Written by Joyce Smith, BS. This study, which found a significant increase in atrial fibrillation in participants who consumed omega-3 carboxylic acid (CA), does not support the use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high risk patients.
According to observational studies, consuming fatty fish or supplementing with omega-3 fatty acids reduce the risk of cardiovascular events 1,2. Serum levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reveal a similar inverse association with cardiovascular risk 3,4. Earlier randomized trials have found that low doses of omega-3 fatty acids were not effective in elevating EPA or DHA levels; however, more recent trials utilizing higher doses did produce cardiovascular benefits. For example, the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) trial of 8,179 statin-treated high cardiovascular risk patients found that a daily dose of 4 grams /day of icosapent ethyl (a pure form of EPA), when compared to a mineral oil placebo, significantly reduced cardiovascular events (17.2 vs 22) 5. In this study, the use of mineral oil actually raised LDL cholesterol and markers of inflammation (C-reactive protein increased by more than 30%) 6, suggesting that its potential functioning as an active substance may have enhanced the apparent benefit of icosapent ethyl 7.
Omega-3CA is a carboxylic acid formulation of EPA and DHA. It offers greater bioavailability than standard omega-3 ethyl ester formulations while increasing DHA levels and reducing plasma triglycerides; thus it was chosen for the following trial 8. This study’s objective was to determine whether supplementation with omega-3 fatty acids and carboxyl acid plus the usual care protocal would improve cardiovascular outcomes in statin-treated patients who had high cardiovascular risk, high triglycerides, and low HDL cholesterol levels. Researchers enrolled 13,078 high cardiovascular risk patients from 675 academic and community hospitals across six continents. Participants were randomized and double-blinded to receive 4 g daily of omega-3 CA or corn oil (placebo), along with usual care therapies, including statin therapy. The primary endpoint included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary artery revascularization and hospitalization for unstable angina.
After a median of 42 months, 1,384 patients had experienced a primary endpoint event. The independent data monitoring committee recommended discontinuing the trial based on insufficient evidence of clinical benefit and a statistically significant increase in atrial fibrillation in the omega-3 CA group compared with the corn oil placebo group (2.2% vs. 1.3%; P < 0.001). At this point, 12.0% (785) patients treated with omega-3 CA had experienced a primary endpoint event compared to 12.2% (795) patients receiving corn oil (P = 0.84. While different doses and proportions of EPA and DNA were not evaluated, elevated concentrations of both were achieved; yet there was no evidence of a benefit in spite of a 268% increase in plasma EPA levels in the omega-3 CA intervention group.
This omega-3 CA formulation did not protect against major adverse cardiovascular events in statin-treated patients at high cardiovascular risk. Why did the Omega-3CA not perform as well as the EPA in the REDUCE-IT trial? Dr. Steven Nissen, the study’s senior author, suggested that the corn oil, when compared to the mineral oil used in the REDUCE-IT trial, was a neutral placebo in that it did not raise LDL cholesterol levels or markers of inflammation. Perhaps the benefits of pure EPA in icosapent ethyl can be offset by DHA, thus making the DHA/EPA used in the STRENGTH and OMEMI studies no more effective than the placebo. DHA and EPA also differ in their effects on inflammatory biomarkers, lipid oxidation rates and endothelial function. Bhatt, lead REDUCE-IT author suggests that pure EPA may work better than a DHA/EPA combo because the effects of fatty acids can vary by dose and formulation. Of note, a presentation of the STRENGTH and OMEMI trials at the virtual meeting of the American Heart Association in 2020 raised questions concerning the safety of omega-3 fatty acid supplements and called for a second trial testing the safety and benefits of icosapent ethyl (used in the REDUCE-IT trial, but this time against a neutral biologically inert placebo such as corn oil. Clinicians should be aware that the omega-3 fatty acids in the REDUCE-IT, STRENGTH and OMEMI trials all demonstrated higher rates of atrial fibrillation in high risk cardiovascular patients.
A study limitation was the inability to extrapolate results to a lower risk primary prevention population.
Source: Nicholls, Stephen J., A. Michael Lincoff, Michelle Garcia, Dianna Bash, Christie M. Ballantyne, Philip J. Barter, Michael H. Davidson et al. “Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial.” JAMA 324, no. 22 (2020): 2268-2280.
© 2020 American Medical Association. All rights reserved.
Posted January 12, 2021.
Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.
References:
- Del Gobbo LC, Imamura F, Aslibekyan S, et al. ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies. JAMA Intern Med. 2016;176(8):1155-1166.
- Jayedi A, Shab-Bidar S. Fish Consumption and the Risk of Chronic Disease: An Umbrella Review of Meta-Analyses of Prospective Cohort Studies. Advances in nutrition (Bethesda, Md). 2020;11(5):1123-1133.
- Mozaffarian D, Lemaitre RN, King IB, et al. Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann Intern Med. 2013;158(7):515-525.
- Virtanen JK, Laukkanen JA, Mursu J, Voutilainen S, Tuomainen TP. Serum long-chain n-3 polyunsaturated fatty acids, mercury, and risk of sudden cardiac death in men: a prospective population-based study. PLoS One. 2012;7(7):e41046.
- Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England journal of medicine. 2019;380(1):11-22.
- FDA. FDA briefing document: Endocrinologic and Metabolic Drugs Advisory Committee meeting. 2019.
- Bhatt D. Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial – REDUCE-IT. Paper presented at: American Heart Association Annual Scientific Sessions 2018; Chicago, IL.
- Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. Jama. 2020;324(22):2268-2280.
