Omega-3 Fatty Acids not effective in prevention of post-operative atrial fibrillation [OPERA trial] {In the Media}

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Our {In the Media} series targets publications with high media coverage with the aim of giving a more in-depth review and background. 

Key study points:

1. 30.7% of participants in the placebo-controlled group and 30.3% of participants in the omega-3 fatty acid supplemented intervention group developed atrial fibrillation (AF) post-operatively. There was no difference in rates of post-operative AF when comparing the two groups (p=0.74)

2.  In the treatment group, pre-operative supplementation achieved 40% increases in plasma n-3-PUFA concentrations by the morning of cardiac surgery.

3. There was no evidence of increased risk of bleeding or major adverse events with n-3-PUFA use compared to control.

Primer: Omega-3 Fatty Acids, particularly the n-3 polyunsaturated fatty acid (n-3 PUFA) subset found in seafood, has long been though to positively affect cardiovascular health. A myriad of possible pathways have been proposed for this effect, from alterations of cell membrane properties via interactions with channels and proteins in the phospholipid bilayer to regulation of gene expression through binding transcription factors. Indeed, numerous prospective observation studies and randomized controlled trials have confirmed this in the clinical setting, with findings that suggest consumption of omega-3 containing fish or fish oil can effectively reduce coronary heart disease (CHD) mortality, including risk of myocardial infarction and sudden cardiac death. Similarly, cohort studies have found that rates of fish consumption are inversely associated with incidence of atrial fibrillation, with high intake lowering atrial fibrillation (AF) risk by over 30%. However, unlike the affirmative conclusions found in CHD studies, randomized controlled trials (RCTs) investigating the efficacy of omega-3 fatty acids in prevention of AF have shown largely mixed results and recently published meta-analyses have failed to find a significant preventative or protective effect for n-3 PUFA.  Given the significant heterogeneity among the published RCTs and the small sample sizes used in these studies, few definitive conclusions can be drawn. Therefore, the authors of this study sought to design a large-scale, multinational, multi-center study to better address this ongoing question and more clearly define the clinical role of n-3 PUFA supplementation in AF risk reduction.
Background reading:

1. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events [J Am Coll Cardiol]

2. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials [Heart]

This [double-blind, placebo-controlled, randomized] clinical trial: This study investigated the use of perioperative n-3-PUFA in the reduction of post-operative AF occurrence. ~1500 participants with normal sinus rhythm were randomized to receive 10g of n-3-PUFA or 10 g of control (olive oil) over 3-5 days (or 8 g over 2 days) before cardiac surgery. This was followed by 2 g/day until hospital discharge or postoperative day 10. Participants were followed using electrocardiogram for the development of AF of at least 30 seconds duration during the post-operative period. The authors studied several secondary endpoints including occurrence of sustained AF (>1 hr), symptomatic AF or AF that required treatment, time to first postoperative AF, number of postoperative AF episodes, as well as adverse effects, including bleeding, arterial thromboembolism, and 30-day mortality. Data analysis revealed several key findings:

1. 30.7% of participants in the placebo group and 30.3% of participants in the n-3 PUFA group developed post operative AF, demonstrating no difference in AF risk between the two groups (p=0.74).
2. Plasma n-3-PUFA concentrations increased by approximately 40% between time of enrollment and morning of the cardiac surgery in the treatment group, compared to no change in serum n-3-PUFA over this time period in the control group (p<0.001),
3. Incidence of arterial thromboembolism was lower in the n-3 PUFA group (p=0.047).
4. Compared to subjects in the placebo group, those who received n-3-PUFA supplementation required fewer packed red blood cell transfusions (p=0.002).
5. Overall risk of serious adverse events was similar between the two groups.

In sum: This study is the largest, most widely representative and well-powered randomized, placebo-controlled clinical trial to date investigating the efficacy of omega-3 fatty acids in the prevention of post-operative atrial fibrillation. Its findings indicate that there is no evidence to support any benefit for the use of n-3-PUFA in this context. (Though the results did indicate reduced risk of arterial thromboembolism in the treatment group, the authors attribute these findings to chance given the relatively small number of events recorded.) However, as the authors note, omega-3 supplementation also pose few risks, with no major adverse side effects and no increased risk of hemorrhage. Indeed, those in the treatment group required fewer blood transfusions with packed red blood cells, further supporting the absence of bleeding risk.

This study faces several limitations. First, the follow-up period was limited to discharge date or 10 days post-op; thus few conclusions can be drawn regarding the long-term efficacy of omega-3 supplementation in preventing AF, though the authors were primarily concerned with prevention in the early post-operative period when AF can pose the greatest danger to the patient. Second, it remains unclear at what minimum dose n-3-PUFA begin to exert their cardioprotective effect, thus there is a possibility that the patients in the treatment group were not adequately dosed to prevent AF occurrence. Most importantly, this trial focuses only on prevention of postoperative AF. Thus, few conclusions can be drawn regarding the use of omega-3 fatty acids in reducing AF risk in other settings.

This final issue was addressed in the FORWARD trial, a sister study which recently presented its conclusions at the 2012 American Heart Association meeting. This trial found that one year of daily 3-n-PUFA supplementation in patients with prior paroxysmal AF or recent cardioversion for persistent AF did not reduce risk of recurrence or improve all-cause mortality or hospitalization. Together, OPERA and FORWARD suggest that omega-3 fatty acids are not effective in the prevention of post-operative AF or recurrent AF.

Click to read the study in [JAMA]

By [MK]

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