EAL

Vitamin E

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The objective of this study was to test efficacy of 600 IU alpha-tocopherol vitamin E supplementation or 100mg aspirin given every other day in reducing risks of cardiovascular disease and cancer among healthy women.

Inclusion Criteria:

Female health care professionals throughout the United States
Age 45 years or older
No previous history of coronary heart disease, cerebrovascular disease, cancer (except non-melanoma skin cancer) or other major chronic illnesses
No history of adverse effects from aspirin
No use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) more than once a week or willingness to forgo their use
No use of anticoagulants or corticosteroids
No use of individual supplements of vitamin A, vitamin E or beta carotene more than once a week.

Exclusion Criteria:

Females who were not health care professionals
Male health care professionals
Equal to or less than age 45 years
Previous history of coronary heart disease, cerebrovascular disease, cancer (except non-melanoma skin cancer) or other major chronic illnesses
History of adverse effects from aspirin
Use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) more than once a week or willingness to forgo their use
Use of anticoagulants or corticosteroids
Use of individual supplements of vitamin A, vitamin E or beta carotene more than once a week.

Description of Study Protocol:

Recruitment

Between September 1992 and May 1995, letters of invitation to participate in the trial and baseline health questionnaires were mailed to more than 1.7 million female health care professionals throughout the United States.

Design

Randomized, double-blind, placebo-controlled, 2x2 factorial trial.

Blinding used

Double-blind.

Intervention

Low-dose aspirin (100mg every other day; Bayer Healthcare) vs. vitamin E (600 IU of alpha-tocopherol every other day (Natural Source Vitamin E Association)
Originally, a third component, beta carotene, was also included. However, this component was terminated early in January 1996 after a median treatment duration of 2.1 years. The reason for the termination is not described further. The results are reported as non-signficant.

Statistical Analysis

Intention-to-treat analysis
Cox proportional hazards regression models to calculate the relative risks (RR) and 95% confidence intervals (95% CIs), comparing event rates in the vitamin E and placebo groups, after adjustment for age and randomized aspirin and beta carotene assignments
Statistical significance was set at P<0.05, using two-sided tests
Sensitivity analysis to censor participants who reported taking less than two thirds of study medications over the previous year.

Data Collection Summary:

Timing of Measurements

Annually: Received dose packs of vitamin and aspirin or placebo
Every six months: Questionnaire to inquire about compliance with pills, potential adverse effects, risk factors and occurrence of endpoints (MI, stroke, CV death).

Dependent Variables

Myocardial infarction
Stroke
Cardiovascular death.

Independent Variables

Vitamin E supplement and low dose aspirin (took vitamin E one day and aspirin the next).

Description of Actual Data Sample:

Initial N: 39,876 women
- 19,937 randomized to vitamin E and aspirin
- 19,939 randomized to placebo.
Attrition: None (intent-to-treat analysis)
Age: Mean 54.6±7.0 years
Ethnicity: Information not provided
Location: United States.

Summary of Results:

Findings

No significant effects of vitamin E on MI or stroke. There was 24% reduction in cardiovascular death attributable to fewer sudden deaths in the vitamin E group (38 vs. 51 among women assigned to placebo) and fewer deaths from other cardiovascular disease (i.e., deaths due to cardiovascular diseases other than ischemia).

Effect of Supplemental Vitamin E and Low Dose Aspirin

Variable	RR (95% CI)	P-Value
Myocardial Infarction (MI)	1.01 (0.82-1.23)	0.96
Stroke	0.98 (0.82-1.17)	0.82
Cardiovascular Death	0.76 (0.59-9.98)	0.03
Total Cancer	1.01 (0.94-1.08)	0.87
Cancer Deaths	1.04 (0.98-1.16)	0.53

Other Findings

Age had a statistically significant effect (P=0.008) on outcomes:
- Age at least 65 years comprised 10% of study participants but contributed 31% of end points
- A significant 26% reduction in major cardiovascular events was observed among women aged at least 65 years assigned to vitamin E (RR, 0.74; 95% CI, 0.59-0.93; P=0.009) due to a 34% reduction in MI (RR, 0.66; 95% CI, 0.45-0.98; P=0.04) and 49% reduction in cardiovascular death (RR, 0.51; 95% CI, 0.33-0.77; P<0.001) rates.

Author Conclusion:

Vitamin E supplementation is not recommended for prevention of cardiovascular disease or cancer.

Funding Source:

Government:

grants HL-43851 and CA-47988 from the National Heart, Lung, and Blood Institute and the National Cancer Institute

Reviewer Comments:

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?		No
	4.1.	Were follow-up methods described and the same for all groups?	No
	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%.)	No
	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?	Yes
	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?	No
	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?	N/A
	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?	No
	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)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	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?	No
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