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Study flow diagram for study for the search April 2016.
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Figure 1

Study flow diagram for study for the search April 2016.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 1 Alzheimer's Disease Assessment Scale ‐ Cognitive subscale (ADAS‐Cog) (least square (LS) mean change from baseline at 6 to 48 months): completers.
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Analysis 1.1

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 1 Alzheimer's Disease Assessment Scale ‐ Cognitive subscale (ADAS‐Cog) (least square (LS) mean change from baseline at 6 to 48 months): completers.

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 2 Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS‐ADL) (LS mean change from baseline at 6 to 48 months): completers.
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Analysis 1.2

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 2 Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS‐ADL) (LS mean change from baseline at 6 to 48 months): completers.

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 3 Deaths (number of deaths over 48 months).
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Analysis 1.3

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 3 Deaths (number of deaths over 48 months).

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 4 Serious adverse events (number of participants reporting ≥ 1 serious adverse event over 48 months).
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Analysis 1.4

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 4 Serious adverse events (number of participants reporting ≥ 1 serious adverse event over 48 months).

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 5 Neuropsychiatric Inventory (NPI) (LS mean change from baseline at 6 to 48 months): completers.
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Analysis 1.5

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 5 Neuropsychiatric Inventory (NPI) (LS mean change from baseline at 6 to 48 months): completers.

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 6 Mini‐Mental State Examination (MMSE) (LS mean change from baseline at 6 to 48 months): completers.
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Analysis 1.6

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 6 Mini‐Mental State Examination (MMSE) (LS mean change from baseline at 6 to 48 months): completers.

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 7 Adverse events (number of participants reporting ≥ 1 adverse event over 48 months).
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Analysis 1.7

Comparison 1 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease, Outcome 7 Adverse events (number of participants reporting ≥ 1 adverse event over 48 months).

Comparison 2 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with mild cognitive impairment, Outcome 1 Progression to Alzheimer's disease (AD) (number of people progressing to AD by 36 months).
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Analysis 2.1

Comparison 2 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with mild cognitive impairment, Outcome 1 Progression to Alzheimer's disease (AD) (number of people progressing to AD by 36 months).

Comparison 2 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with mild cognitive impairment, Outcome 2 Deaths (number of deaths over 36 months).
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Analysis 2.2

Comparison 2 Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with mild cognitive impairment, Outcome 2 Deaths (number of deaths over 36 months).

Summary of findings for the main comparison. Vitamin E (capsules 2000 IU/day in two divided doses) compared to placebo for people with Alzheimer's disease

Vitamin E (capsules 2000 IU/day in 2 divided doses) compared to placebo for people with Alzheimer's disease

Patient or population: people with Alzheimer's disease

Settings: multicentre, US

Intervention: vitamin E (capsules 2000 IU/day in 2 divided doses)

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Vitamin E (capsules 2000 IU/day in 2 divided doses)

Cognitive function
LS mean change from baseline using the ADAS‐Cog

Scale from: 0 to 70

Follow‐up: 6 to 48 months

The LS mean change from baseline in cognitive function in placebo group was 7.78

The LS mean change from baseline in cognitive function in the intervention group was 1.81 lower
(3.75 lower to 0.13 higher)

272
(1 study)

⊕⊕⊕⊝
Moderate1

Higher scores represent worse cognitive function.

A 4‐point difference in ADAS‐cog has been considered the MCID.

Adverse events

Number of participants reporting ≥ 1 serious adverse event

Follow‐up: 6 to 48 months

625 per 1000

538 per 1000
(444 to 656)

RR 0.86
(0.71 to 1.05)

304
(1 study)

⊕⊕⊕⊝
Moderate1

Deaths

Number of deaths

Follow‐up: 6 to 48 months

204 per 1000

171 per 1000
(106 to 273)

RR 0.84
(0.52 to 1.34)

304
(1 study)

⊕⊕⊕⊝
Moderate1

Activities of daily living
LS mean change from baseline using the ADCS‐ADL

Scale from: 0 to 78

Follow‐up: 6 to 48 months

The LS mean change from baseline in activities of daily living in the placebo group was ‐16.96

The LS mean change from baseline in activities of daily living in the intervention group was 3.15 higher
(0.07 to 6.23 higher)

280
(1 study)

⊕⊕⊕⊝
Moderate1

Higher scores represent better activities of daily living.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

ADAS‐Cog: Alzheimer Disease Assessment Scale ‐ Cognitive Subscale; ADCS‐ADL: Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory;CI: confidence interval; LS: least square; MCID: minimum clinically important difference; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Quality downgraded one level due to imprecision. Evidence from a single study of modest size. This is supported by dichotomous data not reaching the optimal information size criterion (assuming α of 0.05, and β of 0.2) (Guyatt 2011).

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Summary of findings for the main comparison. Vitamin E (capsules 2000 IU/day in two divided doses) compared to placebo for people with Alzheimer's disease
Summary of findings 2. Vitamin E (capsules 2000 IU/day in two divided doses) compared to placebo for people with mild cognitive impairment

Vitamin E (capsules 2000 IU/day in 2 divided doses) compared to placebo for people with mild cognitive impairment

Patient or population: people with mild cognitive impairment
Settings: US and Canada
Intervention: vitamin E (capsules 2000 IU/day in 2 divided doses)
Comparison: placeb

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Vitamin E (capsules 2000 IU/day in 2 divided doses)

Progression to Alzheimer's disease

Number of people progressing to AD

Follow‐up: 36 months

284 per 1000

293 per 1000
(224 to 383)

RR 1.03
(0.79 to 1.35)

516
(1 study)

⊕⊕⊕⊝
Moderate1

Cognitive function

Mean change from baseline of ADAS‐Cog

Scale from: 0 to 70

Follow‐up: 36 months

Not possible to extract data for analysis.

Not possible to extract data for analysis.

Unable to evaluate quality of evidence.

Uncertainty about how missing data were handled. Study reports no significant difference between intervention and control groups.

Adverse events

Number of participants reporting ≥ 1 serious adverse event.

Follow‐up: 36 months

Not possible to extract data for analysis.

516
(1 study)

Unable to evaluate quality of evidence.

Overall adverse event rates not reported.

Death

Number of deaths over 36 months

Follow‐up: 36 months

19 per 1000

19 per 1000
(6 to 66)

RR 1.01
(0.3 to 3.44)

516
(1 study)

⊕⊕⊕⊝
Moderate1

Activities of daily living

Mean change from baseline using the ADCS
Mild Cognitive Impairment Activities of Daily Living

Scale from: 0 to 53

Follow‐up: 36 months

Not possible to extract data for analysis.

Not possible to extract data for analysis.

Unable to evaluate quality of evidence.

Uncertainty about how missing data were handled. Study reports no significant difference between intervention and control groups.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

ADAS‐Cog: Alzheimer Disease Assessment Scale ‐ Cognitive Subscale; ADCS‐ADL: Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory;CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Quality downgraded one level due to imprecision. Evidence from a single study of modest size. This was supported by dichotomous data not reaching the optimal information size criterion (assuming α of 0.05, and β of 0.2) (Guyatt 2011).

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Summary of findings 2. Vitamin E (capsules 2000 IU/day in two divided doses) compared to placebo for people with mild cognitive impairment
Comparison 1. Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Alzheimer's Disease Assessment Scale ‐ Cognitive subscale (ADAS‐Cog) (least square (LS) mean change from baseline at 6 to 48 months): completers Show forest plot

1

272

Mean Difference (IV, Random, 95% CI)

‐1.81 [‐3.75, 0.13]

2 Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS‐ADL) (LS mean change from baseline at 6 to 48 months): completers Show forest plot

1

280

Mean Difference (IV, Fixed, 95% CI)

3.15 [0.07, 6.23]

3 Deaths (number of deaths over 48 months) Show forest plot

1

304

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.52, 1.34]

4 Serious adverse events (number of participants reporting ≥ 1 serious adverse event over 48 months) Show forest plot

1

304

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.71, 1.05]

5 Neuropsychiatric Inventory (NPI) (LS mean change from baseline at 6 to 48 months): completers Show forest plot

1

280

Mean Difference (IV, Fixed, 95% CI)

‐1.47 [‐4.26, 1.32]

6 Mini‐Mental State Examination (MMSE) (LS mean change from baseline at 6 to 48 months): completers Show forest plot

1

273

Mean Difference (IV, Fixed, 95% CI)

0.19 [‐0.72, 1.10]

7 Adverse events (number of participants reporting ≥ 1 adverse event over 48 months) Show forest plot

1

304

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.85, 1.23]

Figures and Tables -
Comparison 1. Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with Alzheimer's disease
Comparison 2. Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with mild cognitive impairment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Progression to Alzheimer's disease (AD) (number of people progressing to AD by 36 months) Show forest plot

1

516

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.79, 1.35]

2 Deaths (number of deaths over 36 months) Show forest plot

1

516

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.30, 3.44]

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Comparison 2. Vitamin E (capsules 2000 IU/day in two divided doses) versus placebo in people with mild cognitive impairment