Vitamin E

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

The purpose was to report post-trial effects of alpha-tocopherol and beta-carotene supplementation on major coronary events (MCE) during a six-year follow-up of the alpha-tocopherol, beta-carotene cancer prevention (ATBC) study.

Inclusion Criteria:
  • 50- to 69-year-old men living in southwestern Finland who had participated in the ATBC study between 1985 and 1993 
  • Subjects of this cohort were current smokers (smoked five or more cigarettes per day) at the time of enrollment into the ATBC study, but their current smoking status is unknown
  • Men who were still at risk of first-ever MCE at the beginning of the post-trial follow-up, i.e., they had not suffered from myocardial infarction (MI) during the intervention phase
  • Men who were alive at the beginning of the post-trial follow-up and had not experienced a recurrent non-fatal MI during the intervention phase.
Exclusion Criteria:
  • Men with the following criteria were excluded from the original ATBC study:
    • Prior cancer
    • Severe angina on exertion
    • Any other serious disease limiting long-term participation
    • Use of vitamin E supplements (more than 20mg per day)
    • Use of beta-carotene supplements (more than 6.0mg per day)
    • Use of vitamin A supplements (more than 20,000 IU per day)
    • Anticoagulants
  • Men who had suffered from the first-ever MI during the intervention phase and were still alive at the beginning of the post-trial follow-up
  • Men who reported a history of MI diagnosed by a physician and had experienced a recurrent non-fatal MI during the intervention phase
  • Men who died during the intervention phase.
Description of Study Protocol:

Recruitment

  • Cohort was screened by a postal survey from among original participants in the ATBC study
  • Enrollment for the original ATBC study took place between 1985 and 1988.

Design

Retrospective cohort study.

Blinding Used

  • Double-blinding used in original ATBC study from which cohorts were formed
  • Death registries and objective laboratory tests used to diagnose major coronary events.

Intervention

  • Cohorts determined based on prior supplement use during the ATBC study, which was a RCT:
    • 50mg of dl-alpha-tocopheryl acetate supplement daily
    • 20mg of beta-carotene supplement daily
    • 50mg of dl-alpha-tocopheryl acetate and 20mg of beta-carotene supplements daily
    • Placebo in one capsule per day.

Statistical Analysis

  • Analyses based on intention-to-treat principle
  • Likelihood ratio test was used to test homogeneity of risk estimates between the supplementation groups
  • Relative risk (RR) estimates and their 95% confidence intervals (95% CI) were obtained from Poisson regression models
  • Effect modification by risk factor levels at the baseline of the trial on the post-intervention supplement effect was analyzed by calculation RR estimates in the strata of each factor
  • Likelihood ratio test was used to test homogeneity of post-trial effects in the strata of risk factors
  • To estimate calendar time-specific rates, smoothed rate estimates were calculated using a generalized additive model.

 

Data Collection Summary:

Timing of Measurements

Participants were followed up post-trial for six years through national registers from May 1, 1993 to April 30, 1999, but the use of supplements were not monitored. 

Dependent Variables

Major coronary events (MCE) post-ATBC study:

  • Non-fatal myocardial infarction (MI): Identified through linkage with the national Hospital Discharge Register, which uses International Classification of Disease (ICD) codes
  • Fatal coronary heart disease (CHD): Identified through linkage with the national Register of Causes of Death, which uses International Classification of Disease (ICD) codes.

Independent Variables

  • Alpha-tocopherol supplementation during course of ATBC study
  • Beta-carotene supplementation during course of ATBC study
  • Alpha-tocopherol and beta-carotene supplementation during course of ATBC study
  • Placebo supplementation during course of ATBC study.

 

 

Description of Actual Data Sample:

Initial N

24,399 males in post-trial follow-up:

  • Men who were still at risk of first-ever MCE at the beginning of the post-trial follow-up (23,144 males)
  • Men with reported history of MI diagnosed by a physician that had not experienced a recurrent non-fatal MI during the intervention phase and were still alive at the beginning of the post-trial follow-up (1,255 males).

Age

  • Men who were still at risk of first-ever MCE at the beginning of the post-trial follow-up:
    • Median age, 63 years
    • Age range, 55 to 77 years
  • Men with reported history of MI diagnosed by a physician that had not experienced a recurrent non-fatal MI during the intervention phase and were still alive at the beginning of the post-trial follow-up (median age, 65 years).

Ethnicity

Finnish.

Other Relevant Demographics

Years of smoking and number of cigarettes per day were similar across the four intervention groups at the ATBC study baseline.

Anthropometrics:

  • Body mass indices were similar across the four intervention groups at baseline
  • Coronary risk characteristics were similar across the four intervention groups at baseline.

Location

Southwestern Finland.

 

 

 

Summary of Results:

 

Post Trial Risk for Coronary Heart Disease and Nonfatal Myocardial Infarction
Coronary Event

Placebo

RR

α-tocopherol

RR (95% CI)

β-carotene

RR (95% CI)

α-tocopherol and β-carotene

RR (95% CI)

P-value
First ever MCE 1.0

 

0.94 (0.83-1.07)

1.13 (1.00-1.28) 1.08 (0.95-1.22) 0.02
First ever nonfatal MI 1.0

 

0.94 (0.78-1.14)

 

1.14 (0.95-1.36)

1.12 (0.94-1.34)  0.11 
Fatal MI as first MCE  1.0 0.94 (0.79-1.12) 1.12 (0.94-1.33) 1.04 (0.87-1.24)  0.25
Subsequent nonfatal MI* 1.0 0.72 (0.41-1.26) 0.93 (0.54-1.59)  0.99 (0.59-1.67)  0.61 
Fatal MI among men with previous MI* 1.0

 

0.95 (0.60-1.50) 

 

0.98 (0.61-1.56)

0.96 (0.61-1.52) 1.00 

*Among men who had experienced an MI prior to the ATBC trial, 257 major cardiac events occurred (150 were fatal and 107 were recurrent non-fatal MIs). There was no significant effect due to any of the supplements. 

 

Author Conclusion:

The findings regarding the late effects of alpha-tocopherol and beta-carotene in male smokers indicate against the use of these supplements in prevention of coronary heart disease.

Funding Source:
Government: US National Cancer Institute, National Institutes of Health, Department of Health and Human Services
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) N/A
  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
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? N/A
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? N/A
  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
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
 
Validity Questions
  1. Was the research question clearly stated? Yes
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.1. 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
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
  1.3. Were the target population and setting specified? Yes
  2. Was the selection of study subjects/patients free from bias? 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
  2.1. 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
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? 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
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
  3. Were study groups comparable? 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) N/A
  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
  3.2. 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
  3.3. 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? 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? Yes
  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
  3.5. 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
  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. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? 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%.) 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%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? 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
  4.4. 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
  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. 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
  5.1. 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
  5.2. 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? Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? ???
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? Yes
  5.5. In diagnostic study, were test results blinded to patient history and other test results? 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. 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
  6.1. 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
  6.2. 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
  6.3. 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
  6.4. 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
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? No
  6.6. Were extra or unplanned treatments 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
  6.7. 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? 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. 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
  7.1. 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
  7.2. 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
  7.3. 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
  7.4. 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
  7.5. 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
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? 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. 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
  8.1. 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
  8.2. 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
  8.3. 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
  8.4. 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
  8.5. 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
  8.6. 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
  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. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? 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. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
  10.2. Was the study free from apparent conflict of interest? Yes