The benefits of PUFA have been debated since observational studies in the 1980s suggested a link between regular consumption of fish and lower risk of coronary disease. The majority of trials analyzing the effects of marine-derived PUFA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) for the prevention of major cardiovascular events (MACE) has been neutral. The few exceptions have been criticized for having an open-label design and having patient populations that are not on contemporary treatments for dyslipidemia.¹ The recent publication of several randomized controlled trials has renewed the interest in the use of PUFA.

REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) was a large double-blind, randomized controlled trial that sought to determine the effects of high doses of icosapent ethyl on a composite of cardiovascular outcomes in patients with hypertriglyceridemia and either established coronary disease or high risk for coronary disease who are already on statins. REDUCE-IT was unique in that it used icosapent ethyl, an ester of pure EPA, that achieved higher levels of serum EPA compared with traditional EPA/DHA formulations. After a median of 4.9 years, the investigators found a significant reduction in the number of MACE with the use of icosapent ethyl (17.2% vs. 22%; p < 0.001).²

REDUCE-IT was followed by a second study that purported to show benefits of icosapent ethyl on coronary atherosclerosis called the EVAPORATE (Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy) trial. This trial randomized 80 statin-treated patients to either icosapent ethyl or placebo and tracked changes in low-attenuation plaque (LAP) as measured by multidetector computed tomography at 9 and 18 months. The patients treated with icosapent ethyl had a reduction in LAP by 17% compared to an increase in LAP by 109% in those taking the placebo (p = 0.0061).³

REDUCE-IT and the EVAPORATE trial seemed to finally achieve a breakthrough in the longstanding debate about the use of PUFA to prevent MACE. However, both these trials quickly came under intense scrutiny. Criticisms of REDUCE-IT largely centered on whether mineral oil was an inert placebo. Critics pointed toward an increase from baseline in C-reactive protein, low-density lipoprotein, apolipoprotein B, and non-high-density lipoprotein cholesterol in the placebo arm.⁴ The EVAPORATE trial also came under scrutiny for changes in LAP burden that seemed biologically implausible.⁵ A meta-analysis of trials of other anti-lipid agents that evaluated plaque burden using intravascular ultrasound found the range of change to be ˗5.6% to +3.1% over similar time periods.⁶ Furthermore, plaque burden was strikingly lower in the placebo arm at baseline compared with the icosapent ethyl arm (0.8 mm³ vs. 1.9 mm³), suggesting that the change in LAP was merely regression to the mean.^3,5

These studies were followed by a prominent, neutral trial, STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia). This double-blind, randomized controlled trial investigated the effect of PUFA on MACE. It did not show any benefit and was stopped early due to lack of efficacy. There are key differences between STRENGTH and REDUCE-IT. STRENGTH used a carboxylic acid formulation of PUFA that contained both EPA and DHA. This specific formulation was chosen because of its higher bioavailability, eliminating the need to take it with a high-fat meal, which was a frequent criticism of earlier trials. Additionally, STRENGTH used corn oil as its placebo, which the authors considered an inert comparator.⁵

The OMEMI (Omega-3 Fatty Acids in Elderly with Myocardial Infarction) trial evaluated the use of PUFA after a myocardial infarction in patients aged 70-82 and did not find any statistically significant benefit for prevention of MACE. Of note, the OMEMI trial used a combined EPA and DHA formulation with a combination of fatty acids as the placebo.⁷

Other than differences in the placebos, additional explanations for the discordant results among these trials have been proposed. Some have suggested that difference is due to the significantly higher levels of serum EPA with supplementation of the highly potent icosapent ethyl compared to carboxylic acid formulations. Alternatively, the co-administration of DHA may be causing harm. Lastly, the differences may be specifically related to effects of ethyl ester independent of EPA levels.^5,8

Nissen et al. recently published a secondary analysis of STRENGTH that sought to address whether high EPA levels or co-administration with DHA explained the differences in outcomes. Patients in the highest tertile of EPA levels did not show any significant benefit from PUFA despite achieving similar levels to those found in REDUCE-IT (151 ug/mL vs. 144 ug/mL).⁹ Similarly, the patients in the highest tertile of DHA levels did not show any harm. This study suggests that differences in EPA levels and co-administration of DHA are not the primary reasons for the differences in outcomes. Further investigation is still warranted to determine whether ethyl ester has benefits over carboxylic acid independent of levels of PUFA.

Determining the true effects of PUFA on cardiovascular health is of critical importance because these trials suggest that PUFA may not be a benign intervention. REDUCE-IT, STRENGTH, and the OMEMI trial all saw statistically significant increases in the rate of atrial fibrillation. There was also a trend toward increased serious adverse bleeding events in REDUCE-IT; however, this was not seen in either STRENGTH or the OMEMI trial.^3,5,7

Despite the potential link between PUFA and improved cardiovascular health discovered more than 40 years ago, there remains significant debate about whether supplementation with PUFA improves cardiovascular outcomes. Despite the overwhelming majority of trials not showing any significant benefit, REDUCE-IT, which used a unique formulation, provided new interest in this long-studied topic. However, subsequent analyses of this trial along with neutral competing trials have dampened the enthusiasm. Given that there appears to be some harm with supplementation of PUFA, providers should exercise caution and implement shared decision-making with patients prior to prescribing PUFA for primary or secondary prevention of MACE until further trials have more clearly settled the debate.

References

1. Aung T, Halsey J, Kromhout D, et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol 2018;3:225-34.
2. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2019;380:11-22.
3. Budoff MJ, Bhatt DL, Kinninger A, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J 2020;41:3925-32.
4. Nissen SE, Lincoff AM, Nicholls SJ. Omega-3 Fatty Acids Effect on Major Cardiovascular Events in Patients at High Cardiovascular Risk-Reply. JAMA 2021;325:1334-5.
5. 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;324:2268-80.
6. Bhindi R, Guan M, Zhao Y, Humphries KH, Mancini GBJ. Coronary atheroma regression and adverse cardiac events: A systematic review and meta-regression analysis. Atherosclerosis 2019;284:194-201.
7. Kalstad AA, Myhre PL, Laake K, et al. Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial. Circulation 2021;143:528-39.
8. Olshansky B, Bhatt DL, Chung MK. Omega-3 Fatty Acids Effect on Major Cardiovascular Events in Patients at High Cardiovascular Risk. JAMA 2021;325:1332-3.
9. Nissen SE, Lincoff AM, Wolski K, et al. Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk: A Secondary Analysis of the STRENGTH Trial. JAMA Cardiol 2021;May 16:[Epub ahead of print].

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Imaging, Computed Tomography, Echocardiography/Ultrasound, Nuclear Imaging, Diet, Acute Coronary Syndromes, Stable Ischemic Heart Disease

Keywords: Hydroxymethylglutaryl-CoA Reductase Inhibitors, Eicosapentaenoic Acid, Docosahexaenoic Acids, C-Reactive Protein, Corn Oil, Mineral Oil, Secondary Prevention, Coronary Artery Disease, Lipoproteins, LDL, Fatty Acids, Omega-3, Double-Blind Method, Atrial Fibrillation, Multidetector Computed Tomography, Biological Availability, Cardiovascular Diseases, Esters, Carboxylic Acids, Decision Making, Risk Factors, Hypertriglyceridemia, Dyslipidemias, Myocardial Infarction, Triglycerides, Ultrasonography, Interventional, Apolipoproteins, Dietary Supplements

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