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Cochrane Database of Systematic Reviews

Antioxidant vitamin and mineral supplements for preventing age‐related macular degeneration

Information

DOI:
https://doi.org/10.1002/14651858.CD000253.pub4Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 30 July 2017see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Eyes and Vision Group

Copyright:
  1. Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Jennifer R Evans

    Correspondence to: Cochrane Eyes and Vision, ICEH, London School of Hygiene & Tropical Medicine, London, UK

    [email protected]

  • John G Lawrenson

    Centre for Applied Vision Research, School of Health Sciences, City University of London, London, UK

Contributions of authors

JE assessed studies for inclusion and exclusion, assessed risk of bias, extracted data, entered data and wrote the text of the review.
JL assessed studies for inclusion and exclusion, assessed risk of bias, extracted data, and reviewed and commented on the text of the review.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research (NIHR), UK.

    • Richard Wormald, Co‐ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the NIHR to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.

    • This review was supported by the NIHR, via Cochrane Infrastructure funding to the CEV UK editorial base which funds part of Jennifer Evans's salary.

    The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Declarations of interest

None known.

Acknowledgements

This work was undertaken in collaboration with the National Institute for Health and Care Excellence. The views expressed in this publication are those of the authors and not necessarily those of NICE.

We are grateful to:

  • the Systematic Review Training Unit at the Institute of Child Health, London for advice on the protocol for this review;

  • all the trialists who responded to requests for information;

  • peer reviewers Andrew Ness and Usha Chakravarthy for comments on an earlier version of this review.

  • Carol Mccletchie OBE who reviewed and commented on the plain language summary from the consumer perspective.

We thank Katherine Henshaw who was an author on the original review. The Cochrane Eyes and Vision editorial team prepared and executed the electronic searches for this review. We are grateful to Anupa Shah and Iris Gordon for their assistance with the review process.

Version history

Published

Title

Stage

Authors

Version

2017 Jul 30

Antioxidant vitamin and mineral supplements for preventing age‐related macular degeneration

Review

Jennifer R Evans, John G Lawrenson

https://doi.org/10.1002/14651858.CD000253.pub4

2012 Jun 13

Antioxidant vitamin and mineral supplements for preventing age‐related macular degeneration

Review

Jennifer R Evans, John G Lawrenson

https://doi.org/10.1002/14651858.CD000253.pub3

2008 Jan 23

Antioxidant vitamin and mineral supplements for preventing age‐related macular degeneration

Review

Jennifer R Evans, Katherine S Henshaw

https://doi.org/10.1002/14651858.CD000253.pub2

1999 Oct 25

Antioxidant vitamin and mineral supplements for preventing age‐related macular degeneration

Review

Jennifer R Evans, Katherine S Henshaw

https://doi.org/10.1002/14651858.CD000253

Differences between protocol and review

The original protocol was published in 1999 (Evans 1999). Since that time, there have been methodological improvements within Cochrane, and the methods have been updated to include assessment of risk of bias, 'Summary of findings' tables, GRADE assessment, and better consideration of unit of analysis issues.

For the 2017 update, we modified the outcome measures to ensure they were in line with those being used as part of the macular degeneration guidelines being prepared by NICE (NICE 2016). In previous versions of this review the outcomes were:

  1. number of participants developing AMD;

  2. number of participants with visual loss due to AMD;

  3. quality of life measures;

  4. any adverse outcomes reported.

In previous versions of this review, we pooled all antioxidants into one analysis. This was not possible in the current version because of overlapping participants in two trials.

Keywords

MeSH

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

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

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

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

Comparison 1 Vitamin E versus placebo, Outcome 1 Any AMD.
Figures and Tables -
Analysis 1.1

Comparison 1 Vitamin E versus placebo, Outcome 1 Any AMD.

Comparison 1 Vitamin E versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).
Figures and Tables -
Analysis 1.2

Comparison 1 Vitamin E versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).

Comparison 1 Vitamin E versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.
Figures and Tables -
Analysis 1.3

Comparison 1 Vitamin E versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.

Comparison 2 Beta‐carotene versus placebo, Outcome 1 Any AMD.
Figures and Tables -
Analysis 2.1

Comparison 2 Beta‐carotene versus placebo, Outcome 1 Any AMD.

Comparison 2 Beta‐carotene versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).
Figures and Tables -
Analysis 2.2

Comparison 2 Beta‐carotene versus placebo, Outcome 2 Late AMD (either neovascular AMD or geographic atrophy or both).

Comparison 2 Beta‐carotene versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.
Figures and Tables -
Analysis 2.3

Comparison 2 Beta‐carotene versus placebo, Outcome 3 Neovascular AMD or geographic atrophy separately.

Comparison 3 Vitamin C versus placebo, Outcome 1 AMD.
Figures and Tables -
Analysis 3.1

Comparison 3 Vitamin C versus placebo, Outcome 1 AMD.

Comparison 4 Multivitamin versus placebo, Outcome 1 AMD.
Figures and Tables -
Analysis 4.1

Comparison 4 Multivitamin versus placebo, Outcome 1 AMD.

Summary of findings for the main comparison. Vitamin E versus placebo

Vitamin E versus placebo

Patient or population: general population
Setting: community
Intervention: vitamin E*
Comparison: placebo

Outcomes

Anticipated absolute effects (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo**

Risk with vitamin E

Any AMD

150 per 1000

146 per 1000
(135 to 159)

RR 0.97
(0.90 to 1.06)

55,614
(4 RCTs)

⊕⊕⊕⊕
HIGH

Average duration of treatment and follow‐up ranged from 4 years to 10 years

Late AMD (either neovascular AMD or geographic atrophy or both)

5 per 1000

6 per 1000
(4 to 8)

RR 1.22
(0.89 to 1.67)

55,614
(4 RCTs)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up ranged from 4 years to 10 years

Neovascular AMD

3 per 1000

11 per 1000
(2 to 51)

RR 3.62
(0.77 to 16.95)

941
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2

Average duration of treatment and follow‐up was 6 years

Geographic atrophy

2 per 1000

6 per 1000
(1 to 57)

RR 2.71
(0.28 to 26.00)

941
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2

Average duration of treatment and follow‐up was 6 years

Quality of life

Not reported

Adverse effects (AE)

⊕⊕⊝⊝
LOW3

Two trials reported similar numbers of AEs in vitamin E and placebo group. Another trial reported excess of haemorrhagic strokes in vitamin E group (39 vs 23 events, hazard ratio 1.74, 95% CI 1.04 to 2.91).

Resource use and costs

Not reported

* Dose of vitamin E used in studies were: 50 mg/day, 400 IU/alternate days, 600 IU/alternate days, and 500 IU/day

**The risk in the placebo group is the median risk in the placebo groups in the included studies. The risk in the intervention group (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).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for imprecision due to wide confidence intervals i.e. are below 0.8 or above 1.25.

2 Downgraded one level for indirectness (only one trial in male smokers) and downgraded two levels for imprecision as very few cases (10 neovascular AMD, 4 geographic atrophy)

3 Downgraded one level for imprecision due to wide confidence intervals and lower confidence near 1 and downgraded one level for inconsistency as effect only reported by one trial.

Figures and Tables -
Summary of findings for the main comparison. Vitamin E versus placebo
Summary of findings 2. Beta‐carotene versus placebo

Beta‐carotene versus placebo

Patient or population: general population
Setting: community
Intervention: beta‐carotene*
Comparison: placebo

Outcomes

Anticipated absolute effects (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo**

Risk with beta‐carotene

Any AMD

150 per 1000

150 per 1000
(132 to 171)

RR 1.00
(0.88 to 1.14)

22,083
(2 RCTs)

⊕⊕⊕⊕
HIGH

Average duration of treatment and follow‐up was 6 years in one study and 12 years in the other study

Late AMD (either neovascular AMD or geographic atrophy or both)

5 per 1000

5 per 1000
(3 to 6)

RR 0.90
(0.65 to 1.24)

22,083
(2 RCTs)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up was 6 years in one study and 12 years in the other study

Neovascular AMD

3 per 1000

2 per 1000
(1 to 6)

RR 0.61
(0.17 to 2.15)

941
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2

Average duration of treatment and follow‐up was 6 years

Geographic atrophy

2 per 1000

1 per 1000
(0 to 6)

RR 0.31
(0.03 to 2.93)

941
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2

Average duration of treatment and follow‐up was 6 years

Quality of life

Not reported

Adverse effects

⊕⊕⊕⊕
HIGH

Beta‐carotene associated with increased risk of lung cancer in people who smoke.

Resource use and costs

Not reported

* Dose of beta‐carotene used was 20 mg/day in one study and 50 mg/alternate days in the other study.

**The risk in the placebo group is the median risk in the control groups of the four included studies in summary of findings Table for the main comparison. The risk in the intervention group (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).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for imprecision due to wide confidence intervals i.e. are below 0.8 or above 1.25.

2 Downgraded one level for indirectness (only one trial in male smokers) and downgraded two levels for imprecision as very few cases (10 neovascular AMD, 4 geographic atrophy)

Figures and Tables -
Summary of findings 2. Beta‐carotene versus placebo
Summary of findings 3. Vitamin C versus placebo

Vitamin C versus placebo

Patient or population: general population
Setting: community
Intervention: vitamin C*
Comparison: placebo

Outcomes

Anticipated absolute effects (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo**

Risk with vitamin C

Any AMD

150 per 1000

144 per 1000
(119 to 177)

RR 0.96
(0.79 to 1.18)

14,236
(1 RCT)

⊕⊕⊕⊕
HIGH

Average duration of treatment and follow‐up was 8 years

Late AMD (either neovascular AMD or geographic atrophy or both)

5 per 1000

5 per 1000
(3 to 7)

RR 0.94
(0.61 to 1.46)

14,236
(1 RCT)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up was 8 years

Neovascular AMD

Not reported

Geographic atrophy

Not reported

Quality of life

Not reported

Adverse effects

None reported

Resource use and costs

Not reported

* Dose of vitamin C used was 500 mg/day.

**The risk in the placebo group is the median risk in the control groups of the four included studies in summary of findings Table for the main comparison. The risk in the intervention group (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).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for imprecision due to wide confidence intervals i.e. are below 0.8 or above 1.25.

Figures and Tables -
Summary of findings 3. Vitamin C versus placebo
Summary of findings 4. Multivitamin versus placebo

Multivitamin versus placebo for preventing AMD

Patient or population: general population
Setting: community
Intervention: multivitamin*
Comparison: placebo

Outcomes

Anticipated absolute effects (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo**

Risk with multivitamin

Any AMD

150 per 1000

182 per 1000
(153 to 215)

RR 1.21
(1.02 to 1.43)

14,233
(1 RCT)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up was 11 years

Late AMD

5 per 1000

6 per 1000
(4 to 8)

RR 1.22
(0.88 to 1.69)

14,233
(1 RCT)

⊕⊕⊕⊝
MODERATE 1

Average duration of treatment and follow‐up was 11 years

Neovascular AMD

Not reported

Geographic atrophy

Not reported

Quality of life

Not reported

Adverse effects

⊕⊕⊕⊝
MODERATE 1

"Those taking the active versus placebo multivitamin were more likely to have skin rashes (2111 and 1973 men in corresponding active and placebo multivitamin groups; HR 1.08, 95% CI 1.01 to 1.15; P = 0.016)". PHS II

Resource use and costs

Not reported

* Multivitamin used was Centrum Silver (zinc 15 mg, vitamin E 45 IU, vitamin C 60 mg, beta‐carotene 5000 IU vitamin A, 20% as beta carotene, folic acid 2.5 mg, vitamin B6 50 mg, vitamin B12 1 mg)

**The risk in the placebo group is the median risk in the control groups of the four included studies in summary of findings Table for the main comparison. The risk in the intervention group (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).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for imprecision

Figures and Tables -
Summary of findings 4. Multivitamin versus placebo
Table 1. Mapping the definition of AMD used in included studies to the review outcomes

Definition of AMD used in this review

Study

ATBC 1998

PHS I 2007PHS II 2012; WHS 2010

VECAT 2002

No AMD

0 = no ARM

Did not self‐report or no signs listed below in medical records

Any AMD

I = dry maculopathy, with hard drusen, pigmentary changes, or both

II = soft macular drusen

III = disciform degeneration

IV = geographic atrophy.

Drusen, RPE hypo or hyperpigmentation, geographic atrophy, RPE detachment, subretinal neovascular membrane,
or disciform scar

Early AMD 1: Soft intermediate or soft distinct or soft indistinct or pigment changes (hyperpigmentation or hypopigmentation)

Early AMD 2: Soft intermediate or soft distinct or soft indistinct and pigment changes (hyperpigmentation or hypopigmentation)

Early AMD 3: Soft distinct or soft indistinct or pigment changes (hyperpigmentation or hypopigmentation)

Early AMD 4: Soft distinct or soft indistinct and pigment changes (hyperpigmentation or hypopigmentation)

Late AMD: Serous or haemorrhagic detachment of the RPE or sensory retina, characteristic haemorrhages, or subretinal fibrous scars, central areolar zone of retinal pigment epithelial atrophy with visible choroidal vessels, at least 175 µm in diameter

Late AMD

III = disciform degeneration

IV = geographic atrophy.

Geographic atrophy, RPE detachment, subretinal neovascular membrane, or disciform scar

Serous or haemorrhagic detachment of the RPE or sensory retina, characteristic haemorrhages, or subretinal fibrous scars, central areolar zone of retinal pigment epithelial atrophy with visible choroidal
vessels, at least 175 µm in diameter

Neovascular AMD

III = disciform degeneration

RPE detachment, subretinal neovascular membrane, or disciform scar

Serous or haemorrhagic detachment of the RPE or sensory retina, characteristic haemorrhages, or subretinal fibrous scars

Geographic atrophy

IV = geographic atrophy.

Geographic atrophy

Central areolar zone of retinal pigment epithelial atrophy with visible choroidal
vessels, at least 175 µm in diameter, in the absence of signs of neovascular AMD in the same eye

RPE: retinal pigment epithelial
Method of detection: Grading of fundus photographs (ATBC 1998; VECAT 2002), and medical record review after self‐report of AMD diagnosis (PHS I 2007; PHS II 2012; WHS 2010)

Figures and Tables -
Table 1. Mapping the definition of AMD used in included studies to the review outcomes
Comparison 1. Vitamin E versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Any AMD Show forest plot

4

55614

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.90, 1.06]

2 Late AMD (either neovascular AMD or geographic atrophy or both) Show forest plot

4

55614

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [0.89, 1.67]

3 Neovascular AMD or geographic atrophy separately Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Neovascular AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Geographic atrophy

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 1. Vitamin E versus placebo
Comparison 2. Beta‐carotene versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Any AMD Show forest plot

2

22083

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.88, 1.14]

2 Late AMD (either neovascular AMD or geographic atrophy or both) Show forest plot

2

22083

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.65, 1.24]

3 Neovascular AMD or geographic atrophy separately Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Neovascular AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Geographic atrophy

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 2. Beta‐carotene versus placebo
Comparison 3. Vitamin C versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AMD Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Any AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Late AMD (either neovascular AMD or geographic atrophy or both)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 3. Vitamin C versus placebo
Comparison 4. Multivitamin versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AMD Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Any AMD

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Late AMD (either neovascular AMD or geographic atrophy or both)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 4. Multivitamin versus placebo