DLM: Vitamin E (2001)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To explore the association of supplementary and dietary antioxidant vitamin intake on the progression of coronary artery disease.

Inclusion Criteria:
  • 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.
Exclusion Criteria:

Not described.

Description of Study Protocol:

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.

 

Data Collection Summary:

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.
Description of Actual Data Sample:

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
*Total number whoever smoked=111.

§ P<0.05.

# Determined from seven-day food records.

 

 

Summary of Results:

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).
Author Conclusion:

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.

Funding Source:
Government: NHLBI
Reviewer Comments:
  • 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
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