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Cardiovascular event reduction from omega-3 fish oils due to EPA not DHA

15th July 2021

The cardiovascular benefits of omega-3 fish oils are well established but an updated analysis suggests this might be due more to EPA than DHA

The omega-3 fish oils eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) appear, at least from some trials, to reduce adverse cardiovascular events although the evidence is still inconclusive. The purported mechanisms through which omega-3 fish oils might reduce cardiovascular events include the ability to lower triglycerides, their cell membrane stabilising effects, together with a collective antithrombotic, anti-inflammatory and anti-arrhythmic effect. However, trials published in 2018 produced divergent results; the ASCEND trial showed no benefit in diabetics without cardiovascular disease. In contrast, the REDUCE-IT trial found a 25% reduction in the primary composite efficacy endpoint of cardiovascular death, non-fatal MI, stroke and coronary revascularisation, with a highly purified form of EPA in those with established cardiovascular disease. In fact, other evidence shows that EPA alone led to a 19% reduction in major coronary events in patients with hypercholesterolaemia.

In light of this possible heterogeneity with the two omega-3 fish oils, a team from the Department of Medicine, West Virginia University, US, undertook a meta-analysis of the effects of omega-3 fatty acids on cardiovascular outcomes. The team included only randomised controlled trials in adults that compared omega-3 fish oil intake (EPA or EPA and DHA) to placebo, trials with at least 12 months follow-up and where the cardiovascular outcomes of interest were recorded. There were a number of specified outcomes including cardiovascular mortality, all-cause mortality, non-fatal MI and haemorrhagic stroke. The safety endpoints included atrial fibrillation (AF), major and minor bleeding.

A total of 38 trials including 149,051 patients were included in the final analysis. There were 4 trials with EPA alone with the remainder comparing both omega-3 fish oils against placebo and 22 trials focused on primary prevention. The dose of omega-3 fish oils ranged from 0.4g/day to 5.5g/day and the median duration of follow-up in trials was 2 years. Overall, the use of EPA and DHA was associated with a small, but statistically significant reduction in cardiovascular mortality (relative risk, RR = 0.93, 95% CL 0.88 – 0.98, p = 0.01), but not all-cause mortality (RR = 0.97, 95% CL 0.93 – 1.02, p = 0.27). Interestingly, the use of EPA alone, led to a greater reduction in cardiovascular mortality that the combination of the two (RR = 0.82 vs 0.94, EPA alone vs EPA & DHA). Again, mono-therapy with EPA showed a higher risk reduction in non-fatal MI (RR = 0.72 vs 0.92, EPA alone vs EPA & DHA). Despite these additional benefits, use of EPA alone resulted in a higher risk of total bleeding (RR = 1.49) and development of AF (RR = 1.35) although the authors cautioned that the certainty of this evidence was of low quality.

They concluded that while the available evidence does show that the omega-3 fish oils are associate with a small, but significant cardiovascular benefit, there seems to be a slight advantage to using EPA alone but called for further research to examine this observed effect in more detail.

Khan SU et al. Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis. EClinical Med 2021