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Editor's Note
January 03, 2017

The Unfulfilled Promise of ω-3 Fatty Acid Supplementation

JAMA Intern Med. Published online January 3, 2017. doi:10.1001/jamainternmed.2016.8236

In 1978, Dyerberg and colleagues introduced the novel concept that ω-3 fatty acids in fish may protect against atherosclerosis. Since then there has been fascination with the prospect that ω-3 fatty acids may prevent cardiovascular disease, and in the United States, fish oil supplements are a $1.2 billion–per–year business. The American Heart Association recommends that adults eat fish at least twice weekly, and that patients with coronary disease ingest 1 g per day of eicosapentanoic acid and docosahexanoic acid, the 2 principal ω-3 fatty acids found in fish.

A critical review of clinical trials on ω-3 fatty acid supplementation in patients with cardiovascular disease, however, tells a more complex story. Early trials, such as the GISSI-Prevenzione Study, found a 15% reduction in cardiovascular events with ω-3 fatty acid supplementation after myocardial infarction. The Japan Eicosapentanoic Acid Lipid Intervention Study (JELIS) revealed a 19% reduction in major coronary events in patients with hypercholesterolemia treated with eicosapentanoic acid plus a statin vs a statin alone. Both of these trials were open label and did not include placebo controls. In the randomized, double-blind GISSI Heart Failure Study, there was a 9% reduction in overall mortality in patients with heart failure receiving ω-3 fatty acid supplementation (P = .04).

More recent double-blind, secondary prevention trials, however, have not fulfilled the promise of the earlier work. The Alpha Omega trial, the Risk and Prevention Study Collaborative Group trial, the SU.FOL.OM3 trial, the OMEGA trial, and the ORIGIN trial all found no benefit of ω-3 fatty acid supplementation on cardiovascular end points. With a background of modern cardiovascular preventive therapy, perhaps ω-3 fatty acids have nothing more to offer. A recent meta-analysis of 14 randomized, double-blind trials, including more than 20 000 patients, concluded that there was no protection against overall cardiovascular events by ω-3 fatty acids in patients with preexisting cardiovascular disease (relative risk, 0.99; 95% CI, 0.89-1.09).1

Further doubt is raised by the FAVOURED study in this issue of JAMA Internal Medicine.2 Patients with de novo arteriovenous fistulas for hemodialysis vascular access were randomized to receive 4 g of fish oil per day or placebo for 12 weeks, and after 12 months there was no difference in the graft failure rates (due to thrombosis or maturation failure) between the 2 groups. The arteriovenous fistula, as a direct surgical anastomosis between artery and vein, is a model vascular system, and the lack of benefit of a relatively high dose of fish oil in preventing thrombosis or preserving patency provides negative data in this specific form of vascular pathobiologic disease.

Based on the preponderance of evidence, there is reason for skepticism that ω-3 fatty acid supplementation is effective in the secondary prevention of cardiovascular disease. As for primary prevention, the ongoing VITAL trial (Vitamin D and Omega-3 Trial), due to be completed in 2017, will be pivotal. Until then, the best advice is to continue 2 to 3 times weekly consumption of fish and focus on other lifestyle changes, such as regular physical activity, optimal nutrition and body weight, and smoking cessation.3

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Article Information

Conflict of Interest Disclosures: None reported.

References
1.
Kwak  SM, Myung  S-K, Lee  YJ, Seo  HG; Korean Meta-analysis Study Group.  Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694.
PubMedArticle
2.
Irish  AB, Viecelli  AK, Hawley  CM,  et al; Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) Study Collaborative Group.  Effect of fish oil supplementation and aspirin use on arteriovenous fistula failure in patients requiring hemodialysis: a randomized clinical trial [published online January 3, 2017]. JAMA Intern Med. doi:10.1001/jamainternmed.2016.8029.
3.
Khera  AV, Emdin  CA, Drake  I,  et al.  Genetic risk, adherence to a healthy lifestyle, and coronary disease [published online November 13, 2016]. N Engl J Med. doi:10.1056/NEJMoa1605086.
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