DLM: Vitamin E (2001)
To explore the association of supplementary and dietary antioxidant vitamin intake on the progression of coronary artery disease.
- Participant in the Cholesterol Lowering Atherosclerosis Study (CLAS)
- Male
- 40 years to 59 years of age
- Non-smoker
- Normotensive
- Non-diabetic
- Normal renal function
- Total serum cholesterol between 4.79mmol per L to 9.07mmol per L (185mg per dL to 350mg per dL)
- Prior coronary artery bypass graft.
Not described.
Protocol Description
Brief description of the CLAS trial: Between ember1980 and October 1984, men were randomly assigned to colestipol-niacin plus a cholesterol-lowering diet or placebo plus a cholesterol-lowering diet for two years. Angiography at two years was compared with baseline angiogram. 188 men enrolled in the trial and 162 (86%) of the subjects completed the two-year angiogram; 156 were evaluable. The analyses demonstrated significant therapeutic benefit from the lipid-lowering intervention.
Using the above cohort, data on intakes of vitamins C and E were evaluated with the following:
- Seven-day food records
- Supplementary vitamin (multivitamins, specific vitamins) use, doses and frequency of use
- Computed average on-trial daily intakes of dietary and supplementary vitamin C and vitamin E.
Statistical Analyses
- For each vitamin, subjects were categorized into high-intake and low-intake groups, stratifying the average on-trial daily intake at 100 IU per day for vitamin E and 250mg per day for vitamin C
- Chi-square or independent T-tests were done to establish equivalency of each of the supplementary vitamin groups relative to other risk factors for angiographic progression
- Comparison of average percent diameter stenosis change between each supplementary vitamin intake category was done using a three-factor analysis of variance (ANOVA), with the factors being supplementary vitamin E group (two levels), supplementary vitamin C group (two levels) and treatment group (two levels:
- Analyses done for all lesions and stratified by baseline lesion size
- Because the lipid-lowering regimen produced large reductions in low-density lipoprotein (LDL) cholesterol, two-way ANOVAs within each treatment group were done, with the factors being supplementary vitamin E group (two levels) and supplementary vitamin C group (two levels).
- Interactive effect of supplementary vitamin E and vitamin C intake was assessed with a one-way analysis of co-variance (ANCOVA), with the factor being frequency of use of the two supplementary vitamins (four levels)
- Treatment group (drug vs. placebo) was included as a covariate to control for group differences in on-trial levels of LDL cholesterol.
- Differences in coronary artery lesion progression due to the use of multivitamins was assessed with a one-way ANCOVA comparing the group of subjects not taking any supplementary vitamin E or multivitamins with the group of subjects taking only multivitamins, with treatment group as a model covariate.
- For dietary vitamins C and E, subjects were categorized into high-intake and low-intake groups, stratifying the average on-trial daily intake at the median for all subjects: vitamin E (9.5 IU per day) and vitamin C (96mg per day)
- Percentage diameter stenosis change was compared with one-way ANCOVAs, with the factor being dietary vitamin E group (two levels) or dietary vitamin C group (two levels); covariates included treatment group assignment and total energy intake.
- Subjects using supplementary vitamins or multivitamins were excluded from the analysis to avoid bias in examining the true association between dietary intake of vitamins C and E and percentage in diameter stenosis change.
Timing of Measurements
- Seven-day food records were collected at baseline and at all study visits
- Supplementary vitamin C and vitamin E intakes were assessed at baseline and every six months.
Dependent Variable
Angiographic change as determined by the percentage of vessel diameter obstructed by stenosis. Measured by quantitative coronary angiography (QCA).
- All lesions
- Lesions less than 50% obstructed (mild/moderate)
- Lesions more than 50% obstructed (severe).
Independent Variables
- On-trial vitamin C: intake from diet and supplements
- On-trial vitamin E: intake from diet and supplements.
Control Variables
- Age
- Blood pressure
- Smoking status: ever smoked vs. never smoked
- Lipid levels
- Severity of coronary artery disease (CAD): number of lesions and average percentage diameter stenosis change
- Treatment group assignment: drug vs. placebo
- On-trial lipid levels
- On-trial blood pressure
- On-trial macronutrient intake: total fat, polyunsaturated fatty acids, monounsaturated fatty acids, saturated fatty acids, carbohydrate, protein and dietary cholesterol.
Baseline Characteristics
Randomized | Treatment | Vitamin E | Groups | Vitamin C | Groups | ||
Characteristic |
All Subjects (N=156) (mean±SD) |
Drug (N=78) |
Placebo (N=78) |
High Vitamin (N=29) |
Low Vitamin (N=127) |
High Vitamin (N=35) |
Low Vitamin C (N=121) |
Age, y | 54.1±4.5 | 53.8 | 54.4 | 55.2 | 53.9 | 55.2 | 53/8 |
% Ever smoked | 71* | 71 | 72 | 76 | 70 | 86 | 67§ |
Total cholesterol (mg/dL) | 244±35 | 247 | 244 | 255 | 244§ | 244 | 244 |
LDL-cholesterol (mg/dL) | 170±31 | 170 | 170 | 178 | 170 | 170 | 170 |
HDL-cholesterol (mg/dL) | 42±8 | 46 | 42 | 42 | 42 | 45 | 42 |
TG (mg/dL) | 150±88 | 150 | 150 | 177 | 150 | 169 | 150 |
Systolic BP (mmHg) | 122±13 | 121 | 123 | 124 | 122 | 121 | 122 |
Diastolic BP (mmHg) | 80±9 | 80 | 80 | 82 | 78 | 77 | 81§ |
Total energy (KJ)# | 7,241±1,802 | 7,300 | 7,186 | 6,896 | 7,321 | 7,379 | 7,203 |
Number of lesions | 8.5±4.4 | 8.1 | 9.0 | 8.9 | 8.5 | 7.9 | 8.7 |
% Diameter stenosis | 38.2±7.0 | 36.3 | 36.1 | 36.2 | 36.2 | 34.5 | 36.7 |
§ P<0.05.
# Determined from seven-day food records.
On-Trial Differences Between Study Groups
- No significant differences in lipid levels, blood pressure and dietary intake of macronutrients were found between the high and low supplementary vitamin E users.
- Lower diastolic blood pressure in the high supplementary vitamin C users (P=0.02)
- No significant differences in lipid levels and dietary intake of macronutrients were found between the supplementary vitamin C groups.
Angiographic Change by Supplementary Antioxidant Vitamin Intake
Supplementary | Vitamin E |
P-Value | |
Variable |
High (n=29) | Low (n=127) | |
All subjects | |||
All lesions | -0.6 (-2.4 to 0.9) | 2.0 (1.0 to 3.1) | P<0.04 |
Lesions <50% stenosed | -0.6 (-2.4 to 1.3) | 3.1 (1.9 to 4.3) | P<0.02 |
Lesions >50% stenosed | -2.4 (-6.3 to 1.5) | -2.4 (-4.3 to -0.5) | |
Drug group | |||
All lesions | -3.4 (-5.4 to -1.3) | 1.1 (-0.3 to 2.6) | P<0.03 |
Lesions <50% stenosed | -3.2 (-5.5 to -0.8) | 2.2 (0.5 to 3.8) | P<0.02 |
Lesions >50% stenosed | -6.2 (-9.8 to -2.6) | -4.0 (-6.4 to -1.6) |
- No significant effect in lesion progression was found for a supplementary vitamin C intake of 250mg per day or more
- No significant interactions between treatment and supplementary antioxidant vitamin intake groups were found
- No statistically significant effect due to supplementary vitamins C or E were found in the placebo group.
Interactive Effect of Supplementary Vitamin E and C Intakes on Angiographic Change
- Supplementary vitamin E intake was significantly associated with supplementary vitamin C intake (P<0.001 using the Cochran-Mantel-Haenszel test)
- There was no significant difference in coronary artery lesion progression across the four groups defined by frequency of supplementary intake (P=0.12)
- No significant difference in coronary artery lesion progression was found between high and low users of supplementary vitamin C for high users of supplementary vitamin E (P=0.76) and low users of supplementary vitamin E (P=0.72)
- There was a significant increasing linear trend in coronary artery lesion progression from the group of high users of supplementary vitamin E, regardless of supplementary vitamin C intake (average change in percent diameter stenosis=0.8%) to the group of low users of supplementary vitamin E and high users of supplementary vitamin C (average change in percent diameter stenosis=1.6%) to the group of low users of both supplementary vitamin E and C (average change in percent diameter stenosis=2.1%) (P=0.05).
Effect of Multivitamins on Angiographic Change
There was no significant difference in coronary artery lesion progression between subjects who did not use supplementary vitamin E or multivitamins (N=70) and subjects who used only multivitamins (N=56) (P=0.17).
Angiographic Change by Dietary Antioxidant Vitamin Intake
- No significant differences were found in coronary artery lesion progression between subjects who consumed less than 9.5 IU per day (median dietary vitamin E intake of all subjects) and those consuming less than 0.95 IU per day (P=0.57)
- No significant differences were found in coronary artery lesion progression between subjects who consumed more than 96mg per day (median dietary vitamin C intake of all subjects) and those consuming less than 96mg per day (P=0.27).
There is a beneficial association of supplementary vitamin E intake on the reduction of coronary artery lesion progression. Verification by carefully designed, randomized, double-blind, placebo-controlled, serial arterial imaging end-point trials are needed.
Government: | NHLBI |
- Per authors, the study may be biased by self-selection and self-reporting of antioxidant vitamin intake
- Small sample size.
Quality Criteria Checklist: Primary Research
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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? | N/A | |
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? | N/A | |
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? | N/A | |
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? | 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? | 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? | 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 | |