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Original Contribution |

Efficacy and Safety of Prescription Omega-3 Fatty Acids for the Prevention of Recurrent Symptomatic Atrial Fibrillation:  A Randomized Controlled Trial FREE

Peter R. Kowey, MD; James A. Reiffel, MD; Kenneth A. Ellenbogen, MD; Gerald V. Naccarelli, MD; Craig M. Pratt, MD
[+] Author Affiliations

Author Affiliations: Division of Cardiovascular Diseases, Lankenau Institute for Medical Research, Wynnewood, and Jefferson Medical College, Philadelphia, Pennsylvania (Dr Kowey); Division of Cardiology, Columbia University Medical Center, New York, New York (Dr Reiffel); Clinical Cardiac Electrophysiology and Pacing, Virginia Commonwealth University Medical Center, Richmond (Dr Ellenbogen); Division of Cardiology, Penn State University College of Medicine, Hershey, Pennsylvania (Dr Naccarelli); Methodist DeBakey Heart and Vascular Center, Houston, Texas; and Department of Medicine, Weill Cornell Medical College, New York, New York (Dr Pratt).


JAMA. 2010;304(21):2363-2372. doi:10.1001/jama.2010.1735.
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Published online

Context Atrial fibrillation (AF) is common, yet there remains an unmet medical need for additional treatment options. Current pharmacological treatments have limited efficacy and significant adverse events. Limited data from small trials suggest omega-3 polyunsaturated fatty acids may provide a safe, effective treatment option for AF patients.

Objective To evaluate the safety and efficacy of prescription omega-3 fatty acids (prescription omega-3) for the prevention of recurrent symptomatic AF.

Design, Setting, and Participants Prospective, randomized, double-blind, placebo-controlled, parallel-group multicenter trial involving 663 US outpatient participants with confirmed symptomatic paroxysmal (n = 542) or persistent (n = 121) AF, with no substantial structural heart disease, and in normal sinus rhythm at baseline were recruited from November 2006 to July 2009 (final follow-up was January 2010).

Interventions Prescription omega-3 (8 g/d) or placebo for the first 7 days; prescription omega-3 (4 g/d) or placebo thereafter through week 24.

Main Outcome Measures The primary end point was symptomatic recurrence of AF (first recurrence) in participants with paroxysmal AF. Secondary analyses included first recurrence in the persistent stratum and both strata combined. Participants were followed up for 6 months.

Results At 24 weeks, in the paroxysmal AF stratum, 129 of 269 participants (48%) in the placebo group and 135 of 258 participants (52%) in the prescription group had a recurrent symptomatic AF or flutter event. In the persistent AF stratum, 18 participants (33%) in the placebo group and 32 (50%) in the prescription group had documented symptomatic AF or flutter events. There was no difference between treatment groups for recurrence of symptomatic AF in the paroxysmal stratum (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.90-1.46; P = .26), in the persistent stratum (HR, 1.64; 95% CI, 0.92-2.92; P = .09), and both strata combined (HR, 1.22; 95% CI, 0.98-1.52; P = .08). Other, secondary end points were supportive of the primary result. A total of 5% of those receiving placebo and 4% of those receiving prescription omega-3 discontinued due to adverse events. Eicosapentaenoic and docosahexaenoic acid blood levels were significantly higher in the prescription group than in the placebo group at weeks 4 and 24.

Conclusion Among participants with paroxysmal AF, 24-week treatment with prescription omega-3 compared with placebo did not reduce recurrent AF over 6 months.

Trial Registration clinicaltrials.gov Identifier: NCT00402363

Figures in this Article

Atrial fibrillation (AF) is a highly prevalent disease that is responsible for reduced quality of life, costly hospitalizations, heart failure, stroke, and death.1,2 No current therapy, drug, device, or ablation is uniformly effective, and several available therapies have the potential to cause harm.35 Consequently, useful alternatives are being sought.

Fish oils have demonstrable potent electrophysiological, autonomic-modulating, and anti-inflammatory effects in atrial and ventricular tissue and, most importantly, appear to be well tolerated.6,7 Thus, these products have been studied in clinical trials involving treatment of AF in a wide range of patients and clinical scenarios, using various doses, and in diverse designs. However, the results of these trials have been mixed,813 resulting in confusion among physicians and patients. Many patients use omega-3 polyunsaturated fatty acid supplements or have enhanced their diets heavily with fish products, without a clear idea of why or what they might expect with regard to arrhythmia suppression or safety. Because many omega-3 fatty acid preparations are marketed as food sub/MAINstances, they have not been subjected to the scientific rigor that is necessary to assess net clinical benefit.14

We designed this randomized clinical trial to assess the efficacy of a pure prescription formulation of omega-3 fatty acids (prescription omega-3), at a dose considerably higher than what has been tested in previous trials, for preventing recurrent symptomatic AF in a well-characterized patient population with documented, symptomatic paroxysmal or persistent AF, without significant structural heart disease. Given the AF population we analyzed (ie, a relatively healthy population with a high probability of having a recurrence of AF within 6 months), we theorized that if prescription omega-3 exhibited any pharmacodynamic antiarrhythmic effect, it would occur in this specific patient cohort.

Study Design

The study design for this clinical trial has been published previously.15 This 6-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was designed to assess the efficacy and safety of prescription omega-3 for the prevention of recurrent symptomatic AF. The study was conducted according to the Declaration of Helsinki at 96 US centers. All centers obtained institutional review board approval for the study prior to participant screening. All participants provided written informed consent before enrollment and randomization. Patients were recruited and enrolled in the study from November 2006 to July 2009, with final follow-up on January 21, 2010.

Study Population

A complete description of inclusion and exclusion criteria were previously reported.15 In brief, participants were at least 18 years old and had a confirmed diagnosis of either symptomatic paroxysmal AF that had never been treated by long-term pharmacological or electrical therapy to terminate an AF episode or had a diagnosis of symptomatic persistent AF, defined as AF that had been previously successfully treated with pharmacological or electrical cardioversion at least 1 time and were currently in normal sinus rhythm. Inclusion required at least 1 suspected or documented episode of symptomatic AF within 3 months of screening and at least 1 electrocardiographically documented episode of symptomatic AF within 12 months of screening.

Key exclusion criteria were permanent AF, secondary AF (eg, due to hypothyroidism or valvular heart disease), current use of antiarrhythmic therapy (participant must have ceased drug use for at least 5 half-lives before randomization for inclusion), use of amiodarone within the past 6 months, prior ablation therapy for AF, or specific structural cardiac disorders.

Participants either self-reported race/ethnicity or were classified by the investigator. Racial categories included black, African heritage, Asian, Pacific Islander, Hispanic, American Indian, white, or other. Race was obtained as part of the participants' demographic information.

Study Intervention

Participants were randomized to receive 4 g/d of prescription omega-3 (Lovaza, GlaxoSmithKline, Research Triangle Park, North Carolina) or placebo. For the first 7 days of dosing, participants received a loading dose of 8 g/d or 8 placebo capsules, followed by 4 g/d through week 24. Each 1-g capsule of prescription omega-3 contained approximately 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid. Each placebo capsule contained approximately 1 g of corn oil. The clinical research organization, Kendle International, Cincinnati, Ohio, generated the randomization schedule. Site personnel telephoned into an interactive voice response system to obtain a randomization number and were assigned blinded study medication bottles.

Participants were followed up for 6 months. Biweekly transtelephonic monitoring was used to document asymptomatic recurrences of AF and assess symptomatic events. Investigators were blinded to the monitoring results.

Once a participant experienced the primary end point (first documented symptomatic recurrence of AF or atrial flutter), additional therapies to maintain normal sinus rhythm were allowed, but the participant was encouraged to continue taking the blinded study drug and continue attending the planned follow-up to the study's completion.

Study Outcomes

The primary outcome was the effect of prescription omega-3 on the first symptomatic recurrence of AF or flutter, from the first dose of the study drug, in the paroxysmal AF stratum. Symptomatic atrial flutter was treated as an occurrence of symptomatic AF for the primary end point. The principal secondary outcome was first symptomatic recurrence of AF or flutter in the persistent AF stratum and in both AF strata combined.

Statistical Analysis

A total of 295 primary efficacy events in the paroxysmal AF stratum were required to provide at least 90% power to detect a hazard ratio (HR) of 0.682 for prescription omega-3 vs placebo with a 2-sided α of .05. A sample of 663 participants (330 per treatment group) was randomized 1:1 to receive either prescription omega-3 or placebo, stratified by a baseline diagnosis of paroxysmal or persistent AF in a ratio of 5:1. The primary analysis was based on the paroxysmal AF stratum. Due to challenges enrolling participants in the study, enrollment was stopped when the planned 660 number of participants was achieved. By the time we decided to stop enrolling patients, the number of events exceeded the 220 primary events required to achieve 80% power. Two hundred sixty-four primary events accumulated during the study.

During the study, 47 participants' randomization stratum was changed after randomization but before the data lock and analysis following the monitors' review of the source documentation (39 from paroxysmal to persistent and 8 from persistent to paroxysmal AF). All efficacy analyses were based on the revised classification. As previously described and prespecified,15 efficacy analyses were based on a modified intent-to-treat population as described herein, which comprised all randomized participants with at least 1 postrandomization transtelephonic monitoring electrocardiographic data transfer (or equivalent). The safety analyses were based on the population of all randomized patients who took at least 1 dose of the study medication. The primary analysis was performed using a Cox proportional hazards model adjusting for treatment group, geographical region of enrollment, statin use, and a time-dependent covariate for angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker use to estimate HRs, P values, and 95% confidence intervals (CIs) for prescription omega-3 vs placebo. Participants were censored after initiation of any antiarrhythmic drug, to clearly understand the effect of prescription omega-3. Participants who were event-free at completion of the trial or at early termination were censored at the last available visit date or transmission date, whichever occurred later. Time to event of secondary variables for the paroxysmal and combined strata were analyzed via a Cox proportional hazard model similar to the primary analysis, except using ACE inhibitor or angiotensin II receptor blocker use as a fixed effect because such use had the potential to influence the incidence of AF and flutter events. Given the small number of participants in the persistent stratum, survival analysis was performed using a log-rank test. Analyses of continuous variables were performed using parametric or nonparametric analysis of covariance, t test, or Wilcoxon rank-sum test, as appropriate. All analyses were performed using SAS version 9.1 (SAS Institute Inc, Cary, North Carolina).

In addition, all raw data and analysis data were provided to an external academic biostatistician who independently repeated the analyses and confirmed all findings reported herein. In this analysis, participants were not censored at the time of antiarrhythmic drug use (total of 9 participants were not censored at the time of antiarrhytmic drug use. Of those, 8 were in the prescription group and 1 was in the placebo group), and participants also were not censored at the time of study drug termination (1 prescription group participant with a subsequent recurrence). An additional intention-to-treat analysis was performed for the primary end point for each stratum using the original classification at randomization, including all participants as randomized. Because we used the survival analysis method throughout our study, patients with missing data (including those lost to follow-up or who had withdrawn early) were censored at the last available visit if no event occurred at earlier visits.

Of the 663 participants randomized, 584 (88%) completed the study. Of those, 479 were in the paroxysmal stratum: 246 participants (89%) in the placebo group and 233 (88%) in the prescription group; 105 in the persistent stratum: 45 (82%) in the placebo group and 60 (91%) in the prescription group (Figure 1). Premature withdrawals were comparable across treatment groups and strata, with the most frequent reason being adverse events (occurring in ≤5% of participants in any treatment group or strata) followed by consent withdrawal. Demographic and clinical characteristics, electrocardiographic and echocardiographic data, and concomitant medical therapy were comparable across treatment groups and strata (Table 1).

Place holder to copy figure label and caption
Figure 1. Study Flowchart
Graphic Jump Location

Forty-seven participants' randomization stratum was changed after randomization, based on a review of the participants' past medical history: 39 from paroxysmal to persistent and 8 from persistent to paroxysmal atrial fibrillation. Efficacy analyses were based on the revised classification and are reflected in the modified intention-to-treat efficacy population. ECG indicates electrocardiography.

Table Graphic Jump LocationTable 1. Summary of Mean Randomized Baseline and Demographic Characteristics
Primary and Secondary Outcomes

No statistical difference was observed between treatment groups for the primary efficacy end point in the prespecified modified intention-to-treat analysis, in the approach without censoring participants at time of antiarrhythmic drug use or study drug termination, or in the intention-to-treat analysis including all patients in the groups to which they were randomized. (Table 2 and Figure 2).

Table Graphic Jump LocationTable 2. Summary of Primary and Secondary Efficacy Results for the Paroxysmal Stratum
Place holder to copy figure label and caption
Figure 2. First Recurrence of Symptomatic Atrial Fibrillation for the Paroxysmal Stratum
Graphic Jump Location

Analysis is based on a Cox proportional hazards model adjusting for treatment, region, and use of angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and statin.

In the paroxysmal stratum, there were 129 documented symptomatic AF or flutter events (48%) in the placebo group and 135 (52%) in the prescription group (HR, 1.15; 95% CI, 0.90-1.46; P = .26). The primary efficacy results were consistent for the persistent AF stratum and for the 2 strata combined (Table 3). In the persistent AF stratum, there were 18 documented symptomatic AF or flutter events (33%) in the placebo group and 32 (50%) in the prescription group (HR, 1.64; 95% CI, 0.92-2.92; P = .09), while in the 2 strata combined, there were 147 events (46%) in the placebo group and 167 (52%) in the prescription group (HR, 1.22; 95% CI, 0.98-1.52; P = .08).

Table Graphic Jump LocationTable 3. Summary of Secondary Efficacy Results for the Persistent and Combined Strata

Results of the primary efficacy end point for the paroxysmal AF stratum were also consistent across all subgroups, including age, sex, race, smoking status, alcohol consumption, ACE inhibitor or angiotensin II receptor blocker use, statin use, and region (Figure 3) and all sensitivity analyses (eFigure). None of the secondary efficacy end points achieved statistical significance (Table 3).

Place holder to copy figure label and caption
Figure 3. Analyses of Primary End Point in Paroxysmal Atrial Fibrillation Subgroup
Graphic Jump Location

Analyses were performed using a Cox proportional hazards model fitting separate model for each subgroup. ACEI, indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CI, confidence interval; and HR, hazard ratio.

Tertiary Outcomes

The average heart rate during the first recurrence of symptomatic AF or flutter was lower in the prescription group than in the placebo group (combined strata), with a mean difference between the treatment groups of −6.88/min (95% CI, −13.12 to −0.64; P = .03). Analyses of the median percent change from baseline plasma n-3 fatty acids (combined strata) showed no statistically significant difference in total fatty acids between the 2 groups, statistically significant increases in eicosapentaenoic acid and docosahexaenoic acid at weeks 4 and 24, and a statistically significant decrease in arachidonic acid at weeks 4 and 24. The difference in median percent change between the placebo and prescription groups for eicosapentaenoic acid at week 4 was 276.10% (95% CI, 242.70%-309.20%; P < .001) and at week 24 was 239.0% (95% CI, 202.60%-276.20%; P < .001) in favor of prescription omega-3. The difference in median percent change between the placebo and prescription groups for docosahexaenoic acid at week 4 was 95.6% (95% CI, 81.20%-110.0%; P < .001) and at week 24 was 100.30% (95% CI, 83.60%-118.0%; P < .001) in favor of prescription omega-3. The difference in median percent change between the placebo and prescription groups for arachidonic acid at week 4 was −13.0% (95% CI, −17.60% to −8.20; P < .001) and at week 24 was −15.70% (95% CI, −21.0 to −10.60; P < .001) in favor of the prescription omega-3.

Study Discontinuation and Adverse Events

Sixteen participants (5%) taking placebo and 12 (4%) taking prescription omega-3 discontinued study medication due to an adverse event. Diarrhea and nausea, the most common adverse events leading to discontinuation or withdrawal, were similar across treatment groups. The overall incidence of treatment-emergent drug-related adverse events was similar across treatment groups (13% placebo; 16% prescription omega-3; Table 4); the only drug-related treatment-emergent adverse event that occurred in 3% or more of the participants was nausea noted in 7 participants (2%) in the placebo group and 9 (3%) in the prescription group.

Table Graphic Jump LocationTable 4. Drug-Related Treatment-Emergent Adverse Events Reported by 2 or More Participants in Either Treatment Group (Safety Population)

Two deaths occurred, 1 participant in the placebo group and 1 in the prescription group. According to the investigators, these deaths were considered unrelated to the study drug. A third death occurred approximately 113 days after the participant completed dosing with prescription omega-3 therapy. The investigator considered the death unrelated to the study drug.

Two placebo group participants were discontinued due to abnormal liver function results. High-density lipoprotein and low-density lipoprotein cholesterol levels did not differ between groups. However, the difference between treatment groups in median percent change from baseline was −11.5% (95% CI, −16.70% to −6.50%; P < .001) for triglycerides and −11.40% (95% CI, −16.50% to −6.20%; P < .001) for very low-density lipoprotein cholesterol. The mean (SD) change from baseline to week 24 in hemoglobin A1c in the placebo group was 0.10% (0.47%), whereas that in the prescription group was 0.01% (0.43%). To convert cholesterol to mmol/L, multiply by 0.0259; triglycerides to mmol/L, by 0.0113.

There was a significant mean decrease from baseline in systolic blood pressure at week 24 in the prescription group compared with the placebo group (mean difference, −2.3 mm Hg; 95% CI, −4.6 to 0.0; P = .05). Although the mean heart rate at the time of first recurrence of symptomatic AF or flutter was statistically significantly lower in the prescription group than in the placebo group (combined strata), the decrease from baseline in the heart rate at week 24 in the prescription compared with the placebo group did not reach statistical significance (−1.0/min; 95% CI, −2.8 to 0.7; P = .24).

Previous studies have shown that fish-derived omega-3-acid ethyl esters have membrane-modifying, metabolic, autonomic, anti-ischemic, anti-inflammatory, and electrophysiological actions that may be antiarrhythmic6,15 with direct electrophysiological actions targeting sodium, potassium, calcium, and magnesium channels and membrane conductance.6,16 Observed effects among individuals who have moderate to high consumption of dietary fish, who take prescription omega-3 capsules, or both, have included a reduced frequency of ventricular and atrial arrhythmias in several patient populations, beneficial effects on heart rate variability, and reductions in total mortality by 3 months and risk of sudden death by 4 months in patients after experiencing myocardial infarction in the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto) Prevention Study.15,17 In addition, several preclinical and early clinical studies specifically relating to the utility of prescription omega-3 in AF have suggested potential hemodynamic, autonomic, and electrophysiological effects likely to be antifibrillatory or have demonstrated reduced AF induction, persistence, or both.1822

Moreover, several prior clinical trials of AF prevention or reduction, all smaller than our study and conducted in more specific patient circumstances, appear to show benefit from omega-3 fatty acids for AF prevention. Calò et al9 randomized 160 patients awaiting coronary artery bypass graft (CABG) surgery to usual care or to eicosapentaenoic acid plus docosahexaenoic acid (1.7 g/d) from 5 days before surgery through hospital discharge. The end point, AF lasting longer than 5 minutes or requiring intervention, was reduced from 33% in the control group to 15% in omega-3 fatty acids group. Mean hours of AF were reduced from 24 to 16 (P = .12) and length of stay was reduced from 8.2 to 7.3 days. Biscione et al22 gave 40 patients with dual chamber pacemakers 1 g/d of omega-3 fatty acids or nothing for treatment periods of 4 months. They observed a 59% reduction in AF episodes and a 67% reduction in AF burden during omega-3 fatty acid administration. In a study by Nodari et al,23 AF recurrence was assessed following direct current cardioversion in 70 consecutive persistent AF patients randomized to 1 g/d of prescription omega-3 (n = 30) or placebo (n = 40). All received amiodarone, β-blockers, and renin-angiotensin system inhibitors. At 1, 3, and 6 months after conversion, recurrence rates determined on 24-hour Holter monitoring were 3.3%, 10%, and 13.3% for the prescription omega-3 group and 10%, 25%, and 40% for the placebo group, respectively.

Recently, 3 more post-CABG surgery trials were reported. One trial using prescription omega-3 vs placebo24 failed to show benefit on postoperative atrial fibrillation defined as an episode detected by continuous electrocardiographic monitoring lasting longer than 5 minutes, whereas another trial using intravenous fish oil25 showed efficacy in preventing the occurrence of atrial fibrillation after CABG surgery. In another post-CABG surgery trial in which 260 patients were randomized to receive prescription omega-3 or matching placebo (2 g twice daily for at least 3 doses preoperatively and 2 g/d postoperatively for 14 days or until AF occurred [if sooner]), Sandesara et al11 reported no difference in the incidence of AF or flutter, in length of stay, or in very low adverse event rates. These negative results are consistent with those recently reported by Berry et al26 who found no association between fish or omega-3 fatty intake and incident AF in 44 720 participants in the Women's Health Initiative.

Against this background, our trial—which to our knowledge is the largest cohort to date of mainstream AF patients—was performed. This trial, using a high-dose prescription omega-3 regimen (4 g/d), failed to demonstrate a significant difference from placebo in the primary end point of first recurrence of symptomatic AF or flutter or in any of its secondary end points. In the prescription omega-3 group, we did find a reduction in average ventricular rate during the first AF recurrence, a reduction in triglyceride levels at week 24 that did not occur with placebo, and increased blood levels of the omega-3 fish oils eicosapentaenoic acid and docosahexaenoic acid compared with placebo patients. These observations suggest a biological effect in the patients treated with prescription omega-3, although the reduction in ventricular rate during an AF recurrence may not have been sufficient in degree or consistency to produce a clinically meaningful outcome. There was also no difference between the 2 treatment groups in adverse effects, including bleeding, serious drug-related nonfatal events, or deaths.

Our results were consistent when analyzed using the prespecified modified intention-to-treat analysis, using the independent academic statistician's analysis including participants who were previously censored from the protocol-specified analysis, and using an intention-to-treat analysis that included all randomized patients in the groups to which they were randomized. The results of these latter 2 analyses were not substantially different from the original prespecified analysis and strengthen the conclusion that the omega-3 fatty acids are not useful in the treatment of AF in the study population.

Several factors might contribute to the discordance between our findings and those of other studies. Either the positive results reported in some trials represent a chance effect of small sample sizes or the differences are real. If the latter, there are several possibilities, including differences in the study populations, in population-specific AF mechanisms, in dosing regimens and product formulations, or in concomitant therapies. In our study, nearly half the events occurred during the first 2 weeks of follow-up, suggesting that fish oil may not have rapid effects, even with high-loading doses.

Our large trial showed no effect in a specific population of AF patients with paroxysmal AF (the majority of participants in our trial) and those with persistent AF who did not have severe heart disease, were not elderly, were without recent cardiac surgery, and were not administered concomitant antiarrhythmic drugs but did receive β-blockers, statins, and ACE inhibitors or angiotensin II receptor blockers. Our study does not provide evidence to support a role for prescription omega-3 therapy in such patients to prevent AF recurrence. However, our results do not exclude potential benefit in combination with membrane-active antiarrhythmic drugs, in different patient populations such as a high-risk primary prevention population (eg, heart failure or those with multiple clinical risk factors) or in the absence of concomitant therapies. These possibilities require evaluation in prospective clinical trials.

Our study has several limitations. First, the primary end point was recurrence of symptomatic, documented AF—a clinically meaningful parameter. Our study was not powered to examine “harder” AF-related end points such as stroke or cardiovascular death. Second, we did not have adequate pilot data to estimate the likely effect size of prescription omega-3 and the most appropriate loading and maintenance dose to study. We also do not know whether omega-3 fatty acids given in capsule form is the same as when ingested through dietary sources, and in this study, dietary information on participants' fish consumption during the trial was not collected. Third, errors in the statistical estimates of our event rates and the magnitude of treatment effect could have contributed to a potential type II error. For instance, our estimate of AF recurrence in the placebo group was 64.4% but the actual recurrence rate was 48%, and we projected a rather aggressive treatment effect of 0.682 (HR), by assuming an effect as large as the lowest dose of an antiarrhythmic recently approved by the US Food and Drug Administration for AF. We believe that anything less than such a treatment effect would not be clinically meaningful. Although nonsignificant, the directional change of the rate of recurrent AF largely favors placebo. Therefore, it is unlikely that a larger study would have yielded a different primary outcome. In addition, had this study demonstrated a beneficial effect of omega-3 fatty acids, further trials would be needed to confirm the findings and assess clinical outcomes. Fourth, the technique used for assessing recurrences, transtelephonic monitoring, could underestimate asymptomatic AF recurrences. And fifth, it is impossible to weigh the relevance and relative potency of all of the potential mechanisms by which prescription omega-3 might suppress AF. It is possible that 1 or more of the drug's primary effects may only be manifest in certain types of AF patients not well represented in our patient population.

In this population of patients with symptomatic paroxysmal AF or persistent AF, and no evidence of substantial structural heart disease, prescription omega-3 did not show evidence of reducing the recurrence of symptomatic AF.

Corresponding Author: Peter R. Kowey, MD, 558 Lankenau Medical Office Bldg East, 100 Lancaster Ave, Wynnewood, PA 19096 (KoweyP@mlhs.org).

Published Online: November 15, 2010. doi:10.1001/jama.2010.1735

Author Contributions: Dr Kowey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kowey, Reiffel, Ellenbogen, Naccarelli, Pratt.

Acquisition of data: Kowey, Reiffel, Ellenbogen, Naccarelli.

Analysis and interpretation of data: Kowey, Reiffel, Ellenbogen, Naccarelli, Pratt.

Drafting of the manuscript: Kowey, Reiffel, Ellenbogen, Naccarelli, Pratt.

Critical revision of the manuscript for important intellectual content: Kowey, Reiffel, Ellenbogen, Naccarelli, Pratt.

Statistical analysis: Reiffel.

Obtained funding: Reiffel, Pratt.

Administrative, technical, or material support: Kowey, Reiffel, Ellenbogen, Pratt.

Study supervision: Kowey, Reiffel, Ellenbogen, Naccarelli, Pratt.

Financial Disclosures: Dr Kowey reports serving as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Blue Ash Pharmaceuticals, Gilead, HUYA Biosciences, sanofi-aventis, Solvay, AstraZeneca, Johnson & Johnson, Merck, Astellas, Pfizer, Sequel, Medtronic, Boston Scientific, St Jude Medical, GlaxoSmithKline, Boehringer Ingelheim, and Otsuka; serving on the speakers bureau of sanofi-aventis; holding stock in Cardionet; and receiving honoraria from GlaxoSmithKline. Dr Reiffel reports receiving a research grant from GlaxoSmithKline; receiving honoraria from sanofi-aventis, Gilead, GlaxoSmithKline, and sanofi-aventis; expects receiving honoraria from and Boehringer Ingelheim; and serving as a consultant for or on the advisory boards of Gilead and GlaxoSmithKline. Dr Ellenbogen reports receiving research grants from Boston Scientific Corp, Biosense Webster, Medtronic Inc, St Jude Medical, and Sanofi Aventis; serving on the speakers bureau of Boston Scientific, St Jude Medical, Biotronik, and Medtronic Inc; expects receiving honoraria from Boehringer Ingelheim; receiving honoraria from Boston Scientific Corp, St Jude Medical, Biosense Webster, and sanofi-aventis; serving as a consultant to or on the advisory boards of Boston Scientific Corp, Biosense Webster, Medtronic Inc, sanofi-aventis, St Jude Medical, Cardionet, Modest, Atritech, EBR, Biotronik, Sorin Biomedical, and GlaxoSmithKline. Dr Naccarelli reports receiving research support from GlaxoSmithKline, Boston Scientific Corp, sanofi-aventis, Boehringer Ingelheim, and GlaxoSmithKline; serving as a consultant for or on the advisory boards of Astellas, GlaxoSmithKline, Medtronic, Boston Scientific Corp, Pfizer, Xention, sanofi-aventis, Gilead, Novartis, Portola, AstraZeneca, Bristol-Myers Squibb, Merck, Biosense-Webster, Ortho-McNeil-Janssen, Blue Ash Pharmaceuticals, St Jude's Medical, and Daiichi-Sankyo. Dr Pratt reports serving as a consultant for or on the advisory boards of Merck, Modest; sanofi-aventis, and GlaxoSmithKline.

Study Design and Publication Committee: Drs Kowey, Reiffel, Ellenbogen, Naccarelli, and Pratt.

A list of the investigators is available here.

Funding/Support: Funding for this study was provided by GlaxoSmithKline.

Role of the Sponsor: The sponsor, Reliant Pharmaceuticals (acquired by GlaxoSmithKline in 2007), designed this clinical trial in collaboration with Drs Kowey, Reiffel, Ellenbogen, Naccarelli, and Pratt. The sponsor conducted the statistical analysis, reviewed the manuscript, and provided minor comments. Editorial support, in the form of development, assembling tables and figures, collating author comments, copyediting, fact checking, and referencing, was performed by Cactus Communications Inc, coordinated by Donald Samulack, PhD, United States, and Elvira D’souza, India, and funded by GlaxoSmithKline.

Independent Statistical Analysis: Todd MacKenzie, PhD, associate professor of biostatistics, Dartmouth Medical School, received the analytic data and the raw data, conducted an independent analysis of the data, and verified the results of the efficacy end points, vital statistics, and adverse events. Dr MacKenzie also processed the data to obtain another version of the primary end point, defined as time to recurrence of atrial fibrillation or flutter, and also recommended inclusion of an analysis in which participants were not censored at the time of use of antiarrhythmic agents. Dr MacKenzie verified that the results presented herein were provided by him. This independent statistical analysis was funded by GlaxoSmithKline.

Additional Contributions: We thank the following employees of GlaxoSmithKline for their assistance with study management and critical review of the manuscript: Rose Snipes, MD, Susan Johnson, MD, Grace Pagano, MS, Rosemary Schroyer, MS, Mayadah Shabbout, MS, Debby Mattioli, RN, BSN, Amy Meadowcroft, PharmD, and Doug Wicks, MPH, CMPP, all of whom are employees of GlaxoSmithKline. We also thank Mss Schroyer and Shabbout for providing statistical analysis.

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PubMed   |  Link to Article
Podrid PJ. Proarrhythmia, a serious complication of antiarrhythmic drugs.  Curr Cardiol Rep. 1999;1(4):289-296
PubMed   |  Link to Article
Fuster V, Rydén LE, Cannom DS,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society.  ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.  Circulation. 2006;114(7):e257-e354
PubMed   |  Link to Article
Reiffel JA, McDonald A. Antiarrhythmic effects of omega-3 fatty acids.  Am J Cardiol. 2006;98(4A):50i-60i
PubMed   |  Link to Article
Xiao YF, Sigg DC, Leaf A. The antiarrhythmic effect of n-3 polyunsaturated fatty acids: modulation of cardiac ion channels as a potential mechanism.  J Membr Biol. 2005;206(2):141-154
PubMed   |  Link to Article
Saravanan P, Bridgewater B, West AL, O’Neill SC, Calder PC, Davidson NC. Omega-3 fatty acid supplementation does not reduce risk of atrial fibrillation after coronary artery bypass surgery: a randomized, double-blind, placebo-controlled clinical trial.  Circ Arrhythm Electrophysiol. 2010;3(1):46-53
PubMed   |  Link to Article
Calò L, Bianconi L, Colivicchi F,  et al.  N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial.  J Am Coll Cardiol. 2005;45(10):1723-1728
PubMed   |  Link to Article
Nodari S, Triggiani M, Foresti A,  et al.  Use of N-3 polyunsaturated fatty acids to maintain sinus rhythm after conversion from persistent atrial fibrillation: a prospective randomized study.  J Am Coll Cardiol. 2010;55(10A):e14
Sandesara C, Chung MK, Van Wagoner DR,  et al.  Fish oil to inhibit supraventricular arrhythmias after cardiac surgery: the FISH trial. Paper presented at: the Heart Rhythm Society meeting; May 12-15, 2010; Denver, CO
GISSI-Prevenzione Investigators.  Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico.  Lancet. 1999;354(9177):447-455
PubMed   |  Link to Article
Tavazzi L, Maggioni AP, Marchioli R,  et al; Gissi-HF Investigators.  Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.  Lancet. 2008;372(9645):1223-1230
PubMed   |  Link to Article
Bays HE. Safety considerations with omega-3 fatty acid therapy.  Am J Cardiol. 2007;99(6A):35C-43C
PubMed   |  Link to Article
Pratt CM, Reiffel JA, Ellenbogen KA, Naccarelli GV, Kowey PR. Efficacy and safety of prescription omega-3-acid ethyl esters for the prevention of recurrent symptomatic atrial fibrillation: a prospective study.  Am Heart J. 2009;158(2):163-169
PubMed   |  Link to Article
Muhammad KI, Morledge T, Sachar R, Wolski K, Bhatt DL. Treatment with omega-3 fatty acids reduces serum C-reactive protein levels: results from a randomized, double-blinded, placebo-controlled trial. Paper presented at: the American College of Cardiology meeting; March 29-31, 2009; Orlando, FL. Abstract 1021-79
Marchioli R, Barzi F, Bomba E,  et al; GISSI-Prevenzione Investigators.  Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione.  Circulation. 2002;105(16):1897-1903
PubMed   |  Link to Article
Ninio DM, Murphy KJ, Howe PR, Saint DA. Dietary fish oil protects against stretch-induced vulnerability to atrial fibrillation in a rabbit model.  J Cardiovasc Electrophysiol. 2005;16(11):1189-1194
PubMed   |  Link to Article
Sarrazin JF, Comeau G, Daleau P,  et al.  Reduced incidence of vagally induced atrial fibrillation and expression levels of connexins by n-3 polyunsaturated fatty acids in dogs.  J Am Coll Cardiol. 2007;50(15):1505-1512
PubMed   |  Link to Article
Mavrakis HE, Kanoupakis EM, Kallergis EM,  et al.  Evaluation of the omega-3 fatty acids acute electrophysiological effects in human atrial myocardium.  Heart Rhythm. 2007;4:S184
Kumar S, Sutherland F, Rosso R,  et al.  Chronic fish oil ingestion in humans prevents atrial electrical remodeling and reduces susceptibility to atrial fibrillation.  Heart Rhythm. 2010;7:S108-S109
Link to Article
Biscione F, Totteri A, De Vita A, Lo Bianco F, Altamura G. Effect of omega-3 fatty acids on the prevention of atrial arrhythmias [in Italian].  Ital Heart J Suppl. 2005;6(1):53-59
PubMed
Nodari S, Manerba A, Madureri N,  et al.  Effects of polyunsaturated fatty acids n-3 (PUFA n-3) in the prophylaxis of atrial fibrillation relapses after external electric cardioversion P5161.  Eur Heart J. 2006;(abstract suppl)  887
Heidarsdottir R, Arnar DO, Skuladottir GV,  et al.  Does treatment with n-3 polyunsaturated fatty acids prevent atrial fibrillation after open heart surgery?  Europace. 2010;12(3):356-363
PubMed   |  Link to Article
Heidt MC, Vician M, Stracke SK,  et al.  Beneficial effects of intravenously administered N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a prospective randomized study.  Thorac Cardiovasc Surg. 2009;57(5):276-280
PubMed   |  Link to Article
Berry JD, Prineas RJ, van Horn L,  et al.  Dietary fish intake and incident atrial fibrillation (from the Women's Health Initiative).  Am J Cardiol. 2010;105(6):844-848
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Study Flowchart
Graphic Jump Location

Forty-seven participants' randomization stratum was changed after randomization, based on a review of the participants' past medical history: 39 from paroxysmal to persistent and 8 from persistent to paroxysmal atrial fibrillation. Efficacy analyses were based on the revised classification and are reflected in the modified intention-to-treat efficacy population. ECG indicates electrocardiography.

Place holder to copy figure label and caption
Figure 2. First Recurrence of Symptomatic Atrial Fibrillation for the Paroxysmal Stratum
Graphic Jump Location

Analysis is based on a Cox proportional hazards model adjusting for treatment, region, and use of angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and statin.

Place holder to copy figure label and caption
Figure 3. Analyses of Primary End Point in Paroxysmal Atrial Fibrillation Subgroup
Graphic Jump Location

Analyses were performed using a Cox proportional hazards model fitting separate model for each subgroup. ACEI, indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CI, confidence interval; and HR, hazard ratio.

Tables

Table Graphic Jump LocationTable 1. Summary of Mean Randomized Baseline and Demographic Characteristics
Table Graphic Jump LocationTable 2. Summary of Primary and Secondary Efficacy Results for the Paroxysmal Stratum
Table Graphic Jump LocationTable 3. Summary of Secondary Efficacy Results for the Persistent and Combined Strata
Table Graphic Jump LocationTable 4. Drug-Related Treatment-Emergent Adverse Events Reported by 2 or More Participants in Either Treatment Group (Safety Population)

References

Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: treatment considerations for a dual epidemic.  Circulation. 2009;119(18):2516-2525
PubMed   |  Link to Article
Friberg J, Buch P, Scharling H, Gadsbphioll N, Jensen GB. Rising rates of hospital admissions for atrial fibrillation.  Epidemiology. 2003;14(6):666-672
PubMed   |  Link to Article
Singh SN, Patrick J, Patrick J. Antiarrhythmic drugs.  Curr Treat Options Cardiovasc Med. 2004;6(5):357-364
PubMed   |  Link to Article
Podrid PJ. Proarrhythmia, a serious complication of antiarrhythmic drugs.  Curr Cardiol Rep. 1999;1(4):289-296
PubMed   |  Link to Article
Fuster V, Rydén LE, Cannom DS,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society.  ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.  Circulation. 2006;114(7):e257-e354
PubMed   |  Link to Article
Reiffel JA, McDonald A. Antiarrhythmic effects of omega-3 fatty acids.  Am J Cardiol. 2006;98(4A):50i-60i
PubMed   |  Link to Article
Xiao YF, Sigg DC, Leaf A. The antiarrhythmic effect of n-3 polyunsaturated fatty acids: modulation of cardiac ion channels as a potential mechanism.  J Membr Biol. 2005;206(2):141-154
PubMed   |  Link to Article
Saravanan P, Bridgewater B, West AL, O’Neill SC, Calder PC, Davidson NC. Omega-3 fatty acid supplementation does not reduce risk of atrial fibrillation after coronary artery bypass surgery: a randomized, double-blind, placebo-controlled clinical trial.  Circ Arrhythm Electrophysiol. 2010;3(1):46-53
PubMed   |  Link to Article
Calò L, Bianconi L, Colivicchi F,  et al.  N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial.  J Am Coll Cardiol. 2005;45(10):1723-1728
PubMed   |  Link to Article
Nodari S, Triggiani M, Foresti A,  et al.  Use of N-3 polyunsaturated fatty acids to maintain sinus rhythm after conversion from persistent atrial fibrillation: a prospective randomized study.  J Am Coll Cardiol. 2010;55(10A):e14
Sandesara C, Chung MK, Van Wagoner DR,  et al.  Fish oil to inhibit supraventricular arrhythmias after cardiac surgery: the FISH trial. Paper presented at: the Heart Rhythm Society meeting; May 12-15, 2010; Denver, CO
GISSI-Prevenzione Investigators.  Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico.  Lancet. 1999;354(9177):447-455
PubMed   |  Link to Article
Tavazzi L, Maggioni AP, Marchioli R,  et al; Gissi-HF Investigators.  Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.  Lancet. 2008;372(9645):1223-1230
PubMed   |  Link to Article
Bays HE. Safety considerations with omega-3 fatty acid therapy.  Am J Cardiol. 2007;99(6A):35C-43C
PubMed   |  Link to Article
Pratt CM, Reiffel JA, Ellenbogen KA, Naccarelli GV, Kowey PR. Efficacy and safety of prescription omega-3-acid ethyl esters for the prevention of recurrent symptomatic atrial fibrillation: a prospective study.  Am Heart J. 2009;158(2):163-169
PubMed   |  Link to Article
Muhammad KI, Morledge T, Sachar R, Wolski K, Bhatt DL. Treatment with omega-3 fatty acids reduces serum C-reactive protein levels: results from a randomized, double-blinded, placebo-controlled trial. Paper presented at: the American College of Cardiology meeting; March 29-31, 2009; Orlando, FL. Abstract 1021-79
Marchioli R, Barzi F, Bomba E,  et al; GISSI-Prevenzione Investigators.  Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione.  Circulation. 2002;105(16):1897-1903
PubMed   |  Link to Article
Ninio DM, Murphy KJ, Howe PR, Saint DA. Dietary fish oil protects against stretch-induced vulnerability to atrial fibrillation in a rabbit model.  J Cardiovasc Electrophysiol. 2005;16(11):1189-1194
PubMed   |  Link to Article
Sarrazin JF, Comeau G, Daleau P,  et al.  Reduced incidence of vagally induced atrial fibrillation and expression levels of connexins by n-3 polyunsaturated fatty acids in dogs.  J Am Coll Cardiol. 2007;50(15):1505-1512
PubMed   |  Link to Article
Mavrakis HE, Kanoupakis EM, Kallergis EM,  et al.  Evaluation of the omega-3 fatty acids acute electrophysiological effects in human atrial myocardium.  Heart Rhythm. 2007;4:S184
Kumar S, Sutherland F, Rosso R,  et al.  Chronic fish oil ingestion in humans prevents atrial electrical remodeling and reduces susceptibility to atrial fibrillation.  Heart Rhythm. 2010;7:S108-S109
Link to Article
Biscione F, Totteri A, De Vita A, Lo Bianco F, Altamura G. Effect of omega-3 fatty acids on the prevention of atrial arrhythmias [in Italian].  Ital Heart J Suppl. 2005;6(1):53-59
PubMed
Nodari S, Manerba A, Madureri N,  et al.  Effects of polyunsaturated fatty acids n-3 (PUFA n-3) in the prophylaxis of atrial fibrillation relapses after external electric cardioversion P5161.  Eur Heart J. 2006;(abstract suppl)  887
Heidarsdottir R, Arnar DO, Skuladottir GV,  et al.  Does treatment with n-3 polyunsaturated fatty acids prevent atrial fibrillation after open heart surgery?  Europace. 2010;12(3):356-363
PubMed   |  Link to Article
Heidt MC, Vician M, Stracke SK,  et al.  Beneficial effects of intravenously administered N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a prospective randomized study.  Thorac Cardiovasc Surg. 2009;57(5):276-280
PubMed   |  Link to Article
Berry JD, Prineas RJ, van Horn L,  et al.  Dietary fish intake and incident atrial fibrillation (from the Women's Health Initiative).  Am J Cardiol. 2010;105(6):844-848
PubMed   |  Link to Article

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