EAL

Vitamin E

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine the effects of prolonged low doses of aspirin and vitamin E on cardiovascular disease in women.

Inclusion Criteria:

Female health professional
45 years of age or older
No history of coronary heart disease, cerebrovascular disease or cancer other than melanoma
No major chronic illness
No current use of or contraindications to aspirin or vitamin E.

Exclusion Criteria:

Anyone not meeting inclusion criteria.

Description of Study Protocol:

Recruitment

Letters of invitation were mailed to 1.7 million female health professionals
More than 450,000 returned baseline questionnaires
More than 65,000 entered a preliminary three-month placebo run-in phase to identify those likely to comply with a long-term study
Mean duration of the trial was 10.1 years (range, 8.2 to 10.9 years).

Design

Randomized control trial.

Blinding Used

Subjects blinded to treatment
Blinding of investigators was not described.

Intervention

Group One: 100mg aspirin and 600 IU vitamin E taken on alternate days
Group Two: 100mg aspirin and placebo taken on alternate days
Group Three: 600 IU vitamin E and placebo taken on alternate days
Group Four: Two placebos taken on alternate days.

Statistical Analysis

All analyses on intent-to-treat basis
Relative risk.

Data Collection Summary:

Timing of Measurements

Each participant completed a questionnaire every six months in Year One and once yearly thereafter to report compliance, occurrence of end points and adverse effects.

Dependent Variables

Primary: Combined total major events, including
- Non-fatal MI
- Non-fatal stroke
- CV death
- Cardiovascular death
- Cancer.
Secondary
- Fatal or non-fatal MI
- Fatal or non-fatal stroke
- Ischemic or hemorrhagic stroke
- Site-specific cancer.

Independent Variables

100mg aspirin
600 IU vitamin E.

Description of Actual Data Sample:

Initial N: 39,876 females
Attrition: Attrition was not described, however investigators were able to confirm 97% of endpoint events
Age: Mean age was 54.6 years.

Other Relevant Demographics

Participants were relatively healthy
Only 23.8% had two or more cardiovascular risk factors.

Anthropometrics

Baseline characteristics in the four groups were similar.

Summary of Results:

End Point			Aspirin (N=19,934)	Placebo (N=10,042)	Relative Risk (95% CI)	P-Value
Effects of Aspirin	Major Cardiac Events		477	522	0.91 (0.80 to 1.03)	0.13
	Stroke		221	266	0.83 (0.69 to 0.99)	0.04
		Ischemic	170	221	0.76 (0.63 to 0.93)	0.009
		Non-fatal	198	244	0.81 (0.67 to 0.97)	0.02
	Transient Ischemic Attack		186	238	0.78 (0.64 to 0.94)	0.01
Lack of Effect of Vitamin E	Cardiovascular Death		106	140	0.76 (0.59 to 0.98)	0.03

Other Findings

Although not significant, more major cardiovascular events occurred in the aspirin placebo group
Aspirin use significantly lowered the incidence of total stroke (-17%), ischemic stroke (-24%) and non-fatal stroke (-19%)
Aspirin was associated with a significant reduction in transient ischemic attacks (-22%)
Women 65 years and older attained a significant benefit from aspirin. There were 26% fewer cardiovascular events in this age group. They had a significant increase in cardio-protective effect, resulting in a 34% lower incidence of MI and 22% lower for stroke.
Aspirin resulted in a lower incidence of major cardiovascular event in non-smokers and past smokers
Vitamin E had very little effect in preventing cardiovascular disease
Cardiovascular mortality was 24% lower in the Vitamin E Group compared to the placebo
Women 65 years and older had significantly fewer cardiovascular events
There was no synergistic effect of aspirin and vitamin E on any cardiovascular outcome
No statistical difference was observed in cancer development between the vitamin E and the placebo group.

Author Conclusion:

Low-dose aspirin taken every other day helps protect women age 65 years and older from stroke
Aspirin gave no protection against MI except in women over 65 years old
Vitamin E had no protective effect against stroke, MI of cancer.

Funding Source:

Government:

NIH

Industry:

Dow Corning Corporation, Bayer Health Care, Natural Source Vitamin E Assoc.

Pharmaceutical/Dietary Supplement Company:

Other:

In-Kind support reported by Industry:

Yes

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.)	N/A
	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")?	Yes
4.	Was method of handling withdrawals described?		No
	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%.)	???
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	???
	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?	No
	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?	N/A
	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)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	???
	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