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13th July 2023
Fish oil supplements have been shown to offer cardiovascular benefits in randomised trials, but is this advantage undermined by an increased risk of atrial fibrillation, and do these risks also apply to eating oily fish? Clinical writer Rod Tucker finds out more.
A study by Danish scientists in 1976 first observed how Greenland Eskimos had a fatty acid plasma profile that showed a higher content of long-chain polyunsaturated fatty acids – known as omega-3 fatty acids – derived from marine mammals.
Two key fatty acids perceived as physiologically more important were docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The researchers speculated that a higher intake of marine oils may account for the lower incidence of cardiovascular mortality seen among the indigenous people compared to the wider Danish population.
Other observational data also implies that eating fish may confer a cardiovascular benefit. For instance, one study from 1985 collected dietary information on fish intake from over 800 men without coronary heart disease and followed these individuals for the next 20 years. The results were surprising and impressive: coronary heart disease mortality was more than 50% lower among those who consumed at least 30 g of fish per day.
Later, in 1989, a randomised dietary trial of fatty fish intake in men who had sustained a myocardial infarction confirmed the benefits of eating fish. Among participants advised to eat fatty fish, there was a 29% reduction in two year all-cause mortality compared with those not advised to eat it. Moreover, eating fish also appeared to have a primary preventative role.
In 1995, a study of patients experiencing an out of hospital cardiac arrest observed that eating the equivalent of one fatty fish meal per week halved the risk of a primary cardiac arrest. As oily fish such as salmon and herring contains large amounts of both EPA and DHA, it was assumed that these oils were responsible for the cardioprotective effect.
In fact, a 2021 meta-analysis of 38 randomised controlled trials with nearly 150,000 participants confirmed that there were important cardiovascular benefits in patients receiving EPA and DHA.
Despite these positive findings, concerns began to emerge over the risks associated with fish oil supplementation, particularly when used at higher doses.
In a pairwise and network meta-analysis of the cardiovascular benefits of different doses of fish oil supplement intake, researchers concluded that higher doses appeared to significantly increase the risks of both bleeding events and atrial fibrillation (AF) compared to lower doses.
Subsequent analyses appeared to re-affirm these findings. For instance, a 2021 meta-analysis found a 37% higher risk of incident AF compared with placebo in randomised trials of fish oil supplementation in patients with cardiovascular disease.
Another study that specifically focused on the risk of AF from fish oil supplements found an elevated risk in trials testing a dose greater than 1 g per day. This heightened risk was more recently seen in an analysis of data from the UK Biobank, although the risk was only significant among those with pre-existing cardiovascular disease.
The association between fish oil intake and AF is far from clear, with some data suggesting it might be oil specific. For example, one case-cohort study with over 4,000 incident cases of AF found that those with the highest intake of EPA had a 45% lower risk of AF compared to those with the lowest intake. In contrast, while there was no overall association for DHA, there was a 30% lower risk of incident AF for the highest versus the lowest intake, but only for women.
Other studies reveal no effect of either type of fish oil on incident AF, whereas another analysis suggested that incident AF was significantly lower with higher levels of DHA but not for either EPA or a combination of the two oils.
While there is a lack of clarity with the available data, to date, only one randomised trial has directly examined whether fish oil supplements actually reduces the incidence of AF. The trial included patients scheduled for cardiac surgery and provided perioperative fish oil and the primary outcome was set as postoperative AF. The results showed that perioperative fish oil supplements did not significantly reduce postoperative AF compared to placebo, but also that there was no increased risk of arrhythmia.
Questions remain whether the same lack of clarity exists for the link between eating fish and AF. In a prospective analysis published in June 2023, researchers assessed whether dietary marine omega-3 fatty acid intake was associated with the risk of AF. Data were obtained from 301,294 individuals who had a median intake of omega-3 fatty acids of 219 mg per day.
In fully adjusted regression models, there was a nonlinear and inverse relationship with incident AF. There was an initial 11% lower risk when eating 750 mg per day, which then plateaued. In other words, there was no additional benefit from consuming more fish and, as the authors stated, ‘consumption of marine omega-3 fatty acids was not associated with a higher incidence of AF’.
There was also no detectable difference in risk between EPA and DHA. Even when looking at the highest quintile of fatty acid intake (708-6,085 mg per day), there was still a 7% reduced risk of incident AF (hazard ratio, HR = 0.93, 95% CI 0.88 – 0.98).
While these findings were encouraging, insofar as they suggest that eating fish does not pose a higher risk of AF, a limitation of the study was that it was undertaken in predominately white, older males which means that the findings might not be generalisable. However, earlier work in both genders does appear to support the notion that fish intake does not increase the risk of AF.
There’s good news, too, for vegetarians. Evidence suggests that intake of the plant-based omega-3 fatty acid alpha-linolenic acid (ALA) found, for example, in flaxseed and rapeseed oils, is associated with cardiovascular benefits. In fact, the Cardiovascular Health Study, which was a community-based longitudinal cohort of adults aged 65 or older, found no association of plasma phospholipid or dietary ALA and incident AF.
An important caveat attached to the findings from randomised trials of fish oil supplements is that in many cases AF was not always considered as a pre-specified outcome and, in some cases, not reported in exploratory analysis. Consequently, the trials were not powered for detecting AF as an endpoint so that the findings should be interpreted with caution.
On the basis of the available evidence, it seems plausible that consumption of fish oil supplements, especially at higher doses, could increase the risk of AF. Clinicians and patients therefore need to weigh up the observed cardiovascular benefits against the potential risk of not only AF but increased bleeding.
Given the strength of the observational evidence, it is reasonable to suggest that eating fish, or increasing intake of ALA for those who do not eat fish, offers cardiovascular health benefits that are not eroded by an associated greater risk of atrial fibrillation.
15th July 2021
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