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Vitamin E

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

To evaluate the long-term supplementation with vitamin E and effect on cancer risk, death and major cardiovascular events.

Inclusion Criteria:
  • At least 55 years of age
  • History of prior stroke, coronary or peripheral arterial disease or diabetes mellitus
  • At least one other cardiovascular risk factor.
Exclusion Criteria:

If a subject met the inclusion criteria but had any of the following they were excluded from the recruitment pool:

  • Younger than 55 years of age
  • Heart failure
  • Known ejection fraction below 40%
  • Uncontrolled hypertension
  • Overt nephropathy
  • MI or stroke within four weeks of when study was to begin
  • Planned revascularization surgery
  • Taking ACE inhibitor or vitamin E.
Description of Study Protocol:

Recruitment

  • The Heart Outcomes Prevention Evaluation (HOPE) was an international trial from December 21, 1998 to April 15, 1999, with 267 centers enrolling 9,541 patients
  • The HOPE-The Ongoing Outcomes (HOPE-TOO) trial continued data collection from April 16, 1999 to May 26, 2008. Only 174 centers continued participation and this resulted in 7,030 patients for follow-up.
  • Median duration of follow-up was 7.0 years.

Blinding Used

Randomization sequence concealed and all study personnel and study participants were blinded for study interventions.

Intervention

400 IU natural source alpha-tocopherol Vitamin E or placebo daily.

Statistical Analysis 

  • Intent to treat analysis on all 9541HOPE trial participants, with each patient censored for his or her duration of observation
  • Median duration of follow-up was 7.0 years
  • Kaplan-Meier survival analysis
  • Cox proportional hazards regression
  • Level of significance pre-defined at two-tailed alpha=0.05.

Design

Double-blind, placebo-controlled randomized controlled trial with factorial design.

Data Collection Summary:

Timing of Measurements

  • Some participants had serum vitamin E levels measured
  • Pill counts at one, 1.5 and two years indicated more than 90% compliance.

Dependent Variables

  • Incident cancer and cancer death
  • Major cardiovascular event (MI, stroke, cardiovascular death)
  • Heart failure
  • Unstable angina
  • Revascularization surgery.

Independent Variables

Placebo or 400 IU vitamin E daily.

Description of Actual Data Sample:
  • Initial N: 9,541 (74% male) 
  • Final N: 7,030 HOPE-TOO trial
  • Age: 66±7 years.

Ethnicity

  • White: 8,580 (89.9%)
  • Hispanic: 533 (5.6%)
  • Asian: 155 (1.6%)
  • Black: 141 (1.5%)
  • Native American: 43 (0.5%)
  • Other: 89 (0.9%).

Anthropometrics

No differences on important measures.

Location

Multi-center trial in the United States.

Attrition (Final N)

N/A; intent to treat analysis.

Summary of Results:

Variables

Vitamin E
(N, Percentage)

Placebo
(N, Percentage)

RR (95% CI)
P-Value

Cancer2
464
(13.2%)
482
(13.7%)
0.96
(0.84-1.09)
0.50

Cancer Death2
128
(3.6%)
133
(3.8%)
0.96
(0.75-1.22)
0.75

MI1
580
(16.5%)
534
(15.2%)
1.09
(0.97-1.22) 
>0.99
Stroke1
208
(5.9%)
191
(5.4%)
1.09
(0.90-1.33)
0 .39
Death from Cardiovascular Causes1
364
(10.3%)
361
(10.3%)
1.01
(0.87-1.16)
0.93
Hospitalization for Unstable Angina2
565
(16.1%)
547
(15.6%)
103
(0.92-1.16)
0.57
Hospitalization for Heart Failure2
203
(5.8%)
146
(4.2%)
1.40
(1.13-1.73)
0.002
All Heart Failure2
519
(14.7%)
443
(12.6)
1.19
(1.05-1.35)
0.007

1 Data from HOPE Trial, N=9,541
2 Data from HOPE-TOO trial, N=7,030. Sensitivity analysis, which includes all available data from all patients at the centers continuing in the trial extension.

Author Conclusion:

In patients with cardiovascular disease, Vitamin E supplementation does not prevent cancer or major cardiovascular events and it may increase risk of heart failure.

Funding Source:
Government: Medical Research Council of Canada
Other: Hoechst-Marion Roussel, Astra Zeneca, King Pharmaceuticals, Natural Source vitamin E Association
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? 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? 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? 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