Impact of Expanded FDA Indication for Icosapent Ethyl On Enhanced Cardiovascular Residual Risk Reduction

References

• Benjamin EJ , MuntnerP, AlonsoAet al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation, 139(10), e56–e528 (2019).
   PubMed Web of Science ®Google Scholar
• World Health Organization . The top 10 causes of death. Geneva, Switzerland, 2018. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death.
   Google Scholar
• Mokdad AH , BallestrosK, EchkoMet al. The State of US Health, 1990–2016: Burden of diseases, injuries, and risk factors among US states. JAMA, 319(14), 1444–1472 (2018).
   PubMed Web of Science ®Google Scholar
• Roth GA , JohnsonC, AbajobirAet al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J. Am. Coll. Cardiol., 70(1), 1–25 (2017).
   PubMed Web of Science ®Google Scholar
• Heron M . Deaths: Leading causes for 2017. Natl Vital Stat. Rep., 68(6), 1-77 (2019).
   PubMedGoogle Scholar
• Toth PP , GranowitzC, HullM, LiassouD, AndersonA, PhilipS. High triglycerides are associated with increased cardiovascular events, medical costs, and resource utilization: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J. Am. Heart Assoc., 7(15), e008740 (2018).
   PubMed Web of Science ®Google Scholar
• Ganda OP , BhattDL, MasonRP, MillerM, BodenWE. Unmet need for adjunctive dyslipidemia therapy in hypertriglyderidemia management. J. Am. Coll. Cardiol., 72(3), 330–343 (2018).
   PubMed Web of Science ®Google Scholar
• Vascepa [package insert] Amarin Pharma Inc., Bridgewater, NJ (2019).
   Google Scholar
• Bhatt DL , StegG, MillerMet al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med., 380(1), 11–22 (2019).
   PubMed Web of Science ®Google Scholar
• Miller M , StoneNJ, BallantyneCet al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation, 123(20), 2292–2333 (2011).
   PubMed Web of Science ®Google Scholar
• Quispe R , HendraniAD, Baradaran-NoveiryBet al. Characterization of lipoprotein profiles in patients with hypertriglyceridemic Fredrickson-Levy and Lees dyslipidemia phenotypes: the Very Large Database of Lipids Studies 6 and 7. Arch. Med. Sci., 15(5), 1195–1202 (2019).
   PubMed Web of Science ®Google Scholar
• Rygiel K . Hypertriglyceridemia - common causes, prevention and treatment strategies. Curr. Cardiol. Rev., 14(1), 67–76 (2018).
   PubMedGoogle Scholar
• Dron JS , HegeleRA. Genetics of triglycerides and the risk of atherosclerosis. Curr. Atheroscler. Rep., 19(7), 31 (2017).
   PubMed Web of Science ®Google Scholar
• Sundaram M , CurtisKR, AmirAlipour Met al. The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation. J. Lipid Res., 58(11), 2188–2196 (2017).
   PubMed Web of Science ®Google Scholar
• Stitziel N , StirrupsK, MascaNet al. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N. Engl. J. Med., 374(12), 1134–1144 (2016).
   PubMed Web of Science ®Google Scholar
• Johansen CT , WangJ, LanktreeMBet al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat. Genet., 42(8), 684–687 (2010).
   PubMed Web of Science ®Google Scholar
• Chatterjee C , SparksDL. Hepatic lipase, high density lipoproteins, and hypertriglyceridemia. Am. J. Pathol., 178(4), 1429–1433 (2011).
   PubMed Web of Science ®Google Scholar
• Fan W , PhilipS, GranowitzC, TothP, WongN. Hypertriglyceridemia in statin-treated US adults: The National Health and Nutrition Examination Survey. J. Clin. Lipidol, 13, 100–108 (2019).
   PubMed Web of Science ®Google Scholar
• Palmer MK , TothPP. Trends in lipids, obesity, metabolic syndrome, and diabetes mellitus in the United States: an NHANES analysis (2003–2004 to 2013–2014). Obesity (Silver Spring, Md.), 27(2), 309–314 (2019).
   PubMed Web of Science ®Google Scholar
• Nordestgaard BG . Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ. Res., 118(4), 547–563 (2016).
   PubMed Web of Science ®Google Scholar
• Kushner PA , CobbleME. Hypertriglyceridemia: the importance of identifying patients at risk. Postgrad. Med., 128(8), 848–858 (2016).
   PubMed Web of Science ®Google Scholar
• Case BC , BressAP, KolmPet al. The economic burden of hypertriglyceridemia among US adults with diabetes or atherosclerotic cardiovascular disease on statin therapy. J. Clin. Lipidol., 13(5), 754–761 (2019).
   PubMed Web of Science ®Google Scholar
• Bansal S , BuringJE, RifaiN, MoraS, SacksFM, RidkerPM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA, 298(3), 309–316 (2007).
   PubMed Web of Science ®Google Scholar
• Nordestgaard BG , BennM, SchnohrP, Tybjaerg-HansenA. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA, 298(3), 299–308 (2007).
   PubMed Web of Science ®Google Scholar
• Toth PP , PhilipS, HullM, GranowitzC. Association of elevated triglycerides with increased cardiovascular risk and direct costs in statin-treated patients. Mayo Clin Proc., 94(9), 1670–1680 (2019).
   PubMed Web of Science ®Google Scholar
• Toth PP , FazioS, WongND, HullM, NicholsGA. Risk of cardiovascular events in patients with hypertriglyceridemia: a review of real-world evidence. Diabetes Obes. Metab., 22(3), 279–289 (2020).
   PubMed Web of Science ®Google Scholar
• Nichols GA , PhilipS, ReynoldsK, GranowitzCB, FazioS. Increased cardiovascular risk in hypertriglyceridemic patients with statin-controlled LDL cholesterol. J. Clin. Endocrinol. Metab., 103(8), 3019–3027 (2018).
   PubMed Web of Science ®Google Scholar
• Liu J , ZengFF, LiuZM, ZhangCX, LingWH, ChenYM. Effects of blood triglycerides on cardiovascular and all-cause mortality: a systematic review and meta-analysis of 61 prospective studies. Lipids Health Dis., 12, 159 (2013).
   PubMed Web of Science ®Google Scholar
• Jorgensen AB , Frikke-SchmidtR, WestAS, GrandeP, NordestgaardBG, Tybjaerg-HansenA. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur. Heart J., 34(24), 1826–1833 (2013).
   PubMed Web of Science ®Google Scholar
• Varbo A , BennM, Tybjaerg-HansenA, JorgensenAB, Frikke-SchmidtR, NordestgaardBG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J. Am. Coll. Cardiol., 61(4), 427–436 (2013).
   PubMed Web of Science ®Google Scholar
• Budoff M . Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. Am. J. Cardiol., 118(1), 138–145 (2016).
   PubMed Web of Science ®Google Scholar
• The AIM-HIGH Investigators , BodenWE, ProbstfieldJLet al.Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med., 365(24), 2255–2267 (2011).
   PubMed Web of Science ®Google Scholar
• The HPS2-THRIVE Collaborative Group . Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med., 371(3), 203–212 (2014).
   PubMed Web of Science ®Google Scholar
• Guyton JR , SleeAE, AndersonTet al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J. Am. Coll. Cardiol., 62(17), 1580–1584 (2013).
   PubMed Web of Science ®Google Scholar
• Rubins HB , RobinsSJ, CollinsDet al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N. Engl. J. Med., 341(6), 410–418 (1999).
   PubMed Web of Science ®Google Scholar
• The FIELD Study Investigators , KeechA, SimesRJet 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, 366(9500), 1849–1861 (2005).
   PubMed Web of Science ®Google Scholar
• BIP Study Group . Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation, 102(1), 21–27 (2000).
   PubMed Web of Science ®Google Scholar
• The ACCORD Study Group , GinsbergHN, ElamMBet al.Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med., 362(17), 1563–1574 (2010).
   PubMed Web of Science ®Google Scholar
• Jacobson TA , ZimmermanFH. Fibrates in combination with statins in the management of dyslipidemia. J. Clin. Hypertens. (Greenwich), 8(1), 35–41; quiz 42–33 (2006).
   PubMedGoogle Scholar
• Wiggins BS , SaseenJJ, PageRL2ndet al. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation, 134(21), e468–e495 (2016).
   PubMed Web of Science ®Google Scholar
• Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care, 43(Suppl. 1), S111–s134 (2020).
   PubMed Web of Science ®Google Scholar
• Gustavson LE , SchweitzerSM, BurtDAet al. Evaluation of the potential for pharmacokinetic interaction between fenofibrate and ezetimibe: A phase I, open-label, multiple-dose, three-period crossover study in healthy subjects. Clin. Ther., 28(3), 373–387 (2006).
   PubMed Web of Science ®Google Scholar
• Pradhan AD , PaynterNP, EverettBMet al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am. Heart J., 206, 80–93 (2018).
   PubMed Web of Science ®Google Scholar
• Skulas-Ray AC , WilsonPWF, HarrisWSet al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation, 140(12), e673–e691 (2019).
   PubMed Web of Science ®Google Scholar
• Jacobson TA , GlicksteinSB, RoweJD, SoniPN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J. Clin. Lipidol., 6(1), 5–18 (2012).
   PubMed Web of Science ®Google Scholar
• Nelson JR , TrueWS, LeV, MasonRP. Can pleiotropic effects of eicosapentaenoic acid (EPA) impact residual cardiovascular risk?Postgrad. Med., 129(8), 822–827 (2017).
   PubMed Web of Science ®Google Scholar
• Borow KM , NelsonJR, MasonRP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis, 242(1), 357–366 (2015).
   PubMed Web of Science ®Google Scholar
• Wang H , ChenJ, ZhaoL. N-3 polyunsaturated fatty acids for prevention of postoperative atrial fibrillation: updated meta-analysis and systematic review. J. Interv. Card. Electrophysiol., 51(2), 105–115 (2018).
   PubMed Web of Science ®Google Scholar
• Ramadeen A , ConnellyKA, Leong-PoiHet al. Docosahexaenoic acid, but not eicosapentaenoic acid, supplementation reduces vulnerability to atrial fibrillation. Circ. Arrhythm. Electrophysiol., 5(5), 978–983 (2012).
   PubMed Web of Science ®Google Scholar
• Mason RP . New insights into mechanisms of action for omega-3 fatty acids in atherothrombotic cardiovascular disease. Curr. Atheroscler. Rep., 21(2), (2019).
   Google Scholar
• Mason RP , LibbyP, BhattDL. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler. Thromb. Vasc. Biol., 40(5), 1135–1147 (2020).
   PubMed Web of Science ®Google Scholar
• Deckelbaum RJ , CalderPC. Editorial: Is it time to separate EPA from DHA when using omega-3 fatty acids to protect heart and brain?Curr. Opin. Clin. Nutr. Metab. Care, 23(2), 65–67 (2020).
   PubMed Web of Science ®Google Scholar
• Dyall SC . Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front. Aging Neurosci., 7, 52 (2015).
   PubMed Web of Science ®Google Scholar
• Zhao Z , WenH, FefelovaNet al. Docosahexaenoic acid reduces the incidence of early afterdepolarizations caused by oxidative stress in rabbit ventricular myocytes. Front. Physiol., 3, 252 (2012).
   PubMed Web of Science ®Google Scholar
• GISSI Prevenzione Investigators. 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, 354(9177), 447–455 (1999).
   PubMed Web of Science ®Google Scholar
• Rauch B , SchieleR, SchneiderSet al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation, 122(21), 2152–2159 (2010).
   PubMed Web of Science ®Google Scholar
• ORIGIN Trial Investigators . n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med., 367(4), 309–318 (2012).
   PubMed Web of Science ®Google Scholar
• Kromhout D , GiltayEJ, GeleijnseJM. n-3 Fatty acids and cardiovascular events after myocardial infarction. N. Engl. J. Med., 363(21), 2015–2026 (2010).
   PubMed Web of Science ®Google Scholar
• The Risk and Prevention Study Collaborative Group . n-3 Fatty acids in patients with multiple cardiovascular risk factors: the Risk and Prevention Study Collaborative Group. N. Engl. J. Med., 368, 1800–1808 (2013).
   PubMed Web of Science ®Google Scholar
• ASCEND Study Collaborative Group , BowmanL, MafhamMet al.Effects of n-3 fatty acid supplements in diabetes mellitus. N. Engl. J. Med., 379(16), 1540–1550 (2018).
   PubMed Web of Science ®Google Scholar
• Manson JE , CookNR, LeeIMet al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N. Engl. J. Med., 380(1), 23–32 (2019).
   PubMed Web of Science ®Google Scholar
• GISSI-HF Investigators . 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, 372(9645), 1223–1230 (2008).
   PubMed Web of Science ®Google Scholar
• Neumann FJ , Sousa-UvaM, AhlssonAet al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur. Heart J., 40(2), 87–165 (2019).
   PubMed Web of Science ®Google Scholar
• Rubenfire M . 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. American College of Cardiology, 2019. https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2019/03/07/16/00/2019-acc-aha-guideline-on-primary-prevention-gl-prevention.
   Google Scholar
• Rizos EC , NtzaniEE, BikaE, KostapanosMS, ElisafMS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA, 308(10), 1024–1033 (2012).
   PubMed Web of Science ®Google Scholar
• Siscovick DS , BarringerTA, FrettsAMet al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation, 135(15), e867–e884 (2017).
   PubMed Web of Science ®Google Scholar
• Nicholls SJ , LincoffAM, BashDet al. Assessment of omega-3 carboxylic acids in statin treated patients with high levels of triglycerides and low levels of high density lipoprotein cholesterol: Rationale and design of the STRENGTH trial. Clin. Cardiol., 41(10), 1281–1288 (2018).
   PubMed Web of Science ®Google Scholar
• Slachta A . AstraZeneca stops Epanova trial early due to disappointing results. Cardiovascular Business, 2020. https://www.cardiovascularbusiness.com/node/159661/printable/print.
   Google Scholar
• Update on Phase III STRENGTH trial for Epanova in mixed dyslipidaemia [press release]. AstraZeneca, 2020. https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html.
   Google Scholar
• Yokoyama M , OrigasaH, MatsuzakiMet al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded end point analysis. Lancet, 369(9567), 1090–1098 (2007).
   PubMed Web of Science ®Google Scholar
• Bhatt DL , StegPG, MillerMet al. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J. Am. Coll. Cardiol., 73(22), 2791–2802 (2019).
   PubMed Web of Science ®Google Scholar
• Bhatt DL , MillerM, BrintonEAet al. REDUCE-IT USA: results from the 3,146 patients randomized in the United States. Circulation., 141(5), 367–375 (2020).
   PubMed Web of Science ®Google Scholar
• Bhatt DL , StegPG, MillerMet al. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J. Am. Coll. Cardiol., 74(8), 1159–1161 (2019).
   PubMed Web of Science ®Google Scholar
• Bhatt DL , MillerM, StegGet al. EPA levels and cardiovascular outcomes in the reduction of cardiovascular events with icosapent ethyl-intervention trial [oral presentation]. Presented at: Annual Scientific Session of the American College of Cardiology, Chicago, IL, 2020 (virtual). https://www.tctmd.com/slide/epa-levels-and-cardiovascular-outcomes-reduction-cardiovascular-events-icosapent-ethyl.
   Google Scholar
• Cawood AL , DingR, NapperFLet al. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis, 212(1), 252–259 (2010).
   PubMed Web of Science ®Google Scholar
• Nelson JR , RaskinS. The eicosapentaenoic acid:arachidonic acid ratio and its clinical utility in cardiovascular disease. Postgrad. Med., 131(4), 268–277 (2019).
   PubMed Web of Science ®Google Scholar
• Hasegawa T , OtsukaK, IguchiTet al. Serum n-3 to n-6 polyunsaturated fatty acids ratio correlates with coronary plaque vulnerability: an optical coherence tomography study. Heart Vessels, 29(5), 596–602 (2014).
   PubMed Web of Science ®Google Scholar
• Bays HE , BallantyneCM, BraeckmanRA, StirtanWG, SoniPN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am. J. Cardiovasc. Drugs, 13(1), 37–46 (2013).
   PubMed Web of Science ®Google Scholar
• Arita M , OhiraT, SunYP, ElangovanS, ChiangN, SerhanCN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J. Immunol., 178(6), 3912–3917 (2007).
   PubMed Web of Science ®Google Scholar
• Oh SF , DonaM, FredmanG, KrishnamoorthyS, IrimiaD, SerhanCN. Resolvin E2 formation and impact in inflammation resolution. J. Immunol., 188(9), 4527–4534 (2012).
   PubMed Web of Science ®Google Scholar
• Budoff MJ . Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy - EVAPORATE. Presented at the American Heart Association Annual Scientific Sessions, Philadelphia, PA, November 18, 2019. https://www.acc.org/latest-in-cardiology/clinical-trials/2019/11/15/17/46/evaporate.
   Google Scholar
• Food and Drug Administration . FDA Briefing Document: Endocrinologic and Metabolic Drugs Advisory Committee Meeting. 2019. https://www.fda.gov/advisory-committees/november-14-2019-meeting-endocrinologic-and-metabolic-drugs-advisory-committee-meeting-announcement.
   Google Scholar
• Lakshmanan S , ShekarC, KinningerAet al. Comparison of mineral oil and non-mineral oil placebo on coronary plaque progression by coronary computed tomography angiography. Cardiovasc. Res., 116(3), 479–482 (2020).
   PubMed Web of Science ®Google Scholar
• Radel J , PenderD, ShahS. Effect of mineral oil on plasma lipida: a meta-analysis [abstract]. J. Am. Coll. Cardiol., 75(11 Suppl. 1), 1908 (2020).
   Web of Science ®Google Scholar
• Amarin Corporation . Amarin announced FDA Advisory Committee voted unanimously (16-0) to recommend approval of Vascepa® (icosapent ethyl) capsules label expansion to reduce cardiovascular risk based on landmark REDUCE-IT® outcomes trial [press release]. https://investor.amarincorp.com/news-releases/news-release-details/amarin-announced-fda-advisory-committee-voted-unanimously-16-0.
   Google Scholar
• Food and Drug Administration . FDA approves use of drug to reduce risk of cardiovascular events in certain adult patient groups [news release]. 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-use-drug-reduce-risk-cardiovascular-events-certain-adult-patient-groups.
   Google Scholar
• Baum SJ , TothPP, UnderbergJA, JellingerP, RossJ, WilemonK. PCSK9 inhibitor access barriers-issues and recommendations: Improving the access process for patients, clinicians and payers. Clin. Cardiol., 40(4), 243–254 (2017).
   PubMed Web of Science ®Google Scholar
• Banach M , RizzoM, TothPPet al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch. Med. Sci., 11(1), 1–23 (2015).
   PubMed Web of Science ®Google Scholar
• Lloyd-Jones DM , MorrisPB, BallantyneCMet al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J. Am. Coll. Cardiol., 68(1), 92–125 (2016).
   PubMed Web of Science ®Google Scholar
• Bhatt DL , StegPG, BrintonEAet al. Rationale and design of REDUCE-IT: reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin. Cardiol., 40(3), 138–148 (2017).
   PubMed Web of Science ®Google Scholar
• Kolber MR , ScrimshawC. Family history of cardiovascular disease. Can. Fam. Physician, 60(11), 1016 (2014).
   PubMed Web of Science ®Google Scholar
• Lacoste L , LamJY, HungJ, LetchacovskiG, SolymossCB, WatersD. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation, 92(11), 3172–3177 (1995).
   PubMed Web of Science ®Google Scholar
• Carbone S , CanadaJM, BillingsleyHE, SiddiquiMS, ElagiziA, LavieCJ. Obesity paradox in cardiovascular disease: where do we stand?Vascular Health Risk Manage., 15, 89–100 (2019).
   PubMed Web of Science ®Google Scholar
• Cozzolino M , ManganoM, StucchiA, CiceriP, ConteF, GalassiA. Cardiovascular disease in dialysis patients. Nephrol. Dial. Transplant., 33(Suppl. 3), iii28–iii34 (2018).
   PubMedGoogle Scholar
• National Lipid Association . NLA position on the use of icosapent ethyl in high and very-high risk patients. 2019. https://www.lipid.org/nla/nla-position-use-icosapent-ethyl-high-and-very-high-risk-patients.
   Google Scholar
• Fan W , PhilipS, GranowitzC, TothPP, WongND. Prevalence of US adults with triglycerides ≥150 mg/dl: NHANES 2007–2014. Cardiol. Ther., 9(1), 207–213 (2020).
   PubMed Web of Science ®Google Scholar
• Toth PP , PattiAM, GiglioRVet al. Management of statin intolerance in 2018: still more questions than answers. Am. J. Cardiovasc. Drugs, 18(3), 157–173 (2018).
   PubMed Web of Science ®Google Scholar
• Saeed B , WrightE, EvansM, LewisM, SteinhublS. Prevalence of statin intolerance in a high risk cohort and management strategies in contemporary cardiology [abstract PS1-45]. Clin. Med. Res., 11(3), 136 (2013).
   Google Scholar
• Ollendorf D , McQueenR, FazioliKet al. Additive therapies for cardiovascular disease: effectiveness and value. Institute for Clinical and Economic Review, 2019. http://icer-review.org/material/cvd-final-evidence-report/.
   Google Scholar
• Weintraub WS , BhattDL, ZhangZet al. Cost-effectiveness of icosapent ethyl in REDUCE-IT [abstract]. Presented at the American Heart Association Annual Scientific Sessions, Philadelphia, PANovember 18, 2019.
   Google Scholar
• Weintraub WS , BhattD, ZhangZet al. Cost-effectiveness of icosapent ethyl in US REDUCE-IT patients [abstract]. J. Am. Coll. Cardiol., 75(11 Suppl. 1), 1914 (2020).
   Web of Science ®Google Scholar
• Kones R . Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes. Vascular Health Risk Manage., 9, 617–670 (2013).
   PubMedGoogle Scholar
• Scandinavian Simvastatin Survival Study Investigators . Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 344(8934), 1383–1389 (1994).
   PubMed Web of Science ®Google Scholar
• Sacks FM , PfefferMA, MoyeLAet al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N. Engl. J. Med., 335(14), 1001–1009 (1996).
   PubMed Web of Science ®Google Scholar
• Downs JR , ClearfieldM, WeisSet al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA, 279(20), 1615–1622 (1998).
   PubMed Web of Science ®Google Scholar
• Colhoun HM , BetteridgeDJ, DurringtonPNet al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet, 364(9435), 685–696 (2004).
   PubMed Web of Science ®Google Scholar
• Libby P , NahrendorfM, SwirskiFK. Leukocytes link local and systemic inflammation in ischemic cardiovascular disease: an expanded “Cardiovascular Continuum”. J. Am. Coll. Cardiol., 67(9), 1091–1103 (2016).
   PubMed Web of Science ®Google Scholar
• Serhan CN , ChiangN, Van DykeTE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol., 8(5), 349–361 (2008).
   PubMed Web of Science ®Google Scholar
• Isobe Y , AritaM, MatsuedaSet al. Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. J. Biol. Chem., 287(13), 10525–10534 (2012).
   PubMed Web of Science ®Google Scholar
• Hawthorne AB , FilipowiczBL, EdwardsTJ, HawkeyCJ. High dose eicosapentaenoic acid ethyl ester: effects on lipids and neutrophil leukotriene production in normal volunteers. Br. J. Clin. Pharmacol., 30(2), 187–194 (1990).
   PubMed Web of Science ®Google Scholar
• Obata T , NagakuraT, MasakiT, MaekawaK, YamashitaK. Eicosapentaenoic acid inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells. Clin. Exp. Allergy, 29(8), 1129–1135 (1999).
   PubMed Web of Science ®Google Scholar
• Terano T , SalmonJA, HiggsGA, MoncadaS. Eicosapentaenoic acid as a modulator of inflammation. Effect on prostaglandin and leukotriene synthesis. Biochem. Pharmacol., 35(5), 779–785 (1986).
   PubMed Web of Science ®Google Scholar
• Prescott SM . The effect of eicosapentaenoic acid on leukotriene B production by human neutrophils. J. Biol. Chem., 259(12), 7615–7621 (1984).
   PubMed Web of Science ®Google Scholar
• Kondeti V , Al-AzzamN, DuahE, ThodetiCK, BoyceJA, ParuchuriS. Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3. J. Allergy Clin. Immunol., 137(1), 289–298 (2016).
   PubMed Web of Science ®Google Scholar
• Paschoal VA , VinoloMA, CrismaAR, MagdalonJ, CuriR. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid differentially modulate rat neutrophil function in vitro. Lipids, 48(2), 93–103 (2013).
   PubMed Web of Science ®Google Scholar
• Mickleborough TD , TecklenburgSL, MontgomeryGS, LindleyMR. Eicosapentaenoic acid is more effective than docosahexaenoic acid in inhibiting proinflammatory mediator production and transcription from LPS-induced human asthmatic alveolar macrophage cells. Clin. Nutr., 28(1), 71–77 (2009).
   PubMed Web of Science ®Google Scholar
• Huang CY , SheuWH, ChiangAN. Docosahexaenoic acid and eicosapentaenoic acid suppress adhesion molecule expression in human aortic endothelial cells via differential mechanisms. Mol. Nutr. Food Res., 59(4), 751–762 (2015).
   PubMed Web of Science ®Google Scholar
• Chen CN , ChangSF, LeePLet al. Neutrophils, lymphocytes, and monocytes exhibit diverse behaviors in transendothelial and subendothelial migrations under coculture with smooth muscle cells in disturbed flow. Blood, 107(5), 1933–1942 (2006).
   PubMed Web of Science ®Google Scholar
• Watanabe T , FanJ. Atherosclerosis and inflammation mononuclear cell recruitment and adhesion molecules with reference to the implication of ICAM-1/LFA-1 pathway in atherogenesis. Int. J. Cardiol., 66(Suppl. 1), S45–53; discussion S55 (1998).
   PubMedGoogle Scholar
• Matsumoto M , SataM, FukudaDet al. Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice. Atherosclerosis, 197(2), 524–533 (2008).
   PubMed Web of Science ®Google Scholar
• Zhao Y , Joshi-BarveS, BarveS, ChenLH. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J. Am. Coll. Nutr., 23(1), 71–78 (2004).
   PubMed Web of Science ®Google Scholar
• Jaudszus A , GruenM, WatzlBet al. Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells. J. Lipid Res., 54(4), 923–935 (2013).
   PubMed Web of Science ®Google Scholar
• Kondo H , AbeI, GotohKet al. Interleukin 10 treatment ameliorates high-fat diet-induced inflammatory atrial remodeling and fibrillation. Circ. Arrhythm. Electrophysiol., 11(5), e006040 (2018).
   PubMed Web of Science ®Google Scholar
• Mo Z , TangC, LiHet al. Eicosapentaenoic acid prevents inflammation induced by acute cerebral infarction through inhibition of NLRP3 inflammasome activation. Life Sci., 242, 117133 (2020).
   PubMed Web of Science ®Google Scholar
• Chen S , WangY, PanYet al. Novel role for tranilast in regulating NLRP3 ubiquitination, vascular inflammation, and atherosclerosis. J. Am. Heart Assoc.e015513 (2020).
   PubMed Web of Science ®Google Scholar
• Le PNT , DesboisAP. Antibacterial effect of eicosapentaenoic acid against Bacillus cereus and Staphylococcus aureus: killing kinetics, selection for resistance, and potential cellular target. Mar. Drugs, 15(11), 334 (2017).
   PubMed Web of Science ®Google Scholar
• Shin SY , BajpaiVK, KimHR, KangSC. Antibacterial activity of bioconverted eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) against foodborne pathogenic bacteria. Int. J. Food Microbiol., 113(2), 233–236 (2007).
   PubMed Web of Science ®Google Scholar
• Cheng CL , HuangSJ, WuCLet al. Transgenic expression of omega-3 PUFA synthesis genes improves zebrafish survival during Vibrio vulnificus infection. J. Biomed. Sci., 22, 103 (2015).
   PubMed Web of Science ®Google Scholar
• Desbois AP , LawlorKC. Antibacterial activity of long-chain polyunsaturated fatty acids against Propionibacterium acnes and Staphylococcus aureus. Mar. Drugs, 11(11), 4544–4557 (2013).
   PubMed Web of Science ®Google Scholar
• D’Elia RV , HarrisonK, OystonPC, LukaszewskiRA, ClarkGC. Targeting the “cytokine storm” for therapeutic benefit. Clin. Vaccine Immunol., 20(3), 319–327 (2013).
   PubMedGoogle Scholar
• Das UN . Can bioactive lipids inactivate coronavirus (COVID-19)?Arch. Med. Res. (2020).
   Web of Science ®Google Scholar
• Piazzi G , D’ArgenioG, ProssomaritiAet al. Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis-associated colorectal cancer acting on Notch signaling and gut microbiota. Int. J. Cancer, 135(9), 2004–2013 (2014).
   PubMed Web of Science ®Google Scholar
• Scaioli E , SartiniA, BellanovaMet al. Eicosapentaenoic acid reduces fecal levels of calprotectin and prevents relapse in patients with ulcerative colitis. Clin. Gastroenterol. Hepatol., 16(8), 1268–1275.e1262 (2018).
   PubMed Web of Science ®Google Scholar
• de Souza Fernandes DP , CanaanRezende FA, PereiraRocha G, DeSantis Filgueiras M, SilvaMoreira PR, GonçalvesAlfenas Rde C. Effect of eicosapentaenoic acid and docosahexaenoic acid supplementations to control cognitive decline in dementia and Alzheimer’s disease: a systematic review. Nutr. Hosp., 32(2), 528–533 (2015).
   PubMed Web of Science ®Google Scholar
• Samieri C , FéartC, LetenneurLet al. Low plasma eicosapentaenoic acid and depressive symptomatology are independent predictors of dementia risk. Am. J. Clin. Nutr., 88(3), 714–721 (2008).
   PubMed Web of Science ®Google Scholar
• Bazinet RP , MetherelAH, ChenCTet al. Brain eicosapentaenoic acid metabolism as a lead for novel therapeutics in major depression. Brain. Behav. Immun., 85, 21–28 (2020).
   PubMed Web of Science ®Google Scholar
• Trebatická J , HradečnáZ, SurovcováAet al. Omega-3 fatty-acids modulate symptoms of depressive disorder, serum levels of omega-3 fatty acids and omega-6/omega-3 ratio in children. A randomized, double-blind and controlled trial. Psychiatry Res., 287, 112911 (2020).
   PubMed Web of Science ®Google Scholar