Vitamins and Antioxidants and the Prevention and Treatment of CVD
- age > 55y
- history of coronary artery disease, stroke, or peripheral artery disease OR diabetes plus one additional CV risk factor
- 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
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
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
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
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.
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.
Quality Criteria Checklist: Primary Research
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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 | |