Author + information
- Dariush Mozaffarian, MD, DrPH†,‡,§∥,⁎ (, )
- Jason H.Y. Wu, PhD§,
- Marcia C. de Oliveira Otto, PhD§,
- Chirag M. Sandesara, MD¶,
- Robert G. Metcalf, MD#,
- Roberto Latini, MD⁎⁎,
- Peter Libby, MD†,
- Federico Lombardi, MD††,
- Patrick T. O'Gara, MD†,
- Richard L. Page, MD‡‡,
- Maria G. Silletta, MS§§,
- Luigi Tavazzi, MD∥∥ and
- Roberto Marchioli, MD§§
- ↵⁎Brigham and Women's Hospital, Harvard Medical School, Department of Medicine, Division of Cardiovascular Medicine, 665 Huntington Avenue, Building 2-319, Boston, Massachusetts 02115
To the Editor:
Post-operative atrial fibrillation (PoAF) is among the most common complications of cardiac surgery and substantially increases morbidity and healthcare costs. Despite decades of surgical, anesthetic, and medical advances, rates of PoAF remain largely unchanged. Experiments and animal models suggest that perioperative fish oil (omega-3 fatty acids) may reduce PoAF (1). We recently reported in a large, multinational randomized trial that perioperative fish oil did not reduce PoAF (2). Yet several other trials have evaluated this question, with mixed results. Most of these trials were small, and some were open label (i.e., neither double blind nor placebo controlled).
To compile all peer-reviewed evidence and evaluate reasons for potential heterogeneity, we conducted a meta-analysis, following Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines, of randomized trials of fish oil for preventing PoAF. We searched MEDLINE from earliest available indexing through October 2012, without language restrictions. Search terms were (“fatty acids, omega-3”[MeSH] or “eicosapentaenoic acid”[MeSH/tiab] or “docosahexaenoic acids”[MeSH/tiab] or “fish oils”[MeSH] or “omega-3”[tiab] or “n-3”[tiab] or “long chain n-3”[tiab] or “fish oil”[tiab]) and (“atrial fibrillation”[MeSH/tiab]) and (“clinical trial”[MeSH/tiab] or “cardiac surgical procedures”[MeSH/tiab]). Additional studies were identified by hand searching citation lists and directly contacting experts. Studies were included if they were randomized trials of oral or intravenous fish oil administration that evaluated PoAF after cardiac surgery; trials with additional concomitant interventions, observational studies, and duplicate publications were excluded. Inclusion and exclusion decisions and data extraction were performed in duplicate by 2 investigators. Findings were pooled using inverse-variance−weighted meta-analysis (3). Fixed-effects models were pre-specified on the basis of large differences in sample sizes and results across studies, for which random-effects models could dramatically overweight small, imprecise studies. Pre-specified potential sources of heterogeneity included placebo control (yes or no) and type of surgery (valve surgery, yes or no).
Of 83 identified abstracts, 8 full-text articles were retrieved for review. Eight randomized trials met the inclusion criteria, including 2,687 subjects and 859 PoAF events (Fig. 1). Heterogeneity was evident (I2 = 52%, Q = 14.5, p for heterogeneity = 0.04), principally owing to extreme results in 2 small, open-label (no placebo) studies. The presence or absence of placebo control significantly modified the effect of fish oil on PoAF (p for interaction = 0.028): benefits were seen in open-label, but not placebo-controlled, trials. Also, a preponderance of small trials with risk estimates below the pooled estimate suggested potential publication bias toward small positive trials. Little heterogeneity was evident among placebo-controlled trials (I2 = 16%, Q = 5.9, p for heterogeneity = 0.31), which both individually and together demonstrated no significant effect (pooled odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.78 to 1.10). In sensitivity analyses, we removed each trial individually from the pooled meta-analysis. Finding were similar; for example, removing the large OPERA (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation) trial, the pooled OR in the remaining placebo-controlled trials was 0.86 (95% CI: 0.65 to 1.15; I2 = 28%, Q = 5.6). We note that only 2 open-label trials were identified, so generalizability of these findings to other research questions should not be assumed. Yet the variation in findings of small and especially open-label studies highlights the importance of large, adequately powered, placebo-controlled trials as well as appropriately performed meta-analyses such as the present study.
In the large OPERA trial, subgroup analyses suggested a potential benefit of fish oil treatment in patients undergoing valve surgery (p for interaction = 0.06) (2). We pooled these results with those from 4 other placebo-controlled trials that provided data stratified by type of cardiac surgery. In sum, data were available on 856 patients who underwent valve surgery and experienced 336 PoAF events and 1,249 patients not undergoing valve surgery who experienced 358 PoAF events. Pooling all data, the effects of fish oil on PoAF did not significantly differ according to valve surgery (p for interaction=0.94): the OR was 0.91 (95% CI: 0.76 to 1.09) in patients undergoing valve surgery and 1.00 (95% CI: 0.78 to 1.28) in patients not undergoing valve surgery. Dosing and duration of fish oil treatment were generally similar among trials, limiting the ability to explore heterogeneity by these factors.
We evaluated pooled evidence for safety, including numbers of patients with major bleeding, total mortality, and other reported serious adverse events. Fish oil was associated with less bleeding (n = 165 events, data reported in 5 trials: OR: 0.76; 95% CI: 0.60 to 0.96; I2 = 34.1, Q = 6.1, p for heterogeneity = 0.19), a nonsignificant trend toward lower mortality (n = 32 events, data reported in 6 trials: OR: 0.68; 95% CI: 0.32 to 1.41; I2 = 0%, Q = 1.98, p for heterogeneity = 0.58), and no difference in other reported serious adverse events (n = 528 events, data reported in 6 trials: OR: 1.0; 95% CI: 0.81 to 1.25; I2 = 0%, Q = 4.7, p for heterogeneity = 0.45) The unexpectedly lower bleeding risk could be due to chance. Conversely, this observation could plausibly relate to lower cardiopulmonary bypass–induced activation and loss of platelets and clotting factors (4); further investigation of potential mechanisms is required. At the least, the observed lower bleeding risk counters concerns that antiplatelet effects of fish oil might increase blood loss during cardiac surgery. Overall, the findings indicate that perioperative fish oil use was well tolerated and safe, suggesting little need for its discontinuation in patients who are taking fish oil before cardiac surgery.
In sum, our meta-analysis provides convincing evidence that short-term fish oil use does not appreciably reduce PoAF and indicates that heterogeneity in prior findings results from extreme results of small, open-label trials as well as potential publication bias. In addition, we found little evidence for differing efficacy according to type of cardiac surgery. There is also little evidence that intermediate-term (<1 year) fish oil use reduces recurrent arrhythmias in patients with established atrial fibrillation (5). Fish oil may still prove useful in other clinical contexts, such as long-term use (years) for preventing the initial onset of atrial fibrillation among ambulatory elderly adults with hypertension or other risk factors. Such primary, rather than secondary, prevention approaches must be tested in large, appropriately powered, placebo-controlled clinical trials.
Please note: This study was funded by grant RC2-HL101816 from the National Heart, Lung, and Blood Institute, National Institutes of Health. Dr. Mozaffarian has received research grants from GlaxoSmithKline, Sigma Tau, and Pronova Biopharma for an investigator-initiated, not-for-profit, randomized clinical trial of fish oil supplements for the prevention of post-surgical complications; ad hoc travel reimbursement and/or honoraria for one-time scientific presentations on diet and cardiometabolic diseases from the International Life Sciences Institute, Bunge, SPRIM, Pollock Institute, and Nutrition Impact; and ad hoc consulting fees from Foodminds and McKinsey Health Systems Institute. Dr. Mozaffarian is a member of the scientific advisory board for Unilever North America. Dr. Mozaffarian receives royalties from UpToDate for an online chapter on fish oil. Dr. Mozaffarian is listed as a co-inventor on a provisional patent application filed by Harvard University for the use of transpalmitoleic acid to prevent and treat insulin resistance, type 2 diabetes, and related conditions. Dr. Libby is an unpaid consultant or is involved in clinical trials for AstraZeneca, GlaxoSmithKline, Merck, Novartis, Pfizer, Pronova Biopharma, and Sigma Tau and is a member of the scientific advisory boards for Athera Biotechnologies, Carolus Therapeutics, Interleukin Genetics, and BIND Biosciences. Dr. Tavazzi is a consultant for Servier and a member of boards for Medtronic, St. Jude Medical, Vifor Pharma, Boston Scientific Corporation, Bristol-Myers Squibb, and Cardiorentis. Dr. Marchioli has received institutional grants for trials testing omega-3 polyunsaturated fatty acids from Sigma Tau, GlaxoSmithKline, SPA, Pronova Biopharma and honoraria for presentations from Pronova Biopharma, Ferrer, Sigma Tau, and SPA. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation