Sometime ago there was a discussion in our forum initiated by Dr G Mohan on the role of Omega-3 fatty acids in the prevention of the cardiovascular mortality and morbidity.

Quoting NEJM (2013;368;1800-1809. NEW ENGLAND JOURNAL OF MEDICINE) he pointed out that the studies ‘provide no evidence of the usefulness of n-3 fatty acids for preventing cardiovascular death or disease’ in the patients analysed, despite efforts in the study ‘to optimize medical therapies and control cardiovascular risk factors’.

When I see a few more pharmaceutical companies come out with new products with Omega-3 fatty acids as main content, I just looked into the web to know what is the latest with this molecule. Omega-3 fatty acids as supplements have been tried in various medical conditions including gastrointestinal, rheumatic, psychiatric, metabolic, renal, dermatologic and pulmonary problems. They have been most commonly used for primary and secondary prevention of cardiovascular disease. Over the past 2 decades multiple randomized trials have evaluated the efficacy of omega-3 supplements in various cardiovascular conditions, and have yielded mixed results.

The results of multiple prior randomized trials were mixed, with some suggestive of cardiovascular benefits for omega-3 supplements and some not confirming their efficacy. To address this important clinical dilemma, a recent systematic review investigated all randomized trials that were completed about the cardiovascular effects of omega-3 supplementation in adult participants between 1989 and 2012. This review included 20 studies of a total of 68,680 randomized patients. The median follow-up period for these trials was 2 (1.0-6.2) years, and half of the included trials had been conducted during the period when statins were routinely recommended for cardiovascular risk modification (i.e. 1998 or later).

The study showed that omega-3 fatty acids were not associated with significant decrease or increase in all-cause mortality (relative risk [RR]= 0.96; 95% confidence interval: 0.91-1.02; risk reduction: ?0.004, 95% confidence interval: ?0.01 to 0.02), sudden death, MI, or stroke. Another recent systematic review by Kotwal et al, also showed that omega-3 supplementation was not associated with a significant reduction in composite cardiovascular endpoints (RR=0.96; 95% confidence interval: 0.90-1.03; P=0.24).

Since publication of these systematic reviews, 3 additional trials have been published. OPERA (the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation), a double-blind placebo-controlled randomized trial; which was published later, investigated the effects of perioperative omega-3 supplementation on postoperative atrial fibrillation (AF) among patients undergoing cardiac surgery. The results showed no significant decrease of the risk of postoperative AF by omega-3 supplements compared with placebo.

Now questions are asked why these contradictory views regarding the efficacy of Omega-3 fatty acids. Omega-3 fatty acids are among the most commonly prescribed supplements with a remarkable worldwide market. In 2011, people spent around $25 billion on omega-3 supplements. This amount is estimated to approach $35 billion in 2016.

First, publication bias, selective reporting, or even selective citation in favor of studies suggestive of beneficial effects of omega-3 fatty acids on CVD risk factors is possible. For example, the positive GISSI-Prevenzione trial has been much more frequently cited compared with similar trials that yielded negative results In other words, it is possible that the presumed basic and clinical benefits of these supplements are less robust than widely thought. However, due to selective reporting, publication bias, or selective citation, positive studies get more popularized. Second, it has been known that improving a risk factor would not necessarily lead to an improvement in hard endpoints such as mortality. In fact, it might be reductionist to consider fatty fish identical to omega-3 fatty acids, as some authors do. Fish may contain many more active ingredients that we are not yet fully aware of. Aside from omega-3 fatty acids, fish would contain other proteins, vitamin D, selenium, and several mineral elements. A recent systematic review of 26 prospective cohort studies and 12 randomized controlled trials determined the association between fish consumption and also omega-3 supplements with cerebrovascular diseases including ischemic and haemorrhagic stroke, or transient ischemic attack with aggregate data on 794,000 non-overlapping people (43). The systematic review indicated that although consumption of fish had a moderate inverse association with the risk of cerebrovascular events, there was no such association between circulating levels of omega-3 fatty acids and supplements with cerebrovascular diseases

The widespread use of omega-3 supplements implies huge financial expenditure on products of dubious benefits. Furthermore, contrary to the common public belief, supplements are not necessarily devoid of harm. One potential safety concern with omega-3 supplement use is the risk for haemorrhagic stroke. At very high doses (e.g. 15 grams per day), omega-3 fatty acids increase bleeding time (15). In a randomized trial of more than 18,600 hypercholesterolemia Japanese patients for supplementation with 1.8 gram per day of EPA (the JELIS trial) the adverse experience of haemorrhage (cerebral, fundal, epistaxis, and subcutaneous) was significantly more frequent among the patients in supplement group and though not significant, the incidence of hemorrhagic stroke was also higher.In a secondary prevention trial with 1.7 gram per day omega-3 supplementation among patients undergoing regular hemodialysis, reported cases of bleeding (including gastrointestinal, cerebral, and other) were 15 among 103 patients in treatment group versus 7 among 103 patients in control group (48) . Numerically higher cerebrovascular events were also observed in GISSI-HF and OMEGA trials among patients using supplements (32, 33). Although not significant, GISSI-Prevenzione trial also showed a trend toward excess strokes in the omega-3 arm (30). The systematic review by Chowdhury et al. showed that in secondary prevention trials cerebrovascular events were more common among participants in the supplement group than the control group

Ref: Tanaffos. 2014; 13(1): 6–14.
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Chowdhury R, Stevens S, Gorman D, Pan A, Warnakula S, Chowdhury S, et al. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ. 2012;345:e6698. [PMC free article] [PubMed]

UA Mohammed