DLM: Vitamin E (2001)
Citation:
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To investigate the independent and combined effects of n-3 PUFA and vitamin E on morbidity and mortality after MI.
Inclusion Criteria:
MI at less than or equal to three months of enrollment.
Exclusion Criteria:
- Contraindications to the dietary supplements (n-3 PUFA or vitamin E)
- Congenital defects of coagulation
- Unfavorable short-term health problems (e.g., CHF or cancer).
Description of Study Protocol:
Multicenter trial conducted in Italy using an open-label design. Subjects were followed for 3.5 years.
- Recruitment
- Between October 1993 and September 1995
- Cardiology departments and rehabilitation centers
- 172 centers participated
- Randomized using a biased-coin algorithm (allowed stratification by hospital) to one of four groups:
- n-3 PUFA alone
- vitamin E alone
- n-3 PUFA and vitamin E
- Control
- Study medication:
- n-3 PUFA: 850 to 882mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters with an average ratio of EPA/DHA 1:2 ratio
- 300mg vitamin E as synthetic a-tocopherol
- Taken as one gelatin capsule daily.
- Procedures of the trial intended to mimic routine care following MI. Patients were asked to adhere to recommended preventive treatments such as aspirin, beta blockers and inhibitors of angiotensin-converting enzyme.
- Compliance measured by refilling drug supplies every three months
- Validation of clinical events included in the primary endpoints was assured by an ad hoc committee of expert cardiologists and neurologists blinded to patients' treatment assignment.
Statistical Analysis
- Primary combined efficacy endpoints were:
- Cumulative rate of all causes of death, non-fatal MI and non-fatal stroke
- Cumulative rate of cardiovascular death, non-fatal MI and non-fatal stroke
- Secondary analyses:
- Each component of the primary endpoints
- Main causes of death
- Data safety and monitoring committee completed one interim analysis, masked to treatment assignment
- Sample size calculation:
- Estimated cumulative rate of death, non-fatal MI and stroke in the control group over the planned 3.5 years of the study would be 20%
- Calculated to compare the rate of the main endpoint in each of the three study-drug groups to that of the control group (3,000 patients per group, RR decrease was 20%) and to test the hypothesis that the combined treatment would decrease by a further 20% the rate of the main endpoint compared with n-3 PUFA alone or vitamin E alone
- Analyses
- Follow-up data were right-censored at 42 months when follow-up information was available for 99.9% of the sample
- Intention to treat
- Factorial design with two-way analysis of efficacy of n-3 PUFA supplements compared with no n-3 PUFA and efficacy of vitamin E supplements compared with with no vitamin E
- Four-way analysis of efficacy of n-3 PUFA supplements, vitamin E supplements and the combined treatment compared with control
- To explore interaction, fitted multivariate models including the two experimental treatments, and the interaction term were used
- Kaplan-Meier survival curves and log rank test
- Kruskal-Wallis test for continuous variables
- All P-values were two-sided.
Data Collection Summary:
Data Collection
Baseline, six, 12, 18, 30 and 42 months and included:
- Clinical assessment
- Food frequency questionnaire administration
- Blood lipids.
Dependent Variables
- n-3 PUFA
- Vitamin E
- Combined n-3 PUFA and Vitamin E.
Independent Variables
- Cumulative rate of all causes of death, non-fatal MI and non-fatal stroke
- Cumulative rate of cardiovascular death, non-fatal MI and non-fatal stroke.
Description of Actual Data Sample:
Sample
N=11,324:
- n-3 PUFA: N=2,836
- Vitamin E: N=2,830
- n-3 PUFA and vitamin E: N=2,830
- Control: N=2,828.
Attrition
N=11,324 (for analyses):
- n-3 PUFA:
- Two lost to follow-up
- 768 discontinued supplement
- Vitamin E:
- Four lost to follow-up
- 687 discontinued supplement
- 11 received n-3 PUFA
- n-3 PUFA and Vitamin E:
- Four lost to follow-up
- 848 discontinued n-3 PUFA
- 808 discontinued vitamin E
- Control:
- Two lost to follow-up
- 15 received n-3 PUFA
- Two received vitamin E.
Sample Characteristics
Gender: 9,659 males and 1,665 females:
- n-3 PUFA: 2,403 males and 433 females
- Vitamin E: 2,398 males and 432 females
- n-3 PUFA and vitamin E: 2,451 males and 379 females
- Control: 2,407 males and 421 females.
BMI [mean (SD)]: All:26.5 (3.7%)
- n-3 PUFA: 26.5 (3.9%)
- Vitamin E: 26.5 (3.6%)
- n-3 PUFA and vitamin E: 26.6 (3.6%)
- Control: 26.4 (3.5%)
Age (Years)
| n-3 PUFA | Vitamin E | n-3 PUFA and Vitamin E | Control | All | |
| Mean (SD) | 59.4 (10.7%) | 59.5 (10.5%) | 59.1 (10.5%) | 59.4 (10.5%) | 59.4 (10.6%) |
| Less than or equal to 50, No. (%) | 592 (20.8) | 560 (19.8) | 596 (21.0) | 577 (20.4) | 2,325 (20.5) |
| 51 to 60 No. (%) | 827 (29.1) | 840 (30.0) | 875 (31.0) | 844 (31.0) | 3,395 (30.0) |
| 61 to 70, No. (%) | 943 (33.2) | 946 (33.4) | 930 (32.8) | 937 (33.1) | 3,756 (33.1) |
| 71 to 80, No. (%) | 415 (14.6) | 424 (15.0) | 370 (13.0) | 418 (14.7) | 627 (14.3) |
| More than 80 | 59 (2.0) | 51 (1.8) | 59 (2.0) | 52 (1.8) | 221 (1.9) |
Other Characteristics
| |
n-3 PUFA | Vitamin E | n-3 PUFA and Vitamin E | Control | All |
| Non-smokers, No. (%) | 632 (22.4 ) | 6,363 (22.6) | 618 (22.0) | 613 (21.9) | 2,499 (22.2) |
| Ex-smokers | 996 (35.4) | 1,016 (36.1) | 972 (34.5) | 953 (34.0) | 3,937 (35.0) |
| Smokers | 1,189 (42.2) | 1,161 (41.3) | 1,223 (43.5) | 1,234 (44.0) | 4,807 (42.4) |
| BMI, 30 or more |
419. (14.7) | 403 (4.2) | 432 (15.2) | 390 (3.8) | 1,644 (14.5) |
| Total cholesterol (mg per dL) | 210.2 (42.1%) | 211.1 (42.4%) | 210.6 (4.5%) | 211.6 (42.3%) | 210.9 (42.1%) |
| LDL cholesterol (mg per dL) | 137.3 (39.1%) | 138.0 (38.1%) | 138.2 (38.1%) | 138.5 (37.6%) | 37.4 (38.0%) |
| HDL cholesterol (mg per dL) |
41.5 (11.3%) | 41.3 (11.2%) | 41.6 (11.5%) | 41.7 (12.0%) | 41.5 (11.5%) |
| Triglycerides (mg per dL) |
1,62.6 (81.7%) | 163.3 (85.3%) | 160.3 (80.3%) | 161.9 (94.5%) |
162.1 (85.6%) |
- Baseline demographic and clinical characteristics including diabetes, hypertension, previous MI, claudication, angina (various grades), dyspnea (various grades), ejection fraction, premature ventricular beats, ventricular arrythmias and positive exercise test were well-balanced across groups. Dietary habits, recommended secondary prevention treatments and revascularization procedures at baseline and during the study were also well balanced across all groups.
- Data define a relatively low risk population
- Median time to randomization was 16 days.
Summary of Results:
Overall Efficacy Profile of n-3 PUFA Treatment
| All | Two-way Analysis | Four-way Analysis | |||||
| n-3 PUFA | Control | Relative Risk | n-3 PUFA | Control | Relative Risk | ||
| N=11,324 | N=5,666 | N=5,668 | (95% CI) | N=2 836 | N=2 828 | (95% CI) | |
| Main endpoints | |||||||
| Death, non-fatal MI, and non-fatal stroke | 1,500 (13.3%) | 715 (12.6%) | 785 (13.9%) | 0.90 (0.82 to 0.99) | 356 (12.3%) | 414 (14.6%) | 0.85 (0.74 to 0.98) |
|
Cardiovascular death, non-fatal MI, and non-fatal stroke |
1,155 (10.2%) | 547 (9.7%) | 608 (10.8%) | 0.89 (0.80 to 1.01) | 262 (9.2%) | 322 (11.4%) | 0.80 (0.68 to 0.95) |
| Secondary analyses | |||||||
| All fatal events | 1,017 (9.0%) | 472 (8.3%) | 545 (9.6%) | 0.86 (0.76 to 0.97) | 236 (8.3%) | 293 (10.4%) | 0.80 (0.67 to 0.94) |
| Cardiovascular deaths | 639 (5.6%) | 291 (5.1%) | 348 (6.2%) | 0.83 (0.71 to 0.97) | 136 (4.8%) | 193 (6.8%) | 0.70 (0.56 to 0.87) |
| Cardiac death | 520 (4.6%) | 228 (4.0) | 292 (5.2%) | 0.78 (0.65 to 0.92) | 108 (3.8%) | 165 (5.8%) | 0.65 (0.51 to 0.82) |
| Coronary death | 479 (4.2%) | 214 (3.8%) | 265 (4.7%) | 0.80 (0.67 to 0.96) | 100 (3.5%) | 151 (5.3%) | 0.65 (0.51 to 0.84) |
| Sudden death | 286 (2.5%) | 122 (2.2%) | 164 (2.9%) | 0.74 (0.58 to 0.93) | 55 (1.9%) | 99 (3.5%) | 0.55 (0.40 to 0.76) |
| Other deaths | 378 (3.3%) | 181 (3.2%) | 197 (3.5%) | 0.91 (0.74 to 1.11) | 100 (3.5%) | 100 (3.5%) | 0.99 (0.75 to 1.30) |
| Non-fatal cardiovascular events | 578 (5.1%) | 287 (5.1%) | 291 (5.1%) | 0.98 (0.83 to 1.15) | 140 (4.9%) | 144 (5.1%) | 0.96 (0.76 to 1.21) |
| Other Analyses | |||||||
| CHD death and non-fatal MI | 909 (8.0%) | 424 (7.5%) | 485 (8.6%) | 0.87 (0.76 to 0.99) | 196 (6.9%) | 259 (9.2%) | 0.75 (0.62 to 0.90) |
| Fatal and non-fatal stroke | 178 (1.6%) | 98 (1.7%) | 80 (1.4%) | 1.21 (0.91 to 1.63) | 54 (1.9%) | 41 (1.5%) | 1.30 (0.87 to 1.96) |
- In the two-way factor of analysis, the 10% relative decrease in risk for the combined primary endpoint of death, non-fatal MI and non-fatal stroke was significant [95% CI (one to 18), P=0.48]
- Decrease in risk for the other combined endpoint of cardiovascular death, non-fatal MI and non-fatal stroke was not significant ([11%, one to 20), P=0.053]
- In the four-way analysis, there was a 15% decrease in risk for the combined endpoint [95% CI (two to 26), P=0.023] and for cardiovascular death, non-fatal MI and non-fatal stroke, a 20% decrease in risk [95% CI (five to 32), P=0.008]
- Analyses of the individual components of the main endpoint showed that the decrease in mortality (20% for total deaths, 30% for cardiovascular deaths and 45% for sudden deaths) accounted for all the benefit seen in the combined endpoint
- Tests for interaction were not significant when the two combined endpoints and overall mortality were analyzed
- Tests for interaction for the four-way analysis were conducted for the individual components of the endpoints (P=0.0242 for cardiovascular mortality; P=0.0226 for coronary mortality; P=0.024 for fatal plus non-fatal coronary events and P=0.010 for sudden death), and results showed no influence by an effect modification due to the combination of the two treatments.
Vitamin E Alone
- Patients receiving vitamin E and controls did not differ significantly for the combined endpoint and for its individual components. Results were similar for the combined endpoints and overall mortality.
- In the secondary analyses of the individual components of cardiovascular death of the combined endpoints, there was an indication of potential benefit for vitamin E that was similar to n-3 PUFA. There was a significant decrease in all cardiovascular deaths [20%, 95% CI (0.80, 0.65 to 0.99)], cardiac death [95% CI (0.77, 0.61 to 0.97)], coronary death [95% CI (0.75, 0.59 to 0.96)] and in sudden death [35%, 95% CI (0.65, 0.48 to 0.89)].
Combined PUFA + Vitamin E
- Effects seen on the primary combined endpoint and on total mortality were consistent with those obtained with n-3 PUFA alone
- No increased benefit was apparent when the rate of the combined endpoint of death, non-fatal MI and non-fatal stroke that was seen in patients receiving combined n-3 PUFA and vitamin E was compared with the group receiving n-3 PUFA alone [1.01 (0.87 to 1.17)] or with the vitamin E group alone [0.96 (0.83 to 1.12)].
Other findings
- Small decrease in triglyceride concentrations, which was significant, in patients receiving n-3 PUFA compared to controls
- Side effects were reported as a reason for discontinuing therapy for 3.8% of patients in n-3 PUFA groups and in 2.1% in the vitamin E groups. GI disturbances and nausea were the most frequently reported side effects.
- Cancer occurred in 61 (2.2%) patients in the control group, in 77 (2.7%) in the n-3 PUFA group, in 73 (2.6%) in the vitamin E group and in 65 (2.3%) in the combined PUFA and vitamin E group.
Author Conclusion:
- In this population of patients who had MI and Mediterranean dietary habits, and who were well treated with up-to-date preventive pharmacological interventions, long-term n-3 PUFA (one gram) daily, but not vitamin E (300mg) daily, was beneficial for death and for combined death, non-fatal MI and stroke
- All the benefit was attributable to the decrease in risk for overall and cardiovascular death.
Funding Source:
| Industry: |
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Reviewer Comments:
Open-label study.
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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%.) | Yes | |
| 4.3. | Were all enrolled subjects/patients (in the original sample) accounted for? | Yes | |
| 4.4. | Were reasons for withdrawals similar across groups? | ??? | |
| 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? | No | |
| 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? | N/A | |
| 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? | Yes | |
| 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 | |