Kwak SM, Myung SK, Lee YJ, Seo HG. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172:686-693.
Meta-analysis of previously published data on the efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the secondary prevention of cardiovascular disease (CVD)
The authors searched PubMed, EMBASE, and the Cochrane Library in April 2011. Two of the authors independently reviewed and selected eligible randomized controlled trials. Of the 1,007 articles retrieved, 14 randomized, double-blind, placebo-controlled trials involving 20,485 patients with a history of CVD were chosen to be included in the final analyses.
This study concluded that based on the 14 studies analyzed, supplementation with omega-3 fatty acids did not reduce the risk of overall cardiovascular events (relative risk: 0.99; 95% CI: 0.89–1.09), all-cause mortality, sudden cardiac death, myocardial infarction, congestive heart failure, or transient ischemic attack and stroke. A small reduction in cardiovascular death (RR: 0.91; 95% CI: 0.84–0.99) was found but disappeared when data from one study “with major methodological problems” was excluded.
Do omega 3s protect against cardiovascular disease? According to this study, that remains to be determined; however, based on thousands of other clinical studies that support the use of omega 3s and heart health, this meta analysis should be examined more fully to reflect the totality of evidence to support omega-3 use. Furthermore, while this study attempted to quell some of the inconsistencies found in the evidence from published trials on EPA/DHA supplementation and cardiovascular disease, it may leave the reader puzzled.
In trying to provide a definitive answer regarding the EPA/DHA heart health question, this meta-analysis has provoked justifiable controversy due to its simplistic approach and conclusion. Some of the issues with this paper were addressed in the simultaneously published “Invited Commentary” by Drs. Hu and Manson from the Harvard School of Public Health. They found, among other things, structural problems in this meta-analysis that need to be addressed.
In trying to provide a definitive answer regarding the EPA/DHA heart health question, this meta-analysis has provoked justifiable controversy due to its simplistic approach and conclusion.
The decision of whether to include a study in this meta-analysis was made by just 2 authors and was therefore subjective. While all meta-analyses have this measure of subjectivity, the studies excluded from this analysis have raised questions. For example, the authors’ decision to exclude 2 of the largest trials to date demonstrating positive benefits and reduction in CVD—GISSI and JELIS—diminishes some of the most important omega-3 heart health research to date.1,2 In fact, the GISSI-Heart Failure Trial, which has the largest number of CVD-related endpoints, found that fish oil supplementation reduced fatal CVD by 10%.
In this meta-analysis, the authors chose to address only randomized, double-blind, placebo-controlled trials. However, the decision to give equal weight to studies of varying size and scope (often with incongruous endpoints) and to disregard the significant dosage disparities throughout (range of 0.4 to 4.8 g/d), merely serves to confuse. Additionally, the follow-up period ranged from 1.0 to 4.7 years. This confusion is apparent within the piece, as the evaluators of the data disagreed on the criteria and ensuing eligibility of data inclusion. At one point the authors state, “Omega-3 fatty acid supplementation significantly reduced cardiovascular death,” yet they go on to exclude the study that demonstrated this reduction.
The authors’ inclusion of only 14 out of the 1,007 published studies they retrieved from their literature search is notable; only approximately 1.4% of the available data was included. Of these 14 studies, the authors chose to include 3 recent studies in which 85–94% of participants were also using statins, antithrombotic, and antihypertensive medications (by comparison, only 29% and 23% of patients in the GISSI-Prevenzione and GISSI-Heart Failure trials were using these medications). The additional benefits of fish oil on top of these pharmaceutical interventions are likely to be small, and therefore require a much larger sample size than what was used in this analysis.
Omega-3 supplementation warrants further study; however, at this point Kwak et al’s conclusion that fish oil does not provide benefit in heart disease is premature and should not inform our clinical decision making; rather, clinicians should examine all of the omega-3 data to date. Decision making in evidence-based medicine is a process of weighing evidence that a therapy may provide benefit against the evidence of harm associated with using that therapy. At this point the evidence of harm is minimal to none, in part because the omega-3 family of fatty acids are essential, meaning it is essential we get them through our diet or supplementation regularly. The totality of evidence supporting the role of fish oil for the prevention and treatment of heart disease still remains convincing, and the scale of evidence-based medicine still tips in favor of fish oil.
- Marchioli R, Barzi F, Bomba E, et al. GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)- Prevenzione. Circulation. 2002;105(16):1897-1903.
- Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.