FNOA: Antioxidants (2011-2012)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To test whether alternate-day vitamin E affects the incidence of age-related macular degeneration in a large-scale randomized trial of women.

Inclusion Criteria:
  • Apparently healthy female health professionals participating in the Women's Health Study
  • Aged 45 years or older.
Exclusion Criteria:

Participants reporting a diagnosis of AMD at baseline.

Description of Study Protocol:

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.
Data Collection Summary:

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.
Description of Actual Data Sample:
  • 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.
Summary of Results:

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
(N=19,697)

Placebo
(N=19,724)

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

 

Author Conclusion:
  • 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.
Funding Source:
Government: NIH grants CA 47988, HL 43851, EY 06633
Industry:
Bayer Healthcare
Pharmaceutical/Dietary Supplement Company:
Not-for-profit
Natural Source Vitamin E Association
Foundation associated with industry:
In-Kind support reported by Industry: Yes
Reviewer Comments:

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
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