Introduction
The last few years have seen a resurgence in the interest of omega-3 fatty acid (n-3 FA) in cardiovascular disease (CVD) prevention after the significant cardioprotective benefits observed in the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT).¹ Several previous trials showed no significant cardiovascular benefit of low dose n-3 FA supplements (~1g daily) consisting of a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).^2-5 Unlike these studies, REDUCE-IT evaluated a much higher dose of purified EPA, icosapent ethyl, at 4g daily among a group of high-risk patients. However, data from the recently published Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) and OMega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trials demonstrate that clinical efficacy does not simply depend on the use of a higher dose of n-3 FA.^6,7 Below, we discuss key insights provided by the STRENGTH and OMEMI trials within the landscape of n-3 FA therapies.

Overview of New Studies
The STRENGTH trial randomized 13,078 individuals to either 4g daily of omega-3 carboxylic acid (EPA plus DHA) or a corn oil placebo. Major inclusion criteria were established atherosclerotic cardiovascular disease (ASCVD), age ≥40 years with diabetes mellitus plus at least one additional risk factor, or other high-risk primary prevention patients ≥50 years of age for men and ≥60 years of age for women. Moreover, included participants were required to have elevated triglyceride (180-500mg/dL), low high-density lipoprotein cholesterol (HLD-C: <42mg/dL for men or <47mg/dL for women) and had to be on optimal statin therapy with a low-density lipoprotein cholesterol (LDL-C) <100mg/dL. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization or unstable angina requiring hospitalization. Over a median follow-up period of approximately 3.4 years, there was no significant difference in the primary endpoint between the treatment and placebo arms (12.0% vs. 12.2%; HR 0.99, 95% CI 0.90-1.09, p=0.84). There was a significant increase in new-onset atrial fibrillation among individuals on n-3 FA treatment, though overall event rates were low (2.2% vs. 1.3%; HR 1.69, 95% CI 126-2.21). Of note, the trial was stopped early due to a low probability of demonstrating clinical benefit.

The OMEMI trial assessed the efficacy of 1.8g daily of n-3 PUFA (930mg EPA and 660mg DHA) compared with a corn oil placebo among older adults (mean age 75 years) after acute MI. Of note, all participants were from Norway, where baseline plasma EPA concentrations in the population are overall higher compared to those in North America.⁸ The study randomized 1,027 patients who had an acute MI within 2-8 weeks with a primary composite endpoint of non-fatal MI, stroke, unscheduled revascularization, all-cause death or heart failure hospitalization. Within a follow-up period of 2 years, there was no significant difference between the n-3 FA treatment group compared with the placebo control (21.4% vs. 20.0%; HR 1.08, 95% CI 0.82-1.41, p=0.06). There was a numerically higher rate of new onset atrial fibrillation in the treatment group compared with controls (7.2% vs. 4.0%; HR 1.84, 95% CI 0.98-3.45).

Putting It Together
The reasons for the contrasting results in CVD outcomes of REDUCE-IT compared with STRENGTH and OMEMI are likely multifactorial, which include patient selection, difference in endpoints, dosing, and choice of placebo. Though the inclusion criteria for REDUCE-IT and STRENGTH were similar, the former comprised a higher number of secondary patients (71% vs. 56%). It should be noted, however, that the United States subgroup of REDUCE-IT consisted of a more similar proportion of secondary and primary prevention patients compared with STRENGTH yet still showed significant reduction in ASCVD risk.⁹ Meanwhile, though the OMEMI trial was entirely composed of a high-risk group of older adults with recent MI, unlike REDUCE-IT, no lipid parameters were utilized in patient selection and the trial may be underpowered to show an impact. Moreover, heart failure (HF) hospitalization was added into the primary composite endpoint used in OMEMI, given increased focus on HF in the elderly.

With regard to dosing, there remains much to be learned about the diverse pleotropic effects of EPA and DHA. Present data suggest that these two types of n-3 FA have different biochemical properties. For instance, the molecular structure of EPA is thought to facilitate insertion into and assume stable orientation within lipoprotein particles and cell membranes where it exerts anti-oxidative effects. Unlike EPA, DHA is thought to undergo rapid conformation change, thus associating with different membrane structure and function. It has been speculated that perhaps the dose of EPA studied in the STRENGTH and OMEMI trials were simply not high enough.¹⁰ The dosages used in STRENGTH was chosen based on prior trials of Epanova in the setting of hypertriglyceridemia. However, there was still a significant increase in plasma EPA achieved in STRENGTH and OMEMI, though with a completely neutral impact on CVD risk reduction. Future studies are warranted to investigate whether there is a potential threshold effect for achieved plasma EPA level that is necessary for cardiovascular protection. There has been some concern that DHA supplementation may elevate LDL-C levels. However, present data on the effect of DHA on LDL-C have been inconsistent and thus significant impact of CVD outcomes of DHA mediated by LDL-C is less likely.¹¹

The difference in placebo used is perhaps the most contentious. Whereas control groups from both STRENGTH and OMEMI were treated with corn oil, those in REDUCE-IT were given a mineral oil placebo. There has been concern that mineral oil may interfere with statin absorption, given the increase in lipids and substantial increase in C-reactive protein noted in the control arm of REDUCE-IT. Critics have argued that the use of mineral oil may have exaggerated the effects on ASCVD risk reduction demonstrated in the REDUCE-IT trial. It should be noted that the United States Food and Drug Administration has approved icosapent ethyl for ASCVD risk reduction after exploratory analysis found that the effects of mineral oil cannot fully account for the observed differences in outcomes in REDUCE-IT.¹² Moreover, results from the Japan EPA Lipid Intervention Study (JELIS) also showed significant reduction in major coronary events in the treatment group (1.8g daily of EPA with statin) compared with control (statin alone) among Japanese patients with hypercholesterolemia.¹³ Though JELIS has also faced critiques, including the PROBE design and lower intensity statins used and high baseline cholesterol levels, it provides additional evidence from a large clinical trial showing the efficacy of high dose EPA in ASCVD risk reduction.

Clinical Implications
While the STRENGTH and OMEMI trials yielded neutral results, these studies offer important lessons on the use of n-3 FA based therapies. 

1. The efficacy of high-dose EPA only prescriptions for ASCVD risk reduction should not be extrapolated to agents with mixtures of EPA plus DHA. Prior to the results from these studies, clinicians may be tempted to substitute icosapent ethyl with EPA plus DHA prescriptions given cost consideration as the mixture formulation is currently generic. However, based on current evidence, EPA plus DHA mixtures may not provide significant ASCVD risk reduction. 
2. There appears to be a signal for new-onset atrial fibrillation associated with high doses of n-3 FA treatment. This was observed in STRENGTH and OMEMI as well as REDUCE-IT. No increased incident of stroke was observed in these trials. Given the present data, clinicians should take into account the increased, albeit relatively small, risk for new onset atrial fibrillation when prescribing any high-dose n-3 FA formulations.
3. More studies are warranted to explore why the results were so different between REDUCE-IT with STRENGTH and OMEMI, especially in the context of EPA levels achieved and placebo used. The ongoing RESPECT-EPA trial will hopefully offer further perspective on the efficacy of high-dose n-3 FA therapies in CVD prevention.¹⁴

References

1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
2. Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-18.
3. Kromhout D, Giltay EJ, Geleijnse JM, Alpha Omega Trial G. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010;363:2015-26.
4. Bowman L, Mafham M, Wallendszus K, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-50.
5. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2019;380:23-32.
6. 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.
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 2020;143:528-39.
8. Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Prog Lipid Res 2016;63:132-52.
9. Bhatt DL, Miller M, Brinton EA, et al. REDUCE-IT USA: results from the 3146 patients randomized in the United States. Circulation 2020;141:367-75.
10. Mozaffarian D, Wu JHY. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 2011;58:2047-67.
11. Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation 2019;140:e673-e691.
12. Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document (fda.gov website). 2019. Available at: https://www.fda.gov/media/132479/download. Accessed 01/29/2021.
13. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-98.
14. UMIN-CTR Clinical Trial. Randomized trial for evaluation in secondary prevention efficacy of combination therapy — statin and eicosapentaenoic acid. Identifier UMIN000012069. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014051.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Diet

Keywords: AHA Annual Scientific Sessions, AHA20, Primary Prevention, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Eicosapentaenoic Acid, Docosahexaenoic Acids, Cardiovascular Diseases, C-Reactive Protein, Cholesterol, HDL, Fatty Acids, Omega-3, Triglycerides, Hypercholesterolemia, Control Groups, Patient Selection, United States Food and Drug Administration, Molecular Structure, Carboxylic Acids, Atrial Fibrillation, Follow-Up Studies, Risk Factors, Hypertriglyceridemia, Dietary Supplements, Myocardial Infarction, Angina, Unstable, Stroke, Heart Failure, Treatment Outcome, Risk Reduction Behavior, Hospitalization, Cell Membrane, Prescriptions, Plasma, Diabetes Mellitus

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