Table 2

Methodological shortcomings of five randomised controlled trials on rivastigmine and five on galantamine

Author and yearDoseImbalance of groups at baseline with regard to% of missing patients in endpoint analyses—cholinesterase inhibitor (placebo)*Missing information in publicationNo correction for multiple comparisons†Calculation of mean values may bias resultsOther shortcomings
Rivastigmine
Agid et al 1998174 mg—CGIC—18 (12)Correct: no significant result—Analysis of observed cases only
6 mgCGIC—23 (12)Baseline characteristics
Corey-Bloom et al 199818—1-4 mg———ADAS-cog CIBIC-plus PDSDifferent dropout-rates (P<0.05): placebo 16% 6-12 mg: 35%
6-12 mgSex
Forette et al 1999196-12 mg twice daily—ADAS-cog and CIBIC-plus—49 (21)Baseline characteristicsCorrect: no significant resultADAS-cogAnalysis of observed cases only; no a priori defined primary end point
6-12 mg thrice dailyADAS-cog and CIBIC-plus—38 (21)
Ro¨sler et al 1999201-4 mg—CIBIC-plus—4 (4)Correct: 2 significant resultsDifferent dropout-rates (P<0.05): placebo 13% 6-12 mg: 33%
6-12 mgCIBIC-plus—10 (4)Baseline characteristics per groupADAS-cog CIBIC-plus PDS
Potkin et al 2001213-9 mg——Baseline characteristics not complete——Trial is part of an unpublished multicentre trial, No of patients too small
Galantamine
Raskind et al 20002224 mg—ADAS-cog—5 (3) CIBIC-plus—12 (8)—Correct: 3 significant resultsADAS-cogDifferent dropout rates (P<0.05): placebo 19% 24 mg: 32% 32 mg: 42%; last observation carried forward (missing values inserted)
32 mgADAS-cog—7 (3) CIBIC-plus—19 (8)
Rockwood et al 20012324-32 mg—CIBIC-plus—5 (1)——ADAS-cogDifferent dropout rates (P<0.05): placebo 10% 24-32 mg: 33%; last observation carried forward
Tariot et al 2000248 mg—ADAS-cog—10 (11) CIBIC-plus—9 (9)——ADAS-cogLast observation carried forward
16 mgADAS-cog—9 (11) CIBIC-plus—8 (9)
24 mgADAS-cog—7 (11) CIBIC-plus—7 (9)
Wilcock et al 20002524 mg—CIBIC-plus—6 (6)—Correct: 3 significant resultsADAS-cogDifferent dropout rates (P<0.05): placebo 14%; 32 mg: 25%; last observation carried forward
32 mgCIBIC-plus—9 (6)
Wilkinson et al 20012618 mg—ADAS-cog—8 (6)——ADAS-cogDifferent dropout rates (p<0.05): placebo 16% 36 mg: 48%; last observation carried forward
24 mgADAS-cog—2 (6)
36 mgADAS-cog—6 (6)

  • ADAS-cog=Alzheimer's disease assessment scale—cognitive subscale.

  • CIBIC-plus=Clinician's interview based impression of changewith caregiver input.

  • CGIC=Clinical global impression of change.

  • PDS=Progressive deterioration scale.

  • * Refers to the intention to treat population.

  • † This criterion is satisfied, when several primary end points were calculated without correction for multiplicity and the presented results after correction exceed the significance level of 5%. To adjust for multiple comparisons we used the Bonferroni method. As many trials do not report the number of attempted comparisons, the minimum number of reported independent tests concerning primary end points was used for adjustment. For Example, in the study by Burns et al,8 two dose groups of donepezil and two primary outcome measures were specified: ADAS-cog and CIBIC-plus. Therefore four comparisons were assumed for Bonferronl adjustment, leading to a required level of 0.05/4=0.0125. This, in spite of an ambiguous definition of the evaluation procedure for the CIBIC-plus in the original publication, which allowed for much more methods of comparison, all of which are mentioned in the results section of the study: comparison of means and of fractions, applying various cut-points. Assuming four comparisons, one end point did not reach the adjusted level: the comparison of donepezil 5 mg with placebo on the CIBIC-plus scores ≤3 (P=0.015). The three other results remain significant after adjustment.