CRD summary

The authors concluded that omega-3 polyunsaturated fatty acid supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction or stroke. There were some limitations in the review process and the included studies, but the authors' conclusions are likely to be reliable as they reflect the evidence presented and the evidence was consistent across the studies.

Authors' objectives

To evaluate the effect of omega-3 supplementation on major cardiovascular outcomes.

Searching

PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched to August 2012 for published studies in English. The search strategy was reported online. Reference lists of relevant systematic reviews were screened for further articles.

Study selection

Eligible studies were randomised controlled trials (RCTs) that compared omega-3 polyunsaturated fatty acid (PUFA) supplementation against other diet or placebo for the prevention of primary or secondary cardiovascular disease in adults. The outcomes of interest were all-cause mortality, cardiac death, sudden death, myocardial infarction and all types of stroke. Trials with less than one year of treatment were excluded.

Most of the included trials were from 1989 or after, comprised participants of European origin and focused on dietary supplementation. Two trials assessed dietary counselling. More than half of the included trials were restricted to secondary prevention of cardiovascular disease. The average (median) age of participants was 68 years (range 49 to 70). Some trials were restricted to participants with implantable cardioverter defibrillators. The mean daily omega-3 dose was 1.51g. Median treatment duration was two years (range one to 6.2 years).

The authors did not state how many reviewers carried out the study selection.

Assessment of study quality

The Cochrane risk of bias tool was used to assess the quality of included trials. Assessment criteria included randomisation, allocation concealment, blinding, loss to follow-up and use of intention-to-treat analysis.

Details on methodological quality were identified during the data extraction process.

Data extraction

Using the longest follow-up period, data were extracted to enable calculation of relative risks (RR) or absolute risk reduction (RD), with 95% confidence intervals (CI).

Two reviewers independently extracted data. Discrepancies were resolved by a third reviewer.

Methods of synthesis

Trials that used dietary counselling and supplementation were analysed separately. Meta-analysis was possible only for supplementation trials. Relative risks and risk reductions, with 95% CIs, were pooled using random-effects meta-analysis. Relative risks were presented in forest plots. Statistical heterogeneity was assessed with Q and Ι² statistics.

Subgroup/meta-regression analyses were carried out to explore the potential influences of using an open-label design, omega-3 PUFA dose, the prevention setting and the presence of implantable cardiac defibrillator. An adjusted p value of 0.0063 was used to indicate statistical significance. Cumulative meta-analysis was presented to show intervention effects over time.

Publication bias was assessed using funnel plots, the Begg and Mazumbar test and the trim-and-fill method.

Results of the review

Twenty RCTs (68,680 participants; nine trials had sample sizes over 1,000). Randomisation was conducted in all trials, but clearly described in only 12. Loss to follow-up was described in 19 trials. Intention-to-treat analysis and double-blinding was used in 16 trials. Allocation concealment was carried out in 14 trials. The authors did not give an overall view on the quality of each trial but it seemed that seven trials were of unclear risk of bias and four were at high risk based on the table of results.

There were no statistically significant associations between omega-3 PUFA supplementation and all-cause mortality (RR 0.96, 95% CI 0.91 to 1.02; 17 RCTs, Ι²=12%), cardiac death (RR 0.91, 95% CI 0.85 to 0.98; 13 RCTs, Ι²=6%), sudden death (RR 0.87, 95% CI 0.75 to 1.01; seven RCTs, Ι²=8%), myocardial infarction (RR 0.89, 95% CI 0.76 to 1.04; 13 RCTs, Ι²=35%) and stroke (RR 1.05, 95% CI 0.93 to 1.18; nine RCTs, Ι²=14%). Results for absolute risk reductions were not statistically significant.

Subgroup analyses did not alter the main findings. Cumulative meta-analysis showed a weakened intervention effect over time, although a substantial increase in study size was reported at the point at which the effect levelled out. There was no evidence of publication bias.

Opposite directions of effect were reported for all-cause mortality and cardiac death in two RCTs that evaluated dietary counselling interventions. The differences could not be explained by study-specific characteristics.

Authors' conclusions

Omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction or stroke.

CRD commentary

The review question was clear. Inclusion criteria were potentially replicable in all aspects. Relevant data sources were searched. The restriction to published studies was discussed and considered by the authors to have minimal effect on the robustness of the evidence. Publication bias was assessed. Language bias was a possibility. The process for selection of studies was unclear; the other review processes were carried out with sufficient attempts to minimise error and bias.

An appropriate quality assessment tool was applied and the results indicated that some trials had methodological limitations that could affect their reliability. Adequate study details were supplied. Methods of synthesis were appropriate. Relevant subgroup analysis was carried out.

There were some limitations in the review process and the included studies, but the authors' conclusions are likely to be reliable as they reflect the evidence presented and the evidence was consistent across the studies.

Implications of the review for practice and research

Practice: The authors stated that there was no justification for the use of omega-3 in general clinical practice or in guidelines proposing dietary omega-3 PUFA administration.

Research: The authors stated that an individual patient data meta-analysis was needed to determine associations between intervention effect and (for example) dose, adherence, baseline intake and disease risk.

Funding

Not stated.

Bibliographic details

Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012; 308(10): 1024-1033. [PubMed: 22968891]

Original Paper URL

http://jama.jamanetwork.com/article.aspx?articleid=1357266

Other URL

http://jama.jamanetwork.com/data/Journals/JAMA/24854/JRV120006_supp.pdf

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Cardiovascular Diseases /mortality /prevention & control; Cause of Death; Death, Sudden, Cardiac /epidemiology; Dietary Supplements; Fatty Acids, Omega-3 /therapeutic use; Humans; Middle Aged; Myocardial Infarction /mortality /prevention & control; Randomized Controlled Trials as Topic; Risk; Stroke /mortality /prevention & control

AccessionNumber

12012041252

Database entry date

19/09/2012

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.