Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.331.7512.321 (Published 04 August 2005) Cite this as: BMJ 2005;331:321
Data supplement
Table A Checklist used to assess the RCTs on donepezil, rivastigmine and galantamine
Methodological considerations
Participants
Were inclusion and exclusion criteria clearly defined and strictly followed?
Randomization
Which method was used to generate and implement the random allocation sequence? Who assigned participants to the groups?
Stratification
Was patient allocation stratified according to the prognostic factors?
Blinding
Were the participants, those administering the interventions, those assessing the outcomes, and those analyzing the data blinded to group assignment? Was blinding effective?
Outcome measures
Were the primary and secondary outcome measures, including the tests used, the duration of the study, and the statistical methods applied for analysis clearly defined?
Significance level
Which significance level was defined and did the authors adhere to it?
Power
What was the planned power? Did the planned sample size meet the intended sample size?
Treatment
Were patients of intervention and placebo groups treated equally, apart from the drug given? Were they observed with the same attention?
Results
Baseline data
Were baseline demographic and clinical characteristics comparable between groups?
Multiplicity
Was multiple testing avoided or corrected for? Were all primary outcome measures still statistically significant when corrected according to multiplicity?
Adverse events
Were adverse events registered and reported adequately?
Intention-to-treat-analysis
Was analysis performed using the intention-to-treat (ITT) method? How many patients were excluded from "ITT" analysis? What results would emerge in a worst-case-scenario? How many patients were on treatment at the end of the trial?
Numbers analyzed
Are the numbers of participants in each group included in each analysis stated?
Outcomes and estimation
Are the outcomes for each primary outcome measure described including its confidence interval?
Consistency
Are data shown in text, figures and tables consistent? Does the abstract correctly summarize the results of the study?
Overall interpretation of the study
Methodology
Which impact did methodological insufficiencies have on the results? Can they be ignored or do they jeopardize the conclusions?
Clinical relevance
Are the observed differences between intervention and the placebo group clinically relevant? Was the duration of the study adequate with regard to the natural course of the illness?
Conflict of interest
Was the sponsoring of the study clear? Could it have influenced the interpretation of data?
Table B Results reported in the 22 randomized controlled trials analyzed
Author and year
Characteristics of trial
Primary endpoint(s) based on ITT-population whenever possible
Dose
Treat-ment in weeks
N
Baseline MMSE (mean ± SD #)
ADAS-cog §
CIBIC-plus §
Percentage of patients
with benefit on CIBIC-plus (ChE-Inhibitor : placebo)
Other endpoints §
DONEPEZIL
Rogers 1996 (5)
1 mg
12
42
19.6
1.6 (p=0.11)
CGIC (sc.£ 4) 82:80 (p=0.5)
3 mg
40
18.6
2.1 (p=0.036)‡
CGIC (sc.£ 4) 83:80 (p=0.5)
5 mg
39
18.0
3.2 (p=0.002)
CGIC (sc.£ 4) 90:80 (p=0.23)
placebo
40
18.2
Rogers 1998a (6)
5 mg
12
157
19.4 ± 5.0#
2.5 (1.3..3.6)
0.3 (0.08..0.50)
(sc.£ 3) 32:18 (p=0.004)Ψ †
10 mg
158
19.4 ± 5.0#
3.1 (1.9..4.2)
0.4 (0.13..0.55)
(sc.£ 3) 38:18 (p=0.0001)Ψ
placebo
153
19.8 ± 5.0#
Rogers 1998b (7)
5 mg
24
154
19.0 ± 5.0#
2.49 (p<0.0001)
0.36 (p=0.0047)
(sc.£ 3) 26:11 (p=0.0007)Ψ *
10 mg
157
18.9 ± 5.0#
2.88 (p<0.0001)
0.44 (p<0.0001)
(sc.£ 3) 25:11 (p=0.002)Ψ *
placebo
162
19.2 ± 5.1#
Burns 1999 (8)
5 mg
24
271
20 ± 5#
1.5 (0.5..2.4)&
(sc.£ 3) 21:14 (p=0.03)Ψ ‡
10 mg
273
20 ± 4#
2.9 (1.9..3.9)&
(sc.£ 3) 25:14 (p=0.0008)Ψ
placebo
274
20 ± 5#
Greenberg 2000 (9)
5 mg
6
60
21.8 ± 3.7
2.17 (0.20..4.10)
comment: cross-over-design
Homma 2000 (10)
5 mg
24
136
not reported
2.54 (p<0.001)
J-CGIC (sc.£ 3) 48:19 (p<0.0001)Ψ
placebo
132
adequately
Feldman 2001 (11)
10 mg
24
144
11.7 ± 4.8#
0.54 (0.29..0.79)&
(sc.£ 4) 63:42 (p<0.001)
146
placebo
12 ± 3.6#
Mohs 2001 (12)
10 mg
54
214
17.1 ± 2.9#
median time to clinically evident decline in function in days:
placebo
217
17.1 ± 2.9#
median (CI) 357 (280..¥ ) : 208 (165..252)
Tariot 2001 (13)
10 mg
24
103
14.4 ± 5.4
Neuropsychiatric Inventory – Nursing Home Version (NPI-NH): 2.6 (p>0.05)
placebo
105
14.4 ± 5.8
Winblad 2001 (14)
10 mg
52
142
19.4 ± 4.4
Gottfries-Bråne-Steen-Skala (GBS): 3.4 (p=0.054)
placebo
144
19.3 ± 4.5
AD 2000 2004 (15)
5 or 10 mg
12, 48 or more
283
19 (10-27)Φ
Relative risk of entry to institutional care 0.97 (0.72..1.30)
placebo
283
19 (10-26)Φ
Relative risk of reaching disability endpoint (BADLS): 1.02 (0.72..1.45)
Holmes 2004 (16)
10 mg
12
41
20.8± 3.8#
Neuropsychiatric Inventory, change in the total score: 6.2 (p=0.02)
placebo
55
21.1± 6.7#
comment: drug withdrawal study
RIVASTIGMINE
Agid 1998 (17)
4 mg
13
136
not reported
(CGIC sc.£ 2) 32:30 (p=0.5)
6 mg
133
(CGIC sc.£ 2) 43:30 (p=0.05)‡*
placebo
133
Corey-Bloom 1998 (18)
1-4 mg
26
233
19.5
1.73 (0.64..2.82)Ψ
0.26 (0.03..0.49)‡
PDS - 0.29 (- 2.16..1.58)
6-12 mg
231
19.6
3.78 (2.69..4.87)Ψ
0.29 (0.07..0.51)
PDS 3.38 (1.51..5.25)
placebo
235
20
Forette 1999 (19)
6-12 mg b.i.d.
18
45
not reported
adequately
1.8 (- 1.7..7.1)&
(sc.£ 3) 57:16 (p=0.007)
6-12 mg t.i.d.
45
4.8 (- 0.7..10.2)&
(sc.£ 3) 35:16 (p=0.13)
placebo
24
Rösler 1999 (20)
1-4 mg
26
243
not reported
- 0.03 (p>0.05)
0.14 (p>0.05)
(sc.£ 3) 30:20 (p<0.05)‡*
PDS - 1.19 (p>0.05)
6-12 mg
243
1.60 (p<0.1)
0.47 (p<0.001)
(sc.£ 3) 37:20 (p<0.001)†
PDS 2.23 (p<0.1)
placebo
239
Potkin 2001 (21)
3-9 mg
26
20
not reported adequately
(sc.£ 4) 75:29 (p<0.03)
placebo
7
GALANTAMINE
Raskind 2000 (22)
24 mg
26
212
19.5 ± 4.4#
3.9 (p<0.001)
(sc.£ 4) 73:57 (p<0.05)*
32 mg
211
19.1 ± 4.4#
3.4 (p<0.001)
(sc.£ 4) 69:57 (p<0.05)‡*
placebo
213
19.2 ± 4.4#
Rockwood 2001 (23)
24-32 mg
13
261
19.7 ± 3.2#
1.6 (p<0.01)
(sc.£ 4) 79:63 (p<0.01)
placebo
125
19.6 ± 3.4#
Tariot 2000 (24)
8 mg
22
140
18.0 ± 3.5#
1.3 (p>0.05)
(sc.£ 4) 53:49 (p>0.05)
16 mg
279
17.8 ± 3.3#
3.1 (p<0.001)
(sc.£ 4) 66:49 (p<0.001)*
24 mg
273
17.7 ± 3.3#
3.1 (p<0.001)
(sc.£ 4) 64:49 (p<0.001)*
placebo
286
17.7 ± 3.4#
Wilcock 2000 (25)
24 mg
26
220
19.5 ± 3.4
2.9 (p<0.001)
(sc.£ 4) 62:50 (p<0.05)‡*
32 mg
218
19.0 ± 3.8
3.1 (p<0.001)
(sc.£ 4) 65:50 (p<0.001)*
placebo
215
19.3 ± 3.5
Wilkinson 2001 (26)
18 mg
12
88
18.8 ± 2.8#
1.7 (p>0.05)
24 mg
56
18.2 ± 3.0#
3.0 (p<0.01)
36 mg
54
18.8 ± 3.7#
2.3 (p=0.08)
placebo
87
18.7 ± 2.8#
Legend to table 2
N patients randomized
MMSE Mini-Mental State Examination, SD = standard deviation
ADAS-cog Alzheimer’s Disease Assessment Scale-cognitive Subscale
CIBIC-plus Clinician’s Interview-Based Impression of Change-Scale plus Caregiver supplied information
CGIC Clinical Global Impression of Change Scale, J-CGIC = Japanese version
PDS Progressive Deterioration Scale
b.i.d.; t.i.d. two treatments per day; three treatments per day
sc. score
* p>0.05 in worst-case scenario, i.e. all missing patients in the placebo group are assumed as improved and all missing patients in the intervention groups are assumed as worsened
† after consideration of worst-case scenario and correction for multiplicity p>0.05
‡ p>0.05 after correction for multiplicity
§ mean differences between treatment and placebo (95% confidence interval or p value).
# Following the suggestion of the reviewer original baseline standard errors were transformed into standard deviations. This might have led to rounding errors. Transformed data are marked.
Φ Median and range
& Confidence intervals were not available in the original publication and were extracted from figures.
p values or confidence intervals were not directly available in the original publication and had to be calculated from data given in text or tables.
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