EAL

Cardiovascular Disease and Micronutrients

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate whether vitamin E (500 IU) slowed the progression of carotid atherosclerosis in a population of chronic smokers over four years as measured by ultrasound determination of carotid intima–media thickness (IMT) and systemic arterial compliance (SAC).

Inclusion Criteria:

White
55 years of age or over
Regularly smoke more than five cigarettes per day.

Exclusion Criteria:

Life-threatening illness
Previous carotid artery surgery or existing carotid stenosis warranting surgery
Known sensitivity or intolerance to vitamin E
Treatment with anticoagulant drugs
MI or stroke within the previous six months
Uncontrolled hypertension.

Description of Study Protocol:

Recruitment

An advertising campaign in the local media solicited participants from the general community in metropolitan Melbourne, Australia. Recruitment took place from November, 1994 to November, 1995. Follow-up was completed in November, 1999.

Design

Randomized, double-blind, placebo, controlled trial.

Blinding Used

The randomization schedule, which was kept at a remote site, used an allocation scheme with a random permuted block size of eight. Neither study staff nor participants were aware of treatment allocation.

Intervention

Vitamin E was administered as capsules containing 500 IU of natural vitamin E (d-[alpha] tocopherol) in a soybean oil suspension, encapsulated in gelatine (Henkel Australia, New South Wales, Pty Ltd Australia)
Placebo capsules also contained soybean oil and were of identical appearance.

Statistical Analysis

For 80% power to detect a 30% difference between placebo and treatment groups in the rate of change of IMT over four years, a total of 250 participants were required (two-sided significance level of 0.05). Allowing for a combined dropout and mortality rate totaling approximately 44%, 360 participants were required, 180 in each arm.
IMT was compared between groups using a linear regression model with an interaction between study groups and time (assuming a linear change in IMT over time)
SAC was analyzed for the initial two years of the study because of both missing data in later years and the hypothesis that the treatment effect should have already occurred
All data was analyzed on an intention-to-treat basis.

Data Collection Summary:

Timing of Measurements

At baseline, the following were performed:
- An initial carotid ultrasound examination
- A questionnaire providing information on medical history, intake of drugs, diet and smoking history
- Sitting blood pressure
- Pulse rate
- Weight and height
- Blood glucose (random) and lipid profile with TC, TG and HDL
Participants were telephoned every three months to encourage compliance and to report adverse events
At six, 12, 24, 36 and 48 months after entry into the study:
- Carotid ultrasound
- SAC assessment
- Capsule compliance
- Measurement of the clinical and lipid parameters.

Dependent Variables

Carotid IMT was used as a surrogate for atheroma progression and CVD endpoint. It was measured using a high-resolution ultrasound instrument (Diasonics DRF-400; Diasonics, Santa Clara, California, USA) with a 7.5 MHz mechanical sector transducer (7.5-SPC).
SAC was used as a surrogate for atheroma progression and CVD endpoint. It was estimated using the area method described in detail elsewhere. Brachial blood pressure was measured at 5-minute intervals throughout the entire clinic visit using a Dinamap recorder (Critikon 1846 SX; Critikon Inc., Tampa, Florida, USA). Central blood pressure was measured using applanation tonometry applied to the right common carotid artery with a non-invasive pressure transducer (Millar Mikro-tip; Millar Instruments Inc., Houston, Texas, USA). Carotid artery pressure waveforms were obtained simultaneously with the brachial artery pressure recordings.
Blood glucose (random) and lipid profile of TC, TG and HDL by a commercial assay using an Abbott auto-analyzer
LDL oxidative susceptibility was measured on plasma samples from a randomly selected subset of 60 patients on three occasions by determining the length of time before the onset of conjugated diene accumulation (lag phase).

Independent Variables

Vitamin E supplement intake.

Description of Actual Data Sample:

Initial N

409 participants:

205 randomized to vitamin E
204 randomized to placebo.

Attrition

N=171 completed the Vitamin E arm of trial
N=162 completed the placebo arm of trial.

Age

Mean age was 64 years.

Ethnicity

White.

Other Relevant Demographics

56.6% were women
Mean self-reported intake of 20 cigarettes daily (range five to 80 cigarettes a day).

Anthropometrics

There was close similarity in most characteristics, except:

The vitamin E group had greater body mass index (BMI) and was more likely to use calcium channel blockers
The placebo group was more likely to use angiotensin-converting enzyme (ACE) inhibitors
The mean pack–years of smoking was similar in the two groups.

Location

Melbourne, Australia.

Summary of Results:

Variables

Vitamin E Group

N=171

Measures and Confidence Intervals

Placebo Group

N=162

Measures and Confidence Intervals

Statistical Significance of Group Difference

Annual IMT change

N=331

0.0035mm per year

95% CI: -0.0008. to 0.0078

-0.0005mm per year

95% CI: -0.0049 to 0.0039

P=0.20

95%CI: -0.0102 to 0.0021

SAC

N=107, or (70%)

-0.030mm Hg per year

95% CI: -0.0008 to 0.338

0.005mm Hg per year

95% CI: -0.025 to 0.036

P=0.11

95% CI: -0.008 to 0.079

LDL oxidative susceptibility*

N=63

P<0.001

95% CI: 1.1 to 2.2

HDL*

-0.0008mmol per year

P<0.001

95% CI: -0.12 to -0.04

*Further data is not provided in the article.

Other Findings

Overall 75.0% and 73.6% of the vitamin E and placebo groups, respectively, consumed 80% or more of their capsules
After four years of follow-up, 83.4% of the vitamin E group and 79.4% of the placebo group remained on their assigned medication.

Author Conclusion:

Vitamin E had no effect on the progression of carotid atherosclerosis despite a high dose being used in a setting where oxidation is strongly enhanced. The absence of an effect in this environment, coupled with the lack of effect in a variety of other settings, suggests that this compound is ineffective in slowing the progression of carotid atherosclerosis in humans.

Funding Source:

Government:

National Health and Medical Research Council of Australia

Reviewer Comments:

This study appeared to be underpowered as 180 participants were required in each arm for 80% power to detect a 30% difference between placebo and treatment groups in the rate of change of intima–media thickness over four years, given two-sided significance level of 0.05 and an allowance for a combined dropout and mortality rate totaling approximately 44%.

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?	No
	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?	N/A
	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?	No
	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?		No
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	No
	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)?	No
	8.6.	Was clinical significance as well as statistical significance reported?	N/A
	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