The eicosapentaenoic acid:arachidonic acid ratio and its clinical utility in cardiovascular disease

References

• Jump DB, Depner CM, Tripathy S. Omega-3 fatty acid supplementation and cardiovascular disease. J Lipid Res. 2012;53(12):2525–2545.
   PubMed Web of Science ®Google Scholar
• Siriwardhana N, Kalupahana NS, Moustaid-Moussa N. Health benefits of n-3 polyunsaturated fatty acids: eicosapentaenoic acid and docosahexaenoic acid. Adv Food Nutr Res. 2012;65:211–222.
   PubMedGoogle Scholar
• Lamon BD, Hajjar DP. Inflammation at the molecular interface of atherogenesis: an anthropological journey. Am J Pathol. 2008;173(5):1253–1264.
   PubMed Web of Science ®Google Scholar
• Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis. 2015;242(1):357–366.
   PubMed Web of Science ®Google Scholar
• Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, plAcebo-controlled, randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108(5):682–690.
   PubMed Web of Science ®Google Scholar
• Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110(7):984–992.
   PubMed Web of Science ®Google Scholar
• Calder PC. n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006;83(6Suppl):1505S–1519S.
   PubMed Web of Science ®Google Scholar
• Sonnweber T, Pizzini A, Nairz M, et al. Arachidonic acid metabolites in cardiovascular and metabolic diseases. Int J Mol Sci. 2018;19(11):3285.
   PubMed Web of Science ®Google Scholar
• Larsson SC, Kumlin M, Ingelman-Sundberg M, et al. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. Am J Clin Nutr. 2004;79(6):935–945.
   PubMed Web of Science ®Google Scholar
• Lopez LR, Guyer KE, Torre IG, et al. Platelet thromboxane (11-dehydro-Thromboxane B2) and aspirin response in patients with diabetes and coronary artery disease. World J Diabetes. 2014;5(2):115–127. Epub 2014/ 04/22.
   PubMedGoogle Scholar
• Tallima H, El Ridi R. Arachidonic acid: physiological roles and potential health benefits - A review. J Advance Res. 2017;11:33–41.
   PubMed Web of Science ®Google Scholar
• Goldman DW, Pickett WC, Goetzl EJ. Human neutrophil chemotactic and degranulating activities of leukotriene B5 (LTB5) derived from eicosapentaenoic acid. Biochem Biophys Res Commun. 1983;117(1):282–288.
   PubMed Web of Science ®Google Scholar
• Lee TH, Mencia-Huerta JM, Shih C, et al. Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils. J Clin Invest. 1984;74(6):1922–1933.
   PubMed Web of Science ®Google Scholar
• Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012;120(15):e60–72.
   PubMed Web of Science ®Google Scholar
• Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood). 2008;233(6):674–688.
   PubMed Web of Science ®Google Scholar
• Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr. 2006;83(6Suppl):1467S–1476S.
   PubMed Web of Science ®Google Scholar
• Nakamura N, Hamazaki T, Ohta M, et al. Joint effects of HMG-CoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia. Int J Clin Lab Res. 1999;29(1):22–25.
   PubMedGoogle Scholar
• Bays HE, Ballantyne CM, Doyle RT Jr., et al. Icosapent ethyl: eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies. Prostaglandins Other Lipid Mediat. 2016;125:57–64.
   PubMed Web of Science ®Google Scholar
• Dyerberg J, Bang HO, Stoffersen E, et al. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet. 1978;2(8081):117–119.
   PubMed Web of Science ®Google Scholar
• Ohnishi H, Saito Y. Eicosapentaenoic acid (EPA) reduces cardiovascular events: relationship with the EPA/arachidonic acid ratio. J Atheroscler Thromb. 2013;20(12):861–877.
   PubMed Web of Science ®Google Scholar
• Nishizaki Y, Shimada K, Daida H. The balance of omega-3 polyunsaturated fatty acids for reducing residual risks in patients with coronary artery disease. Acta Cardiol. 2017;72(3):240–248.
   PubMed Web of Science ®Google Scholar
• Cranmer-Byng MM, Liddle DM, De Boer AA, et al. Proinflammatory effects of arachidonic acid in a lipopolysaccharide-induced inflammatory microenvironment in 3T3-L1 adipocytes in vitro. Appl Physiol Nutr Metab. 2015;40(2):142–154.
   PubMed Web of Science ®Google Scholar
• Chisaki K, Okuda Y, Suzuki S, et al. Eicosapentaenoic acid suppresses basal and insulin-stimulated endothelin-1 production in human endothelial cells. Hypertens Res. 2003;26(8):655–661.
   PubMed Web of Science ®Google Scholar
• Shimojo N, Jesmin S, Zaedi S, et al. Effect of eicosapentaenoic acid on the different endothelin system components in endothelin-1-induced hypertrophied cardiomyocytes. Exp Biol Med (Maywood). 2006;231(6):888–892.
   PubMed Web of Science ®Google Scholar
• Domei T, Yokoi H, Kuramitsu S, et al. Ratio of serum n-3 to n-6 polyunsaturated fatty acids and the incidence of major adverse cardiac events in patients undergoing percutaneous coronary intervention. Circ J. 2012;76(2):423–429.
   PubMed Web of Science ®Google Scholar
• Kondo T, Ogawa K, Satake T, et al. Plasma-free eicosapentaenoic acid/arachidonic acid ratio: a possible new coronary risk factor. Clin Cardiol. 1986;9(9):413–416.
   PubMed Web of Science ®Google Scholar
• Itakura H, Yokoyama M, Matsuzaki M, et al. Relationships between plasma fatty acid composition and coronary artery disease. J Atheroscler Thromb. 2011;18(2):99–107.
   PubMed Web of Science ®Google Scholar
• Serikawa T, Miura S, Okabe M, et al. Ratio of eicosapentaenoic acid to arachidonic acid is a critical risk factor for acute coronary syndrome in middle-aged older patients as well as younger adult patients. J Cardiol. 2014;63(1):35–40.
   PubMed Web of Science ®Google Scholar
• Nishizaki Y, Shimada K, Tani S, et al. Significance of imbalance in the ratio of serum n-3 to n-6 polyunsaturated fatty acids in patients with acute coronary syndrome. Am J Cardiol. 2014;113(3):441–445.
   PubMed Web of Science ®Google Scholar
• Nosaka K, Miyoshi T, Iwamoto M, et al. Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study. Int J Cardiol. 2017;228:173–179.
   PubMed Web of Science ®Google Scholar
• Suzuki A, Ando H, Takashima H, et al. Effects of polyunsaturated fatty acids on periprocedural myocardial infarction after elective percutaneous coronary intervention. EuroIntervention. 2014;10(7):792–798.
   PubMed Web of Science ®Google Scholar
• Hashimoto T, Ako J, Nakao K, et al. A lower eicosapentaenoic acid/arachidonic acid ratio is associated with in-hospital fatal arrhythmic events in patients with acute myocardial infarction: a J-MINUET substudy. Heart Vessels. 2018;33(5):481–488.
   PubMed Web of Science ®Google Scholar
• Ikeya Y, Fukuyama N, Kitajima W, et al. Comparison of eicosapentaenoic acid concentrations in plasma between patients with ischemic stroke and control subjects. Nutrition. 2013;29(1):127–131.
   PubMed Web of Science ®Google Scholar
• Tanaka K, Ishikawa Y, Yokoyama M, et al. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke. 2008;39(7):2052–2058.
   PubMed Web of Science ®Google Scholar
• Okamoto K, Sato A, Matsukawa K, et al. Impact of eicosapentaenoic acid/arachidonic acid ratio on left ventricular structure in patients with diabetes. Diabetol Int. 2015;6(1):46–54.
   Web of Science ®Google Scholar
• Watanabe S, Yoshihisa A, Kanno Y, et al. Associations with eicosapentaenoic acid to arachidonic acid ration and mortality in hospitalized heart failure patients. J Card Fail. 2016;22(12):962–969.
   PubMed Web of Science ®Google Scholar
• Kohashi K, Nakagomi A, Saiki Y, et al. Effects of eicosapentaenoic acid on the levels of inflammatory markers, cardiac function and long-term prognosis in chronic heart failure patients with dyslipidemia. J Atheroscler Thromb. 2014;21(7):712–729.
   PubMed Web of Science ®Google Scholar
• Fujihara M, Fukata M, Odashiro K, et al. Reduced plasma eicosapentaenoic acid-arachidonic acid ratio in peripheral artery disease. Angiology. 2013;64(2):112–118.
   PubMed Web of Science ®Google Scholar
• Gautam M, Izawa A, Shiba Y, et al. Importance of fatty acid compositions in patients with peripheral arterial disease. PLoS One. 2014;9(9):e107003.
   PubMed Web of Science ®Google Scholar
• Hishikari K, Kimura S, Yamakami Y, et al. The prognostic value of the serum eicosapentaenoic acid to arachidonic acid ratio in relation to clinical outcomes after endovascular therapy in patients with peripheral artery disease caused by femoropopliteal artery lesions. Atherosclerosis. 2015;239(2):583–588.
   PubMed Web of Science ®Google Scholar
• Okada K, Kotani K, Ishibashi S. Ankle-brachial index and eicosapentaenoic acid/arachidonic acid ratio in smokers with type 2 diabetes mellitus. Tob Induc Dis. 2016;14:2.
   PubMed Web of Science ®Google Scholar
• Ito R, Satoh-Asahara N, Yamakage H, et al. An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with dyslipidemia. J Atheroscler Thromb. 2014;21(3):248–260.
   PubMed Web of Science ®Google Scholar
• Baek SH, Kim M, Kim M, et al. Relationship between changes in polyunsaturated fatty acids and aging-related arterial stiffness in overweight subjects 50 years or older over a 3-year period. J Clin Lipidol. 2017;11(1):185–194.e2.
   PubMed Web of Science ®Google Scholar
• Hiki M, Miyazaki T, Shimada K, et al. Significance of serum polyunsaturated fatty acid level imbalance in patients with acute venous thromboembolism. J Atheroscler Thromb. 2017;24(10):1016–1022.
   PubMed Web of Science ®Google Scholar
• Ishikawa Y, Yokoyama M, Saito Y, et al. Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease. Circ J. 2010;74(7):1451–1457.
   PubMed Web of Science ®Google Scholar
• Tani S, Takahashi A, Nagao K, et al. Association of fish consumption-derived ratio of serum n-3 to n-6 polyunsaturated fatty acids and cardiovascular risk with the prevalence of coronary artery disease. Int Heart J. 2015;56(3):260–268.
   PubMed Web of Science ®Google Scholar
• Iwamatsu K, Abe S, Nishida H, et al. Which has the stronger impact on coronary artery disease, eicosapentaenoic acid or docosahexaenoic acid? Hypertens Res. 2016;39(4):272–275.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Matsuzaki M, Yokoyama M, Saito Y, et al. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J. 2009;73(7):1283–1290.
   PubMed Web of Science ®Google Scholar
• Tani S, Nagao K, Kawauchi K, et al. The ratio of eicosapentaenoic acid (EPA) to arachidonic acid may be a residual risk marker in stable coronary artery disease patients receiving treatment with statin following EPA therapy. Am J Cardiovasc Drugs. 2017;17(5):409–420.
   PubMed Web of Science ®Google Scholar
• Nelson JR, Wani O, May HT, et al. Potential benefits of eicosapentaenoic acid on atherosclerotic plaques. Vascul Pharmacol. 2017;91:1–9.
   PubMed Web of Science ®Google Scholar
• Hasegawa T, Otsuka K, Iguchi T, et al. Serum n-3 to n-6 polyunsaturated fatty acids ratio correlates with coronary plaque vulnerability: an optical coherence tomography study. Heart Vessels. 2014;29(5):596–602.
   PubMed Web of Science ®Google Scholar
• Kashiyama T, Ueda Y, Nemoto T, et al. Relationship between coronary plaque vulnerability and serum n-3/n-6 polyunsaturated fatty acid ratio. Circ J. 2011;75(10):2432–2438.
   PubMed Web of Science ®Google Scholar
• Nozue T, Yamamoto S, Tohyama S, et al. Effects of serum n-3 to n-6 polyunsaturated fatty acids ratios on coronary atherosclerosis in statin-treated patients with coronary artery disease. Am J Cardiol. 2013;111(1):6–11.
   PubMed Web of Science ®Google Scholar
• Nagahara Y, Motoyama S, Sarai M, et al. Eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio as an associated factor of high risk plaque on coronary computed tomography in patients without coronary artery disease. Atherosclerosis. 2016;250:30–37.
   PubMed Web of Science ®Google Scholar
• Wakabayashi Y, Funayama H, Ugata Y, et al. Low eicosapentaenoic acid to arachidonic acid ratio is associated with thin-cap fibroatheroma determined by optical coherence tomography. J Cardiol. 2015;66(6):482–488.
   PubMed Web of Science ®Google Scholar
• Hayakawa S, Yoshikawa D, Ishii H, et al. Association of plasma omega-3 to omega-6 polyunsaturated fatty acid ratio with complexity of coronary artery lesion. Intern Med News Suppl. 2012;51(9):1009–1014.
   PubMed Web of Science ®Google Scholar
• Ariyoshi K, Okuya S, Kunitsugu I, et al. Ultrasound analysis of gray-scale median value of carotid plaques is a useful reference index for cerebro-cardiovascular events in patients with type 2 diabetes. J Diabetes Investig. 2015;6(1):91–97.
   PubMed Web of Science ®Google Scholar
• Watanabe T, Ando K, Daidoji H, et al. A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins. J Cardiol. 2017;70(6):537–544.
   PubMed Web of Science ®Google Scholar
• Nakahara S, Komatsu T, Taguchi I. Eicosapentaenoic acid added to strong statin therapy. Circ J. 2016;80(2):321–322.
   PubMed Web of Science ®Google Scholar
• Yagi S, Aihara K, Fukuda D, et al. Reduced ratio of eicosapentaenoic acid and docosahexaenoic acid to arachidonic acid is associated with early onset of acute coronary syndrome. Nutr J. 2015;14:111.
   PubMed Web of Science ®Google Scholar
• Sakamoto A, Saotome M, Hosoya N, et al. Aberrant serum polyunsaturated fatty acids profile is relevant with acute coronary syndrome. Heart Vessels. 2016;31(8):1209–1217.
   PubMed Web of Science ®Google Scholar
• Ohwada T, Yokokawa T, Kanno Y, et al. Vascular composition data supporting the role of N-3 polyunsaturated fatty acids in the prevention of cardiovascular disease events. Data Brief. 2016;7:1237–1247.
   PubMed Web of Science ®Google Scholar
• Ueeda M, Doumei T, Takaya Y, et al. Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction. Heart Vessels. 2011;26(2):145–152.
   PubMed Web of Science ®Google Scholar
• Takahashi M, Ando J, Shimada K, et al. The ratio of serum n-3 to n-6 polyunsaturated fatty acids is associated with diabetes mellitus in patients with prior myocardial infarction: a multicenter cross-sectional study. BMC Cardiovasc Disord. 2017;17(1):41.
   PubMed Web of Science ®Google Scholar
• He K, Song Y, Daviglus ML, et al. Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke. 2004;35(7):1538–1542.
   PubMed Web of Science ®Google Scholar
• Hikita H, Shigeta T, Kimura S, et al. Coronary artery disease severity and cardiovascular biomarkers in patients with peripheral artery disease. Int J Angiol. 2015;24(4):278–282.
   PubMed Web of Science ®Google Scholar
• Aikawa T, Miyazaki T, Shimada K, et al. Low serum levels of EPA are associated with the size and growth rate of abdominal aortic aneurysm. J Atheroscler Thromb. 2017;24(9):912–920.
   PubMed Web of Science ®Google Scholar
• Rizzo AM, Montorfano G, Negroni M, et al. A rapid method for determining arachidonic: eicosapentaenoicacid ratios in whole blood lipids: correlation with erythrocyte membrane ratios and validation in a large Italian population of various ages and pathologies. Lipids Health Dis. 2010;9:7.
   PubMed Web of Science ®Google Scholar
• Sherratt SCR, Mason RP. Eicosapentaenoic acid and docosahexaenoic acid have distinct membrane locations and lipid interactions as determined by X-ray diffraction. Chem Phys Lipids. 2018;212:73–79.
   PubMed Web of Science ®Google Scholar
• Mason RP, Jacob RF, Shrivastava S, et al. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta. 2016;1858(12):3131–3140.
   PubMed Web of Science ®Google Scholar
• Sherratt SCR, Mason RP. Eicosapentaenoic acid inhibits oxidation of high density lipoprotein particles in a manner distinct from docosahexaenoic acid. Biochem Biophys Res Commun. 2018;496(2):335–338.
   PubMed Web of Science ®Google Scholar
• Tanaka N, Ishida T, Nagao M, et al. Administration of high dose eicosapentaenoic acid enhances anti-inflammatory properties of high-density lipoprotein in Japanese patients with dyslipidemia. Atherosclerosis. 2014;237(2):577–583.
   PubMed Web of Science ®Google Scholar
• Cawood AL, Ding R, Napper FL, et 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. 2010;212(1):252–259.
   PubMed Web of Science ®Google Scholar
• Harris WS, Varvel SA, Pottala JV, et al. Comparative effects of an acute dose of fish oil on omega-3 fatty acid levels in red blood cells versus plasma: implications for clinical utility. J Clin Lipidol. 2013;7(5):433–440.
   PubMed Web of Science ®Google Scholar
• von Schacky C, Fischer S, Weber PC. Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans. J Clin Invest. 1985;76(4):1626–1631.
   PubMed Web of Science ®Google Scholar
• Yanagisawa N, Shimada K, Miyazaki T, et al. Polyunsaturated fatty acid levels of serum and red blood cells in apparently healthy Japanese subjects living in an urban area. J Atheroscler Thromb. 2010;17(3):285–294.
   PubMed Web of Science ®Google Scholar
• Harris WS, von Schacky C. The Omega-3 index: a new risk factor for death from coronary heart disease? Prev Med. 2004;39(1):212–220.
   PubMed Web of Science ®Google Scholar
• Harris WS, Sands SA, Windsor SL, et al. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation. 2004;110(12):1645–1649.
   PubMed Web of Science ®Google Scholar
• Harris WS, Tintle NL, Etherton MR, et al. Erythrocyte long-chain omega-3 fatty acid levels are inversely associated with mortality and with incident cardiovascular disease: the Framingham Heart Study. J Clin Lipidol. 2018;12(3):718–727.
   PubMed Web of Science ®Google Scholar
• Baylin A, Campos H. Arachidonic acid in adipose tissue is associated with nonfatal acute myocardial infarction in the central valley of Costa Rica. J Nutr. 2004;134(11):3095–3099.
   PubMed Web of Science ®Google Scholar
• Kark JD, Kaufmann NA, Binka F, et al. Adipose tissue n-6 fatty acids and acute myocardial infarction in a population consuming a diet high in polyunsaturated fatty acids. Am J Clin Nutr. 2003;77(4):796–802.
   PubMed Web of Science ®Google Scholar
• Shishehbor MH, Zhang R, Medina H, et al. Systemic elevations of free radical oxidation products of arachidonic acid are associated with angiographic evidence of coronary artery disease. Free Radic Biol Med. 2006;41(11):1678–1683.
   PubMed Web of Science ®Google Scholar
• Delgado GE, Marz W, Lorkowski S, et al. Omega-6 fatty acids: opposing associations with risk-The ludwigshafen risk and cardiovascular health study. J Clin Lipidol. 2017;11(4):1082–1090.e14.
   PubMed Web of Science ®Google Scholar
• Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids. 2005;73(3–4):141–162.
   PubMed Web of Science ®Google Scholar
• Node K, Huo Y, Ruan X, et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science. 1999;285(5431):1276–1279.
   PubMed Web of Science ®Google Scholar
• Yang L, Maki-Petaja K, Cheriyan J, et al. The role of epoxyeicosatrienoic acids in the cardiovascular system. Br J Clin Pharmacol. 2015;80(1):28–44.
   PubMed Web of Science ®Google Scholar
• Ferrucci L, Cherubini A, Bandinelli S, et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab. 2006;91(2):439–446.
   PubMed Web of Science ®Google Scholar
• Harris WS. The omega-6: omega-3ratio: a critical appraisal and possible successor. Prostaglandins Leukot Essent Fatty Acids. 2018;132:34–40.
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Steg G, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22.
   PubMed Web of Science ®Google Scholar
• American Diabetes Association® issues critical updates to the 2019 standards of medical care in diabetes. Arlington, VA, 2019. Available at: www.diabetes.org/newsroom/press-releases/2019/ada-issues-critical-updates-to-2019-standards-of-care.html. Accessed: March 27, 2019.
   Google Scholar
• Budoff M, Brent Muhlestein J, Le VT, et al. Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: rationale and design of the EVAPORATE study. Clin Cardiol. 2018;41(1):13–19.
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Lincoff AM, Bash D, et 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. 2018;41(10):1281–1288.
   PubMed Web of Science ®Google Scholar