Table A16-24Acetylcholinesterase inhibitors (donepezil) vs. placebo for the treatment of people with mild cognitive impairment

Quality assessmentSummary of findings
No of patientsEffectQualityImportance
No of studiesDesignLimitationsConsistencyDirectnessOther considerationscholinesterase inhibitorsplaceboRelative (95% CI)Absolute (95% CI)
Delayed recall (LOCF) (NYU Paragraph Test, Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)1130132-WMD −0.30 (−1.01 to 0.41)⊕⊕⊕○
Moderate
9
Delayed recall (Observed case) (NYU Paragraph Test, Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyHigh probability of reporting bias (− 1)389110-WMD −0.50 (−1.38 to 0.38)⊕⊕⊕○
Moderate
6
Immediate recall (LOCF) (NYU Paragraph Test, Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)1130132-WMD −0.60 (−1.31 to 0.11)⊕⊕⊕○
Moderate
9
Immediate recall (Observed case) (NYU Paragraph Test, Range: to . Better indicated by: higher scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)1
High probability of reporting bias (− 1)3
89110-WMD −1.00 (−1.71 to −0.29)⊕⊕○○
Low
6
Cognitive symptoms (LOCF) (ADAS-cog,9 Range: 0 to 70. Better indicated by: lower scores)
2Randomised trialsNo limitationsImportant inconsistency (−1)2No uncertaintyNone383391-WMD −0.72 (−1.28 to −0.15)⊕⊕⊕○
Moderate
7
Cognitive symptoms (Observed case) (ADAS-cog, Range: 0 to 70. Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyHigh probability of reporting bias (− 1)3,89110-WMD −1.40 (−2.66 to −0.14)⊕⊕⊕○
Moderate
6
Activities of Daily Living (projection method used for imputation of missing data) (ADCS MCI-ADL5 Range: 0 to 53. Better indicated by: higher scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyNone253259-WMD −0.85 (−1.55 to −0.15)⊕⊕⊕⊕
High
9
Digit Span Backwards (LOCF) (WMS-R,10 Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)1130132-WMD −0.50 (−1.05 to 0.05)⊕⊕⊕○
Moderate
7
Digit Span Backwards (Observed case) (WMS-R, Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyHigh probability of reporting bias (− 1)389110-WMD −0.60 (−1.16 to −0.04)⊕⊕⊕○
Moderate
5
Symbol digit modalities (LOCF) (Symbol Digit Modalities test, Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)1130132-WMD −1.70 (−3.51 to 0.11)⊕⊕⊕○
Moderate
7
Symbol digit modalities (Observed case) (Symbol Digit Modalities test, Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyHigh probability of reporting bias (− 1)3,89110-WMD −2.40 (−4.52 to −0.28)⊕⊕⊕○
Moderate
5
MMSE (projection method used for imputation of missing data) (Mini Mental State Exam, Range: 0 to 30. Better indicated by: higher scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyNone253259-WMD −0.42 (−0.77 to −0.07)⊕⊕⊕⊕
High
7
CDR Sum of boxes (projection method used for imputation of missing data) ( Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)4253259-WMD −0.09 (−0.22 to 0.04)⊕⊕⊕○
Moderate
7
Global Deterioration (projection method used for imputation of missing data) (Global Deterioration Scale, Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)4253259-WMD −0.08 (−0.17 to 0.01)⊕⊕⊕○
Moderate
7
Cognitive Domains - Overall score (projection method used for imputation of missing data) (Overall score on cognitive domains: memory, executive, language, visiospatial, Range: to . Better indicated by: lower scores)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)4253259-WMD −0.30 (−0.44 to −0.16)⊕⊕⊕○
Moderate
9
Overall clinical improvement (observed case) (Minimal or moderate improvement on CGIC-MCI,11 Follow up: at end of treatment (24 wks))
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)1
High probability of reporting bias (− 1)3
29/89 (32.6%)27/110 (24.5%)RR 1.33 (0.85 to 2.07)80/1 000 (−50 to 210)⊕⊕○○
Low
6
Adverse events ( Follow up: at end of treatment (24 wks))
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyNone116/132 (87.9%)100/137 (73%)RR 1.20 (1.07 to 1.36)150/1 000 (60 to 240)⊕⊕⊕⊕
High
9
Serious adverse events ( Follow up: at end of treatment (24 wks))
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)15/132 (3.8%)6/137 (4.4%)RR 0.86 (0.27 to 2.77)10/1 000 (−50 to 40)⊕⊕⊕○
Moderate
9
Leaving the study early for any reason ( Follow up: at end of treatment (24 – 144 wks))
2Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyNone135/386 (35%)89/396 (22.5%)RR 1.56 (1.24 to 1.95)120/1 000 (60 to 190)⊕⊕⊕⊕
High
9
Leaving the study early due to adverse events ( Follow up: at end of treatment (24 wks))
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyNone29/133 (21.8%)10/137 (7.3%)RR 2.99 (1.52 to 5.88)150/1 000 (60 to 230)⊕⊕⊕⊕
High
9
Diarrhea (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (24 – 144 wks))
2Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyStrong association (+1)12,78/385 (20.3%)26/396 (6.6%)RR 3.09 (2.03 to 4.70)140/1 000 (90 to 180)⊕⊕⊕⊕
High
7
Nausea (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (24 – 144 wks))
2Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyStrong association (+1)12,41/385 (10.6%)14/396 (3.5%)RR 3.02 (1.68 to 5.44)70/1 000 (40 to 110)⊕⊕⊕⊕
High
7
Vomiting (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (24 – 144 wks))
2Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyVery strong association (+2)13,27/385 (7%)5/396 (1.3%)RR 5.14 (2.08 to 12.70)60/1 000 (30 to 90)⊕⊕⊕⊕
High
7
Leg/muscle cramps (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (24 – 144 wks))
2Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyVery strong association (+2)13,53/385 (13.8%)7/396 (1.8%)RR 7.78 (3.58 to 16.89)120/1 000 (80 to 160)⊕⊕⊕⊕
High
7
Abnormal dreams (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (24 – 144 wks))
2Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyStrong association (+1)12,37/385 (9.6%)9/396 (2.3%)RR 4.24 (2.08 to 8.65)70/1 000 (40 to 110)⊕⊕⊕⊕
High
7
Depression (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (24 wks))
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)86/132 (4.5%)1/137 (0.7%)RR 6.23 (0.76 to 51.03)40/1 000 (0 to 80)⊕⊕⊕○
Moderate
7
Insomnia (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (24 – 144 wks))
2Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyStrong association (+1)12,41/385 (10.6%)12/396 (3%)RR 3.52 (1.88 to 6.60)80/1 000 (40 to 110)⊕⊕⊕⊕
High
7
Bronchitis (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (144 wks))
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)816/253 (6.3%)8/259 (3.1%)RR 2.05 (0.89 to 4.70)30/1 000 (0 to 70)⊕⊕⊕○
Moderate
7
Loose stools (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (144 wks))
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyStrong association (+1)12,15/253 (5.9%)4/259 (1.5%)RR 3.84 (1.29 to 11.41)40/1 000 (10 to 80)⊕⊕⊕⊕
High
7
Arthritis (Adverse event occurring in >= 5% of patients receiving donepezil and at a min. of twice the rate of placebo Follow up: at end of treatment (144 wks))
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyNone13/253 (5.1%)4/259 (1.5%)RR 3.33 (1.10 to 10.07)40/1 000 (0 to 70)⊕⊕⊕⊕
High
7
Number converting to dementia by 12 months ( Follow up: 12 months)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyNone16/253 (6.3%)38/259 (14.7%)RR 0.43 (0.25 to 0.75)80/1 000 (30 to 140)⊕⊕⊕⊕
High
9
Number converting to dementia by 36 months ( Follow up: 36 months)
1Randomised trialsNo limitationsNo important inconsistencyNo uncertaintyImprecise or sparse data (−1)163/253 (24.9%)73/259 (28.2%)RR 0.88 (0.66 to 1.18)30/1 000 (110 fewer to 40 more)⊕⊕⊕○
Moderate
9
1

CI compatible with both benefit and no benefit

2

Random effects model used due to heterogeneity

3

Observed case analysis with higher attrition in the active treatment group

4

One study

5

ADCS MCI-ADL = Alzheimer's Disease Cooperative Study Mild Cognitive Impairment-Activities of Daily Living Scale

6

Calculated using a random effects model

7

Unless otherwise indicated, negative effect sizes favour active treatment

8

CI compatible with both harm and no harm

9

ADAS-cog = Alzheimer's Disease Assessment Scale - cognitive subscale

10

WMS-R = Wechsler Memory Scale-Revised

11

CGIC-MCI = Clinical Global Impression of Change instrument - for Mild Cognitive Impairment

12

RR > 2, p < .01

13

RR > 5, p < .01

From: APPENDIX 16, EVIDENCE PROFILE TABLES FOR QUANTITATIVE REVIEWS

Cover of Dementia
Dementia: A NICE-SCIE Guideline on Supporting People With Dementia and Their Carers in Health and Social Care.
NICE Clinical Guidelines, No. 42.
National Collaborating Centre for Mental Health (UK).
Leicester (UK): British Psychological Society; 2007.
Copyright © 2007, The British Psychological Society & The Royal College of Psychiatrists.

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