FNOA: Antioxidants (2011-2012)
To test whether alternate-day vitamin E affects the incidence of age-related macular degeneration in a large-scale randomized trial of women.
- Apparently healthy female health professionals participating in the Women's Health Study
- Aged 45 years or older.
Participants reporting a diagnosis of AMD at baseline.
Recruitment
- Participants in the Women's Health Study
- Recruitment methods published elsewhere
- 1.7 million women were invited to participate and 453,787 completed the baseline questionnaire
- 65,169 women were willing and eligible to enter the run-in phase
- 25,293 women were excluded after run-in due to non-compliance, unwillingness or ineligibility
- 39,876 women were randomized.
Design
Randomized placebo-controlled trial.
Blinding Used
Double-blind.
Intervention
Participants were randomized to receive either 600 IU of natural-source vitamin E on alternate days or placebo, as well as low dose aspirin (100mg) every other day.
Statistical Analysis
- Cox proportional-hazards regression models were used to estimate the relative risks and 95% confidence intervals of AMD among those assigned to receive vitamin E, compared with those assigned to receive placebo after adjustment for age (years) at baseline and randomized aspirin and beta-carotene assignments
- Sub-group analyses were conducted by categories of baseline variables that are possible risk factors for AMD.
Timing of Measurements
Women completed annual questionnaires for 10 years.
Dependent Variables
Incident age-related macular degeneration responsible for a reduction in best-corrected visual acuity to 20/30 or worse, based on self-report and confirmed by medical record interview.
Independent Variables
- Participants were randomized to receive either 600 IU of natural-source vitamin E on alternate days or placebo, as well as low-dose aspirin (100mg) every other day
- Women completed annual questionnaires, in which they provided information on their compliance with pill-taking and the occurrence of any relevant events.
- Initial N: 39,876 women
- Attrition (final N): 39,421 did not report a diagnosis of AMD at baseline and are included in the analyses; 19,697 in the Vitamin E Group and 19,724 in the Placebo Group
- Age: Mean age, 54.5 years in both groups
- Ethnicity: Not reported
- Anthropometrics: No significant differences between groups at baseline
- Location: Boston, Massachusetts.
Key Findings
- Compliance (defined as taking two-thirds of the study capsules) was 78.9% at five years and 71.6% at 10 years and averaged 75.8% throughout the trial
- After 10 years of treatment and follow-up, there were 117 cases of AMD in the Vitamin E Group and 128 cases in the Placebo Group (relative risk, 0.93; 95% confidence interval, 0.72-1.19)
- There was no apparent benefit of vitamin E on visually-significant AMD at any point during the follow-up
- There was no evidence for any modification of the lack of effect of vitamin E on AMD by baseline categories of possible risk factors for AMD, although relative risks tended to be lower in younger women.
Confirmed Cases of Age-Related Macular Degeneration
Variables |
Vitamin E |
Placebo |
Relative Risk |
95% Confidence Interval | P-Value |
Visually significant AMD |
117 |
128 |
0.93 |
0.72-1.19
|
0.54
|
Advanced AMD |
29 |
26 |
1.13 |
0.67-1.92
|
0.65
|
AMD with or without vision loss |
280 |
313 |
0.90 |
0.77-1.06
|
0.20
|
- In summary, these randomized trial data from a large population of healthy women indicate that 10 years of alternate-day treatment with 600 IU of natural source vitamin E alone has no material beneficial or harmful effect on AMD occurrence
- Whether vitamin E as a component of an antioxidant combination can help to reduce risks of AMD, as suggested by the findings in AREDS, warrants continued investigation.
Government: | NIH grants CA 47988, HL 43851, EY 06633 | ||
Industry: |
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Not-for-profit |
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In-Kind support reported by Industry: | Yes |
Authors note the following limitations:
- Dose of vitamin E (600 IU every other day) was lower than that used in AREDS (400 IU daily), but compliance was similar to AREDS
- Identification of AMD based on participant reports, but medical records used to confirm participant reports
Quality Criteria Checklist: Primary Research
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Relevance Questions | |||
1. | Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) | Yes | |
2. | Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? | Yes | |
3. | Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? | Yes | |
4. | Is the intervention or procedure feasible? (NA for some epidemiological studies) | Yes | |
Validity Questions | |||
1. | Was the research question clearly stated? | Yes | |
1.1. | Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? | Yes | |
1.2. | Was (were) the outcome(s) [dependent variable(s)] clearly indicated? | Yes | |
1.3. | Were the target population and setting specified? | Yes | |
2. | Was the selection of study subjects/patients free from bias? | Yes | |
2.1. | Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? | Yes | |
2.2. | Were criteria applied equally to all study groups? | Yes | |
2.3. | Were health, demographics, and other characteristics of subjects described? | Yes | |
2.4. | Were the subjects/patients a representative sample of the relevant population? | Yes | |
3. | Were study groups comparable? | Yes | |
3.1. | Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) | Yes | |
3.2. | Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? | Yes | |
3.3. | Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) | Yes | |
3.4. | If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? | N/A | |
3.5. | If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) | N/A | |
3.6. | If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? | N/A | |
4. | Was method of handling withdrawals described? | Yes | |
4.1. | Were follow-up methods described and the same for all groups? | Yes | |
4.2. | Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) | Yes | |
4.3. | Were all enrolled subjects/patients (in the original sample) accounted for? | Yes | |
4.4. | Were reasons for withdrawals similar across groups? | Yes | |
4.5. | If diagnostic test, was decision to perform reference test not dependent on results of test under study? | N/A | |
5. | Was blinding used to prevent introduction of bias? | Yes | |
5.1. | In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? | Yes | |
5.2. | Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) | Yes | |
5.3. | In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? | N/A | |
5.4. | In case control study, was case definition explicit and case ascertainment not influenced by exposure status? | N/A | |
5.5. | In diagnostic study, were test results blinded to patient history and other test results? | N/A | |
6. | Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? | Yes | |
6.1. | In RCT or other intervention trial, were protocols described for all regimens studied? | Yes | |
6.2. | In observational study, were interventions, study settings, and clinicians/provider described? | N/A | |
6.3. | Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? | Yes | |
6.4. | Was the amount of exposure and, if relevant, subject/patient compliance measured? | Yes | |
6.5. | Were co-interventions (e.g., ancillary treatments, other therapies) described? | Yes | |
6.6. | Were extra or unplanned treatments described? | N/A | |
6.7. | Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? | Yes | |
6.8. | In diagnostic study, were details of test administration and replication sufficient? | N/A | |
7. | Were outcomes clearly defined and the measurements valid and reliable? | Yes | |
7.1. | Were primary and secondary endpoints described and relevant to the question? | Yes | |
7.2. | Were nutrition measures appropriate to question and outcomes of concern? | Yes | |
7.3. | Was the period of follow-up long enough for important outcome(s) to occur? | Yes | |
7.4. | Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? | Yes | |
7.5. | Was the measurement of effect at an appropriate level of precision? | Yes | |
7.6. | Were other factors accounted for (measured) that could affect outcomes? | Yes | |
7.7. | Were the measurements conducted consistently across groups? | Yes | |
8. | Was the statistical analysis appropriate for the study design and type of outcome indicators? | Yes | |
8.1. | Were statistical analyses adequately described and the results reported appropriately? | Yes | |
8.2. | Were correct statistical tests used and assumptions of test not violated? | Yes | |
8.3. | Were statistics reported with levels of significance and/or confidence intervals? | Yes | |
8.4. | Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? | N/A | |
8.5. | Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? | Yes | |
8.6. | Was clinical significance as well as statistical significance reported? | Yes | |
8.7. | If negative findings, was a power calculation reported to address type 2 error? | N/A | |
9. | Are conclusions supported by results with biases and limitations taken into consideration? | Yes | |
9.1. | Is there a discussion of findings? | Yes | |
9.2. | Are biases and study limitations identified and discussed? | Yes | |
10. | Is bias due to study's funding or sponsorship unlikely? | Yes | |
10.1. | Were sources of funding and investigators' affiliations described? | Yes | |
10.2. | Was the study free from apparent conflict of interest? | Yes | |