Cardiovascular Disease

A 'Check' in the 'Fish Oil Doesn't Work' Column: Results from a Meta-analysis

Abstract & Commentary

By David Kiefer, MD

Synopsis: A meta-analysis of 20 human randomized, controlled clinical trials of at least 1 year in duration found that there was no relationship between diet or supplement-derived omega-3 supplementation and cardiovascular disease outcomes.

Source: Rizos EC, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: A systematic review and meta-analysis. JAMA 2012;308:1024-1033.

The authors of this trial were interested in clarifying the use of marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs) for cardiovascular protection, recognizing that there are conflicting results in the medical literature on the topic. The overall goal was to determine the association between n-3 PUFAs and "major patient-oriented cardiovascular outcomes."

The authors included any randomized clinical trial involving n-3 PUFA supplementation in adults, including supplementation that was either from diet or supplements. The trials had to have a control (another diet or placebo), involved primary or secondary cardiovascular disease (CVD) prevention, and could have any of a number of outcomes, such as all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke. The trials had to be at least 1 year in duration.

All of the typical databases (i.e., PubMed, EMBASE) were searched, and the trials were assessed for risk of bias using a modification of the Cochrane collaboration tool. The authors separately analyzed the data from trials where the n-3 PUFAs were obtained from diet vs supplements, and for each of the major CVD outcomes, calculating relative risks (RR), absolute risk reductions (ARR), and 95% confidence intervals (CI). In addition, the omega-3 dose was considered as a continuous variable.

Twenty clinical trials, with a median duration of 2 years and mostly considered "high quality," were included out of 3635 citations originally found in their search mechanism; these 20 trials included data on 68,680 patients, and documented 7044 deaths, 3993 cardiac deaths, 1150 sudden deaths, 1837 myocardial infarctions, and 1490 strokes. Two of the 20 trials involved dietary counseling to achieve the n-3 PUFA intervention, while the other 18 used supplements. The mean total n-3 dose was 1.51 grams daily, which included 0.77 grams daily of eicosapentaenoic acid (EPA) and 0.60 grams daily of docosahexaenoic acid (DHA).

The two trials that used a dietary intervention examined secondary prevention of CVD and were done by the same European research group. Each trial aimed for an n-3 PUFA intake of about 1 gram daily and compared the intervention to a non-fish oil diet. The results showed both benefits for n-3 supplementation and benefits for the control groups, some of which were statistically significant. Because of this discrepancy, which was difficult to explain given the research methods as described in the trials, the authors of the review decided not to include these results in the final analysis.

For the trials that used fish oil supplementation as the n-3 PUFA source, there was no observed reduction in all-cause mortality (RR, 0.96; CI, 0.91-1.02), and, interestingly, the researchers found that more recent research refuted earlier benefits, accounting for the overall lack of documented effect. Similarly, there was not an association between n-3 PUFAs and improvements in the other parameters, minus one: for cardiac death, there was a slight reduction in risk (RR, 0.91; CI, 0.85-0.98), though the researchers claimed that the improvement disappeared after correction for multiple comparisons.


Although there is accumulating evidence for the use of n-3 PUFAs in mood disorders and inflammatory conditions, the cardiovascular system is probably the most well-known site of physiological activity and benefit for n-3 PUFAs; we are all familiar with the published trials on dietary fish consumption or fish oil supplementation and the morbidity and mortality related to cardiovascular conditions such as coronary artery disease, arrhythmias, heart failure, and hypertension.1,2,3,4,5 Most experts recommend two servings of fish weekly for primary CVD prevention, and 1000 milligrams of EPA + DHA supplementation daily for secondary CVD prevention,3 though, as the authors of this meta-analysis point out, there is controversy about efficacy in many of these diagnoses. What does seem to be well-accepted is the positive effect of n-3 PUFAs on hypertriglyceridemia (approximately 2-4 grams of EPA + DHA daily).2,6,7

So, how do we put this all together in the context of the current meta-analysis, where none of the CVD outcomes showed a benefit associated with n-3 intake? The authors themselves state that the individual trials might be underpowered to detect a small effect, which would lead to a meta-analysis also unable to show benefits to n-3 PUFA supplementation. Also, there is the issue of dose. The mean n-3 PUFA intake for the 20 trials is lower than what we know would account for an appreciable effect on triglycerides, probably the most convincing physiological effect that would have a tangible benefit. The authors did analyze the n-3 dose variably and failed to find significant effects on the CVD outcomes examined. It is unclear whether interstudy n-3 dose variability would be given due justice in the analysis presented here. Such a nuance, and an important one clinically, might be lost. Furthermore, we do not know about baseline values for triglycerides (or many other relevant variables) for most of the trials in this meta-analysis, clearly an important issue and one that reminds us how distant a meta-analysis is from our one-on-one interactions with patients in clinic. An individual may decide, for instance, that, given the low possibility for adverse effects with n-3 PUFAs, they would like to continue their daily "slug" of fish oil anyway, awaiting, as we all are, further clarification of this issue from researchers.

So, there are some shortcomings that might explain why past n-3 research was not validated in this meta-analysis. That said, the researchers bring several strengths to the literature on n-3 PUFAs. Not only is the quantity of patients (and trials originally reviewed) that were included in this meta-analysis impressive, but the authors provide an interesting chronological perspective about n-3 clinical trials, namely that perhaps the more recent trials are trumping the older published research by showing primarily neutral CVD effects.

Perhaps we are starting to learn, via this meta-analysis and other recent research, that n-3 PUFAs aren't a cure-all, standalone treatment for serious CVD. It will likely remain a part of an integrative approach to CVD, together with lifestyle change, dietary modifications, and a handful of supplements and pharmaceuticals. Hopefully, future work will address some of the pitfalls and gaps alluded to here, and add to these results.


1. Deckelbaum RJ, Torrejon C. The omega-3 fatty acid nutritional landscape: Health benefits and sources. J Nutr 2012;142:587S-591S.

2. Mozaffarian D, Wu JH. (n-3) fatty acids and cardiovascular health: Are effects of EPA and DHA shared or complementary? J Nutr 2012;142:614S-625S.

3. Kromhout D, et al. Fish oil and omega-3 fatty acids in cardiovascular disease: Do they really work? Eur Heart J 2012;33:436-443.

4. Kwak SM, et al. 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;172:686-694.

5. De Caterina R. n-3 fatty acids in cardiovascular disease. N Engl J Med 2011;364:2439-2450.

6. Covington MB. Omega-3 fatty acids. Am Fam Physician 2004;70:133-140.

7. Bernstein AM, et al. A meta-analysis shows that docosahexaenoic acid from algal oil reduces serum triglycerides and increases HDL-cholesterol and LDL-cholesterol in persons without coronary heart disease. J Nutr 2012;142:99-104.