EAL

Vitamin E

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To assess the individual effects of vitamins E and C supplementation on the risk of major cardiovascular events over eight years among male physicians at a lower risk of CVD compared to participants of previous trials.

Inclusion Criteria:

Male
Physician in the United States
Age 50 years or older
Willingness to forgo any current MVI or individual nutrient supplement containing more than 100% RDA of vitamin C, E, A, or beta-carotene
12-week run-in period conducted; men who took at least two-thirds of their pills randomized.

Exclusion Criteria:

History of cirrhosis, active liver disease
Anti-coagulant use
Serious illness that may preclude participation.

Description of Study Protocol:

Recruitment-

Occurred in two phases:

Beginning July 1997, 18,763 PHS I participants asked to participate in PHS II
In 1999, invitations to participate and baseline questionnaires mailed to 254,597 male physicians in the United Stages age 50 or older (list provided by American Medical Association), excluding PHS I participants.

Design

Randomized, placebo-controlled, 2x2x2x2 factorial trial

Blinding used

Double-blinded

Intervention

Four groups

N= 3,656 received 400 IU vitamin E every other day and 500mg vitamin C daily
N=3,659 received 400 IU vitamin E every other day and a placebo (no vitamin C)
N=3,673 placebo (no vitamin E) and 500mg per day vitamin C
N=3,653 two placebos (no vitamin E or vitamin C).

Statistical Analysis:

Primary analyses based on intention-to-treat
Two-sided tests with statistical significance set at P<0.05
Designed for 80% power to detect 16% relative reduction in hazard of primary end-point
Cox proportional hazards models used to calculate HR and 95% CI
Sensitivity analysis for adherence
Sub-group analyses stratified by major coronary risk factors.

Data Collection Summary:

Timing of Measurements

Questionnaires sent annually to participants (assessed adherence, adverse events, occurrence of new end points and updated risk factors)

Dependent Variables

Major cardiovascular events (non-fatal MI, non-fatal stroke, and cardiovascular mortality)-
- Non-fatal MI or stroke:
  - Self-reported by participants in follow-up questionnaire, letter, telephone call and other correspondence
  - Relevant medical records reviewed by an end points committee of physicians blinded to treatment to confirm self-reports
- Cardiovascular mortality:
  - Reported by family members or postal authorities
  - Death certificates obtained or autopsy results reviewed by end points committee to confirm
  - Web searches along with National Death Index searches.

Independent Variables

Supplement(s) or placebo

N=3,656 received 400 IU vitamin E every other day and 500mg vitamin C daily
N=3,659 received 400 IU vitamin E every other day and a placebo (no vitamin C)
N=3,673 placebo (no vitamin E) and 500mg per day vitamin C
N=3,653 two placebos (no vitamin E or vitamin C).

Control Variables

Age
PHS I participant status
Prior diagnosis CVD
Prior diagnosis cancer
Original beta-carotene treatment assignment (for PHS I participants only).

Description of Actual Data Sample:

Initial N

14,641 males

Attrition

None as 14,641 included in primary analysis

Age

More than 50 years old. Mean (SD) age is 64.3 (9.2) years. No significant baseline differences between groups.

Ethnicity

Not provided. May have been provided in previous publication of PHS I participants

Other relevant demographics

U.S. physicians, 5.1% with prevalent CVD at baseline

Anthropometrics

Mean BMI (SD)=26.0 (3.65). No significant differences between groups at baseline.

Location

United States

Summary of Results:

Variables	Vitamin E Placebo Group N=7,326	Vitamin E N=7,315	Adjusted HR (95% CI); P-value	Vitamin C Placebo Group N=7,312	Vitamin C N=7,329	Adjusted HR (95% CI); P-value
Overall Major CV Events	625	620	1.01 (0.90-1.13); P=0.86	626	619	0.99 (0.89-1.11); P=0.91
Total MI	271	240	0.90 (0.75-1.07); P=0.22	251	260	1.04 (0.87-1.24); P=0.65
Fatal MI	30	22	0.75 (0.43-1.31)	22	30	1.37 (0.79-2.38)
Total Stroke	227	237	1.07 (0.89-1.29); P=0.45	246	218	(1.07); P=0.21
Hemorrhagic stroke	23	39	1.74 (1.04-2.91); P=0.04	32	30	0.95 (0.57-1.56)
Cardiovascular Mortality	251	258	1.07 (0.90-1.28); P=0.43	253	256	1.02 (0.85-1.21); P=0.86
Total Mortality	820	841	1.07 (0.97-1.18); P=0.15	804	857	1.07 (0.97-1.18); P=0.16

Other Vitamin E Findings:

Censoring for non-adherences did not affect results for major CV events (HR, 0.97 [95%CI, 0.85-1.11]; P=0.68)
Vitamin E had no effect on rate of CHF (HR, 1.02 [95% CI, 0.87-1.20]; P=0.80)
When analyzed according to baseline history of CVD, vitamin E had no effect on the primary prevention of CVD, total MI, total stroke, cardiovascular mortality or total mortality
- The statistically significant increased risk of hemorrhagic stroke remained among men who did not have CVD at baseline
- Among the men with history of CVD at baseline, there was a non-significant reduction in risk of major CV events (HR, 0.82 [.62-1.09]; P=0.18), total MI (HR, 0.88 [0.50-1.55]; P=0.67), total stroke (HR, 0.74 [0.47-1.16]; P=0.18), cardiovascular mortality (HR, 0.83 [0.57-1.19]; P=0.31), and total mortality (HR, 0.91 [0.70-1.17]; P=0.45).
Participants in the vitamin E group with a parental history of MI before age 60 years had a non-significant reduction major cardiovascular events
There was no significant effect modification by randomized beta-carotene or the ongoing multivitamin treatment.

Other Vitamin C Findings

Censoring for non-adherence did not affect results for major CV events (HR, 0.98 [95%CI, 0.86-1.13]; P=0.81)
When analyzed according to baseline history of CVD, vitamin C had no effect on the primary prevention of CVD, total MI, total stroke, cardiovascular mortality, or total mortality.
- Among the men with history of CVD at baseline, vitamin C did not affect incident major CV events. For total MI, there were 18 and 31 cases in active and placebo groups, respectively (HR, 0.57 [0.32-1.02] P=0.06)
No significant modification found between vitamin C and various baseline factors, randomized beta-carotene or the ongoing multivitamin treatment.

Other

No significant differences in adverse events between active and placebo groups
Men assigned to active vitamin E only had a lower risk of total MI than those assigned to placebo vitamins E and C (HR, 0.74; 95% CI, 0.58-0.96), but no reduction was seen in men receiving both active vitamins E and C (HR, 0.94; 95% CI, 0.74-1.19).

Author Conclusion:

Neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events among 14,641 middle-aged and older men after eight years of treatment and follow-up.

Funding Source:

Government:

National Institutes of Health (NIH)

Industry:

BASF Corporation

Pharmaceutical/Dietary Supplement Company:

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.)	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?	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?	Yes
	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?	No
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	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