281(15):1401-6
    1. Dement Geriatr Cogn Disord. 1999 Nov-Dec;10(6):534-40
    1. N Engl J Med. 1999 Nov 25;341(22):1670-9
    1. Arch Gen Psychiatry. 2000 Feb;57(2):157-64
    1. Int J Geriatr Psychiatry. 2000 Mar;15(3):203-7
    1. Dement Geriatr Cogn Disord. 2000 Jul-Aug;11(4):230-7
    1. Neurology. 2000 Jun 27;54(12):2269-76
    1. Alzheimer Dis Assoc Disord. 2000 Jul-Sep;14(3):182-5
    1. Dement Geriatr Cogn Disord. 2000 Nov-Dec;11(6):299-313
    1. Int Psychogeriatr. 2000 Sep;12(3):403-13
    1. Alzheimer Dis Assoc Disord. 2000 Oct-Dec;14(4):209-11
    1. Cochrane Database Syst Rev. 2000;(4):CD001190
    1. Dement Geriatr Cogn Disord. 2001 May-Jun;12(3):232-6
    1. Arch Neurol. 2001 Mar;58(3):417-22
    1. Neuroepidemiology. 2001 May;20(2):51-6
    1. Aging (Milano). 2001 Jun;13(3):143-62
    1. Neurology. 2001 Aug 14;57(3):481-8
    1. Neurology. 2001 Aug 14;57(3):489-95
    1. J Neurol. 2001 Jul;248(7):551-7
    1. Neurology. 2001 Aug 28;57(4):613-20
    1. Int J Geriatr Psychiatry. 2001 Sep;16(9):852-7
    1. J Neurol Neurosurg Psychiatry. 2001 Nov;71(5):589-95
    1. Ann Neurol. 2002 Feb;51(2):145-55
    1. Neurology. 2002 Feb 12;58(3):433-7
    1. Cochrane Database Syst Rev. 2002;(3):CD001747
    1. Cancer. 2002 Sep 1;95(5):950-9
    1. Int J Technol Assess Health Care. 2002 Summer;18(3):497-507
    1. J Neurol Neurosurg Psychiatry. 2002 Nov;73(5):500-7
    1. Int J Geriatr Psychiatry. 2002 Nov;17(11):1006-11
    1. Dement Geriatr Cogn Disord. 1999 May-Jun;10(3):237-44
    1. Arch Neurol. 1999 Jun;56(6):735-7
    1. J Geriatr Psychiatry Neurol. 1999 Spring;12(1):39-48
    1. Bipolar Disord. 2002;4 Suppl 1:66-8

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