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• W2546771350 abstract "There are limited data on the efficacy and safety of triglyceride (TG)-lowering agents in women. We conducted subgroup analyses of the effects of icosapent ethyl (a high-purity prescription form of the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid) on TG levels (primary efficacy variable) and other atherogenic and inflammatory parameters in a total of 215 women with a broad range of TG levels (200–2000 mg/dl) enrolled in two 12-week placebo-controlled trials: MARINE (n = 18; placebo, n = 18) and ANCHOR (n = 91; placebo, n = 88). Icosapent ethyl 4 g/day significantly reduced TG levels from baseline to week 12 versus placebo in both MARINE (−22.7%; p = 0.0327) and ANCHOR (−21.5%; p <0.0001) without increasing low-density lipoprotein cholesterol levels. Significant improvements were also observed in non–high-density lipoprotein cholesterol levels in MARINE (−15.7%; p = 0.0082) and ANCHOR (−14.2%; p <0.0001) and total cholesterol levels in MARINE (−14.9%; p = 0.0023) and ANCHOR (−12.1%; p <0.0001), along with significant increases of >500% in eicosapentaenoic acid levels in plasma and red blood cells (all p <0.001). Icosapent ethyl was well tolerated, with adverse-event profiles comparable with findings in the overall studies. In conclusion, icosapent ethyl 4 g/day significantly reduced TG levels and other atherogenic parameters in women without increasing low-density lipoprotein cholesterol levels compared with placebo; the clinical implications of these findings are being evaluated in the REDUCtion of Cardiovascular Events With Eicosapentaenoic Acid [EPA]–Intervention Trial (REDUCE-IT) cardiovascular outcomes study. There are limited data on the efficacy and safety of triglyceride (TG)-lowering agents in women. We conducted subgroup analyses of the effects of icosapent ethyl (a high-purity prescription form of the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid) on TG levels (primary efficacy variable) and other atherogenic and inflammatory parameters in a total of 215 women with a broad range of TG levels (200–2000 mg/dl) enrolled in two 12-week placebo-controlled trials: MARINE (n = 18; placebo, n = 18) and ANCHOR (n = 91; placebo, n = 88). Icosapent ethyl 4 g/day significantly reduced TG levels from baseline to week 12 versus placebo in both MARINE (−22.7%; p = 0.0327) and ANCHOR (−21.5%; p <0.0001) without increasing low-density lipoprotein cholesterol levels. Significant improvements were also observed in non–high-density lipoprotein cholesterol levels in MARINE (−15.7%; p = 0.0082) and ANCHOR (−14.2%; p <0.0001) and total cholesterol levels in MARINE (−14.9%; p = 0.0023) and ANCHOR (−12.1%; p <0.0001), along with significant increases of >500% in eicosapentaenoic acid levels in plasma and red blood cells (all p <0.001). Icosapent ethyl was well tolerated, with adverse-event profiles comparable with findings in the overall studies. In conclusion, icosapent ethyl 4 g/day significantly reduced TG levels and other atherogenic parameters in women without increasing low-density lipoprotein cholesterol levels compared with placebo; the clinical implications of these findings are being evaluated in the REDUCtion of Cardiovascular Events With Eicosapentaenoic Acid [EPA]–Intervention Trial (REDUCE-IT) cardiovascular outcomes study. Management of triglycerides (TGs) represents a clinical challenge and may be particularly important among women, given that TG levels are a stronger predictor of cardiovascular disease (CVD) in women than in men.1Castelli W.P. Epidemiology of triglycerides: a view from Framingham.Am J Cardiol. 1992; 70: 3H-9HAbstract Full Text PDF PubMed Scopus (305) Google Scholar, 2Nordestgaard B.G. Benn M. Schnohr P. Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women.JAMA. 2007; 298: 299-308Crossref PubMed Scopus (1607) Google Scholar, 3Hokanson J.E. Austin M.A. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.J Cardiovasc Risk. 1996; 3: 213-219Crossref PubMed Google Scholar, 4Berger J.S. McGinn A.P. Howard B.V. Kuller L. Manson J.E. Otvos J. Curb J.D. Eaton C.B. Kaplan R.C. Lynch J.K. Rosenbaum D.M. Wassertheil-Smoller S. Lipid and lipoprotein biomarkers and the risk of ischemic stroke in postmenopausal women.Stroke. 2012; 43: 958-966Crossref PubMed Scopus (46) Google Scholar, 5Freiberg J.J. Tybjaerg-Hansen A. Jensen J.S. Nordestgaard B.G. Nonfasting triglycerides and risk of ischemic stroke in the general population.JAMA. 2008; 300: 2142-2152Crossref PubMed Scopus (400) Google Scholar Recommendations from the American Heart Association and the Institute of Medicine's Committee of Women's Health Research support reporting of gender-specific analyses for both the efficacy and adverse effects of preventative interventions in CVD.6Mosca L. Benjamin E.J. Berra K. Bezanson J.L. Dolor R.J. Lloyd-Jones D.M. Newby L.K. Pina I.L. Roger V.L. Shaw L.J. Zhao D. Beckie T.M. Bushnell C. D'Armiento J. Kris-Etherton P.M. Fang J. Ganiats T.G. Gomes A.S. Gracia C.R. Haan C.K. Jackson E.A. Judelson D.R. Kelepouris E. Lavie C.J. Moore A. Nussmeier N.A. Ofili E. Oparil S. Ouyang P. Pinn V.W. Sherif K. Smith Jr., S.C. Sopko G. Chandra-Strobos N. Urbina E.M. Vaccarino V. Wenger N.K. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association.Circulation. 2011; 123: 1243-1262Crossref PubMed Scopus (1236) Google Scholar, 7Institute of MedicineWomen's Health Research: Progress, Pitfalls, and Promise. The National Academies Press, Washington, DC2010: 1-422Google Scholar Icosapent ethyl (Vascepa; Amarin Pharma Inc., Bedminster, NJ) is a high-purity prescription form of the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA).8Vascepa [package Insert]. Amarin Pharma Inc., Bedminster, NJ2016Google Scholar In the MARINE and ANCHOR (also placebo-controlled, randomized, double-blind, and 12 weeks long) trials, icosapent ethyl significantly lowered levels of TGs and other atherogenic parameters without raising low-density lipoprotein cholesterol (LDL-C) levels in patients with very high TG levels in MARINE (TGs ≥500 and ≤2000 mg/dl) and high TG levels and on statin therapy in ANCHOR (TGs ≥200 and <500 mg/dl) compared with placebo.9Bays H.E. Ballantyne C.M. Kastelein J.J. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 682-690Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 10Ballantyne C.M. Bays H.E. Kastelein J.J. Stein E. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 984-992Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar As there are limited clinical trial data on TG-lowering agents in women, we evaluated subgroup data from MARINE and ANCHOR to provide robust information on the efficacy and safety of icosapent ethyl at the Food and Drug Administration–approved dose of 4 g/day among women who participated in these studies. Details of the MARINE and ANCHOR study designs and participants were previously reported.9Bays H.E. Ballantyne C.M. Kastelein J.J. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 682-690Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 10Ballantyne C.M. Bays H.E. Kastelein J.J. Stein E. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 984-992Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar Briefly, patients were randomized to icosapent ethyl 4 g/day, 2 g/day, or placebo.9Bays H.E. Ballantyne C.M. Kastelein J.J. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 682-690Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 10Ballantyne C.M. Bays H.E. Kastelein J.J. Stein E. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 984-992Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar Both studies were conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki with protocol approval by the appropriate institutional review boards and written informed consent provided by all participants. In MARINE, patients were required to have very high TG levels (≥500 and ≤2000 mg/dl) and were allowed, but not required, to be on stable statin therapy with or without ezetimibe.9Bays H.E. Ballantyne C.M. Kastelein J.J. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 682-690Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar ANCHOR included patients with elevated TG levels (≥200 and <500 mg/dl) at high risk for CVD; patients were also required to be on a stable statin therapy with or without ezetimibe.10Ballantyne C.M. Bays H.E. Kastelein J.J. Stein E. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 984-992Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar In both studies, the primary efficacy variable was the median percent change in plasma TG levels from baseline to week 12 versus placebo. Additional efficacy assessments included the median percent change from baseline to week 12 versus placebo in plasma levels of other lipid parameters (LDL-C, high-density lipoprotein cholesterol [HDL-C], non-HDL-C, total cholesterol, very low–density lipoprotein cholesterol [VLDL-C], VLDL-TGs, and remnant lipoprotein cholesterol), apolipoproteins (apolipoprotein B and apolipoprotein C-III), inflammatory markers (oxidized LDL, lipoprotein-associated phospholipase A2, and high-sensitivity C-reactive protein), and plasma and red blood cell (RBC) levels of EPA. Measurement methods for these parameters have previously been described.9Bays H.E. Ballantyne C.M. Kastelein J.J. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 682-690Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 11Bays H.E. Ballantyne C.M. Braeckman R.A. Stirtan W.G. Soni P.N. 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. 2013; 13: 37-46Crossref PubMed Scopus (105) Google Scholar, 12Brinton E.A. Ballantyne C.M. Bays H.E. Kastelein J.J. Braeckman R.A. Soni P.N. Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study.Cardiovasc Diabetol. 2013; 12: 100Crossref PubMed Scopus (48) Google Scholar, 13Braeckman R.A. Manku M.S. Bays H.E. Stirtan W.G. Soni P.N. Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on plasma and red blood cell fatty acids in patients with very high triglyceride levels (results from the MARINE study).Prostaglandins Leukot Essent Fatty Acids. 2013; 89: 195-201Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 14Braeckman R.A. Stirtan W.G. Soni P.N. Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects.Clin Pharmacol Drug Dev. 2014; 3: 101-108Crossref PubMed Scopus (36) Google Scholar, 15Ballantyne C.M. Bays H.E. Braeckman R.A. Philip S. Stirtan W.G. Doyle Jr., R.T. Soni P.N. Juliano R.A. Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies.J Clin Lipidol. 2016; 10: 635-645Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 16Ballantyne C.M. Bays H.E. Philip S. Doyle R.T.J. Braeckman R.A. Stirtan W.G. Soni P.N. Juliano R.A. Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies.Atherosclerosis. 2016; 253: 81-87Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Safety assessments included and treatment-emergent adverse events (TEAEs), which were defined as any adverse event (AE) that began after the first dose or occurred before the first dose and worsened in severity during the double-blind treatment period. For the primary efficacy variable, subgroup analysis by gender was prespecified in MARINE and ANCHOR (patients were stratified by gender at randomization). The analyses were based on the intent-to-treat population, defined as all randomized patients who had a baseline TG measurement, received ≥1 dose of study drug, and had ≥1 post-randomization efficacy measurement. For missing week 12 measurements, the last post-baseline measurement was carried forward as the end point measurement (last observation carried forward). The Hodges-Lehmann method was used to estimate median percent changes from baseline in differences between the icosapent ethyl 4 g/day and placebo groups. The Wilcoxon rank-sum test was used to calculate p values. MARINE and ANCHOR were powered to examine the change from baseline in fasting TG levels. For all prespecified subgroup analyses in MARINE and ANCHOR, 0.05 was the prespecified alpha for significance, which was also used in all post hoc analyses, including those reported here, which were exploratory in nature. Baseline characteristics of women in this subgroup analysis are provided in Table 1. In MARINE, 2 women discontinued treatment: in the icosapent ethyl 4 g/day group, 1 withdrew consent; in the placebo group, 1 discontinued due to an AE. A total of 8 women receiving icosapent ethyl 4 g/day and 9 women receiving placebo discontinued treatment in ANCHOR: in the icosapent ethyl 4 g/day group, 4 discontinued due to AEs, 2 withdrew consent, 1 was lost to follow-up, and 1 discontinued for other reasons; in the placebo group, 4 discontinued due to AEs, 4 withdrew consent, and 1 discontinued for other reasons.Table 1Baseline characteristics (women randomized to icosapent ethyl 4 g/day or placebo in MARINE and ANCHOR)VariableMARINEANCHORIcosapent Ethyl4 g/day(n = 18)Placebo(n = 18)Icosapent Ethyl4 g/day(n = 91)Placebo(n = 88)Age, mean (SD) (years)58 ± 960 ± 761 ± 1063 ± 10Body mass index, mean (SD) (kg/m2)31 ± 431 ± 432 ± 533 ± 5White, n (%)16 (89%)17 (94%)89 (98%)85 (97%)Statin use, n (%)6 (33%)3 (17%)AllAll Open table in a new tab For the primary end point, significant median percent reductions in TG levels from baseline to week 12 versus placebo were demonstrated in women treated with icosapent ethyl 4 g/day in both MARINE (−22.7%; p = 0.0327) and ANCHOR (−21.5%; p <0.0001) (Table 2; Figure 1). Reductions in TG levels versus placebo in women were comparable with those observed in men. In men treated with icosapent ethyl 4 g/day from MARINE and ANCHOR, respectively, TG levels were reduced by −36.1% and −21.4% versus placebo (both p <0.0001); it may be worth noting the sample size was smaller in MARINE than ANCHOR. For both studies, there was no significant interaction between gender as a baseline characteristic and treatment with respect to the percent change in TG levels from baseline versus placebo (both p = not significant for interaction; data not shown). In MARINE, among women receiving icosapent ethyl 4 g/day, there was a trend toward greater TG-lowering efficacy versus placebo in women on statin therapy than women not on statin therapy, although the sample size was small.Table 2Median percent change in lipid and lipoprotein parameters and inflammatory markers from baseline to week 12 (women from intent-to-treat populations randomized to icosapent ethyl 4 g/day or placebo in the MARINE and ANCHOR studies)ParameterIcosapent Ethyl 4 g/dayPlaceboMedian Change From BaselineBaselineEnd of TreatmentChange From Baseline, %BaselineEnd of TreatmentChange From Baseline, %Icosapent Ethyl 4 g/day vs Placebo, %, PLipid Parameters Triglycerides (mg/dl) (primary efficacy variable)MARINEn = 18, 18733 (257)433 (303)−27 (39)550 (148)585 (252)−8.6 (54)−230.0327ANCHORn = 87, 86267 (93)215 (78)−20 (25)258 (78)269 (117)4.5 (40)−22<0.0001 Low-density lipoprotein cholesterol (mg/dl)MARINEn = 18, 1898 (40)95 (69)−2.7 (19)113 (83)121 (102)11 (55)−120.2114ANCHORn = 87, 8687 (29)88 (30)0 (25)83 (28)86 (34)9.5 (32)−5.80.1454 Non-high-density lipoprotein cholesterol (mg/dl)MARINEn = 18, 18228 (141)219 (101)−14 (20)230 (88)249 (79)2.7 (17)−160.0082ANCHORn = 87, 86132 (30)123 (35)−5.6 (19)128 (36)135 (40)8.9 (31)−14<0.0001 Total cholesterol (mg/dl)MARINEn = 18, 18258 (143)248 (125)−11 (15)260 (79)285 (80)1.9 (14)−150.0023ANCHORn = 87, 86178 (37)170 (44)−4.6 (17)171 (32)184 (42)8.1 (19)−12<0.0001 High-density lipoprotein cholesterol (mg/dl)MARINEn = 18, 1832 (14)32 (16)−1.9 (30)30 (8)32 (14)11 (30)−9.30.1591ANCHORn = 87, 8642 (15)41 (13)0 (22)43 (14)46 (19)6.2 (22)−3.90.0940 Very-low-density lipoprotein cholesterol (mg/dl)MARINEn = 18, 18123 (133)122 (102)−20 (39)114 (93)115 (83)9.1 (71)−220.1173ANCHORn = 87, 8643 (20)36 (22)−20 (43)42 (21)47 (30)10 (58)−25<0.0001 Very-low-density lipoprotein triglycerides (mg/dl)MARINEn = 18, 18485 (372)330 (333)−25 (49)411 (251)400 (354)−9.2 (79)−180.2114ANCHORn = 87, 86186 (77)142 (77)−25 (34)182 (100)186 (117)2.3 (69)−28<0.0001 Remnant lipoprotein cholesterol (mg/dl)MARINEn = 18, 1741 (68)32 (42)−15 (59)33 (39)31 (50)5.3 (113)−200.2760ANCHOR∗Remnant lipoprotein cholesterol was only measured in approximately the first 35% of patients randomized in ANCHOR.n = 30, 3314 (5.0)9.0 (6.0)−29 (38)15 (8.0)14 (8.0)13 (74)−340.0014Lipoprotein Parameters Apolipoprotein B (mg/dl)MARINEn = 18, 17138 (29)136 (31)−5.1 (21)132 (37)140 (42)3.1 (7.2)−9.10.1131ANCHORn = 82, 8197 (20)93 (27)−4.2 (15)92 (22)98 (27)7.0 (23)−100.0003 Apolipoprotein C-III (mg/dl)MARINE†Apolipoprotein C-III levels were measured in the subset of all patients with available archived plasma samples from MARINE and ANCHOR.n = 11, 1026 (15)19 (11)−15 (26)24 (12)26 (13)6.7 (43)−200.0620ANCHOR†Apolipoprotein C-III levels were measured in the subset of all patients with available archived plasma samples from MARINE and ANCHOR.n = 80, 7416 (4.5)14 (4.2)−11 (26)15 (4.1)16 (4.2)5.5 (26)−19<0.0001Inflammatory Markers Oxidized low-density lipoprotein (U/l)MARINEn = 17, 1791 (24)81 (30)−7.8 (27)82 (26)81 (43)2.1 (25)−8.20.4282ANCHOR‡Oxidized low-density lipoprotein was only measured in approximately the first 35% of patients randomized in ANCHOR.n = 31, 3256 (16)52 (14)−9.6 (23)54 (17)65 (18)16 (26)−230.0002 Lipoprotein-associated phospholipase A2 (ng/ml)MARINEn = 17, 16234 (177)201 (88)−13 (34)230 (116)226 (86)−1.6 (27)−3.30.6525ANCHORn = 82, 77177 (53)154 (44)−15 (19)182 (62)193 (61)3.9 (23)−18<0.0001 High-sensitivity C-reactive protein (mg/l)MARINEn = 18, 173.4 (4.2)3.5 (5.4)−0.5 (116)2.2 (3.0)2.9 (2.8)32 (66)−130.7165ANCHORn = 82, 812.9 (3.6)2.9 (4.3)1.4 (82)3.4 (4.1)3.9 (6.6)20 (109)−240.0238Data are presented as median (interquartile range) for endpoint values. Median percent changes versus placebo are Hodges-Lehmann medians. Patient numbers are presented as icosapent ethyl 4 g/day and placebo, respectively.∗ Remnant lipoprotein cholesterol was only measured in approximately the first 35% of patients randomized in ANCHOR.† Apolipoprotein C-III levels were measured in the subset of all patients with available archived plasma samples from MARINE and ANCHOR.‡ Oxidized low-density lipoprotein was only measured in approximately the first 35% of patients randomized in ANCHOR. Open table in a new tab Data are presented as median (interquartile range) for endpoint values. Median percent changes versus placebo are Hodges-Lehmann medians. Patient numbers are presented as icosapent ethyl 4 g/day and placebo, respectively. Median percent changes in the levels of other lipids, lipoproteins, and additional parameters from baseline to week 12 versus placebo are summarized in Table 2 and Figure 1. Significant reductions in non-HDL-C and total cholesterol with icosapent ethyl 4 g/day versus placebo were observed in women in both studies. VLDL-C, VLDL-TG, remnant lipoprotein cholesterol, apolipoprotein B, and ApoC-III were significantly reduced in ANCHOR. Changes in LDL-C and HDL-C were not significant among women in either study versus placebo. Median percent changes from baseline to week 12 versus placebo in the inflammatory markers oxidized LDL, lipoprotein-associated phospholipase A2, and high-sensitivity C-reactive protein showed significant reductions among women in ANCHOR. Plasma and RBC EPA levels were measured and/or available for a subset of women in MARINE and ANCHOR (Table 3). In the MARINE study, there were significant increases in mean (standard error) EPA levels from baseline to 12 weeks versus placebo in both plasma EPA (583.4% [143.0%]; p = 0.0002) and RBC EPA (532.6% [85.1%]; p <0.0001). Similarly, in the ANCHOR study, there were significant increases from baseline to 12 weeks versus placebo in both plasma and RBC mean (standard error) EPA levels of 667.2% (57.4%) and 618.7% (64.6%), respectively (both p <0.0001).Table 3Change in plasma and red blood cell eicosapentaenoic acid levels from baseline to week 12 (women from intent-to-treat populations randomized to icosapent ethyl 4 g/day or placebo in the MARINE and ANCHOR studies)ParameterIcosapent Ethyl 4 g/dayPlaceboChange From BaselineBaselineEnd of TreatmentChange From BaselineBaselineEnd of TreatmentChange From BaselineIcosapent Ethyl 4 g/day vs Placebo, %, PPlasma eicosapentaenoic acid (μg/mL; active ingredient of icosapent ethyl) MARINE∗n = 15 icosapent ethyl; n = 13 placebo.59 (51)315 (233)239 (39)65 (34)67 (38)−33 (45)583 (143)0.0002 ANCHOR†n = 29 icosapent ethyl; n = 32 placebo.29 (16)207 (86)187 (14)27 (11)31 (13)13 (13)667 (57)<0.0001Red blood cell eicosapentaenoic acid, μg/mL (active ingredient of icosapent ethyl) MARINE‡n = 15 icosapent ethyl; n = 14 placebo.16 (8.9)76 (35)60 (5.7)18 (11)15 (12)−6.0 (6.3)533 (85)<0.0001 ANCHOR§n = 27 icosapent ethyl; n = 31 placebo.12 (6.3)74 (38)66 (4.6)11 (6.5)10 (4.3)2.5 (4.2)619 (65)<0.0001Eicosapentaenoic acid levels are presented as mean (standard deviation). Change from baseline values are least squares mean (standard error).∗ n = 15 icosapent ethyl; n = 13 placebo.† n = 29 icosapent ethyl; n = 32 placebo.‡ n = 15 icosapent ethyl; n = 14 placebo.§ n = 27 icosapent ethyl; n = 31 placebo. Open table in a new tab Eicosapentaenoic acid levels are presented as mean (standard deviation). Change from baseline values are least squares mean (standard error). TEAEs were reported in 5 (27.8%) and 11 (61.1%) women treated with icosapent ethyl 4 g/day and placebo, respectively, in MARINE. TEAEs were reported in 46 (50.5%) and 42 women (47.7%) treated with icosapent ethyl 4 g/day and placebo, respectively, in ANCHOR. Arthralgia is the most commonly reported adverse reaction listed in the icosapent ethyl prescribing information8Vascepa [package Insert]. Amarin Pharma Inc., Bedminster, NJ2016Google Scholar; myalgia is an adverse reaction of particular interest for icosapent ethyl use in addition to a statin given the safety profile of statins with respect to this symptom. In the original MARINE study, TEAEs occurring in >3% of patients in any group included nausea, diarrhea, and eructation; none of these TEAEs occurred with greater frequency in the icosapent ethyl 4 g/day group than in the placebo group.9Bays H.E. Ballantyne C.M. Kastelein J.J. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 682-690Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar In the subgroup of women from MARINE, no patients in the icosapent ethyl 4 g/day group experienced any of these TEAEs, arthralgia, or myalgia. In the original ANCHOR study, TEAEs occurring in >3% of patients in any group included nausea, diarrhea, nasopharyngitis, and arthralgia and only arthralgia occurred with greater frequency in the icosapent ethyl 4 g/day group than in the placebo group.10Ballantyne C.M. Bays H.E. Kastelein J.J. Stein E. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 984-992Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar In the subgroup of women from ANCHOR (placebo and icosapent ethyl 4 g/day groups, respectively), 2 (2.3%) and 3 (3.3%) experienced nausea, 7 (8.0%) and 5 (5.5%) experienced diarrhea, 2 (2.3%) and 1 (1.1%) experienced nasopharyngitis, and 0 and 2 (2.2%) experienced arthralgia. Among women with TGs ≥500 mg/dl at risk for pancreatitis (MARINE study) and women on stable statin therapy with TGs ≥200 and <500 mg/dl at elevated risk of CVD (ANCHOR study), icosapent ethyl 4 g/day was shown to significantly reduce TG levels without a subsequent increase in LDL-C levels. Icosapent ethyl 4 g/day produced generally favorable effects on the other atherogenic lipid, lipoprotein, and inflammatory parameters in women in both studies and was well tolerated. The reductions in lipid and lipoprotein parameters in these subgroups of women from the MARINE and ANCHOR studies were generally comparable with those observed in the overall study populations.9Bays H.E. Ballantyne C.M. Kastelein J.J. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 682-690Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 10Ballantyne C.M. Bays H.E. Kastelein J.J. Stein E. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 984-992Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 15Ballantyne C.M. Bays H.E. Braeckman R.A. Philip S. Stirtan W.G. Doyle Jr., R.T. Soni P.N. Juliano R.A. Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies.J Clin Lipidol. 2016; 10: 635-645Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 16Ballantyne C.M. Bays H.E. Philip S. Doyle R.T.J. Braeckman R.A. Stirtan W.G. Soni P.N. Juliano R.A. Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies.Atherosclerosis. 2016; 253: 81-87Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar The reductions in inflammatory parameters in women were also generally comparable with those observed in the overall populations in the MARINE and ANCHOR studies.11Bays H.E. Ballantyne C.M. Braeckman R.A. Stirtan W.G. Soni P.N. 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. 2013; 13: 37-46Crossref PubMed Scopus (105) Google Scholar The observed reductions in levels of TG and other atherogenic parameters, along with the known beneficial effects of EPA on multiple cellular and molecular mechanisms involved in the development and progression of atherosclerosis,17Borow K.M. Nelson J.R. Mason R.P. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.Atherosclerosis. 2015; 242: 357-366Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar support the biologic plausibility of EPA as a treatment that may have cardiovascular benefits in women. The Japan EPA Lipid Intervention Study conducted among 18,645 statin-treated patients demonstrated a 19% relative reduction in major coronary events (p = 0.011) in patients taking 1.8 g/day EPA ethyl esters compared with controls.18Yokoyama M. Origasa H. Matsuzaki M. Matsuzawa Y. Saito Y. Ishikawa Y. Oikawa S. Sasaki J. Hishida H. Itakura H. Kita T. Kitabatake A. Nakaya N. Sakata T. Shimada K. Shirato K. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.Lancet. 2007; 369: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (1936) Google Scholar Effects in women (69% of total group) and men (31%) were comparable (p = 0.43 for interaction).18Yokoyama M. Origasa H. Matsuzaki M. Matsuzawa Y. Saito Y. Ishikawa Y. Oikawa S. Sasaki J. Hishida H. Itakura H. Kita T. Kitabatake A. Nakaya N. Sakata T. Shimada K. Shirato K. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.Lancet. 2007; 369: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (1936) Google Scholar Icosapent ethyl is a high-concentration EPA prescription product and its biologic effects may differ from dietary supplements and other prescription omega-3 fatty acid products that contain variable amounts of EPA and the omega-3 fatty acid docosahexaenoic acid (DHA), which may increase LDL-C levels in some patients.19Zargar A. Ito M.K. Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database.Metab Syndr Relat Disord. 2011; 9: 255-271Crossref PubMed Scopus (33) Google Scholar, 20Hilleman D. Smer A. Prescription omega-3 fatty acid products and dietary supplements are not interchangeable.Manag Care. 2016; : 46-52BGoogle Scholar, 21Kleiner A.C. Cladis D.P. Santerre C.R. A comparison of actual versus stated label amounts of EPA and DHA in commercial omega-3 dietary supplements in the United States.J Sci Food Agric. 2015; 95: 1260-1267Crossref PubMed Scopus (61) Google Scholar Potential mechanisms for the LDL-C increase observed with DHA, but not EPA, include differences in how EPA and DHA affect LDL clearance (DHA has been found to increase cholesteryl ester transfer protein activity and decrease LDL receptor expression in an animal model22Ishida T. Ohta M. Nakakuki M. Kami H. Uchiyama R. Kawano H. Notsu T. Imada K. Shimano H. Distinct regulation of plasma LDL cholesterol by eicosapentaenoic acid and docosahexaenoic acid in high fat diet-fed hamsters: participation of cholesterol ester transfer protein and LDL receptor.Prostaglandins Leukot Essent Fatty Acids. 2013; 88: 281-288Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar and to downregulate the LDL receptor gene in humans23Dawson K. Zhao L. Adkins Y. Vemuri M. Rodriguez R.L. Gregg J.P. Kelley D.S. Hwang D.H. Modulation of blood cell gene expression by DHA supplementation in hypertriglyceridemic men.J Nutr Biochem. 2012; 23: 616-621Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar), DHA-mediated increased conversion of VLDL to LDL, and DHA-mediated increased LDL particle size.24Jacobson T.A. Glickstein S.B. Rowe J.D. Soni P.N. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review.J Clin Lipidol. 2012; 6: 5-18Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar Omega-3 fatty acid dietary supplements have been documented to not only have variable/inconsistent amounts of omega 3 fatty acids but also high saturated fat content and oxidation products.19Zargar A. Ito M.K. Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database.Metab Syndr Relat Disord. 2011; 9: 255-271Crossref PubMed Scopus (33) Google Scholar, 20Hilleman D. Smer A. Prescription omega-3 fatty acid products and dietary supplements are not interchangeable.Manag Care. 2016; : 46-52BGoogle Scholar, 21Kleiner A.C. Cladis D.P. Santerre C.R. A comparison of actual versus stated label amounts of EPA and DHA in commercial omega-3 dietary supplements in the United States.J Sci Food Agric. 2015; 95: 1260-1267Crossref PubMed Scopus (61) Google Scholar As expected, the significant increase in plasma and RBC EPA levels observed with icosapent ethyl treatment among women in these subgroup analyses was comparable with previous reports13Braeckman R.A. Manku M.S. Bays H.E. Stirtan W.G. Soni P.N. Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on plasma and red blood cell fatty acids in patients with very high triglyceride levels (results from the MARINE study).Prostaglandins Leukot Essent Fatty Acids. 2013; 89: 195-201Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 14Braeckman R.A. Stirtan W.G. Soni P.N. Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects.Clin Pharmacol Drug Dev. 2014; 3: 101-108Crossref PubMed Scopus (36) Google Scholar, 25Bays H.E. Ballantyne C.M. Doyle Jr., R.T. Juliano R.A. Philip S. Icosapent ethyl: eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies.Prostaglandins Other Lipid Mediat. 2016; 125: 57-64Crossref PubMed Scopus (32) Google Scholar and is consistent with the observed therapeutic effects. The safety profile of icosapent ethyl observed among women in these subanalyses was similar to that in the overall MARINE and ANCHOR study populations.9Bays H.E. Ballantyne C.M. Kastelein J.J. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 682-690Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 10Ballantyne C.M. Bays H.E. Kastelein J.J. Stein E. Isaacsohn J.L. Braeckman R.A. Soni P.N. 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: 984-992Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar As there are very little data available regarding the safety and lipid-lowering efficacy of prescription omega-3 fatty acid therapies in women, this analysis helps to address this gap. An important limitation of the current subgroup analyses is that differences in the MARINE and ANCHOR study populations precluded pooling of data. Thus, the findings are based on relatively small samples of women. The clinical implications of lowering TG levels with icosapent ethyl 4 g/day need confirmation. The large ongoing cardiovascular outcomes trial, REDUCtion of Cardiovascular Events With Eicosapentaenoic Acid [EPA]–Intervention Trial (REDUCE-IT), should help to address this; notably, subanalyses in women will be needed.26A study of AMR101 to evaluate its ability to reduce cardiovascular events in high risk patients with hypertriglyceridemia and on statin (REDUCE-IT). ClinicalTrials gov: Available at: https://clinicaltrials.gov/show/NCT01492361. Accessed on August 31, 2016.Google Scholar This analysis was designed, sponsored, and funded by Amarin Pharma, Inc. Medical writing assistance was provided by Peloton Advantage, LLC (Parsippany, New Jersey), and funded by Amarin Pharma, Inc. Dr. Mosca has provided consultancy services for Amarin Pharma, Inc., Aralez (New York, New York), and CocoaVia (Germantown, Maryland). Dr. Ballantyne has received research/grant support from Abbott Diagnostics (Abbott Park, Illinois), Amarin Pharma Inc., Amgen (Thousand Oaks, California), Eli Lilly (Indianapolis, Indiana), Esperion (Plymouth, Michigan), Ionis (Carlsbad, California), Novartis Pharmaceuticals Corp. (East Hanover, New Jersey), Otsuka (Rockville, Maryland), Pfizer (New York, New York), Regeneron (Tarrytown, New York), Roche Diagnostic (Indianapolis, Indiana), Sanofi-Synthelabo (Paris, France), Takeda (San Diego, California), National Institutes of Health (Bethesda, Maryland), American Diabetes Association (Alexandria, Virginia), and American Heart Association (Dallas, Texas, all paid to institution, not individual) and is a consultant for Abbott Diagnostics, Amarin Pharma Inc., Amgen, AstraZeneca (Wilmington, Delaware), Eli Lilly, Esperion, Genzyme (Cambridge, Massachusetts), Matinas Biopharma (Bedminster, New Jersey), Merck & Co. (Whitehouse Station, New Jersey), Novartis Pharmaceuticals Corp., Pfizer, Regeneron, Roche Diagnostics, and Sanofi-Synthelabo. Dr. Bays owns no pharmaceutical stocks or patents. Dr. Bays' research site has received research grants from Amarin Pharma Inc., Amgen, Ardea Biosciences (San Diego, California), Arisaph (Boston, Massachusetts), AstraZeneca, Bristol-Meyers Squibb (New York, New York), Catabasis (Cambridge, Massachusetts), Cymabay Therapeutics (Newark, California), Eisai (Woodcliff Lake, New Jersey), Elcelyx (San Diego, California), Eli Lilly, Esperion, Ferrer/Chiltern (Wilmington, North Carolina), Gilead (Foster City, California), GlaxoSmithKline (Philadelphia, Pennsylvania), Hanmi (Seoul, Korea), Hisun (Princeton, New Jersey), Hoffman LaRoche (South San Francisco, California), Janssen (Titusville, New Jersey), Johnson & Johnson (New Brunswick, New Jersey), Kowa (Torrance, California), Merck & Co., Nektar (San Francisco, California), Novartis Pharmaceuticals Corp., NovoNordisk (Plainsboro, New Jersey), Omthera (Princeton, New Jersey), Orexigen (La Jolla, California), Pfizer, Pronova (Miami, Florida), Regeneron, Sanofi (Bridgewater, New Jersey), Takeda, and TIMI (Boston, Massachusetts). Dr. Bays has served as a consultant/advisor for Akcea (Cambridge, Massachusetts), Alnylam (Cambridge, Massachusetts), Amgen, AstraZeneca, Catabasis, Eli Lilly, Ionis, Janssen, Johnson & Johnson, Merck & Co., Novartis Pharmaceuticals Corp., Pronova, Regeneron, Sanofi, and Takeda and as a speaker for Amarin Pharma Inc., Amgen, Astra Zeneca, Eisai, Orexigen, Regeneron, Sanofi, and Takeda. Dr. Guyton has received research/grant support from Amarin Pharma Inc., Amgen, Regeneron, and Sanofi and has provided advisory services for Amgen and the FH Foundation (Pasadena, California). Dr. Philip, Mr. Doyle, and Dr. Juliano are employees and stock shareholders of Amarin Pharma Inc." @default.
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• W2546771350 title "Usefulness of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) in Women to Lower Triglyceride Levels (Results from the MARINE and ANCHOR Trials)" @default.
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