CardioNerds Tommy Das (Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic), Rick Ferraro (cardiology fellow at the Johns Hopkins Hospital), and Dr. Aliza Hussain (cardiology fellow at Baylor College Medicine) take a deep dive on the REDUCE-IT trial with Dr. Peter Toth, director of preventive cardiology at the CGH medical center in Sterling, Illinois, clinical professor in family and community medicine at the University of Illinois School of Medicine, and past president of the National Lipid Association and the American Board of Clinical Lipidology.  Special introduction to CardioNerds Clinical Trialist Dr. Jeff Wang (Emory University). Audio editing by CardioNerds academy intern, Shivani Reddy.

This episode is part of the CardioNerds Lipids Series which is a comprehensive series lead by co-chairs Dr. Rick Ferraro and Dr. Tommy Das and is developed in collaboration with the American Society For Preventive Cardiology (ASPC).

Relevant disclosures: None

Pearls • Notes • References • Guest Profiles • Production Team

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The Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) trial was a large randomized controlled trial that showed a significant reduction in atherosclerotic cardiovascular disease (ASCVD) events with use of icosapent ethyl ester in secondary prevention patients and high risk primary prevention patients with diabetes and residual elevated triglycerides between 135 to 499 mg/dL on top of maximally tolerated statin therapy1.

1. Despite the use of high intensity statin therapy, considerable residual risk for future atherosclerotic cardiovascular disease exists in patients with ASCVD.
2. Elevated triglycerides (TGs) are an important marker of increased residual ASCVD risk2.
3. There are two primary types of Omega-3 fish oils: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omege-3 fish oils have been shown to lower triglyceride levels.
4. Low-dose combination EPA and DHA has not exhibited incremental cardiovascular benefit in either primary prevention and secondary prevention patients on top of statin therapy3-5.
5. REDUCE-IT showed the use of high dose EPA in patients with either ASCVD or DM and one additional risk factor, and relatively well-controlled LDL-C levels on maximally tolerated statin therapy and residual hypertriglyceridemia (TG 135-499 mg/dL) results in significant reductions in cardiovascular events over a median follow-up period of 4.9 years1.

• Multiple epidemiologic and Mendelian randomization studies have established elevated triglyceride (TG) levels as an important risk factor for atherosclerotic cardiovascular events6-8. However previous clinical trials using TG-lowering medication such as niacin, fibrates and low dose omega-3 fish oil have not shown to reduce cardiovascular events when added to statin therapy in patients with or without ASCVD,9,10.
• The JELIS trial first demonstrated a significant reduction in cardiovascular events when 1.8g daily of eicosapentaenoic acid (EPA) was added to low-intensity statin therapy in patients with ASCVD and hypercholesterolemia, However, the trial was limited due to open label design without placebo, use of low doses of background statin therapy, and geographic/demographic limitations to participants in Japan11.
• In a large international multicenter randomized controlled trial, the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) randomized 8,179 patients with established atherosclerotic heart disease or diabetes and an additional risk factor, on maximally tolerated statin therapy, to 4 gm/day of icosapent ethyl (a highly purified and stable EPA ethyl ester) or mineral oil1. 
• Over a median follow up of 4.9 years, the use of icosapent ethyl ester was associated with significant reductions in major cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) compared to placebo, with an absolute risk reduction of 4.8% and NNT of 21.
• There were similar reductions in the key components of the primary endpoint, including a 20% relative risk reduction in cardiovascular death with icosapent ethyl.
• Median TG levels were reduced by 18% in the icosapent ethyl group and rose by 2.2% in the placebo group. LDL levels increased in both groups, although to a lesser degree in the icosapent ethyl group.
• There was a trend towards increased bleeding (2.7% with icosapent ethyl versus 2.1% with placebo, p=0.06) and a modest but significant increase in hospitalizations for atrial fibrillation or flutter with icosapent ethyl (3.1% versus 2.1%).
• Since the publication of REDUCE-IT, several clinical practice guidelines, including those of the American Diabetes Association (ADA), National Lipid Association (NLA) and the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS), have endorsed the use of icosapent ethyl in their recommendations to further reduce ASCVD risk in select patients.

1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi: 10.1056/NEJMoa1812792. https://www.nejm.org/doi/full/10.1056/nejmoa1812792
2. Libby P. Triglycerides on the rise: Should we swap seats on the seesaw? Eur Heart J. 2015;36(13):774-776. doi: 10.1093/eurheartj/ehu500.  https://academic.oup.com/eurheartj/article/36/13/774/475534
3. 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(9177):447-455. doi: S0140673699070725. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)07072-5/fulltext
4. Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, et al. N-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19):1800-1808. doi: 10.1056/NEJMoa1205409. https://www.nejm.org/doi/10.1056/NEJMoa1205409?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov
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(16):1540-1550. doi: 10.1056/NEJMoa1804989. https://www.nejm.org/doi/10.1056/NEJMoa1804989?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov
6. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, et al. Triglyceride-mediated pathways and coronary disease: Collaborative analysis of 101 studies. Lancet. 2010;375(9726):1634-1639. doi: 10.1016/S0140-6736(10)60545-4. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60545-4/fulltext
7. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45(11):1345-1352. doi: 10.1038/ng.2795. https://www.nature.com/articles/ng.2795
8. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 western prospective studies. Circulation. 2007;115(4):450-458. doi: CIRCULATIONAHA.106.637793. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.106.637793?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
9. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet. 2005;366(9500):1849-1861. doi: S0140-6736(05)67667-2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67667-2/fulltext
10. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563-1574. doi: 10.1056/NEJMoa1001282. https://www.nejm.org/doi/full/10.1056/nejmoa1001282
11. 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(9567):1090-1098. doi: S0140-6736(07)60527-3. https://www.thelancet.com/article/S0140-6736(07)60527-3/fulltext
12. 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. doi: 10.1001/jama.2020.22258. https://doi.org/10.1001/jama.2020.22258. .

Dr. Peter Toth is the Director of Preventive Cardiology at CGH Medical Center in Sterling, IL, and Professor of Clinical Family and Community Medicine at the University of Illinois College of Medicine in Peoria, and adjunct associate professor of medicine, Johns Hopkins University School of Medicine. He received his medical degree from Wayne State University School of Medicine in Detroit, MI, and PhD in Biochemistry from Michigan State University in East Lansing. He has written extensively on the topic of lipids and is Co-Editor of twenty textbooks in preventive cardiology, diabetes, hypertension, and lipidology. Additionally, Dr. Toth is the President of the American Society of Preventive Cardiology, past President of the National Lipid Association, as well as incoming chair of the American Heart Association’s Council on Lipoproteins, Lipid Metabolism, and Thrombosis.

Dr. Aliza Hussain is a cardiology fellow at Baylor College of Medicine. She completed a fellowship in prevention at Baylor College of Medicine Cardiovascular Research Institute, and internal medicine residency at UPCM.