EAL

DLM: Omega-3 Fatty Acids (2009-2010)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To test the efficacy of PUFA and vitamin E on preventing cardiovascular events.

Inclusion Criteria:

Patients with recent myocardial infarction (previous three months)
No known contraindications to dietary supplements
Written consent.

Exclusion Criteria:

Unfavorable short-term outlook (CHF or cancer).

Description of Study Protocol:

Recruitment

Multi-center trial with 172 clinics.

Design

RCT.

Blinding Used

Unable to determine if blinding was used: The original article was in Italian.

Intervention

PUFA alone (N=2,835): Daily dose of n-3 PUFA as one gelatin capsule containing 850mg to 882mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters
Vitamin E alone (N=2,830): 300mg vitamin E given as one capsule of synthetic alpha-tocopherol
Both PUFA and vitamin E (N=2,830)
No supplement control group (N=2,828).

Statistical Analysis

Data right-censored at 42 months
Multivariate analyses with Cox regression models (variables included: Age and sex; complications after MI such as electrical instability; residual ischemia; positive exercise testing; smoking habits; history of diabetes; arterial hypertension; total blood cholesterol; HDL-cholesterol; presence of PVD; use of antiplatelet agents; ACE inhibitors and beta blockers)
X² tests for trend and heterogeneity.

Data Collection Summary:

Timing of Measurements

Follow-up visits were scheduled at six, 12, 18, 30 and 42 months and included clinical assessment and the administration of a food-frequency questionnaire.

Dependent Variables

Cumulative rate of all-cause death
Non-fatal myocardial infarction, and non-fatal stroke
Cumulative rate of cardiovascular death
Secondary analyses for each component of the primary end points and for the main causes of death.

Independent Variables

n-3 PUFA containing 850mg to 882mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters (N=2,835)
300mg vitamin E in one capsule of synthetic alpha-tocopherol (N=2,830)
Combined n-3 PUFA and vitamin E (N=2,830).

Control Variable

No supplement (control, N=2,828)
Usual care after MI (covariates listed in statistical analyses).

Description of Actual Data Sample:

Initial N

11,323 (85% male).

Age

59.3±10.6 years
16.4% of subjects were aged more than 70 years.

Ethnicity

Italian.

Other Relevant Demographics

50% of subjects recruited within 16 days of MI
43% had smoked previous to event and one third continued smoking
36% hypertensive
15% had diabetes

Location

Italy.

Summary of Results:

**Effect of PUFA Supplement on Outcome**
Endpoint	PUFA *Relative Risk and (95% Confidence Interval)**
Primary Endpoints:
Death, non-fatal MI and non-fatal stroke	0.85 (0.74 to 0.98)
Cardiovascular death, non-fatal MI and non-fatal stroke	0.80 (0.68 to 0.94)
Secondary Endpoints:
Cardiovascular mortality	0.70 (0.56 to 0.86)
Coronary mortality	0.68 (0.53 to 0.88)
Sudden death	0.56 (0.40 to 0.79)
CHD death and non-fatal MI	0.78 (0.65 to 0.94)
Fatal and non-fatal stroke	1.24 (0.82 to 1.87)
Non-fatal MI	0.95 (0.79 to 1.14)
Non-fatal stroke	1.08 (0.75 to 1.55)

*Relative risk calculated by Cox regression analysis adjusted for vitamin E and interaction term; analysis by intention-to-treat; follow-up right-censored at 3.5 years.

Other Findings

Vitamin E at 300mg daily, was not beneficial for death and for combined death, nonfatal myocardial infarction and stroke.

Author Conclusion:

After 42 months, supplementation with n-3 PUFA at one gram daily was beneficial for reducing risk of death and for combined death, nonfatal myocardial infarction and stroke. There was no benefit from supplementation with 300mg vitamin E.

Funding Source:

Industry:

Unrestricted grants from Bristol-Myers Squibb, Pharmacia-Upjohn, Societa Prodotti Antibiotici and Pfizer

Pharmaceutical/Dietary Supplement Company:

In-Kind support reported by Industry:

Yes

Reviewer Comments:

This appears to be an excellent study; however, the analyst assigned a neutral quality rating because of Validity Question three (Were the study groups comparable?). This information was likely in the original reports, which were in Italian. There was also an issue with Validity Question four (Was method of handling withdrawals described?) as the authors did not give information about compliance to the supplement regimen.

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?	???
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
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?	Yes
	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?		No
	4.1.	Were follow-up methods described and the same for all groups?	???
	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?	???
	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?		???
	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?	Yes
	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?	Yes
	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?	???
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	???
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	???
	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?	N/A
	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?		N/A
	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