Treatment of residual cardiovascular risk for patients with prior atherosclerotic cardiovascular disease (ASCVD) or those with high risk of developing ASCVD has remained a challenge in the statin era. Those with elevated triglycerides (TGs) represent a particularly high-risk population that continues to pose a clinical challenge. Traditionally, the group of patients with TGs ranging between 150-500 mg/dL had been treated mostly with lifestyle changes (i.e. weight loss, changes in diet, exercise, reduction in alcohol intake) along with statin therapy and this was also recommended in the 2018 ACC/AHA Guideline on Management of Blood Cholesterol. Medications (i.e. fibrates, niacin) were mostly reserved for those with TG ≥ 500mg/dL and were largely intended to reduce TG level to prevent complications like pancreatitis, having no success in reducing this residual adverse cardiovascular outcomes, despite improvements in TG levels. Fish oils, i.e. omega-3 fatty acids (FA), which are traditionally composed of both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are thought to have anti-inflammatory properties. Disappointingly, however, previous trials of FAs had also resulted in conflicting results with respect to modifying cardiovascular risk, likely due to differences in patient population, fish oil formulations, dosages, inconsistent baseline statin use and variable follow-up time in prior studies. Prior randomized studies and meta-analyses of FA are summarized in Table 1.

Table 1: Summary of Important Cardiovascular Outcome Trials of Omega-3 or EPA Supplementation

	Type of Trial	Drug and Patient Population	Outcome	Notes
Trials of EPA and DHA
GISSI-P1	RCT, n=11,324, f/u 3.5 years	omega-3 ethyl esters 850mg/day in patients with recent myocardial infarction (MI)	significant reduction in primary endpoint (death, nonfatal MI and nonfatal stroke) in patients treated with omega-3 FA	Only 5% statin use
GISSI-HF2	RCT, n=6975, f/u 3.9 years	omega-3 FA in patients with chronic heart failure (HF)	significant reduction in primary endpoints of all-cause mortality and HF hospitalization in patients taking omega-3 ethyl ester	Only 22% statin use
Aung et al.3	Meta-analysis	Included large trials with >500 pts, >1- year fu, used omega-3 FA, assessed full study population and prespecified subgroups.	No difference in risk of fatal coronary heart disease, nonfatal MI, stroke, major vascular events, and all-cause mortality, major vascular events
Abdelhamid et al.4	Meta-analysis	79 trials lasting least 12 months and compared supplementation and/or advice to increase long chain omega-3 FA or alpha linolenic acid intake versus usual or lower intake	Little or no effect of increasing long chain omega-3 FA on all-cause mortality, CV mortality, CV events, stroke or arrhythmia
ASCEND5	RCT, n=15,480, f/u 7.4 years	Omega-3 FA 840 mg/day or an olive oil placebo in patients with diabetes mellitus (DM) but without known ASCVD	No significant difference was noted in rates of major vascular events (nonfatal MI, stroke, transient ischemic attack, vascular death), all-cause mortality	75% statin use
VITAL6	RCT, n=25,871, f/u 5.3 years	Omega-3 FA 840 mg/day of omega–3 fatty acids with and without vitamin D3 supplementation in 25,871 healthy patients for primary prevention of cardiovascular events without a triglyceride cut-off for enrollment
STRENGTH7	RCT, n=13,086, median f/u 3 years	Epanova® 4g daily (omega-3 carboxylic acids) in statin-treated patients with low HDL and elevated ASCVD risk, TG 180-<500 mg/dL)	Time to first event of cardiovascular death, MI, stroke, coronary revascularization or hospitalization for unstable angina	Stopped 1/2020 by Data and Safety Monitoring Board (DSMB) for low likelihood of demonstrating benefit.
OMEGA8	RCT, n=3851, f/u 1 year	Omega-3 acid ethyl ester 90 (1 gram/day for 1 year) in post-MI patients	No significant difference in rate of sudden cardiac death	Event rate was low
ORIGIN9	RCT, n=12,536, f/u 6/2 years	Omega-3 FA ethyl ester >900 mg/day in high risk ASCVD patients with impaired glucose tolerance of DM	No significant difference in cardiovascular death
ALPHA_OMEGA-310	RCT, n=4837	Randomized to one of four trial margarines: EPA/DHA (400 mg), ALA (2 gr), EPA/DHA and ALAL or placebo in patients 60-80 year who had a prior MI.	No reduction in MACE (fatal and nonfatal cardiovascular events and cardiac interventions)
Trials of EPA Alone
REDUCE-IT11 (first event)	RCT, n=8,179, f/u 4.9 years	2 grams BID of icosapent ethyl or mineral oil placebo in patients with established ASCVD or DM + risk factors	Significantly reduced composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina with 25% RRR; increased hospitalization for atrial fibrillation/flutter	100% background statin use; Fasting TG 135-499 mg/dL; LDL-C 41-100 mg/dL; median follow-up 4.9 years.  Icosapent ethyl decreased TGs by 18.3% (vs. increase of 2.2% in placebo) and increased LDL-C by 3.1% (vs. 10.2% in placebo) at 1 year.
JELIS13	RCT, n=18,645	Efficacy of EPA in addition in patients with hypercholesterolemia (Total Chol³250 mg/dL)	Significant reduction in primary composite endpoint of MACE and in unstable angina	16% diabetics, 20% with known CAD, 19% smokers.  Mean TC 275 mg/dL, Mean LDL-C 182 mg/dL

More recently, the REDUCE-IT¹¹ trial, demonstrated an impressive 25% relative risk reduction in major cardiovascular events with icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, which also lowers triglyceride levels. This intervention reduced risk of ischemic events, including first, subsequent and total events.¹² The risk reduction, however, was independent of baseline or achieved triglyceride level and resulted in an number needed to treat (NNT) of only 6 patients for 5 years to reduce one event, making a compelling case for this therapy in selected patients with increased risk. Further pre-specified analyses of the REDUCE-IT trial looking only at the U.S cohort (REDUCE-IT USA)¹⁴ also demonstrated a more robust risk reduction across multiple endpoints, including all-cause mortality (which was not statistically significant in the parent trial). With respect to safety events, there was a trend towards more serious adverse bleeding (2.7% vs. 2.1%, p=0.06) and a statistically significant increase in rates of atrial fibrillation/flutter (5.3% vs. 3.9%) with the use of icosapent ethyl. Based on these data, the Food and Drug Administration approved icosapent ethyl in December 2019 for the indication of cardiovascular risk reduction in patients with elevated triglyceride levels and either established cardiovascular disease or diabetes with two or more additional risk factors (i.e. secondary prevention or high-risk primary prevention).¹⁵ The role of icosapent ethyl in primary prevention patients with 0-1 risk factors is not yet established and the findings of REDUCE-IT cannot be extrapolated to other prescription and non-prescription omega-3 supplements.

On the tail of the benefit demonstrated in REDUCE-IT, the STRENGTH trial, which was a large scale cardiovascular outcomes trial of Epanova^® (composed of a mixture of EPA and DHA rather than purified EPA) in patients with elevated TGs, was discontinued for futility, based on DSMB recommendations. The whirlwind of information from omega-3 FA trials in 2019 (i.e. ASCEND and VITAL), from REDUCE-IT and now from the FDA approval may have left the clinicians who are treating complex patients with elevated triglycerides confused about how to approach these individuals. Here, we present a simplified approach to cardiovascular risk reduction for the clinician, which includes non-pharmacologic and pharmacologic approaches. In high-risk primary prevention and secondary prevention patients, we also advocate addressing LDL-C first and then turning attention to triglycerides as a secondary target (Figure 1).

Figure 1

References

1. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999;354:447-55.
2. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1223-30.
3. 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.
4. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev 2018;7:CD003177.
5. ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-50.
6. 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.
7. Update on Phase III STRENGTH trial for Epanova^® in mixed dyslipidaemia. (AstraZeneca website). 2020. Available at: https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html Accessed February 15, 2020.
8. Rauch B, Schiele R, Schneider S, et al. Omega, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern gyuidelines-adjusted therapy after myocardial infarction. Circulation 2010;122:2152-59.
9. 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.
10. Kromhout D, Giltay EJ, Geleijnse JM; Alpha Omega Trial Group. N-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010;363:2015-26.
11. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
12. Bhatt DL, Steg PG, Miller M, et al. Effects of icosapent ethyl on total ischemic events from REDUCE-IT. J Am Coll Cardiol 2019;73:2791-2802.
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;369:1090-8.
14. Bhatt DL, Miller M, Brinton EA, et al. REDUCE-IT USA. Circulation 2020;141:367–75.
15. FDA approves use of drug to reduce risk of cardiovascular events in certain adult patient groups. (FDA website). 2019. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-use-drug-reduce-risk-cardiovascular-events-certain-adult-patient-groups. Accessed January 5, 2020.

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

Keywords: Primary Prevention, Secondary Prevention, Eicosapentaenoic Acid, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ischemic Attack, Transient, Cardiovascular Diseases, Fibric Acids, Docosahexaenoic Acids, Cholesterol, LDL, Triglycerides, Hypercholesterolemia, Risk Factors, Fish Oils, Glucose Intolerance, Cholecalciferol, Weight Loss, United States Food and Drug Administration, Atrial Fibrillation, Medical Futility, Hypertriglyceridemia, Cholesterol, Drug Combinations, Angina, Unstable, Myocardial Infarction, Stroke, Heart Failure, Coronary Disease, Diabetes Mellitus, Death, Sudden, Cardiac, Risk Reduction Behavior, Hospitalization, Anti-Inflammatory Agents, Life Style, Cohort Studies, Longitudinal Studies

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