Corresponding Author:  Dr Peter Kowey Lankenau Medical Center, MLH Heart Center, 100 Lancaster Avenue, 558 MOB East Wynnewood.

Abstract

Many physicians recommend the use of fish oil or omega-3 polyunsaturated fatty acids (n-3 PUFA) in atrial fibrillation (AF) patients. N-3 PUFA have demonstrated anti-fibrillatory properties in several animal studies, however, data regarding their efficacy in preventing AF in humans have been mixed. This article critically reviews studies that have investigated the use of n-3 PUFA for the secondary prevention of paroxysmal and persistent AF and the primary prevention of post-operative AF. We conclude that n-3 PUFA should no longer be recommended for use in any of these AF subtypes until more data are available.

Introduction

Atrial fibrillation (AF) is highly prevalent. It is responsible for significant morbidity and mortality, primarily because it increases the risk of stroke and congestive heart failure.¹ Current therapies are not always effective, and many anti-arrhythmic drugs have toxic side effects. As such, there is an unmet need to find a safe and effective anti-fibrillatory drug. Fish oil, which contains variable ratios of the long chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) depending on the source, has demonstrated anti-fibrillatory properties in several animal studies.^2-6 However, human studies have shown mixed results and a recent meta-analysis of randomised controlled trials demonstrated no significant effect of fish oils in the prevention of AF.⁷ Most studies have indicated that omega-3 polyunsaturated fatty acids (n-3 PUFA) have an excellent drug safety profile, however, some studies in pigs suggest that they may facilitate the initiation of AF by shortening the effective refractory period and action potential duration.^8,9 or even promote ventricular arrhythmias during episodes of myocardial ischaemia.¹⁰ There is also evidence that n-3 PUFA may be pro-arrhythmic in humans. A randomised controlled trial (RCT) of patients with implantable cardioverter defibrillators found an increase in the number of ventricular tachycardia and fibrillation episodes in patients taking fish oil supplements.¹¹ This was statistically significant in patients who had ventricular tachycardia as their qualifying arrhythmia for study entry. Another RCT in men with angina found that those who were advised to increase their intake of n-3 PUFA through diet or supplements had a significantly higher incidence of cardiac and sudden cardiac death than those who were not; especially in the sub-population taking n-3 PUFA capsules.¹²

By critically reviewing some of the major literature, this article will explore the question of whether fish oil should be recommended for use in AF. Since atrial fibrillation is a heterogeneous disease, studies for paroxysmal, persistent and post-operative AF will be presented separately.

Studies Investigating the Use of Fish Oil in Paroxysmal AF

To our knowledge, there have been four adequate studies specifically on the use of fish oil in patients with paroxysmal AF (defined as arrhythmia that spontaneously terminates)^13-16 (Table 1). Two small prospective observational studies demonstrated a beneficial effect of fish oil in the secondary prevention of paroxysmal AF.^13,14 One small RCT demonstrated that n-3 PUFA prolonged atrial and pulmonary vein effective refractory periods and significantly reduced the number of AF episodes able to be induced from the pulmonary veins.¹⁶ However, the largest multicentre, double-blind RCT conducted to date showed no benefit of n-3 PUFA in the secondary prevention of paroxysmal AF.¹⁵

Table 1: Studies investigating the use of fish oil in patients with paroxysmal atrial fibrillation DB= double blind; RCT = randomised controlled trial; d= day; n-3 PUFA = ω-3 polyunsaturated fatty acids; NS = non-significant EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; EP = electrophysiology.

Studies Investigating the Use of Fish Oil in Persistent AF

In this context, persistent AF is defined as atrial fibrillation that requires cardioversion for termination. To our knowledge, there are nine adequate studies in the literature involving patients with persistent AF^15,17-24 (Table 2). Three studies claimed a statistically significant effect of n-3 PUFA in maintaining sinus rhythm post cardioversion,^19,21,24 and one paper showed that n-3 PUFA significantly reduced the incidence of transient mechanical dysfunction of the atria, "atrial stunning", after electrical cardioversion.²² The remaining studies showed no benefit of n-3 PUFA therapy.

Table 2: Studies investigating the use of fish oil in patients with persistent atrial fibrillation OL = open label; DB= double blind; RCT = randomised controlled trial; n-3 PUFA = ω-3 polyunsaturated fatty acids d=day; EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; ECV = electrical cardioversion; RRR= relative risk reduction; CRP = C Reactive Protein; NS= non-significant.

Studies Investigating the Use of Fish Oil in Post-Operative AF

We found eight satisfactory studies investigating the use of n-3 PUFA in the prevention of post-operative AF (POAF)^25-32 (Table 3). Five of these eight studies claimed a statistically significant decrease in the incidence of POAF with the use of fish oil supplements.^25-27,30,32

Table 3: Studies investigating the use of fish oil in post-operative AF OL = open label; DB= double blind; RCT = randomised controlled trial; n-3 PUFA = ω-3 polyunsaturated fatty acids d=day; EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; ECV = electrical cardioversion; RRR= relative risk reduction; CRP = C Reactive Protein; NS= non-significant.

Why are the Results of These Studies Inconsistent?

Heterogeneity in study design

The most significant reason for disparity in the literature is the many methodological differences in studies conducted to date. There are very few double-blind randomised placebo-controlled trials (DB-RCT), the gold standard for assessing the efficacy of a pharmacological intervention. There has been only one DB-RCT conducted in patients with paroxysmal AF,¹⁵ two in patients with persistent AF,^15,21 and five in POAF.^{26,28,29,31,32} However, even when considering DB-RCTs alone, their results are still mixed. Liu et al.⁷ and Armaganijan et al,³³conducted meta-analyses of the available RCTs investigating n-3 PUFA in the prevention of all AF subtypes, and post-operative AF respectively. Neither meta-analysis found sufficient evidence to support the use of n-3 PUFA supplements, but they were significantly limited by the many differences in trial design, the most significant of which will be discussed in the following sections of this review.

Population Size

Many published studies have small sample sizes and are therefore likely to be statistically underpowered. The largest DB-RCT conducted to date by Kowey et al¹⁵ (n= 645), was powered to detect a 32% relative risk reduction (RRR) in symptomatic AF recurrence with the use of n-3 PUFA. This trial showed no significant difference in AF recurrence for either paroxysmal or persistent AF or for these groups combined. For post-operative AF, the largest DB-RCTs to date involve about 200 patients^31,32 powered to detect a RRR of roughly 53%; however, they yielded inconsistent results. In their meta-analysis, Liu et al highlight that underpowered studies are a significant problem in the current literature, particularly in studies investigating POAF.⁷ Most studies of POAF in their analysis were powered to detect unrealistic treatment effects (RRR 35-55%). They argue that with a baseline AF occurrence of 30-40% in the post-operative setting, studies would need to have 1000-1500 participants in order to detect a relative risk reduction of 25%, a figure which was not reached even with pooled data.

Population Heterogeneity

Age

There are many differences in the patient populations of current studies that could account for conflicting results. Though there was no significant difference in population age among the studies included in this review; age could influence the efficacy of fish oil. A recent prospective cohort study,³⁴ which includes a considerably older patient population than that of other studies (mean = 74 years), found that higher plasma levels of n-3 PUFA were inversely associated with the incidence of new-onset AF. It is also possible that in younger patients, in whom AF may be vagally mediated, the ability of n-3 PUFA to increase parasympathetic tone might even render them pro-arrhythmic in this population.³⁵

Comorbidities and atrial remodelling

Comorbidities are a potential confounder in the current literature. N-3 PUFA may not be directly anti-arrhythmic, but could secondarily prevent AF by inhibiting structural or electrical atrial remodelling, therefore lessening the ability of atrial tissue to initiate and sustain further AF episodes.^36-38 An example of one such co-morbidity that may result in atrial remodelling is congestive heart failure.³⁹ Rupp and colleagues recently proposed that patients with heart failure are under-represented in the current fish oil literature,⁴⁰ possibly accounting for the many non-significant results. In addition to the potential for atrial remodelling in heart failure patients, Rupp et al also argue that these patients are deficient in n-3 PUFA, as shown by their study in which patients with left ventricular (LV) dilatation had lower serum docosahexaenoic acid (DHA) levels.⁴¹ Therefore, studies without a high proportion of heart failure patients would be unlikely to show a demonstrable benefit of n-3 PUFA supplementation, as their patients were not deficient at baseline.

In support of n-3 PUFA preventing AF recurrence by improving congestive heart failure, Rupp and colleagues cite a study by Nodari et al.⁴² This study found that 12 months of n-3 PUFA supplementation improved left ventricular function in patients with dilated non-ischaemic cardiomyopathy. However, one disparity between these studies is that the Rupp et al paper found a DHA deficit mainly in patients with very advanced LV dilatation, whereas the Nodari paper used patients with a relatively mild New York Heart Association (NYHA) functional class (mean = 1.86), excluding NYHA class IV patients. It is important to note that the very large GISSI Heart Failure trial (n=6975), which included patients with NHYA class II-IV heart failure, only demonstrated a minor decrease in all-cause mortality in patients taking n-3 PUFA supplements (6% RRR), with no statistically significant reduction in heart failure hospitalisations.⁴³ Considering these studies as a whole, it is possible that n-3 PUFA confers a benefit in LV function only in the earlier and not more advanced stages of congestive heart failure.⁴⁰

It is difficult to determine whether the proportion of heart failure patients in studies has influenced the results of the current literature. On the one hand, there is not a great difference in mean left ventricular ejection fraction (LVEF) among the populations of published studies (53.5-64.5%). On the other hand, two well-designed DB-RCTs investigating persistent AF by Bianconi et al20 and Nodari et al21 arrived at opposite conclusions. There was very little difference between their study populations, perhaps the most significant being that the Nodari paper contained many more heart failure patients (55.3% vs. 25.7%). However, the Bianconi paper contained significantly more patients with "lone AF" than the Nodari paper (31% vs. 9.5%), a form of AF unlikely to be the result of atrial remodelling.

Only a DB-RCT addressing the anti-fibrillatory effects of n3-PUFA specifically in heart failure patients can answer this important question. Likewise, future studies will need to be careful to adequately describe and account for other comorbidities such as hypertension, ischemic and valvular heart disease, all of which are potential substrates for AF and lead to atrial remodelling.

Concomitant Drug Use

There is evidence to show that drugs such as ACE inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers, ß-blockers and statins can inhibit atrial remodelling.³⁹ It is often mentioned in the literature that differences in the use of anti-remodelling drugs between studies could explain their conflicting results. Many studies have not adequately described background therapy, or they have had imbalances in treatment between groups that could magnify or reduce differences. Kowey and colleagues found no difference in the incidence of paroxysmal AF between their patient subpopulations who were or were not taking ACEi/ARBs and who had a similar use of other confounding therapies, arguing that the impact of anti-remodelling agents is likely to be small.¹⁵

There is an argument that differences in antiarrhythmic drug use between study populations could account for conflicting results, either because they mask the potential benefits of n-3 PUFA, or because they are required for a synergistic action with n-3 PUFA supplements. However, the study by Ozaydin et al,²³ which compared patients treated with n-3 PUFA and amiodarone versus amiodarone alone, showed no significant difference in the number of recurrences of persistent AF. Although this is a small study, the results suggest that the impact of concomitant anti-arrhythmic drug use is also minimal. The most recent publication by Kumar and colleagues demonstrated a significant benefit of long term n-3 PUFA supplementation in the prevention of persistent AF recurrence after electrical cardioversion.²⁴ A subgroup analysis demonstrated that n-3 PUFA supplementation reduced the chance of AF recurrence with or without the concurrent use of sotalol or amiodarone (patients in this study at randomisation commenced treatment with amiodarone or sotalol is they had persistent AF for > 3 months). However, in this study, patients who had been in persistent AF for < 3 months at randomisation were placed on other drugs which also have antiarrythmic properties: beta blockers, rate-limiting calcium channel blockers or digoxin. This makes it more difficult to determine how much of an effect concomitant drug use had on the prevention of AF in this study population. Larger studies will be required to answer this important question.

AF subtype and Duration

AF itself can cause structural and electrical remodelling of the atrium. "AF begets AF",³⁹ therefore differences in the time between the initial diagnosis of AF and study entry could account for differences in study results. This is a variable not commonly presented in the literature. AF is a heterogeneous disease, with different pathophysiological mechanisms likely to be underlying the various subtypes. It is therefore possible that n-3 PUFA supplements may confer a greater benefit for secondary prevention of persistent rather than paroxysmal AF due to a potentially greater degree of atrial remodelling in the former. Indeed, the latest study by Kumar and colleagues which demonstrated a benefit of n-3 PUFA supplementation in the prevention of persistent AF found that the n-3 PUFA group had a significantly longer duration of AF prior to cardioversion than the controls.²⁴ However, there are no studies which directly demonstrate a clear advantage of n-3 PUFA use in AF of longer duration, and although there is evidence to suggest that fish oils prevent structural remodelling,⁴⁴ there is no evidence to suggest that they can reverse that process.³⁵ There are clearly more studies supporting an anti-fibrillatory effect of n-3 PUFA in the post-operative AF setting. The traumatic nature of cardiothoracic surgery and resultant inflammation provides a substrate for the initiation of AF, which might be inhibited by anti-inflammatory effects of n-3 PUFA. The evidence implicating inflammation as the substrate for POAF is substantial. For example, a study by Halonen et al demonstrated that intravenous administration of hydrocortisone after cardiothoracic surgery reduced the incidence of POAF.⁴⁵ There are also considerable data supporting the anti-inflammatory effects of n-3 PUFA.⁴⁶ However, in the studies included in this review, there are inconsistencies in results that make it difficult to prove this hypothesis. For POAF, the study conducted by Mariscalco et al²⁷ showed that post-operative levels of C-reactive protein (CRP) were significantly lower in patients treated with n-3 PUFA, yet the studies by Saravanan et al²⁸ and Heidarsdottir et al²⁹ did not. Likewise of the trials for persistent AF, the study by Patel et al¹⁹ demonstrated lower CRP levels in n-3 PUFA treated patients, but the study by Ozaydin et al²³ did not. These differences could yet again be attributed to differences and limitations in study design among papers.

Duration of n-3 PUFA Supplementation

A commonly cited reason as to why the large Kowey et al¹⁵ trial for patients with paroxysmal AF yielded non-significant results is that almost 50% of AF recurrences occurred in the first two weeks after fish oil supplementation began, therefore not allowing membrane levels of n-3 PUFA to peak. Early recurrence of AF is also a feature of the Bianconi et al²⁰ paper, which is the largest RCT conducted to date in patients with persistent AF. This argument is based on a study by Metcalf and colleagues, which showed that high dose fish oil supplementation at 6g per day, resulted in continued incorporation of n-3 PUFA into the myocyte membranes until a peak was reached at roughly 30 days.⁴⁷ When one looks at the five studies to date that have started fish oil supplementation at least 4 weeks before end point measurement,^{16,19,21,22,24} they show a statistically significant benefit of n-3 PUFA in the prevention of AF recurrence. However, two of these studies by Kumar and colleagues^{16, 22} had very small sample sizes, and measured electrophysiological endpoints, which do not necessarily translate to a clinical benefit. None of the studies conducted in post-operative atrial fibrillation started fish oil supplementation 30 days prior to measuring their end points, yet a number of these studies have yielded significant results. A more recent study by Saravanan et al,²⁸ used a low dose (2g/day) of fish oil supplements for a median of 16 days and achieved successful incorporation of EPA and DHA into atrial tissue at similar levels to the Metcalf et al study. At day 30 in the Metcalf et al study, EPA and DHA amounted to roughly 12% of total fatty acids in atrial tissue. In the Saravanan study, DHA alone made up 14% of total fatty acids in a major membrane phospholipid, phosphatidyl-ethanolamine in the atrial tissue. To further refute the argument that fish oil supplementation should be carried out for a minimum of 30 days prior to measuring study endpoints, it is very unlikely that n-3 PUFA exert their antiarrhythmic effects through incorporation into myocyte membranes alone. It has been shown that plasma levels of n-3 PUFA significantly rise after a short duration of supplementation²⁹ and some studies have achieved positive results after acute administration of fish oil supplements.^27,48

Differences in n-3 PUFA Supplements and their Delivery to Patients

The difference in dosage of fish oil supplements used among studies is another possible reason for inconsistent results. Clearly, attaining some minimal dose and concentration is necessary but some argue that fish oil supplements are pro-arrhythmic, which could explain why studies that use high doses of n-3 PUFA (~4g/d), such as the Kowey 15 and Farquharson³¹ studies produced non-significant results. However, the three studies by Kumar and colleagues^16,22,24 and most animal studies⁴⁹ used doses of ~ 6g/d and yielded significant results. A study that effectively addresses the effect of dosage on the anti-arrhythmic effects of n-3 PUFA is necessary to clarify this issue.

Another area of debate is the optimal ratio of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) in supplements. A large cohort study in men⁵⁰ and the Kumar et al open-label RCT investigating persistent AF²⁴ both demonstrated that higher plasma levels of DHA but not EPA were associated with a statistically significant reduction in the incidence of AF. A study using isolated rabbit hearts demonstrated different electrophysiological effects of DHA and EPA and hypothesised that this was due to these fatty acids influencing potassium and sodium channels respectively.⁵¹ The studies that have been performed to date have used a varying amount of DHA within their n-3 PUFA capsules, but there is no consistent trend as to how this influences study outcome. The two largest DB-RCTs conducted to date, Kowey et al¹⁵ and Bianconi et al²⁰ for paroxysmal and persistent AF respectively, achieved a higher percentage increase in plasma EPA than in DHA at 4 weeks (Kowey: 276.10% vs. 95.6%) (Bianconi: 133.3% vs. 23.2%), and both produced non-significant results. These percentage increases are very different despite the two studies using similar doses of EPA and DHA.

We clearly need more information to determine which factors influence percentage increase in n-3 PUFA levels, both in plasma and tissue. Interestingly, all studies conducted to date that used a lower dose of EPA compared to DHA produced statistically significant results in favour of n-3 PUFA use. The question of whether high levels of EPA inhibit the effects of DHA would also be interesting to address in future research. It is possible that delivering fish oil via oral supplements is not as effective as receiving n-3 PUFA through dietary intake. Differences in dietary consumption of n-3 PUFA among studies has not been reported and may be a reason for conflicting results. A study in which patients were infused intravenously²⁶ with n-3 PUFA demonstrated a decreased incidence of post-operative AF, which might indicate that the rate of delivery of fish oil supplements may also influence their efficacy.

Conclusions

There are few large, high quality randomised double blind placebo control trials investigating the anti-fibrillatory effects of n-3 PUFA for paroxysmal, persistent and post-operative atrial fibrillation, and there is considerable heterogeneity in study design, both in RCTs and prospective observational studies. The result is a confusing literature with many variables that could confound the analyses. These include population age; comorbidities potentially associated with atrial remodelling such as congestive heart failure; concomitant drug use; duration of AF before study entry; and the n-3 PUFA dosage, ratio of EPA to DHA, duration of treatment and its method of delivery. Large DB-RCTs need to be conducted that account for and investigate the influence of these variables on the efficacy of n-3 PUFA, particularly for persistent and post-operative AF, where the available DB-RCTs show contrasting results. Trials should seek to use the methodology used by Kowey et al,¹⁵ but incorporating other, older and sicker patient populations, perhaps with longer periods of observation to observe clinical effects. These studies should employ 2-sided efficacy analyses since n-3 PUFA could be proarrhythmic under some circumstances and in specific patient populations. The American Heart Association guidelines for diet and lifestyle recommendations currently recommend the consumption of oily fish at least twice per week, with fish oil supplements as an alternative.⁵² This may be beneficial for general health and improving other cardiovascular endpoints. However, until more and better data are available, physicians should not recommend n-3 PUFA for the primary or secondary prevention of AF using either commercial supplements or prescription formulations.

Disclosures

• Dr. Peter Kowey has previously consulted for GlaxoSmithKline.
• No disclosures relevant to this article were made by the other authors.

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