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Cited by 29Fatty Acid Research and HealthAtrial Fibrillation Management and OutcomesAcute Myocardial Infarction Research

Cardiovascular benefits of icosapent ethyl in patients with and without atrial fibrillation in REDUCE-IT

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Olshansky, Brian, Bhatt, Deepak L., Miller, Michael, Steg, Ph. Gabriel, Brinton, Eliot A., Jacobson, Terry A., Ketchum, Steven B., Doyle, Ralph T. +8 more·2023·Journal of the American Heart Association
DOI 10.1161/jaha.121.026756PMC PMC10111466
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Abstract

Background: In REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), icosapent ethyl (IPE) versus placebo) reduced cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization, but was associated with increased atrial fibrillation/atrial flutter (AF) hospitalization (3.1% IPE versus 2.1% placebo; P =0.004). Methods and Results: We performed post hoc efficacy and safety analyses of patients with or without prior AF (before randomization) and with or without in‐study time‐varying AF hospitalization to assess relationships of IPE (versus placebo) and outcomes. In‐study AF hospitalization event rates were higher in patients with prior AF (12.5% versus 6.3%, IPE versus placebo; P =0.007) versus without prior AF (2.2% versus 1.6%, IPE versus placebo; P =0.09). Serious bleeding rates trended higher in patients with (7.3% versus 6.0%, IPE versus placebo; P =0.59) versus without prior AF (2.3% versus 1.7%, IPE versus placebo; P =0.08). With IPE, serious bleeding trended higher regardless of prior AF (interaction P value [ P int ]=0.61) or postrandomization AF hospitalization ( P int =0.66). Patients with prior AF (n=751, 9.2%) versus without prior AF (n=7428, 90.8%) had similar relative risk reductions of the primary composite and key secondary composite end points with IPE versus placebo ( P int =0.37 and P int =0.55, respectively). Conclusions: In REDUCE‐IT, in‐study AF hospitalization rates were higher in patients with prior AF especially in those randomized to IPE. Although serious bleeding trended higher in those randomized to IPE versus placebo over the course of the study, serious bleeding was not different regardless of prior AF or in‐study AF hospitalization. Patients with prior AF or in‐study AF hospitalization had consistent relative risk reductions across primary, key secondary, and stroke end points with IPE. Registration: URL: https://clinicaltrials.gov/ct2/show/NCT01492361 ; Unique Identifier: NCT01492361

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  • In the REDUCE-IT trial, high-dose EPA (4,000 mg/d) reduced relative risk of stroke by 28% despite increasing relative risk of AF by 35%.

    “Similarly, in the REDUCE-IT trial69, 125, which was comprised of high-CVD risk patients, high-dose EPA (4,000 mg/d) reduced relative risk of stroke by 28% despite increasing relative risk of AF by 35%126.”

    From Effects of Omega-3 Fatty Acid Treatment on Risk for Atrial Fibrillation: An Updated Meta-Analysis of 35 Trials including 114 592 Individuals (2026) · cites this paper as [69]

    The introductory passage (page unavailable) reports that REDUCE-IT tested icosapent ethyl at 4 g/day in patients with cardiovascular risk and reduced stroke by 28%. The Results (page unavailable) report more AF hospitalizations with treatment (3.1% versus 2.1%), but do not establish a 35% increase in relative risk of AF overall; the reported HR of 1.33 applies only to patients without prior AF, and the paper notes that AF events not requiring hospitalization could not be assessed. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • For high-risk individuals with a history of AF, Olshansky et al. reported a non-significantly higher risk for developing AF on EPA than similar patients in REDUCE-IT without a history of AF.

    “Still, for high-risk individuals with a history of AF, Olshansky et al. reported a non-significantly higher risk for developing AF on EPA than similar patients in REDUCE-IT without a history of AF69.”

    From Effects of Omega-3 Fatty Acid Treatment on Risk for Atrial Fibrillation: An Updated Meta-Analysis of 35 Trials including 114 592 Individuals (2026) · cites this paper as [69]

    The Results report that the risk of AF hospitalization with icosapent ethyl appeared higher among patients with prior AF than among those without it, but the difference between subgroups was not statistically significant (interaction P=0.21). The claim calls this a risk of developing AF; the Limitations clarify that AF was adjudicated only when hospitalization occurred, not that all AF episodes were assessed. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In REDUCE-IT, the 1.0% absolute increase in AF hospitalization with 4 g/day EPA was offset by a 4.8% absolute reduction in MACE.

    “For example, in REDUCE-IT, the 1.0% absolute increase in AF hospitalization with 4 g/day EPA was offset by a 4.8% absolute reduction in MACE69”

    From Effects of Omega-3 Fatty Acid Treatment on Risk for Atrial Fibrillation: An Updated Meta-Analysis of 35 Trials including 114 592 Individuals (2026) · cites this paper as [69]

  • Across several major RCTs (REDUCE-IT, RESPECT-EPA, GISSI-HF, ASCEND), the magnitude of CV benefit equaled or exceeded the observed increase in AF risk.

    “Across several major RCTs, such as REDUCE-IT69, 125, RESPECT-EPA76, GISSI-HF77 and ASCEND79, 105; the magnitude of CV benefit equaled or exceeded the observed increase in AF risk.”

    From Effects of Omega-3 Fatty Acid Treatment on Risk for Atrial Fibrillation: An Updated Meta-Analysis of 35 Trials including 114 592 Individuals (2026) · cites this paper as [69]

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Research works printed but not linked: 35

  1. [1]Lombardi M, Chiabrando JG, Vescovo GM, Bressi E, Del Buono MG, Carbone S, Koenig RA, Van Tassell BW, Abbate A, Biondi‐Zoccai G, et al. Impact of different doses of omega‐3 fatty acids on cardiovascular outcomes: a pairwise and network meta‐analysis. Curr Atheroscler Rep. 2020; 22: 45. doi: 10.1007/s11883-020-00865-5 32671519 · DOI · Paper page
  2. [3]Kumar S, Sutherland F, Stevenson I, Lee JM, Garg ML, Sparks PB. Effects of long‐term omega‐3 polyunsaturated fatty acid supplementation on paroxysmal atrial tachyarrhythmia burden in patients with implanted pacemakers: results from a prospective randomised study. Int J Cardiol. 2013; 168: 3812– 3817. doi: 10.1016/j.ijcard.2013.06.030 23890856 · DOI
  3. [4]Sandesara CM, Chung MK, Van Wagoner DR, Barringer TA, Allen K, Ismail HM, Zimmerman B, Olshansky B. A randomized, placebo‐controlled trial of omega‐3 fatty acids for inhibition of supraventricular arrhythmias after cardiac surgery: the FISH trial. J Am Heart Assoc. 2012; 1: e000547. doi: 10.1161/JAHA.111.000547 23130134 PMC3487324 · DOI
  4. [5]Mozaffarian D, Marchioli R, Macchia A, Silletta MG, Ferrazzi P, Gardner TJ, Latini R, Libby P, Lombardi F, O'Gara PT, et al. Fish oil and postoperative atrial fibrillation: the Omega‐3 Fatty Acids for Prevention of Post‐operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012; 308: 2001– 2011. doi: 10.1001/jama.2012.28733 23128104 PMC3694745 · DOI
  5. [7]Saber H, Yakoob MY, Shi P, Longstreth WT Jr, Lemaitre RN, Siscovick D, Rexrode KM, Willett WC, Mozaffarian D. Omega‐3 fatty acids and incident ischemic stroke and its atherothrombotic and cardioembolic subtypes in 3 US cohorts. Stroke. 2017; 48: 2678– 2685. doi: 10.1161/STROKEAHA.117.018235 28830976 PMC5769157 · DOI
  6. [8]Akintoye E, Sethi P, Harris WS, Thompson PA, Marchioli R, Tavazzi L, Latini R, Pretorius M, Brown NJ, Libby P, et al. Fish oil and perioperative bleeding. Circ Cardiovasc Qual Outcomes. 2018; 11: e004584. doi: 10.1161/CIRCOUTCOMES.118.004584 30571332 PMC6376981 · DOI
  7. [9]Begtrup KM, Krag AE, Hvas AM. No impact of fish oil supplements on bleeding risk: a systematic review. Dan Med J. 2017; 64: A5366. Accessed January 26, 2023. https://www.omega3galil.com/wp‐content/uploads/2017/06/no‐impact‐on‐bleding‐denmark‐2017‐002.pdf 28552094
  8. [13]Boden WE, Bhatt DL, Toth PP, Ray KK, Chapman MJ, Luscher TF. Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE‐IT trial: why these results usher in a new era in dyslipidaemia therapeutics. Eur Heart J. 2020; 41: 2304– 2312. doi: 10.1093/eurheartj/ehz778 31872245 PMC7308541 · DOI
  9. [16]Olshansky B, Bhatt DL, Chung MK. Omega‐3 fatty acids effect on major cardiovascular events in patients at high cardiovascular risk. JAMA. 2021; 325: 1332– 1333. doi: 10.1001/jama.2021.0824 33821905 · DOI
  10. [18]Bhatt DL. REDUCE‐IT: residual cardiovascular risk in statin‐treated patients with elevated triglycerides: now we can REDUCE‐IT! Eur Heart J. 2019; 40: 1174– 1175. doi: 10.1093/eurheartj/ehz179 30982067 · DOI · Paper page
  11. [19]Peterson BE, Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Juliano RA, Jiao L, Doyle RT Jr, et al. Reduction in revascularization with icosapent ethyl: insights from REDUCE‐IT revascularization analyses. Circulation. 2021; 143: 33– 44. doi: 10.1161/CIRCULATIONAHA.120.050276 33148016 PMC7752247 · DOI · Paper page
  12. [20]Wang X, Verma S, Mason RP, Bhatt DL. The road to approval: a perspective on the role of icosapent ethyl in cardiovascular risk reduction. Curr Diab Rep. 2020; 20: 65. doi: 10.1007/s11892-020-01343-7 33095318 PMC7584545 · DOI · Paper page
  13. [21]Gaba P, Bhatt DL, Giugliano RP, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Juliano RA, Jiao L, et al. Comparative reductions in investigator‐reported and adjudicated ischemic events in REDUCE‐IT. J Am Coll Cardiol. 2021; 78: 1525– 1537. doi: 10.1016/j.jacc.2021.08.009 34620410 · DOI
  14. [22]Sarrazin JF, Comeau G, Daleau P, Kingma J, Plante I, Fournier D, Molin F. Reduced incidence of vagally induced atrial fibrillation and expression levels of connexins by n‐3 polyunsaturated fatty acids in dogs. J Am Coll Cardiol. 2007; 50: 1505– 1512. doi: 10.1016/j.jacc.2007.05.046 17919572 · DOI
  15. [23]Ferrier GR, Redondo I, Zhu J, Murphy MG. Differential effects of docosahexaenoic acid on contractions and L‐type Ca2+ current in adult cardiac myocytes. Cardiovasc Res. 2002; 54: 601– 610. doi: 10.1016/S0008-6363(02)00275-4 12031706 · DOI
  16. [24]Mozaffarian D, Wu JH. Omega‐3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011; 58: 2047– 2067. doi: 10.1016/j.jacc.2011.06.063 22051327 · DOI · Paper page
  17. [25]Guizy M, David M, Arias C, Zhang L, Cofan M, Ruiz‐Gutierrez V, Ros E, Lillo MP, Martens JR, Valenzuela C. Modulation of the atrial specific Kv1.5 channel by the n‐3 polyunsaturated fatty acid, alpha‐linolenic acid. J Mol Cell Cardiol. 2008; 44: 323– 335. 18155022
  18. [26]Moreno C, de la Cruz A, Valenzuela C. In‐depth study of the interaction, sensitivity, and gating modulation by PUFAs on K(+) channels; interaction and new targets. Front Physiol. 2016; 7: 578. Accessed January 26, 2023. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121229/ 27933000 PMC5121229
  19. [27]Xiao YF, Ma L, Wang SY, Josephson ME, Wang GK, Morgan JP, Leaf A. Potent block of inactivation‐deficient Na+ channels by n‐3 polyunsaturated fatty acids. Am J Physiol Cell Physiol. 2006; 290: C362– C370. doi: 10.1152/ajpcell.00296.2005 16207794 · DOI
  20. [28]Ander BP, Hurtado C, Raposo CS, Maddaford TG, Deniset JF, Hryshko LV, Pierce GN, Lukas A. Differential sensitivities of the NCX1.1 and NCX1.3 isoforms of the Na+–Ca2+ exchanger to alpha‐linolenic acid. Cardiovasc Res. 2007; 73: 395– 403. doi: 10.1016/j.cardiores.2006.09.013 17059813 · DOI
  21. [29]Li GR, Sun HY, Zhang XH, Cheng LC, Chiu SW, Tse HF, Lau CP. Omega‐3 polyunsaturated fatty acids inhibit transient outward and ultra‐rapid delayed rectifier K+currents and Na+current in human atrial myocytes. Cardiovasc Res. 2009; 81: 286– 293. doi: 10.1093/cvr/cvn322 19029136 · DOI
  22. [30]London B, Albert C, Anderson ME, Giles WR, Van Wagoner DR, Balk E, Billman GE, Chung M, Lands W, Leaf A, et al. Omega‐3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements, Omega‐3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop. Circulation. 2007; 116: e320– e335. doi: 10.1161/CIRCULATIONAHA.107.712984 17768297 · DOI
  23. [31]Den Ruijter HM, Berecki G, Opthof T, Verkerk AO, Zock PL, Coronel R. Pro‐ and antiarrhythmic properties of a diet rich in fish oil. Cardiovasc Res. 2007; 73: 316– 325. doi: 10.1016/j.cardiores.2006.06.014 16859661 · DOI
  24. [32]Den Ruijter HM, Berecki G, Verkerk AO, Bakker D, Baartscheer A, Schumacher CA, Belterman CN, de Jonge N, Fiolet JW, Brouwer IA, et al. Acute administration of fish oil inhibits triggered activity in isolated myocytes from rabbits and patients with heart failure. Circulation. 2008; 117: 536– 544. doi: 10.1161/CIRCULATIONAHA.107.733329 18195172 · DOI
  25. [33]Xiao YF, Ke Q, Chen Y, Morgan JP, Leaf A. Inhibitory effect of n‐3 fish oil fatty acids on cardiac Na+/Ca2+ exchange currents in HEK293t cells. Biochem Biophys Res Commun. 2004; 321: 116– 123. doi: 10.1016/j.bbrc.2004.06.114 15358223 · DOI
  26. [34]Xiao YF, Ke Q, Wang SY, Yang Y, Chen Y, Wang GK, Morgan JP, Cox B, Leaf A. Electrophysiologic properties of lidocaine, cocaine, and n‐3 fatty‐acids block of cardiac Na+ channels. Eur J Pharmacol. 2004; 485: 31– 41. doi: 10.1016/j.ejphar.2003.11.042 14757121 · DOI
  27. [35]Dujardin KS, Dumotier B, David M, Guizy M, Valenzuela C, Hondeghem LM. Ultrafast sodium channel block by dietary fish oil prevents dofetilide‐induced ventricular arrhythmias in rabbit hearts. Am J Physiol Heart Circ Physiol. 2008; 295: H1414– H1421. doi: 10.1152/ajpheart.01219.2007 18676685 · DOI
  28. [36]Leifert WR, McMurchie EJ, Saint DA. Inhibition of cardiac sodium currents in adult rat myocytes by n‐3 polyunsaturated fatty acids. J Physiol. 1999; 520(Pt 3): 671– 679. doi: 10.1111/j.1469-7793.1999.00671.x 10545135 PMC2269607 · DOI
  29. [37]Kumar S, Sutherland F, Teh AW, Heck PM, Lee G, Garg ML, Sparks PB. Effects of chronic omega‐3 polyunsaturated fatty acid supplementation on human pulmonary vein and left atrial electrophysiology in paroxysmal atrial fibrillation. Am J Cardiol. 2011; 108: 531– 535. doi: 10.1016/j.amjcard.2011.03.082 21624541 · DOI
  30. [38]Kumar S, Sutherland F, Wheeler M, Heck PM, Lee G, Teh AW, Garg ML, Morgan JG, Sparks PB. Effects of chronic omega‐3 polyunsaturated fatty acid supplementation on human atrial mechanical function after reversion of atrial arrhythmias to sinus rhythm: reversal of tachycardia‐mediated atrial cardiomyopathy with fish oils. Heart Rhythm. 2011; 8: 643– 649. doi: 10.1016/j.hrthm.2011.01.014 21232631 · DOI
  31. [39]Kumar S, Sutherland F, Lee JM, Robinson T, Heck PM, Wong MC, Kelland NF, Garg ML, Sparks PB. Effects of high dose intravenous fish oil on human atrial electrophysiology: implications for possible anti‐ and pro‐arrhythmic mechanisms in atrial fibrillation. Int J Cardiol. 2013; 168: 2754– 2760. doi: 10.1016/j.ijcard.2013.03.053 23602291 · DOI
  32. [40]Kumar S, Sutherland F, Rosso R, Teh AW, Lee G, Heck PM, Feldman A, Medi C, Watt S, Garg ML, et al. Effects of chronic omega‐3 polyunsaturated fatty acid supplementation on human atrial electrophysiology. Heart Rhythm. 2011; 8: 562– 568. doi: 10.1016/j.hrthm.2010.12.017 21147262 · DOI
  33. [42]Albert CM, Cook NR, Pester J, Moorthy MV, Ridge C, Danik JS, Gencer B, Siddiqi HK, Ng C, Gibson H, et al. Effect of marine omega‐3 fatty acid and vitamin D supplementation on incident atrial fibrillation: a randomized clinical trial. JAMA. 2021; 325: 1061– 1073. doi: 10.1001/jama.2021.1489 33724323 PMC7967086 · DOI · Paper page
  34. [44]Myhre PL, Kalstad AA, Tveit SH, Laake K, Schmidt EB, Smith P, Nilsen DWT, Tveit A, Solheim S, Arnesen H, et al. Changes in eicosapentaenoic acid and docosahexaenoic acid and risk of cardiovascular events and atrial fibrillation: a secondary analysis of the OMEMI trial. J Intern Med. 2022; 291: 637– 647. doi: 10.1111/joim.13442 34982486 · DOI
  35. [45]Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, et al. Effect of high‐dose omega‐3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA. 2020; 324: 2268– 2280. doi: 10.1001/jama.2020.22258 33190147 PMC7667577 · DOI · Paper page

Cited by

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Authors
Olshansky, B., Bhatt, D. L., Miller, M., Steg, P. G., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Kowey, P. R., Reiffel, J. A., Tardif, J., Ballantyne, C. M., Chung, M. K., & the REDUCE‐IT Investigators
Affiliations
  • University of Iowa (US)
  • Mount Sinai Health System (US)
  • Hospital of the University of Pennsylvania (US)
  • French Alliance for Cardiovascular Trials, Hôpital Bichat Paris France
  • Utah Lipid Center Salt Lake City UT USA
  • Emory University (US)
  • Amarin (United States) (US)
  • Lankenau Institute for Medical Research (US)
  • Columbia University (US)
  • Montreal Heart Institute (CA)
  • Baylor College of Medicine (US)
  • Cleveland Clinic (US)
Corresponding author
Olshansky, Brian
ORCID
Venue
Journal of the American Heart Association
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-03-07
Volume
12
Issue
5
Pages
e026756-e026756
ISSN
2047-9980 (ISSN-L)
DOI
10.1161/jaha.121.026756
PMC
PMC10111466
OpenAlex
W4321455716
Cited by
29
References
10
Citations by year
2026: 5 · 2025: 9 · 2024: 12 · 2023: 3
FWCI
5.09
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Journal of the American Heart Association (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Veterans Affairs (IK6 BX006185)
  • Amgen
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Sanofi
  • Yale University
  • University of Pennsylvania
  • George Washington University
  • Syracuse University
  • Wake Forest University
  • Joslin Diabetes Center
  • Pennsylvania State University
  • CSL Behring
  • Amarin Corporation
  • Yale New Haven Hospital
  • Belvoir Media Group
  • York University
  • Novo Nordisk
  • Servier
  • Idorsia Pharmaceuticals
  • National Institutes of Health
  • School of Medicine, New York University
  • National Heart, Lung, and Blood Institute (R01HL111314, R01HL158071, P01HL158502)
  • Duke Clinical Research Institute
  • Daiichi Sankyo Europe
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
Keywords
icosapent ethyl, omega-3 fatty acids, atrial fibrillation, major bleeding, cardiovascular events, REDUCE-IT trial, eicosapentaenoic acid, myocardial infarction, coronary revascularization, unstable angina, cardiovascular mortality, time-varying covariates
MeSH terms
Atrial Fibrillation, Humans, Risk Factors, Eicosapentaenoic Acid, Treatment Outcome, Stroke

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