• Increase Font Size
  • Decrease Font Size
  • View as PDF

DLM: Vitamin E (2001)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To assess the effects of vitamin E on CV events, on microvascular outcomes and on glycemic control in the HOPE study participants with diabetes.
Inclusion Criteria:

High risk for CV events (one of the following):

  • 55 years or older
  • History of CV disease (CAD, stroke or PAD) or diabetes in the presence of at least one other CV risk factor [total cholesterol above 5.2, HDL-cholesterol below 0.9, HTN (on meds or more than 160 systolic or more than 90 diastolic)]
  • Known microalbuminuria
  • Current smoker.
Exclusion Criteria:
  • Dip-stick-positive proteinuria
  • Diabetic nephropathy
  • Serum creatinine over 200umol per L
  • History CHF or known left ventricular ejection fraction under 40%
  • Hyperkalemia
  • Uncontrolled HTN
  • MI
  • Unstable angina or stroke within one month before study enrollment
  • Use of or intolerance to vitamin E or ACE inhibitors.
Description of Study Protocol:
  • Analyses restricted to patients with a baseline diagnosis of diabetes
  • 2x2 factorial design with randomization to 400 IU natural vitamin E (RRR-a-tocopheryl acetate) or placebo and to 10mg of ramipril or placebo, administered once per day
  • Mean follow-up, 4.5 years.
Data Collection Summary:

Patients were evaluated one month after randomization and every six months thereafter.

 

Measurements

  • HgA1c
  • Serum creatinine
  • Urinary albumin
  • Plasma vitamin E, measured in 163 randomly-selected patients in the vitamin E group and 34 in the placebo group.

Primary Outcome

Composite of non-fatal MI, stroke or CV death.

Secondary

  • Total mortality
  • Hospital admission for unstable angina
  • Revascularization procedures
  • Development of overt nephropathy.
Description of Actual Data Sample:

3,654 patients with diabetes at baseline

  • 1,358 women; 2,296 men
  • 2,511 had a history of CVD
  • Mean age: 64.4 years
  • 1,838 vitamin E; 1,816 placebo.

No statistically significant differences between the two groups at baseline, including baseline plasma vitamin E levels.

Summary of Results:
  • Non-study vitamin E use ranged from 0.7% to 3.3% of patients (no difference between groups)
  • No significant side-effects with vitamin E use
  • Year Two: Plasma vitamin E ­ to 48.7±17.6mmol per L (P<0.0001) and remained unchanged in the placebo group (30.4±21.1mmol per L)
  • No significant interaction between study treatments (ramipril and vitamin E) for the primary (P=0.93) and secondary outcomes.

Outcomes

Vitamin E

Placebo

Relative Risk

P-Value
Outcome Results

1o Comp

325

313

1.03

0.7

MI

212

209

1.01

0.96

Stroke

103

84

1.21

0.2

CV Death

142

145

0.97

0.82

T. Mort  

218

232

0.93

0.44

Revasc

279

278 

0.99

0.95
Hospitalization For

Unstable Angina      

227

199

1.13

0.21

Heart Failure  

85

76

1.11

0.52
Other CV Outcomes

Any Heart Failure      

241

201

1.21

0.05
(95% CI, 1.00-1.46)
Microvascular Outcomes

Nephropathy

146

131

1.12

0.37

New Micro-Albuminuria 

442

466

0.91

0.14

Dialysis

9

9

0.099

0.97

Laser Therapy Nephropathy 

182

182

0.99

0.96

New Cataract 

304

318

0.97

0.7

Limb Infect

53

58

0.9

0.59
Glycemic Control Hospitalization

Hyperglycemia 

76

76

 

0.87

Hypoglycemia  

26

37

 

0.12

DKA                 

8

4

 

0.27

  • HgA1c: Increased by absolute amounts above the upper limit of normal by 1.96% vitamin E vs. 2% in the placebo (P=0.89).

Hospital Admission

  • Effects on CV Outcomes
    • No significant treatment effects in any subgroups (women, men, older or younger than 65 years, type 1 vs. type 2 diabetes)
    • BMI above or below 27
    • With or without h/o HTN, smoking, hypercholesterolemia, nicroalbuminuria, CV disease, CAD, MI, stroke, PAD
    • On various pharmacological therapies
    • Those taking or not taking vitamin C and multi-vitamins.
  • 5,887 HOPE study participants without diabetes mellitus at baseline. Diagnosis of new diabetes mellitus: 124 vitamin E vs. 137 on placebo (P=0.55).
Author Conclusion:

400 IU per day of RRR-a-tocopheryl acetate administered for an average of 4.5 years to people with diabetes and at high risk for CV events had a neutral effect on CV outcomes, on microvascular complications and on glycemic control.

Funding Source:
Government: MRC of Canada
University/Hospital: Cleveland Clinic Foundation, McMaster University (Canada), University of Toronto, Laval University (Canada), Ludwig Maximilians University (Germany)
Reviewer Comments:

Study Strengths

Large number of subjects and events.

Other Comments

Only measured plasma vitamin E in a sample of the participants.

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) No
  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? ???
  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? 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)? No
  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
  8.7. 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
  9.1. 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? No
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? ???