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n-3 Polyunsaturated fatty acids for the prevention of arrhythmia recurrence after electrical cardioversion of chronic persistent atrial fibrillation: a randomized, double-blind, multicentre study

Leopoldo Bianconi, Leonardo Calò, Mauro Mennuni, Luca Santini, Paolo Morosetti, Paolo Azzolini, Giuseppe Barbato, Francesco Biscione, Paolo Romano, Massimo Santini
DOI: http://dx.doi.org/10.1093/europace/euq386 174-181 First published online: 8 November 2010


Aims Persistent atrial fibrillation (AF) often recurs after direct current electrical cardioversion (ECV). As several experimental and clinical studies suggest that n-3 polyunsaturated fatty acids (PUFAs) may have antiarrhythmic properties even at the atrial level, we aimed to evaluate whether oral supplementation with PUFAs, in addition to conventional antiarrhythmic drugs, could reduce the recurrence rate of the arrhythmia after ECV of persistent AF.

Methods and results Two hundred and four patients (mean age 69.3 years, 33% females) with persistent AF were randomly assigned to receive 3 g/day of PUFAs until ECV and 2 g/day thereafter (104 patients) or placebo (100 patients) for 6 months, beginning at least 1week before ECV. Selection of conventional antiarrhythmic prophylaxis was left to local medical advice. The cardiac rhythm was assessed by both trans-telephonic monitoring and clinical visits. Primary end-point was the recurrence rate of AF. Sinus rhythm was restored, either spontaneously or after ECV, in 187 patients (91.7%); 95 patients (91.4%) on PUFAs and 92 patients (92.0%) on placebo (P = not significant). AF relapsed in 56 (58.9%) of the PUFAs patients and in 47 (51.1%) of the placebo patients (P = 0.28). The mean time to AF recurrence was 83 ± 8 days in the PUFAs group and 106 ± 9 days in the placebo group (P = 0.29).

Conclusion Our results do not support the hypothesis that, in patients undergoing ECV of chronic persistent AF, supplementation with PUFAs in addition to the usual antiarrhythmic treatment reduces recurrent AF.

  • Atrial fibrillation
  • Placebo-controlled
  • trial
  • Omega 3
  • Electrical cardioversion


Persistent atrial fibrillation (AF) can be successfully terminated by direct current electrical cardioversion (ECV). However, the arrhythmia recurs in the majority of cases, usually soon after cardioversion. Treatment with antiarrhythmic drugs reduces the recurrence rate, but drug efficacy is far from being satisfactory, and untoward effects are not infrequent.1 Several non-antiarrhythmic drugs, such as statins, angiotensin-converting enzyme inhibitors (ACE) and angiotensin II receptor blockers (ARBs), have been tested in this field, with contrasting results.26

In the last decade, some experimental studies have supported the hypothesis that n-3 polyunsaturated fatty acids (PUFAs) could have antiarrhythmic properties, even at the atrial level.711 In man, consumption of fish, inducing high plasma concentrations of PUFAs, has been found to be associated with a lower incidence of AF after 12 years follow-up.12 Furthermore, pre-operative administration of PUFAs reduced the recurrence of AF after coronary artery bypass graft.13

We therefore conducted this study in order to assess whether supplementation with PUFAs, in patients undergoing ECV for persistent AF, could reduce the recurrence rate of the arrhythmia.


Patient population and study design

The study was a double-blind, randomized, placebo-controlled, multicentre study carried out in 12 cardiological centres in Italy, from July 2006 to December 2008. Inclusion criteria for subjects were persistent AF lasting more than 1 month and being scheduled for ECV. The duration of the arrhythmia was considered to be from the date of the first available ECG showing AF. The patients had to be older than 18 years and in a stable clinical condition. All subjects provided written informed consent. Exclusion criteria were as follows: ongoing treatment with PUFAs, recent myocardial infarction (<3 months), hyperthyroidism, uncompensated congestive heart failure and any serious co-morbidity implying a life expectancy of less than 6 months.

Before randomization, a full medical history was obtained from every patient, followed by physical examination, 12-lead ECG and biochemistry screening, which included thyroid function, renal and liver function tests, lipid assessment, international normalized ratio and blood cell count. Trans-thoracic echocardiography was performed.

At inclusion, patients were assigned, on a individual basis, to receive either n-3 PUFAs or placebo at a dose of one capsule (1 g) three times a day until ECV, starting at least 7 days before cardioversion, and twice a day for 6months thereafter. A computer-generated randomization list, using blocks of six, was used. Each active treatment capsule contained not less than 850 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters in an average EPA/DHA ratio of 1.2 (allowed range 0.9–1.5), supplied by Società Prodotti Antibiotici, Milan, Italy. Placebo capsules contained olive oil and were identical in size, colour and weight to the active treatment capsules, and the assignment of treatment was fully blinded. Olive oil was chosen as placebo because oleic acid has no antiarrhythmic properties14,15 and olive oil supplementation was shown not to affect n-3 PUFAs in atrial tissue.16 Compliance was monitored at cardioversion and at each subsequent visit by pill count.

ECV was then carried out according to local standard clinical practice, after a sufficient oral anticoagulation or after trans-oesophageal echocardiography, following the current guidelines.17 Cardioversion was performed by delivering a biphasic shock, following a step-up protocol (usually 200, 300 and 360 J) and it was considered successful if sinus rhythm was present 2 h after the procedure. The maximal energy and the total energy delivered were recorded. In case of unsuccessful ECV, a second attempt could be made, based on local medical judgement, by following the same procedure, after modification of the antiarrhythmic treatment.

Antiarrhythmic drug therapy was left to the decision of the local investigator. Generally, patients experiencing their first episode of AF of less than 3 months duration were not given antiarrhythmic drugs. In the absence of contraindications, the antiarrhythmic drugs used as first choice were flecainide, propafenone or sotalol, while amiodarone was usually used as second choice.


Patients had the first follow-up visit after 48–72 h from ECV and then after 7 days, and 1, 3 and 6 months. After a successful ECV, each patient received a trans-telephonic monitoring device (Cardiobios 1; Telbios SpA, Milan, Italy). Patients were instructed to perform an electrocardiographic recording three times during the first week after ECV, and then twice a week until the 3month follow-up visit. Patients were also instructed to perform a supplementary recording and to contact the study team between scheduled visits if they experienced symptoms suggestive of AF. In cases of AF recurrence, a clinical visit and ECG were performed as soon as possible.

If a relapse of persistent AF was diagnosed, ECV was again performed if clinically indicated, and the patient was maintained within the study. If the AF was considered permanent, the study was terminated. Even in this case, a 6 month final visit was performed.

At each visit, an ECG and all the ongoing medications were recorded. Laboratory analyses were performed at the screening and 6 month visits. The investigators were blinded to the treatment assignment when they adjudicated the AF events.

Blood levels of PUFAs were assessed by collecting a drop of whole blood on a strip of chromatographic paper, stored at a temperature lower than 4°C and then centrally measured at the Department of Pharmacological Sciences, University of Milan, by gas–liquid chromatography18 (DANI 8610, Monza, Italy). Samples were collected at the screening visit, then on the day of ECV and at 1 and 3 month visits.

Study end-points

The primary end-point was the percentage of patients with AF recurrence.

Secondary end-points were as follows: (i) the percentage of effective ECV; (ii) the time to AF recurrence; and (iii) the incidence of adverse events.

Sample size and statistical analysis

Published data on the efficacy of PUFAs in preventing supra-ventricular arrhythmias13,19 show a recurrence rate of about 50% in control patients, compared with 35% in patients treated with PUFAs. Based on these data, a conventional randomized, placebo-controlled study would require a sample size of 266 patients (133 for each treatment arm) to reject the null hypothesis with one-tailed α of 0.05 and an 80% power. However, since the experimental conditions of our study were different from those of the above-mentioned trials, we planned a two-stage adaptive design20 with α1 of 0.0183, to reject the null hypothesis, and α0 of 0.7, to accept the null hypothesis at the end of the first stage, with a power of 80%. The dimension of the first stage was fixed at 140 patients, this being about one-half of the sample size required for a corresponding conventional randomized, placebo-controlled study. On the basis of the interim analysis at the end of the first stage, the study would end for efficacy (P ≤ 0.0183) or inefficacy (P ≥ 0.7), or the sample size for the second stage would be calculated. However, the number of patients recruited and included into the interim analysis turned out to be higher than planned owing to the decision to randomize all the patients already under screening at centres when the 140th patient was enrolled.

Continuous variables are expressed as means ± standard deviation and categorical variables as frequencies and percentages. The comparisons between groups were performed by Student's unpaired t test applied to continuous variables and the χ2 test applied to dichotomous or nominal variables. Analysis of AF recurrence included the Kaplan–Meier method and log-rank test. Logistic regression analysis was used to compare the AF recurrence between groups adjusting by the patients’ clinical features at baseline.


The study complied with the Declaration of Helsinki and was approved by the local ethics committee of every participating centre. Written informed consent was obtained from all patients.


Recruitment was started in July 2006, and last patient completed treatment in December 2008. The interim analysis showed no statistically significant differences in the recurrence rate of AF between the two groups of patients; the null hypothesis was thus accepted according to the mentioned inefficacy criteria, and the study was discontinued.


Two hundred and fourteen patients were randomized, 111 to PUFAs and 103 to placebo. Between randomization and ECV 10 patients (seven in the PUFAs group and three in the placebo group) discontinued the study. The reasons were consent withdrawal in nine cases and protocol violation in one case (hyperthyroidism). Two hundred and four patients (104 in the PUFAs group and 100 in the placebo group) underwent ECV and were then included in the study analyses (Figure 1).

Figure 1

Study design and subject numbers at each stage. ECV, electrical cardioversion; PUFAs, polyunsaturated fatty acids; and SR, sinus rhythm.

Baseline characteristics of the patients are listed in Table 1. There are no differences in any of the characteristics considered between the two groups of patients. At baseline, the majority of the patients were on ACE inhibitors or ARBs, and more than 40% were on β-blockers. Sixty-four per cent were taking antiarrhythmic drugs at the time of ECV.

View this table:
Table 1

Comparison of demographic and clinical characteristics at baseline by treatment assignment

Cardioversion results

The mean time from randomization to ECV was 20.9 ± 24.3 days in the PUFAs group and 21.1 ± 24.6 days in the placebo group [P = not significant (NS)].

At the time of the scheduled ECV, nine patients (four on PUFAs and five on placebo) were in sinus rhythm. One hundred and ninety-five patients underwent ECV that was successful in 170 cases (87%): 89 of 100 patients (89%) on PUFAs and 81 of 95 patients (85%) on placebo (P = NS). The total energy used was respectively 249 ± 161 vs. 248 ± 185 J (P = NS).

Fifteen of the 25 patients still in AF at the end of ECV underwent a second ECV after modification of the antiarrhythmic drug treatment. Sinus rhythm was achieved at the end of the procedure in eight of them (two of five on PUFAs and six of 10 on placebo).

Overall, sinus rhythm was restored in 187 patients, those in whom either the first or the second ECV was successful and those who converted spontaneously before the procedure. Those patients were available for the follow-up; 95 patients in the PUFAs group and 92 patients in the placebo group (Figure 1). The 6 month follow-up was completed for all the patients.

First atrial fibrillation recurrence

Among the 187 patients in sinus rhythm available for follow-up, there was no difference in the recurrence rate of AF between the two study groups. Atrial fibrillation relapsed in 51.1% (47 of 92) and in 59% (56 of 95) of the placebo and the PUFAs patients, respectively (P = 0.28). The mean time to AF recurrence was 83 ± 8 days in the PUFAs group and 106 ± 9 days in the placebo group (log rank test 1.141, P = 0.29; Figure 2). AF was persistent in all but six cases (three PUFAs and three placebo) in which spontaneous reversion to sinus rhythm was observed.

Figure 2

Time to the first recurrence of atrial fibrillation in the PUFAs group and the placebo group.

Forty-five patients, 25 on PUFAs and 20 on placebo, did not receive antiarrhythmic drugs either before or after ECV. Among these, AF recurred in seven patients (35%) in the PUFAs group and in 10 patients in the placebo group (40%; P = 0.73).

One hundred and forty-two patients received antiarrhythmic drugs. Among these, AF recurrence rates in PUFAs and placebo groups were 65.7% (46 of 70 patients) and 55.6% (40 of 72 patients), respectively (P = 0.22).

Fifty-two patients (26 on PUFAs and 26 on placebo) received amiodarone, alone or in combination, with corresponding recurrence rates of 65.4% (17 of 26 patients) and 61.5% (16 of 25 patients; P = 0.77).

None of the clinical features considered in Table 1 (first episode of AF, previous ECV, previous antiarrhythmic drugs, hypertension, diabetes, coronary heart disease, valvular heart disease, lone AF NYHA class II–III) was found to have a significant role in AF relapse. Only in patients who had already been treated with antiarrhythmic drugs did AF recurrence show a trend towards a higher recurrence rate (64.9 vs. 50.8%; P = 0.076).

Sinus rhythm at the end of follow-up

Fifty-six patients among the 103 who had AF recurrence (28 of 56 in the PUFAs group and 28 of 47 in the placebo group) had their sinus rhythm restored, whether spontaneously, pharmacologically or by ECV, and continued study treatment. Overall, at the end of the 6month follow-up, sinus rhythm was present in 67 of the 95 PUFAs patients (70.5%) and in 73 of the 92 placebo patients (79.3%; P = 0.16)

Blood concentrations of PUFAs

Compliance with treatment, as assessed from capsule accountability during study visits, was high, with 93.7% and 93.5% of patients in the PUFAs and placebo group, respectively, attaining more than 80% of due administration.

Mean concentrations of EPA and DHA are reported in Table 2. Baseline levels were similar in the two groups of patients. The EPA and DHA levels in the treated group were significantly higher compared with placebo at all the study assessments. At cardioversion, after a mean of about 3 weeks of treatment with 3 g daily of PUFAs, EPA concentration in blood was nearly double with respect to baseline (P < 0.01) and DHA levels had increased by 25% (P < 0.01). After a further 3 months of treatment with 2 g daily of PUFAs, DHA concentration did not increase further, while EPA values became about 22% higher with respect to the time of cardioversion. A similar increasing trend was found in the ratio between omega 3 and omega 6 as expressed by highly unsaturated fatty acid index.

View this table:
Table 2

Concentrations of polyunsaturated fatty acids in whole blood at different time points during the study

In the placebo group, levels of both EPA and DHA were not found to be different with respect to baseline at all the evaluation times.

Adverse events

No differences were found between treated and placebo groups in the number of adverse events (AEs) or patients involved. In the PUFAs and placebo group, respectively, 19 (17%) and 24 patients (23%) experienced a total of 20 and 24 AEs, which led to treatment withdrawal (either temporarily or permanently) in five and 10 patients. More often, AEs involved cardiovascular (six AEs in the PUFAs group and six in the placebo group) gastrointestinal (four AEs in the PUFAs group and four in the placebo group) and bleeding systems (two AEs in the PUFAs group and four in the placebo group). All AEs were judged mild or moderate in intensity, except for one episode in the PUFA group (lower back pain) and two among placebo subjects (peptic ulcer and heart failure) that were considered to be severe.


Main finding

The main result of the present study is that, in patients with persistent AF, supplementation with 3 g/day of PUFAs before ECV and 2 g/day thereafter, in addition to the usual antiarrhythmic treatment, does not prevent the arrhythmia recurrence.

Previous experimental studies

At present, there are several experimental studies supporting an atrial antiarrhythmic effect of PUFAs.

Jahangiri7 reported an anti-asynchronous effect of an n-3 PUFAs perfusion on isolated atrial rat myocytes and hypothesized a mechanism involving changes in membrane fluidity.

Ninio8 found that tuna fish oil supplementation reduced the stress-induced susceptibility to AF induction in a rabbit model.

Da Cunha9 studied 18 dogs treated with rapid atrial pacing for 6 h. Concomitantly, six of them received intravenously n-3 PUFAs, six of them n-6 PUFAs and six of them saline. The n-3 PUFAs significantly reduced the shortening of atrial effective refractory periods compared with the other groups, although they did not alter effective refractory period during normal sinus rhythm.

Sarrazin10 reported that supplementation with 1.2 g/day of n-3 PUFAs in dogs doubled atrial tissue levels without affecting atrial refractory periods. Indeed, AF inducibility with the extrastimulus technique and burst induction resulted decreased by 79% and 42%, respectively, in comparison with control animals. Both connexins Cx40 and Cx43 were significantly reduced in the treated dogs compared with control animals, by 60% and 42%, respectively, and protection against AF was mostly related to reduced Cx40 expression. Moreover, intravenous administration of n-3 PUFAs in control dogs reduced AF inducibility from 75% to 29%.

Laurent11 found that supplementation with 1 g/day of n-3 PUFAs reduced AF vulnerability in a canine model of atrial cardiomyopathy, by inducing less local slowing of conduction and conduction heterogeneity, together with a smaller increase in atrial matrix metalloprotein-9 activity and in collagen type I and III mRNA expression (index of attenuated collagen turnover).

Previous epidemiological studies

Epidemiological studies gave conflicting results. In a prospective study by Mozaffarian,12 consumption of tuna or other broiled or baked fish was associated with a 35% lower risk of incident AF, after adjustment for other risk factors, over a 12 year follow-up period. In a population study that included consecutive patients with acute myocardial infarction over a 12 month follow-up period,21 prescription of n-3 PUFAs was associated with a reduced risk of hospitalization for AF.

In contrast, in three other population-based studies, the Rotterdam study22 the Danish Diet, Cancer and Health study,23 and a report from the Women's Heath Initiative clinical trials,24 no association was found between dietary fish intake and reduced AF incidence.

Previous clinical studies

Several studies in different clinical setting are available.

In patients with paroxysmal AF and implanted pacemakers, Biscione et al.19 reported a significant reduction of both atrial tachyarrhythmia episodes and AF burden, as assessed by pacemaker interrogation, during a 4 month treatment period with 1 g/day of PUFAs. Both the parameters returned to the baseline level after drug withdrawal.

In patients undergoing open heart surgery, conflicting results are reported. An open-label study from our group13 demonstrated that a short course of 2 g/day of PUFAs, in patients undergoing coronary artery bypass graft, reduced the incidence of post-operative AF by about 50% and was associated with a shorter hospital stay. Very similar results (43% AF reduction and a shorter hospital stay) were reported by another group25 by using intravenous supplementation with PUFAs. Conversely, in two recent double-blind, placebo-controlled studies26,27 no association was found between oral supplementation with PUFAs and post-operative AF.

Recently, a randomized open-label study on 199 patients found that treatment with 1 g/day PUFAs and amiodarone was associated with a greater probability of maintaining sinus rhythm at 1year after ECV than treatment with amiodarone alone.28

The present study

To our knowledge, this was the first prospective, double-blind, placebo-controlled clinical study designed to assess the effects of supplementation with PUFAs on atrial fibrillation, specifically addressing the unresolved problem of AF recurrence after ECV.

Our findings do not support the hypothesis that the atrial antiarrhythmic properties of PUFAs could reduce the arrhythmia recurrence after ECV of persistent AF.

How can we reconcile this fact with our previous observation that PUFAs were effective in reducing the incidence of post-operative AF?

In our opinion, this cannot be considered surprising, as AF is not a disease, but rather an electrophysiological disorder that represents a clinical manifestation of many different pathological and aetiological factors.

In particular, post-operative AF develops in otherwise normal or nearly normal atria, as a consequence of acute electrophysiological derangements, mainly due to adrenergic drive and inflammation,29,30 while persistent AF usually occurs in chronically diseased atria, as a consequence of anatomical disorders, such as chronic strain and fibrosis.31 Therefore, it is conceivable that the effects of PUFAs on some electrophysiological parameter could antagonize post-operative AF, while they could be irrelevant in a setting in which severe atrial anatomical disarrays and/or heavy electrophysiological disorders play a preponderant role in the genesis of the arrhythmia. In addition, the protective effect of PUFAs against post-operative AF could be attributed, at least in part, to their anti-inflammatory action,32,33 a property that could be less relevant in the prevention of persistent AF recurrence.

In the light of previous experimental studies showing an antifibrillatory action of PUFAs, how can we explain our negative results? Several factors must be taken into account.

Firstly, experimental studies are conducted in normal animal hearts, a setting that is completely different from that of the diseased human heart. In fact, an antifibrillatory action observed in experimentally induced atrial fibrillation in otherwise normal animal hearts might not be effective in preventing the recurrence of the arrhythmia in human atria with longstanding atrial fibrillation, which are already heavily remodelled from both anatomical and electrophysiological points of view.

Secondly, some of the antifibrillatory actions of the PUFAs have been observed with acutely administered compounds, obtaining very high plasma concentrations. In this situation, their effects on cardiac ion channels and transporters may be different from those obtainable after chronic administration of PUFAs, which is associated with a more gradual incorporation into cell membranes. In fact, in contrast to what is observed with intravenous administration,9 oral supplementation of PUFAs in dogs subjected to atrial tachypacing did not affect atrial refractory periods.10,11

Thirdly, the antifibrillatory effects of PUFAs could vary depending on the substrate of AF. In fact, a very elegant experimental study34 in dogs showed that chronic oral administration of PUFAs, admittedly at very high doses, had no effects on electrical remodelling induced by atrial tachypacing, while it suppressed atrial structural remodelling induced by congestive heart failure.

Fourthly, the mechanism by which EPA and DHA might have exerted their antiarrhythmic properties after oral administration in animal models could arise from their incorporation into the phospholipids of the cardiac membrane, rather than from their plasma levels, and the magnitude of incorporation could depend on the dosage and the duration of administration of PUFAs.

An interesting study16 showed that fish oil supplementation in humans, at a dose of 6 g/day, induced a progressive increase in n-3 PUFA content in phospholipids at the atrial level. The degree of the increase was dependent on the duration of PUFAs supplementation, being 35%, 59% and 80% after a treatment period of 7–10, 11–25 and 26–63 days, respectively. In contrast, plasma levels were more than doubled after the shorter period of administration, while they remained substantially stable for the longer periods. This observation suggests that, after oral supplementation of PUFAs, their incorporation into atrial cells continues to increase over time, in spite of plasma levels remaining constant after an initial surge. Therefore, we cannot exclude the possibility that, in our study, the dose of PUFAs could have been too small and/or the period of administration before electrical cardioversion too short to allow a sufficient incorporation of PUFAs in atrial membranes.

Fifth, in our study, blood concentrations of PUFAs were significantly increased by oral supplementation with 3g/day, although their relative increment was limited, being of only about one-third at the time of ECV. In particular, EPA concentrations were more than doubled, while DHA concentrations were increased by about 25%. The increase in EPA and DHA was smaller than those previously reported in populations with similar baseline fatty acid levels, by using similar doses of PUFAs (1.5–3 g/day) for 3 months.35,36 In these studies, the EPA concentrations were increased by about three times and DHA concentrations were respectively increased by 43% and 80%. This is important, especially for DHA, as a recent study37 found that serum DHA was the strongest predictor of reduced incidence of AF in men. The smaller increase in EPA and DHA in our patients could have contributed to the lack of effect of n-3 fatty acid supplementation.


Our results do not support the hypothesis that supplementation with n-3 polyunsaturated fatty acids, in addition to the usual antiarrhythmic treatment, has a beneficial effect in reducing the relapse of the arrhythmia in patients with persistent atrial fibrillation undergoing electrical cardioversion.


This study was supported by SPA-Società Prodotti Antibiotici (Milan, Italy).


The authors are grateful to Patrizio Sala BSc of Data Management & Biometry, Cremona, Italy, for his support in data management and statistics.

Conflict of interest: P.R. was employed by SPA-Società Prodotti Antibiotici, Milan, Italy at the time that this study was conducted. All other authors have no conflict of interest.


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