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Impact of Different Doses of Omega-3 Fatty Acids on Cardiovascular Outcomes: a Pairwise and Network Meta-analysis

  • Evidence-Based Medicine, Clinical Trials and Their Interpretations (L. Roever,Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Omega-3 fatty acid (O3FA) supplementation has shown conflicting evidence regarding its benefit in cardiovascular events. We performed a pairwise and network meta-analysis to elucidate the benefit of different doses of O3FA supplementation in cardiovascular prevention.

Recent Findings

Fourteen studies were identified providing data on 125,763 patients. A prespecified cut-off value of < 1 g per day was set for low-dose (LD) O3FA and > 1 g per day for high-dose (HD) O3FA. The efficacy outcomes of interest were total death, cardiac death, sudden cardiac death, myocardial infarction, stroke, coronary revascularization, unstable angina, and major vascular events. Safety outcomes of interest were bleeding, gastrointestinal disturbances, and atrial fibrillation events. HD treatment was associated with a lower risk of cardiac death (IRR 0.79, 95% CI [0.65–0.96], p = 0.03 versus control), myocardial infarction (0.71 [0.62–0.82], p < 0.0001 versus control and 0.79 [0.67–0.92], p = 0.003 versus LD), coronary revascularization (0.74 [0.66–0.83], p < 0.0001 versus control and 0.74 [0.66–0.84], p < 0.0001 versus LD), unstable angina (0.73 [0.62–0.86], p = 0.0001 versus control and 0.74 [0.62–0.89], p = 0.002 versus LD), and major vascular events (0.78 [0.71–0.85], p < 0.0001 versus control and 0.79 [0.72–0.88], p < 0.0001 versus LD). HD treatment was associated with increased risk for bleeding events (1.49 [1.2–1.84], p = 0.0002 versus control and 1.63 [1.16–2.3], p = 0.005 versus LD) and increased atrial fibrillation events compared to control (1.35 [1.1–1.66], p = 0.004).

Summary

HD O3FA treatment was associated with lower cardiovascular events compared to LD and to control, but increased risk for bleeding and atrial fibrillation events.

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Abbreviations

CENTRAL:

Cochrane Central Register of Controlled Trials

95% CI:

95% Confidence interval

CVD:

Cardiovascular disease

DHA:

Docosahexaenoic acid

EPA:

Eicosapentaenoic acid

FDA:

Food and Drug Administration

HD:

High dose

HDL-C:

High-density lipoprotein cholesterol

IQR:

Interquartile range

IRR:

Incidence rate ratio

LD:

Low dose

LDL-C:

Low-density lipoprotein cholesterol

O3FA:

Omega-3 fatty acids

PCSK9:

Proprotein convertase subtilisin-kexin type 9

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-analysis

RCT:

Randomized clinical trial

TG:

Triglyceride

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics—2017. Update. 135:2017. https://doi.org/10.1161/CIR.0000000000000485.Heart.

  2. Sacks FM, Lichtenstein AH, Wu JHY, et al. Dietary fats and cardiovascular disease: a presidential advisory from the American Heart Association. Circulation. 2017;136(3). https://doi.org/10.1161/CIR.0000000000000510.

  3. Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet. 2010;376(9740):540–50. https://doi.org/10.1016/S0140-6736(10)60445-X.

    Article  CAS  PubMed  Google Scholar 

  4. Chang CL, Deckelbaum RJ. Omega-3 fatty acids: mechanisms underlying ‘protective effects’ in atherosclerosis. Curr Opin Lipidol. 2013;24(4):345–50. https://doi.org/10.1097/MOL.0b013e3283616364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Elagizi A, Lavie CJ, Marshall K, DiNicolantonio JJ, O'Keefe JH, Milani RV. Omega-3 polyunsaturated fatty acids and cardiovascular health : a comprehensive review. Prog Cardiovasc Dis. 2018;61(1):76–85. https://doi.org/10.1016/j.pcad.2018.03.006.

    Article  PubMed  Google Scholar 

  6. Biondi-Zoccai G. In: Biondi-Zoccai G, editor. Network meta-analysis: evidence synthesis with mixed treatment comparison. New York: Nova publishers; 2014.

    Google Scholar 

  7. • Lombardi M, Chiabrando JG, Vescovo GM, et al. Efficacy of different dose of omega 3 fatty acid on cardiovascular outcomes: rationale and design of a network meta-analysis. Minerva Cardioangiol. 2020;68:47–50. https://doi.org/10.23736/S0026-4725.19.05117-XRationale and design of the present meta-analysis.

    Article  PubMed  Google Scholar 

  8. Haynes RB, Wilczynski NL. Optimal search strategies for retrieving scientifically strong studies of diagnosis from Medline: analytical survey. Br Med J. 2004;328(7447):1040–2. https://doi.org/10.1136/bmj.38068.557998.ee.

    Article  Google Scholar 

  9. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:1–8. https://doi.org/10.1136/bmj.l4898.

    Article  Google Scholar 

  10. • Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22. https://doi.org/10.1056/NEJMoa1812792In REDUCE-IT among patients with high trygliceride levels the risk of ischemic events was significantly lower among those who received 4 g/daily of O3FA.

    Article  CAS  PubMed  Google Scholar 

  11. Kromhout D, Giltay EJ, Geleijnse JM. For the AOTG. N-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363:2015–26. https://doi.org/10.1056/nejmc1014112.

    Article  CAS  PubMed  Google Scholar 

  12. Bowman L, Mafham M, Wallendszus K, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540–50. https://doi.org/10.1056/NEJMoa1804989.

    Article  CAS  PubMed  Google Scholar 

  13. Manson JAE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380(1):23–32. https://doi.org/10.1056/NEJMoa1811403.

    Article  CAS  PubMed  Google Scholar 

  14. 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. 2008;372(9645):1223–30. https://doi.org/10.1016/S0140-6736(08)61239-8.

    Article  CAS  Google Scholar 

  15. Marchioli R. Dietary supplementation with N-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354(9177):447–55. https://doi.org/10.1016/S0140-6736(99)07072-5.

    Article  Google Scholar 

  16. • 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):1090–8. https://doi.org/10.1016/S0140-6736(07)60527-3JELIS trial demonstrated tha 1.8 g/daily of EPA is protective for prevention of coronary events in Japanese hypercholesterolaemic patients.

    Article  CAS  PubMed  Google Scholar 

  17. Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, et 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. 2010;122:2152–9. https://doi.org/10.1161/CIRCULATIONAHA.110.948562.

    Article  CAS  PubMed  Google Scholar 

  18. Einvik G, Ole Klemsdal T, Sandvik L, Hjerkinn EM. A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk. Eur J Prev Cardiol. 2010;17(5):588–92. https://doi.org/10.1097/HJR.0b013e328339cc70.

    Article  Google Scholar 

  19. Bonds DE, Harrington M, Worrall BB, et al. Effect of long-chain ω-3 fatty acids and lutein+zeaxanthin supplements on cardiovascular outcomes: results of the age-related eye disease study 2 (AREDS2) randomized clinical trial. JAMA Intern Med. 2014;174(5):763–71. https://doi.org/10.1001/jamainternmed.2014.328.

    Article  CAS  PubMed  Google Scholar 

  20. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S, et al. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. Bmj. 2011;342(7787):36. https://doi.org/10.1136/bmj.c6273.

    Article  Google Scholar 

  21. Roncaglioni MC, Tombesi M, Avanzini F, et al. N-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19):1800–8. https://doi.org/10.1056/NEJMoa1205409.

    Article  CAS  PubMed  Google Scholar 

  22. Bosch J, Gerstein HC, Dagenais GR, et al. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309–18. https://doi.org/10.1056/NEJMoa1203859.

    Article  CAS  PubMed  Google Scholar 

  23. Brouwer IA, Zock PL, Camm AJ, Böcker D, Hauer RN, Wever EF, et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients. Jama. 2006;295(22):2613–9.

    Article  CAS  Google Scholar 

  24. Wiggins BS, Dixon D, Bellone J, Gasbarro N, Marrs JC, Tran R. Key articles and guidelines in the management of dyslipidemia: 2019 update. J Pharm Pract. 2019:089719001986841. https://doi.org/10.1177/0897190019868413.

  25. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019;2019:1–78. https://doi.org/10.1093/eurheartj/ehz455.

    Article  Google Scholar 

  26. Harris WS. Understanding why REDUCE-IT was positive – mechanistic overview of eicosapentaenoic acid. Prog Cardiovasc Dis. 2019;62(5):401–5. https://doi.org/10.1016/j.pcad.2019.10.008.

    Article  PubMed  Google Scholar 

  27. Bittner V. Implications for REDUCE IT in clinical practice. Prog Cardiovasc Dis. 2019;62(5):395–400. https://doi.org/10.1016/j.pcad.2019.11.003.

    Article  PubMed  Google Scholar 

  28. Shapiro MD, Tavori H, Fazio S. PCSK9 from basic science discoveries to clinical trials. Circ Res. 2018;122(10):1420–38. https://doi.org/10.1161/CIRCRESAHA.118.311227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sheikh O, Vande Hei AG, Battisha A, Al E. Cardiovascular, electrophysiologic, and hematologic effects of omega-3 fatty acids beyond reducing hypertriglyceridemia: as it pertains to the recently published REDUCE-IT trial. Cardiovasc Diabetol. 2019;18(1):1–12. https://doi.org/10.1186/s12933-019-0887-0.

    Article  CAS  Google Scholar 

  30. Wachira JK, Larson MK, Harris WS. N-3 fatty acids affect haemostasis but do not increase the risk of bleeding: clinical observations and mechanistic insights. Br J Nutr. 2014;111(9):1652–62. https://doi.org/10.1017/S000711451300425X.

    Article  CAS  PubMed  Google Scholar 

  31. • Walker RE, Jackson KH, Tintle NL, et al. Predicting the effects of supplemental EPA and DHA on the omega-3 index. Am J Clin Nutr. 2019;110(4):1034–40. https://doi.org/10.1093/ajcn/nqz161This predictive model demonstrated that a dose ≥ 2 g/daily of O3FA is protective against CV events.

    Article  PubMed  Google Scholar 

  32. Hu Y, Hu FB, Manson JE. Marine omega-3 supplementation and cardiovascular disease: an updated meta-analysis of 13 randomized controlled trials involving 127 477 participants. J Am Heart Assoc. 2019;8(19). https://doi.org/10.1161/jaha.119.013543.

  33. Innes JK, Calder PC. The differential effects of eicosapentaenoic acid and docosahexaenoic acid on cardiometabolic risk factors: a systematic review. Int J Mol Sci. 2018;19(2). https://doi.org/10.3390/ijms19020532.

  34. Ito MK. A comparative overview of prescription omega-3 fatty acid products. P T. 2015;40(12):826–836.

  35. • 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):1281–8. https://doi.org/10.1002/clc.23055Ongoing trial regarding high dose O3FA supplementation has been stopped due to futility.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Weintraub WS, Bhatt D, Zhang Z, et al. Cost-effectiveness of icosapent ethyl in US REDUCE-IT patients. J Am Coll Cardiol. 2020;75(11, Suppl 1). https://doi.org/10.1016/S0735-1097(20)32541-9.

  37. Dixon DL, Sharma G, Sandesara PB, Yang E, Braun LT, Mensah GA, et al. Therapeutic inertia in cardiovascular disease prevention: time to move the bar. J Am Coll Cardiol. 2019;74(13):1728–31.

    Article  Google Scholar 

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Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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Authors and Affiliations

  1. VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA

    Marco Lombardi, Edoardo Bressi, Marco Giuseppe Del Buono, Salvatore Carbone, Benjamin W. Van Tassell, Antonio Abbate & Dave L. Dixon

  2. Department of Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart, Rome, Italy

    Marco Lombardi & Marco Giuseppe Del Buono

  3. Interventional Cardiology Service, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

    Juan G. Chiabrando

  4. Health Science Statistics Applied Laboratory (LEACS), Pharmacology and Toxicology Department, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina

    Juan G. Chiabrando

  5. Department of Cardiac Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy

    Giovanni M. Vescovo

  6. Division of Cardiology, Policlinico Casilino, Rome, Italy

    Edoardo Bressi

  7. Department of Kinesiology & Health Sciences, College of Humanities & Sciences, Virginia Commonwealth University, Richmond, VA, USA

    Salvatore Carbone

  8. Tompkins-McCaw Library for the Health Sciences, VCU Libraries Virginia Commonwealth University, Richmond, VA, USA

    Rachel A. Koenig

  9. Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA

    Benjamin W. Van Tassell & Dave L. Dixon

  10. Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy

    Giuseppe Biondi-Zoccai

  11. Mediterranea Cardiocentro, Napoli, Italy

    Giuseppe Biondi-Zoccai

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Contributions

All authors contributed to the conception or design of the work. ML, JGC, GMV, EB, MDB contributed to the acquisition, analysis, or interpretation of data for the work; RK contributed to the acquisition of the data, CS, BVT, DLD contributed to interpretation of the data, AA and GBZ contributed to analysis and interpretation of the data. ML, JGC, GMV, EB, MDB drafted the manuscript. CS, BVT, DLD, AA, GBZ critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

All authors confirm that tables and figures were not published previously.

Corresponding author

Correspondence to Dave L. Dixon.

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Conflict of Interest

None of the authors have any disclosure related to the contents of this paper. Salvatore Carbone is supported by a Career Development Award 19CDA34660318 from the American Heart Association. Marco Lombardi, Juan G. Chiabrando, Giovanni M. Vescovo, Edoardo Bressi, Marco Giuseppe Del Buono, Salvatore Carbone, Rachel Koenig, Benjamin W. Van Tassell, Dave L. Dixon, Antonio Abbate, and Giuseppe Biondi-Zoccai declare they have no conflict of interest.

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Lombardi, M., Chiabrando, J.G., Vescovo, G.M. et al. Impact of Different Doses of Omega-3 Fatty Acids on Cardiovascular Outcomes: a Pairwise and Network Meta-analysis. Curr Atheroscler Rep 22, 45 (2020). https://doi.org/10.1007/s11883-020-00865-5

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