Omega-3 carboxylic acids (OM3-CA) can lower triglyceride levels.
Our objective was to assess the effects of OM3-CA on warfarin pharmacokinetics and pharmacodynamics and on acetylsalicylic acid (ASA)-dependent and independent platelet activation when co-administered with ASA in two phase I studies.
In ECLIPSE II (NCT01431690), 26 participants received warfarin 25 mg on days 1 and 22 and OM3-CA 4 g once daily from day 8 to day 28. In OM-EPA-007 (NCT01486433), 52 participants received simvastatin 40 mg plus ASA 81 mg once daily for 14 days, with or without OM3-CA 4 g. Lack of a drug–drug interaction was indicated when 90% confidence intervals (CIs) fell entirely within the range 80–125% for least-squares mean (LSM) ratios of area under the concentration–time curve (AUC), maximum observed plasma concentration (C max), international normalized ratio (INR) AUC to 168 h and maximum INR.
In ECLIPSE II, 90% CIs for LSM ratios of with:without OM3-CA fell within 80–125% for AUC and C max of S- and R-warfarin enantiomers. The 90% CIs for LSM ratios of with:without OM3-CA fell within 80–125% for INR AUC to 168 h after dosing and for maximum INR of warfarin. In OM-EPA-007, no significant effect of OM3-CA was observed on ASA-dependent or ASA-independent platelet activation. No deaths or serious adverse events occurred in either study.
OM3-CA did not affect the pharmacokinetics or pharmacodynamics of warfarin or the pharmacodynamic effects of ASA. OM3-CA did not affect platelet function when co-administered with ASA.
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Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384(9943):626–35. doi:10.1016/S0140-6736(14)61177-6.
Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor. Cardiovasc Diabetol. 2014;13:159. doi:10.1186/s12933-014-0159-y.
Kastelein JJ, Maki KC, Susekov A, Ezhov M, Nordestgaard BG, Machielse BN, et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. J Clin Lipidol. 2014;8(1):94–106. doi:10.1016/j.jacl.2013.10.003.
Davidson MH, Johnson J, Rooney MW, Kyle ML, Kling DF. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova® compared to Lovaza® in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol. 2012;6(6):573–84. doi:10.1016/j.jacl.2012.01.002.
Offman E, Marenco T, Ferber S, Johnson J, Kling D, Curcio D, et al. Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: the ECLIPSE II study. Vasc Health Risk Manag. 2013;9:563–73. doi:10.2147/VHRM.S50464.
Department of Health and Human Services US Food, and Drug Administration. Substances affirmed as generally recognized as safe: menhaden oil. Fed Regist. 1997;62(108):30751–7.
Harris WS, Windsor SL. N-3 fatty acid supplements reduce chylomicron levels in healthy volunteers. J Appl Nutr. 1991;43(1):5–15.
Jain AP, Aggarwal KK, Zhang PY. Omega-3 fatty acids and cardiovascular disease. Eur Rev Med Pharmacol Sci. 2015;19(3):441–5.
Mortensen JZ, Schmidt EB, Nielsen AH, Dyerberg J. The effect of N-6 and N-3 polyunsaturated fatty acids on hemostasis, blood lipids and blood pressure. Thromb Haemost. 1983;50(2):543–6.
Vanschoonbeek K, de Maat MP, Heemskerk JW. Fish oil consumption and reduction of arterial disease. J Nutr. 2003;133(3):657–60.
Larson MK, Ashmore JH, Harris KA, Vogelaar JL, Pottala JV, Sprehe M, et al. Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects. Thromb Haemost. 2008;100(4):634–41.
Eritsland J, Arnesen H, Seljeflot I, Kierulf P. Long-term effects of n-3 polyunsaturated fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease. Blood Coagul Fibrinolysis. 1995;6(1):17–22.
Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother. 2004;38(1):50–2.
Jalili M, Dehpour AR. Extremely prolonged INR associated with warfarin in combination with both trazodone and omega-3 fatty acids. Arch Med Res. 2007;38(8):901–4. doi:10.1016/j.arcmed.2007.05.004.
Breckenridge A, Orme M, Wesseling H, Lewis RJ, Gibbons R. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther. 1974;15(4):424–30.
Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther. 1997;73(1):67–74.
Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol. 1992;5(1):54–9.
Harder S, Thurmann P. Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet. 1996;30(6):416–44.
BioCytex. PLT VASP/P2Y12 for the monitoring of specific platelet ADP receptor antagonists (test kit brochure). Marseilles, France.
Corgenix Inc. AspirinWorks® test kit brochure.
Gao LG, Cao J, Mao QX, Lu XC, Zhou XL, Fan L. Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized controlled trials. Atherosclerosis. 2013;226(2):328–34. doi:10.1016/j.atherosclerosis.2012.10.056.
McEwen BJ, Morel-Kopp MC, Chen W, Tofler GH, Ward CM. Effects of omega-3 polyunsaturated fatty acids on platelet function in healthy subjects and subjects with cardiovascular disease. Semin Thromb Hemost. 2013;39(1):25–32. doi:10.1055/s-0032-1333309.
Serebruany VL, Miller M, Pokov AN, Lynch D, Jensen JK, Hallen J, et al. Early impact of prescription omega-3 fatty acids on platelet biomarkers in patients with coronary artery disease and hypertriglyceridemia. Cardiology. 2011;118(3):187–94. doi:10.1159/000329300.
Braeckman RA, Stirtan WG, Soni PN. Phase 1 study of the effect of icosapent ethyl on warfarin pharmacokinetic and anticoagulation parameters. Clin Drug Investig. 2014;34(7):449–56. doi:10.1007/s40261-014-0194-1.
Pryce R, Bernaitis N, Davey AK, Badrick T, Anoopkumar-Dukie S. The use of fish oil with warfarin does not significantly affect either the international normalised ratio or incidence of adverse events in patients with atrial fibrillation and deep vein thrombosis: a retrospective study. Nutrients. 2016;8(9):578.
Guirguis-Blake JM, Evans CV, Senger CA, Rowland MG, O’Connor EA, Whitlock EP. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force Rockville (MD): Agency for Healthcare Research and Quality (US); 2015. Report No: 13-05195-EF-1.
Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–60. doi:10.1016/S0140-6736(09)60503-1.
Medical writing support was provided by Dr. Anja Becher of Oxford PharmaGenesis, Oxford, UK, and was funded by AstraZeneca. The authors thank Doug Kling and Judith Johnson for their participation in aspects of the study design, Sandra Connolly for her involvement in the study conduct, and David Katzer for the statistical analyses.
These studies were sponsored by AstraZeneca.
Conflict of interest
Elliot Offman was an employee of Celerion at the time that the manuscript was developed; Celerion received research funding for participation in these studies from Omthera Pharmaceuticals, which is a subsidiary of AstraZeneca. Michael Davidson was an employee of AstraZeneca at the time that the manuscript was developed. Catarina Nilsson is an employee of AstraZeneca.
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Offman, E., Davidson, M. & Nilsson, C. No Effect of Omega-3 Carboxylic Acids on Pharmacokinetics/Pharmacodynamics of Warfarin or on Platelet Function When Co-administered with Acetylsalicylic Acid: Results of Two Phase I Studies in Healthy Volunteers. Am J Cardiovasc Drugs 17, 251–260 (2017). https://doi.org/10.1007/s40256-017-0217-4