EAL

Vitamin E

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To test the effect of ascorbic acid, vitamin E and beta carotene on the prevention of CVD among high risk women

Inclusion Criteria:

Women
At least 40 years of age
Post-menopausal or no with intention of becoming pregnant
Self-reported history of CVD or at least three cardiac risk factors
- Self-reported history of hypertension, high cholesterol or diabetes mellitus
- Parental history of premature MI (before age 60)
- Obesity (BMI above 30)
- Current cigarette smoking
- Inconsistent report of prior CVD.
Willing to forgo use of individual supplements of vitamins A, C, E and beta carotene at levels beyond the US RDA during the trial.

Exclusion Criteria:

Self-reported history of cancer (excluding non-melanoma skin cancer) within the past 10 years
Any serious non-CVD illness
Current use of warfarin sodium or other anticoagulants.

Description of Study Protocol:

Recruitment: Not described
Design: Randomized, double-blind placebo-controlled in a 2x2x2 factorial design
Blinding used: End-points committee of physicians, blinded to treatment assignment, confirmed presence of end-points in subjects via medical record review, autopsy report, death certificate or information obtained from next of kin or other family members.

Intervention

12-week run-in period prior to randomization into the trial from June 1995 through October 1996
Randomized to receive:
- 500mg per day synthetic ascorbic acid or placebo
- 600 IU natural vitamin E (d-alpha tocopherol acetate) or placebo every other day
- 50mg beta carotene (Lurotin) or placebo every other day.
Subjects were followed until January 31, 2005 (mean follow-up was 9.4 years, with a range of 8.3 years to 10.1 years).

Statistical Analysis

Primary analyses were performed on an intent-to-treat basis, including all randomized women
Baseline characteristics were compared by randomized groups using two-sample T-tests, X² tests for proportions and tests for trend for ordinal categories
Kaplan Meier curves were used to estimate cumulative incidence over time by randomized group and the log rank test was used to compare curves
Cox proportional hazards model was used to estimate the relative risk
- Models included main effect terms for each of the three antioxidants along with age
- Tests of proportionality of the hazards ratio over time used an interaction term for treatment multiplied by the logarithm of time.
To examine the impact of non-compliance, a post-hoc sensitivity analysis censored women if and when they stopped taking at least two-thirds of their study medication, reported taking outside supplements containing study agents or were missing compliance information
Statistical analyses were conducted using two-sided tests with a significance level of P<0.05
Interaction terms were used to test for additivity of the three antioxidant agents. All two-way as well as three-way interactions were tested using multiplicative terms.
- Sub-group analyses were conducted according to the presence or absence of age, prior CVD, smoking alcohol use, BMI, history of hypertension, high cholesterol level, diabetes, parental history of MI before age 60 years, menopausal status and hormone therapy use and current multivitamin use
- Tests for effect modification by sub-group used interaction terms between sub-group indicators and randomized assignment, with a test for trend for ordinal sub-group categories, or a multi-degree of freedom test for unordered categories.

Data Collection Summary:

Timing of Measurements

Following randomization, every six months for the first year and then annually, women were sent monthly calendar packs containing active agents or placebos, along with questionnaires on compliance, adverse effects and medical events
Information obtained on outside of study supplement use for at least four days per month.

Dependent Variables

Primary outcome was a combined end-point of CVD morbidity and mortality, including
- MI: Confirmed if symptoms met WHO criteria and cardiac enzymes or diagnostic electrocardiograms were abnormal
- Coronary revascularization: Confirmed by medical record review
- Stroke: Defined as new neurological deficit of sudden onset that persisted for more than 24 hours or until death within 24 hours; hemorrhagic distinguished from ischemic events
- CVD death: Confirmed by examination of authopsy reports, death certificates, medical records and info obtained from next of kin or other family members.
Secondary outcomes
- Individual components of MI, stroke, coronary revascularization and CVD death
- Information on TIA and total mortality also collected and reviewed: Death from any cause confirmed by end-points committee or on the basis of a death certificate.
Adverse effects
- Bleeding (gastrointestinal, hematuria, easy bruisng, epistaxis)
- Gastrointestinal symptoms (peptic ulcer, gastric upset, nausea, constipation, diarrhea)
- Fatigue
- Drowsiness.

Independent Variables

Vitamin C
Vitamin E
Beta carotene.

Description of Actual Data Sample:

Initial N: 8,171 women
Attrition (final N): 8,171
Age: Range, 40 to 65 years
Ethnicity: Not described
Location: Authors have affiliations with Harvard Medical School, Harvard School of Public Health, Brigham and Women's Hospital or Veterans Affairs Boston Healthcare System in Boston, MA.

Summary of Results:

Ascorbic Acid

No effect on primary end point with RR of 1.02 (95% CI, 0.92-1.13; P=0.71)
Cumulative incidence curves showed no variation of the effect over time and the test result for proportionality of the RR over time was not significant
Individual components of the primary end-point also did not differ significantly, although there was some suggestion of a benefit for ischemic stroke
When participants were censored on non-compliance, results were similar with RR of 0.95 (95% CI, 0.83-1.09; P=0.47)
No significant effects of randomized ascorbic acid on the primary end-point in any cardiovascular risk factor sub-group.

Vitamin E

No differences were seen in the primary end-point with RR of 0.94 (95% CI, 0.85-1.04; P=0.23), with no significant variation in the RR over time
Non-significant 16% reduction in total stroke with a 21% reduction in ischemic stroke (P=0.06) and an increase in hemorrhagic stroke, based on small numbers (no P-value reported)
Overall 10% reduction in the combination of MI, stroke and CVD death with a non-significant decrease in benefit over time (P=0.08)
No difference in total mortality
Censoring participants on non-compliance led to a significant 13% reduction in the primary end-point (RR, 0.87; 95% CI, 0.76-0.99; P=0.04)
- Reductions in secondary end points were also stronger with a 22% reduction in MI (RR, 0.78; 95% CI, 0.58-1.06; P=0.11)
- 27% reduction in stroke (RR, 0.73; 95% CI, 0.54-0.98; P=0.04)
- 9% reduction in CVD mortality (RR, 0.91; 95% CI, 0.66-1.25; P=0.55)
- 23% reduction in the combination of MI, stroke or CVD death (RR, 0.77; 95% CI, 0.64-0.92; P=0.005)
- Among those with prior CVD, the active vitamin E group experienced fdwer major CVD events (RR, 0.89; 95% CI, 0.79-1.00; P=0.04; P-value for interation, 0.07).

Beta Carotene

No difference in the primary end-point with RR of 1.02 (95% CI, 0.92-1.13; P=0.71), with no variation over time
No significant treatment effects on individual secondary end-points
Non-significant 14% increase in CVD mortality in the active group, with a significant decline over time in the effect on CVD deaths (P=0.04), but no difference in total mortality
When participants were censored on non-compliance, the effect on the primary end-point remained non-significant (RR for major vascular disease, 1.09; 95% CI, 0.96-1.24; P=0.18), but an increase in CVD mortality appeared to emerge (RR, 1.48; 95% CI, 1.08-2.02; P=0.02)
No statistically significant sub-group effects were seen for the primary end-point.

Combinations of Antioxidants

No significant two- or three-way interactions among the agents for the primary end-point
No interactions for the secondary end-points or MI or cardiovascular death
For stroke, there was a signficant two-way interaction between ascorbic acid and vitamin E (P=0.03). Those in the active groups for both agents experienced fewer strokes, compared with those in the placebo group for both agents (RR, 0.69; 95% CI, 0.49-0.98; P=0.04).

Adverse Effects

No statistically significant differences by any of the randomized antioxidant groups, except for a small increase in reports of symptoms suggestive of gastric upset among those in the active beta carotene group (2,785 vs. 2,717 reports; RR, 1.06; 95% CI, 1.00-1.11; P=0.05).

Other Findings

Mortality follow-up was 93% complete at the end of the trial
Morbidity status was known as of eight years for 93% of survivors and response to the final follow-up questionnaire among surviving women was 89%
Compliance
- Reported compliance, on average, was 76% at four years and 68% at eight years of follow-up for each antioxidant, with no significant difference between active and placebo groups, except for ascorbic acid at eight years (70% vs. 67% in the active vs. placebo group; P=0.01)
- Mean compliance over follow-up was approximately 73% for all active and placebo agents

Author Conclusion:

No overall effects of vitamin E, ascorbic acid or beta carotene on the primary end-point of major vascular disease over more than nine years of follow-up
When combinations of agents were examined, there were no significant interactions, except for a possible reduction in stroke among those taking both active ascorbic acid and active vitamin E
No detrimental effects of antioxidants on total or CVD mortality were found
Widespread use of these individual antioxidants for cardiovascular proctection does not appear warranted.

Funding Source:

Other:

Reviewer Comments:

Compliance was self-reported
Antioxidants provided by pharmaceutical sponsors.

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?	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?	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?	N/A
	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)?	Yes
	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