No Antiarrhythmic Protection With Fish Oil, New Meta-Analysis Shows

From Heartwire — a professional news service of WebMD

January 6, 2009 — Fish-oil supplementation is associated with a significant reduction in death from cardiac causes but has no significant effect on arrhythmias, a new meta-analysis has shown [1].

The analysis, driven primarily by the results of two large clinical trials, showed that fish oil was associated with a 20% reduction in the risk of cardiac death, report investigators. There were trends toward a reduction in the risk of appropriate implantable cardioverter defibrillator (ICD) interventions and a reduction in the risk of sudden cardiac death, but the results failed to achieve statistical significance.

"In light of currently available evidence, the role of fish oil in reducing arrhythmic events in people at risk still remains to be elucidated," write Dr Hernando León (University of Alberta, Edmonton) and colleagues in a report published online December 23, 2008, in BMJ.

In an editorial accompanying the study [2], Drs Eric Brunner (University College London, UK) and Hiroyasu Iso (Osaka University Graduate School of Medicine, Japan) note that the review does not provide answers to questions about the benefit of using fish oil in the secondary prevention of mortality and arrhythmias because little new high-quality evidence is available.

"The review highlights the neglect of an important area of research into nutrient health, and hopefully it will lead to increased investment in research to solve the uncertainty," they write. "Such research is needed not only because of the millions of people with heart disease worldwide, but also because the world's marine fauna is being pushed toward extinction largely for commercial gain, but partly in the name of public health."

Meta-Analysis Includes the JELIS Study

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione study was the first to suggest potential antiarrhythmic properties of fish oil when investigators randomized 11,324 patients to a mixture of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and showed significant reductions in all-cause and cardiovascular mortality, primarily driven by a reduction in sudden cardiac death.

In their meta-analysis, the investigators included 12 studies, including GISSI-Prevenzione and the Japan EPA Lipid Intervention Study (JELIS) studies, which accounted for 92% of the patients, where the primary outcomes of interest were antiarrhythmic end points of appropriate ICD intervention and sudden cardiac death.

In three studies evaluating the benefits of fish oil on ICD firing, there was a nonsignificant 10% reduction in appropriate interventions with treatment. In addition, in six studies with sudden cardiac death as an end point, there was only a trend toward a reduction in risk with fish oil. There was, however, a significant reduction in the risk of death from cardiac causes with fish oil. Again, only a trend toward a reduction in all-cause mortality was observed with the intervention.

Effect of Fish Oil on Arrhythmic Events and Mortality

End point	Patients, n	Odds ratio (95% CI)
Appropriate ICD intervention	1148	0.90 (0.55 - 1.46)
Sudden cardiac death	31,111	0.81 (0.52 - 1.25)
All-cause mortality	32,439	0.92 (0.82 - 1.03)
Death from cardiac causes	32,519	0.80 (0.69 - 0.92)
Sudden cardiac death in subjects with coronary artery disease	15,528	0.74 (0.59 - 0.92)
Death from cardiac causes in subjects with coronary artery disease	16,390	0.80 (0.69 - 0.93)

A subgroup analysis looking at patients with established coronary artery disease showed that fish oil reduced the risk of sudden cardiac death and death from cardiac causes when compared with placebo.

The meta-analysis included a variety of fish-oil products with various formulations, but the researchers did not observe a dose-response relationship between the dose of EPA or DHA and the effect on deaths from cardiac causes. "Therefore, an ideal formulation for fish-oil supplementation cannot be determined with the currently available evidence," according to León and colleagues. They suggest, however, it is reasonable to use a daily formulation similar to that used in the GISSI-Prevenzione trial, which was 465 mg EPA and 386 mg DHA.

In their editorial, Brunner and Iso note that the JELIS study showed a 20% reduction in the risk of nonfatal coronary outcomes, primarily driven by reductions in unstable angina, but fish oil had no effect on fatal outcomes.

"This evidence challenges the proposition, supported by the dramatic reduction in deaths from cardiac disease in a subgroup analysis of GISSI, that the effect of fish oil is mainly the result of electrical stabilization of the myocardium," they write.

The conflicting findings of GISSI and JELIS, however, might be explained by differences in DHA and EPA used in the trials, as well as the low rate of fatal coronary disease in Japan. JELIS, despite enrolling more than 18,000 patients, might have been underpowered to detect the effect of EPA on fatal end points, they note.

Both the editorialists and León and colleagues point out that more data are coming soon with the presentation and publication of the OMEGA trial. That trial includes approximately 4000 acute-myocardial infarction (MI) patients treated with highly purified omega-3 fatty-acid ethyl esters. The primary end point is the rate of sudden cardiac death within one year after acute MI, and secondary end points include total mortality, nonfatal cardiovascular events, and various rhythm abnormalities assessed by Holter monitoring.

Dr. León is a recipient of a research fellowship from the Alberta Heritage Foundation for Medical Research. Coauthor Ross T Tsuyuki is supported by the University of AlbertaMerck Frosst chair in patient health management. The other study authors have disclosed no relevant financial relationships.

Sources

1. León H, Shibata MC, Dorgan M, et al. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 2008;DOI:10.1136/bmj.a2931. Available at: http://www.bmj.com/cgi/content/full/337/dec23_2/a2931
2. Brunner E, Iso H. Fish oil and secondary prevention of cardiovascular disease. BMJ. 2008;DOI:10.1136/bmj.a2931. Available at: http://www.bmj.com

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