Does atrial fibrillation risk increase with fish oil supplementation?

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.

Large pool of evidence

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.

Fish oil supplements and atrial fibrillation

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.

EPA vs DHA

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.

The latest on fish consumption and atrial fibrillation risk

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.

Fish oil: proceed with caution

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.

Fish oil supplement use and atrial fibrillation

7th October 2022

Whether fish oil supplement use affects the risk of incident atrial fibrillation was examined in a large UK prospective cohort study

Fish oil supplement use in patients with cardiovascular disease has been shown to provide a small beneficial advantage in terms of mortality and admission to hospital for cardiovascular reasons in patients with heart failure. However, not all studies with fish oils has have been positive.

For instance, other data in patients with atherogenic dyslipidaemia and high cardiovascular risk, have found that among statin-treated patients at high cardiovascular risk, the addition of omega-3 fatty acids, resulted in no significant difference in a composite outcome of major adverse cardiovascular events when compared with corn oil.

Despite these ambiguous findings with respect to cardiovascular disease, there is some evidence that fish oil supplement use among patients with atrial fibrillation (AF) is beneficial. For example, in one trial among patients with persistent atrial fibrillation on amiodarone and a renin-angiotensin-aldosterone system inhibitor, the addition of fish oil supplementation improved the probability of maintaining sinus rhythm after direct current cardioversion, possibly through prevention of atrial fibrillation recurrence.

In contrast, a recent study with both fish oils and vitamin D supplementation observed that compared with placebo, neither supplement had a significant effect on the risk of incident atrial fibrillation over a follow-up of more than 5 years. But when data has been pooled, one 2021 meta-analysis found that fish oil supplement use was associated with an increased risk of AF which was greater in trials testing >1 g/d.

With some evidence to suggest that both monogenic and polygenic factors contribute to AF risk in the general population, in the present study, a team of Australian researchers sought to examine whether habitual fish oil supplement use was associated with the risk of incident AF after adjustment for several factors including individual’s genetic risk score.

Using the UK Biobank data, individuals were dichotomised (Yes/No) as habitual fish oil users. After calculation of an AF genetic risk score, individuals were categorised to be at either low, immediate or high genetic risk.

The primary outcome of the study was set as incident AF and the researchers also considered the risk of AF in those with and without cardiovascular disease at the study baseline point. The results were adjusted for several factors including age, gender, consumption of oily fish and genetic risk score.

Fish oil supplement use and incident atrial fibrillation

A total of 468,665 individuals with a mean age of 56.5 years (45.2% male) were included in the analysis and followed for a median of 11.1 years.

During the period of follow-up, the risk of developing incident AF was significantly higher among fish oil supplement users (adjusted hazard ratio, aHR = 1.10, 95% CI 1.07 – 1.13, p < 0.0001).

When considering the risk of AF based on genetic risk scores, this was significantly higher for low (HR = 1.08), intermediate (aHR = 1.10) and high risk (aHR = 1.11) fish oil supplement users.

Finally, while there was no increased risk among those with existing cardiovascular disease (CVD), the risk was elevated (aHR = 1.13) among those without CVD at baseline.

The authors concluded that habitual fish oil supplement use was associated with a higher risk of incident atrial fibrillation and that this risk remained regardless of genetic AF risk and consumption of oily fish but was only observed in those without cardiovascular disease.

Citation
Zhang J et al. Habitual fish oil supplementation and the risk of incident atrial fibrillation: findings from a large prospective longitudinal cohort study Eur J Prev Cardiol 2022