Table 2.

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

Author and year	Dose	Imbalance of groups at baseline with regard to	% of missing patients in endpoint analyses—cholinesterase inhibitor (placebo)*	Missing information in publication	No correction for multiple comparisons†	Calculation of mean values may bias results	Other shortcomings
Rivastigmine
Agid et al 199817	4 mg	—	CGIC—18 (12)	Baseline characteristics	Correct: no significant result	—	Analysis of observed cases only
	6 mg		CGIC—23 (12)
Corey-Bloom et al 199818	1-4 mg		—	—	—	ADAS-cog CIBIC-plus PDS	Different dropout-rates (P<0.05): placebo 16% 6-12 mg: 35%
	6-12 mg	Sex
Forette et al 199919	6-12 mg twice daily	—	ADAS-cog and CIBIC-plus—49 (21)	Baseline characteristics	Correct: no significant result	ADAS-cog	Analysis of observed cases only; no a priori defined primary end point
	6-12 mg thrice daily		ADAS-cog and CIBIC-plus—38 (21)
Rösler et al 199920	1-4 mg	—	CIBIC-plus—4 (4)	Baseline characteristics per group	Correct: 2 significant results	ADAS-cog CIBIC-plus PDS	Different dropout-rates (P<0.05): placebo 13% 6-12 mg: 33%
	6-12 mg		CIBIC-plus—10 (4)
Potkin et al 200121	3-9 mg	—	—	Baseline characteristics not complete	—	—	Trial is part of an unpublished multicentre trial, No of patients too small
Galantamine
Raskind et al 200022	24 mg	—	ADAS-cog—5 (3) CIBIC-plus—12 (8)	—	Correct: 3 significant results	ADAS-cog	Different dropout rates (P<0.05): placebo 19% 24 mg: 32% 32 mg: 42%; last observation carried forward (missing values inserted)
	32 mg		ADAS-cog—7 (3) CIBIC-plus—19 (8)
Rockwood et al 200123	24-32 mg	—	CIBIC-plus—5 (1)	—	—	ADAS-cog	Different dropout rates (P<0.05): placebo 10% 24-32 mg: 33%; last observation carried forward
Tariot et al 200024	8 mg	—	ADAS-cog—10 (11) CIBIC-plus—9 (9)	—	—	ADAS-cog	Last observation carried forward
	16 mg		ADAS-cog—9 (11) CIBIC-plus—8 (9)
	24 mg		ADAS-cog—7 (11) CIBIC-plus—7 (9)
Wilcock et al 200025	24 mg	—	CIBIC-plus—6 (6)	—	Correct: 3 significant results	ADAS-cog	Different dropout rates (P<0.05): placebo 14%; 32 mg: 25%; last observation carried forward
	32 mg		CIBIC-plus—9 (6)
Wilkinson et al 200126	18 mg	—	ADAS-cog—8 (6)	—	—	ADAS-cog	Different dropout rates (p<0.05): placebo 16% 36 mg: 48%; last observation carried forward
	24 mg		ADAS-cog—2 (6)
	36 mg		ADAS-cog—6 (6)

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

CIBIC-plus=Clinician's interview based impression of change with 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.