Vitamins and Antioxidants and the Prevention and Treatment of CVD

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To evaluate the effects of vitamin E supplementation on major CVD outcomes and on the development of nephropathy.
Inclusion Criteria:
  • age > 55y
  • history of coronary artery disease, stroke, or peripheral artery disease OR diabetes plus one additional CV risk factor

 

Exclusion Criteria:
  • dipstick-positive proteinuria
  • diabetic nephropathy
  • serum creatinine > 200 micromol/l
  • history of congestive heart failure or known low left ventricle ejection fraction < 40%
  • hyperkalemia
  • uncontrolled hypertension
  • myocardial infarction
  • stroke or unstable angina within one month before study enrollment
  • use of, or intolerance to, vitamin E or ACE inhibitors
Description of Study Protocol:

Recruitment: subjects were a subset of the HOPE study; this analysis included only those with a baseline diagnosis of diabetes

Design

  • 2 x 2 factorial design with randomization to 400 IU natural source vitamin E or placebo and to 10 mg of ramipril or placebo
  • both study drugs administered once daily

Blinding used (if applicable):

  • protocols were published elsewhere
  • all primary and secondary outcomes were adjudicated by an events adjudication commitee unaware of the participants assigned treatments

Intervention (if applicable)

  • 400 IU vitamin E or placebo
  • 10 mg ramipril or placebo

Statistical Analysis

  • analyses done using intention to treat
  • baseline characteristics were compared by t tests or chi-square tests as appropriate
  • all outcome analyses were stratified according to randomization to ramipril or placebo by Cox regression in order to account for the factorial study design
  • relative risks and 95% CIs reported for primary, secondary, and other outcomes of interest
  • Kaplan-Meier curves were used to estimate survival and were compared by log-rank tests
  • treatment effect in subgoups and potential interactions were evaluated by Cox regression analysis.
  • Changes in continuous variables from baseline were compared by ANOVA, adjusted for baseline values
  • albumin-to-creatinine ratios were transformed to account for nonnormality and values were adjusted for the laboratories in which the assays were performed

 

Data Collection Summary:

Timing of Measurements

  • after randomization patients evaluated at one month and then every 6 months thereafter
  • HbA1c and creatinine measured at baseline and at one year
  • urinary albumin excretion (albumin-to-creatinine ratio) measured at baseline, 1 year, and end of study

Dependent Variables:  composite of nonfatal MI, stroke, or CV death

  • total mortality
  • hospital admission for congestive heart failure
  • hospital admission for unstable angina
  • revascularization procedures
  • development of over nephropathy

Independent Variables

  • plasma vitamin E levels measured by liquid chromatography at baseline and at 2 years in 163 randomly selected patients in the vitamin E group and in 34 randomly selected patients in the placebo group

Control Variables

 

Description of Actual Data Sample:

Initial N: 3654; 37% women

Attrition (final N): 92.3% of patients were taking the study drug at one year; 90.3% at two years; 84.6% at 4 years, and 83.4% at study end.  These percentages were similar for the placebo group.

Age: 65.4 y

Ethnicity: not specified

Other relevant demographics: 69% of total sample had a history of heart disease

Anthropometrics:  Baseline characteristics were similar between the vitamin E and placebo groups

Location: Canada, United Kingdom, Argentina, Brazil

 

Summary of Results:

Vitamin E levels were similar in the two groups at baseline, but rose significantly in the vitamin E group at 2 years (p<0.0001) and remained unchanged in the placebo group.

 CV Events in the vitamin E and placebo groups

Outcomes

Vitamin E

n=1838

Placebo Group

n=1816

Relative Risk

(95% CI)

Statistical Significance of Group Difference

Composite of MI, stroke or CV death

325 313  1.030.88-1.21  0.70

Total Mortality

 218

232

 0.93(0.77-1.12)

 0.44

Hospitalization for unstable angina

 227

199

 1.13(0.93-1.37)

 0.20

Hospitalization for heart failure  85 76  1.11(0.81-1.51)  0.52
Revascularization procedures  279  278  0.99(1.82-1.17)  0.95
Overt nephropathy  146  131  1.12(0.88-1.42)  0.37
New microalbuminuria  442  466  0.91(0.79-1.03)  0.14
Dialysis  9  9  0.99(0.81-1.22)  0.97
laser therapy for diabetic nephropathy  182  182  0.99(0.81-1.22)  0.96
Cataract surgery  304  318  0.97(0.88-1.21)  0.70
Limb infection  53  58  0.90(0.63-1.31)  0.59

 Other Findings

 Effects of vitamin e on glycemic control

There was no significant difference between vitamin E and placebo groups at baseline, 1 year, or the the end of the study for HbA1c, for hosptial admissions for hyperglycemia, diabetic ketoacidosis, or hypoglycemia.

 

Author Conclusion:

Adminstration of 400 IU/day of vitamin E for an average of 4.5 years to people with diabetes and at high risk for CV events had a neutral effect of CV outcomes, on microvascular complications, and on glycemic control.

The widespread use of supplemental vitamin E cannot be endorsed as a means to reduce vascular complications in people with diabetes.

Funding Source:
Reviewer Comments:
Some information, such as details about study withdrawals and power calculations for sample size were not reported in this study, but may have been noted in earlier reports.
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%.) No
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? No
  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? Yes
  6.6. Were extra or unplanned treatments described? 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? 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? N/A
  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