EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To test the effect of vitamin E supplements on cognitive function using data from the Women's Health Study.

Inclusion Criteria:

Women's Health Study participants
Women at least 45 years old
Had no history of coronary heart disease, cerebrovascular disease, cancer (except for nonmelanoma skin cancer) or other major chronic illnesses
Did not actively use any of the study medications or have any history of adverse effects from the medications
Eligible women completed baseline questionnaires and were enrolled in a three-month run-in period of placebo administration to determine those likely to maintain high compliance to treatment.

Exclusion Criteria:

Excluded if not included above.

Description of Study Protocol:

Design

Randomized, placebo-controlled trial.

Blinding Used

Double-blind.

Intervention

Vitamin E supplements (600 IU) and low-dose aspirin (100mg) every other day.

Statistical Analysis

Repeated measures analyses were conducted to examine mean performance and mean differences in cognitive change
Logistic regression was used to estimate relative risks of substantial decline
All models were fitted by maximum likelihood, incorporating the longitudinal correlation within study subjects using unstructured covariance structures
Wald test were used for statistical testing.

Data Collection Summary:

Timing of Measurements

Subjects started supplementation between 1992 and 1995
From 1998, a subset of women participated in a cognitive sub-study
Three cognitive assessments were administered by telephone at two-year intervals.

Dependent Variables

Cognitive function assessed by global composite score averaging performance on three tests for general cognition, verbal memory and category fluency
General cognition assessed with Telephone Interview of Cognitive Status, a telephone adaptation of the Mini-Mental State Examination
Verbal memory assessed with the immediate and delayed recalls of the East Boston Memory Test
Category fluency assessed with naming as many animals as possible in one minute.

Independent Variables

Vitamin E supplements (600 IU) and low-dose aspirin (100mg) every other day
Women completed mailed questionnaires annually to update information on compliance, adverse effects, health and lifestyle characteristics, and the occurrence of clinical end points.

Control Variables

Age
Baseline score
Dietary vitamin E intake
Perceived change in memory
Education
Cigarette smoking
Alcohol drinking
BMI
Physical activity
Post-menopausal hormone use
History of
- Diabetes
- Hypertension
- Elevated cholesterol level
- Depression
- Cardiovascular disease

Description of Actual Data Sample:

Initial N

39,876 women were originally randomized to four treatment groups from 1992 to 1995. In 1998, a sub-study was initiated among 7,175 women aged 65 years or older at that time.

Attrition (final N)

296 women were unreachable and 502 declined participation.
6,377 (89%) completed the initial telephone cognitive assessment in 1998
3,184 women in vitamin E group, 3,193 women in placebo group
5,845 completed the two-year follow-up in 2000 (2% died, 1% was unreachable, 5% refused)
5,073 completed all three assessments.

Age

66.2±4.0 years at randomization in vitamin E group
66.3±4.1 years at randomization in placebo group

Anthropometrics

There were no significant differences between groups in terms of demographic and health characteristics except for education; the placebo group included more women with higher levels of education than the vitamin E group (34.3% vs. 31.4%, P=0.01).

Location

Boston, Massachusetts.

Summary of Results:

Key Findings

There were no differences in global score between the vitamin E and placebo groups at the first assessment [5.6 years after randomization (mean difference, -0.01), 95% CI: -0.04 to 0.03] or at the last assessment [9.6 years of treatment (mean difference, 0.00), 95% CI: -0.04 to 0.04)
Mean cognitive change over time was also similar in the vitamin E group compared with the placebo group for the global score (mean difference in change, 0.02; 95% CI: -0.01 to 0.05, P=0.16)
The relative risk of substantial decline in the global score in the vitamin E group compared with the placebo group was 0.92 (95% CI interval: 0.77 to 1.10).

Author Conclusion:

In this randomized placebo-controlled trial among more than 6,000 healthy women, vitamin E supplementation did not provide overall cognitive benefits or reduce cognitive decline over four years. Although some questions remain (e.g., the possibility of using mixed tocopherols or initiating use at young ages for very long durations), the findings of this trial, combined with results of other studies, indicate that vitamin E supplementation of 10 years or less does not provide neuroprotection.

Funding Source:

Government:

NIH grants CA47988 and AG 15933

Reviewer Comments:

Large trial with 10 years of treatment and four years of follow-up.
Only women were studied.
Differences between groups in terms of education.

Authors note the following limitations:

Cognitive testing began a mean 5.6 years after randomization; thus we were unable to evaluate change in cognitive performance from randomization
Noncompliance (23% to 25%).

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)	No
	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?	???
	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?	N/A
	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?	N/A
	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