Introduction

In the 1970's, around the same time that saturated fat was being linked to a higher risk of cardiovascular disease (CVD), an association between polyunsaturated fat and lower risk of CVD was noted by Bang et al. in the Greenlandic Inuit population.¹ In the subsequent decades, there has been great interest in the potential cardiovascular benefits of polyunsaturated fatty acids, particularly omega-3 polyunsaturated fatty acids (n-3 PUFA). Fish, particularly fatty fish such as salmon and tuna, are rich in two variants of n-3 PUFA: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oil supplements containing various combinations of EPA and DHA are one of the most commonly used supplements in the United States (US),² and while these and other supplements are required by law to state that they are not intended to treat, diagnose, prevent, or cure disease, they frequently are marketed as agents to improve cardiovascular health. While randomized data is typically sparse in the world of supplements, for fish oil we are fortunate to have multiple large, randomized trials, allowing for more definite recommendations on the optimal approach to the intake of n-3 PUFA for cardiovascular health.

Fish Intake and Cardiovascular Risk

The Physician's Health Study prospectively followed 20,551 US male physicians for 11 years and examined the association between fish intake and CVD outcomes.³ The study found individuals who consumed fish one to two times per week had a lower risk of sudden cardiac death than individuals who consumed fish less than once a month. More frequent fish consumption did not confer further CVD benefit. This 'threshold' relationship between dietary fish intake and CVD was seen in other observational studies and a 2006 meta-analysis found that the dietary consumption of approximately 250-500 mg per day of EPA and DHA resulted in a 36% relative risk reduction of cardiovascular death with further risk reduction not seen with a higher intake of EPA and DHA.⁴ Based on these data, a science advisory from the American Heart Association (AHA) in 2018 recommended the consumption of 1-2 servings of fish per week, ideally replacing less healthy foods.⁵

Fish Oil Supplementation to Reduce CVD Risk

Understandably, there has been interest in whether the fish oil supplementation can achieve the same cardiovascular benefits as fish intake. The GISSI-Prevenzione trial randomized 5,664 individuals with a recent myocardial infarction (MI) to receive 1 gram (g) of n-3 PUFA (850-882 milligram [mg] of EPA + DHA in a 1:2 ratio) or placebo and followed them for 3.5 years, demonstrating a reduction in cardiovascular deaths (hazard ratio [HR] 0.80 [0.65–0.99]) driven by a reduction in sudden cardiac death (HR 0.65 [0.48–0.89]).⁶ The OMEGA trial randomized 3,851 individuals who had recently been hospitalized for MI. They were given either 1g of n-3 PUFA (460 mg EPA + 380 mg DHA) or placebo. At 1 year, no reduction in major adverse cardiovascular events (MACE) was apparent.⁷ Several more recent studies have found no cardiovascular benefit with routine fish oil supplementation for primary or secondary cardiovascular prevention. The ORIGIN trial, Risk & Prevention trial, and ASCEND trial each randomized over 12,000 high risk individuals to receive 1 g of fish oil with various combinations of EPA/DHA or placebo and followed them for 6.2 years, 5 years, and 7.4 years, respectively.^8-10 All three of these trials found no benefit in terms of a reduction in MACE. More recently, the OMEMI trial (2021) randomized 1,014 elderly individuals with a recent MI to receive 1.8 mg of n-3 PUFA (930 mg EPA + 660 DHA mg) or placebo for 2 years and, again, found no difference in outcomes between the two groups.¹¹

The VITAL trial randomized 25,871 individuals to receive 1 g of fish oil (460 mg EPA + 380 mg DHA) or placebo for 5.3 years. This trial also found no reduction in its primary outcome of cardiovascular death or MACE. However, sub-group analysis did show a significant reduction in MACE with fish oil supplementation in participants who consumed less than 1.5 servings of fish per week at baseline (HR 0.81 [0.67–0.98]) compared to no benefit in individuals who consumed more than 1.5 servings per week (HR 1.08 [0.88–1.32], p-value for interaction 0.045). While this sub-group analysis needs to be interpreted cautiously given that there was no reduction in the primary outcome, this finding is consistent with the concept of the threshold effect of n-3 PUFA intake and CVD outcomes seen in the observational dietary studies.¹²

The STRENGTH trial sought to investigate if a higher dose of fish oil was needed to confer cardiovascular benefit. The trial studied 13,078 high risk individuals who received either 4 g of fish oil (2200 mg EPA + 800 md DHA) per day or corn oil (placebo) and found no difference in MACE. The trial was stopped early at 3.5 years for futility.¹³ It is worth noting that the STRENGTH trial did demonstrate an approximate 20% reduction in triglycerides, yet no benefit was seen in cardiovascular outcomes. The American College of Cardiology (ACC) recently released an expert consensus decision pathway for atherosclerotic cardiovascular disease (ASCVD) risk reduction in individuals with elevated triglycerides.¹⁴ The pathway includes a recommendation for consumptions of 2 servings of fatty fish per week as well as consideration of prescription grade fish oil (up to 4 g/day of EPA+DHA) in individuals with very high triglycerides (≥500mg/dl). The document also notes that use of non-prescription grade fish oil is generally not recommended due to lack of proven efficacy, a potential higher risk of side effects, and inconsistent content and purity.¹⁴

EPA Supplementation Alone to Reduce CVD Risk

There are data to suggest that EPA may confer more cardiovascular benefit than DHA. EPA has been shown to improve cellular membrane stabilization and inhibit cholesterol domain formation in the phospholipid membrane, while DHA has the opposite effect, potentially counteracting the benefit of EPA when co-administered.¹⁵ These findings suggest that administration of purified EPA may be anti-atherosclerotic.

The results of the JELIS trial (2007) support this hypothesis. The study followed 18,645 individuals with a mean low-density lipoprotein (LDL) of 181 mg/dl for 4.6 years. The treatment arm was treated with a statin + 1.8 g of EPA versus statin alone. Nearly all individuals in both arms were treated with low-intensity statin therapy (10-20 mg of pravastatin or 5-10 mg of simvastatin) and had a high baseline level of fish intake. In the setting of low intensity statin therapy, and therefore higher residual risk compared to modern approaches to LDL-lowering, there was a 19% reduction in both major coronary events and non-fatal coronary events.¹⁶

Further support for the use of purified EPA was seen in the REDUCE-IT trial, which followed 8,179 high-risk individuals (established CVD or diabetes mellitus plus two other major CVD risk factors with high triglycerides despite evidence-based lipid lowering therapy). Participants were given either icosapent ethyl, a derivative of EPA, at a dose of 2 g twice daily (equivalent to nearly 12 servings of wild-caught salmon) or a mineral oil placebo. At 4.9 years, the treatment arm had a 25% relative reduction in MACE and a 4.8% absolute risk reduction, which is large compared to the absolute risk reductions seen in other recent primary and secondary prevention studies.¹⁷ Reconciling the significant cardiovascular benefit in the REDUCE-IT trial with the results of the STRENGTH trial has been difficult. Both trials demonstrated a similar reduction in serum triglycerides and significant increases in serum EPA levels, yet no cardiovascular benefit was seen in the STRENGTH trial. A secondary analysis of the STRENGTH trial divided the cohort into tertiles based on achieved serum EPA or DHA levels and found no difference in event rates.¹⁸ Concern has been raised that the mineral oil placebo used in the REDUCE-IT trial may have negatively affected LDL cholesterol levels, but a Food and Drug Administration (FDA) review of this issue concluded that this was unlikely to meaningfully affect the outcome of the trial.

The EVAPORATE trial aimed to study the potential mechanism of the cardiovascular benefit of purified EPA. The trial studied 68 individuals with elevated triglycerides and non-obstructive coronary artery disease on computerized tomography (CT) coronary angiography who were then given either 4 g of icosapent ethyl or placebo. The CT coronary angiography was repeated after 18 months and found plaque regression in the treatment group as opposed to plaque progression in the placebo group.¹⁹ The most significant plaque regression was seen in low-attenuation soft plaque, which is typically associated with the highest risk for atherothrombotic events, suggesting that the reduction in CVD events with purified EPA intake is mediated through an anti-atherosclerotic mechanism.

Conclusion

In conclusion, dietary fish intake is associated with a reduction in fatal CVD events in a threshold manner, with a benefit seen with approximately 2 servings per week of fish. The use of non-prescription fish oil is generally not recommended due to concerns about the content and purity as well as multiple randomized studies showing no benefit in CVD risk reduction with low or high dose fish oil supplementation. The use of purified EPA has been shown to reduce CVD events in individuals at high cardiovascular risk. Recommendations for fish intake and fish oil supplementation are shown in Table 1. While prescription fish oils, especially purified EPA, may be indicated in certain individuals, for most of our patients instead of taking over the counter fish oil, it's probably better to just eat the real thing.

Table 1: Courtesy of Haq A, White S, Miedema M.

Table 1: Recommendations for consumption of fish and use of fish oil to improve cardiovascular health.

All individuals, regardless of baseline CVD risk, should aim to consume ~2 servings of fish, preferably fatty fish*, per week.

Routine supplementation with non-prescription fish oil is not recommended for primary or secondary prevention of CVD.

For individuals with very high hypertriglyceridemia (≥ 500 mg/dl), use of prescription grade fish oil (up to 4 grams/day of EPA/DHA), can be considered.

For individuals with mild-moderate hypertriglyceridemia and at high CVD risk, such as those with established CVD or diabetes with multiple other risk factors, prescription icosapent ethyl (2 grams twice daily) should be considered.

*Salmon, Sardine, Atlantic Mackerel, Herring, Trout, Tuna, Anchovy

References

1. Bang HO, Dyerberg J, Nielsen AB. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet 1971;1:1143-45.
2. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report 2008;10:1-23.
3. Albert CM, Hennekens CH, O'Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA 1998;279:23-28.
4. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 2006;296:1885-89.
5. Rimm EB, Appel LJ, Chiuve SE, et al. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association. Circulation 2018;138:e35-e47.
6. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447-55.
7. Rauch B, Schiele R, Schneider S, 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;122:2152-59.
8. The ORIGIN Trial Investigators. N–3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-18.
9. The Risk and Prevention Study Collaborative Group. N–3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med 2013;368:1800-08.
10. The ASCEND Study Collaborative Group. Effects of n−3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-50.
11. Kalstad AA, Myhre PL, Laake K, et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 2021;143:528-39.
12. Manson JE, Cook NR, Lee IM, et al. Marine n−3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2019;380:23-32.
13. Nicholls SJ, Lincoff AM, Garcia M, 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;324:2268-80.
14. Virani SS, Morris PB, Agarwala A, et al. 2021 ACC expert consensus decision pathway on the management of ASCVD risk reduction in patients with persistent hypertriglyceridemia: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;78:960-93.
15. Mason RP, Jacob RF, Shrivastava S, Sherratt SCR, Chattopadhyay A. Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta Biomembr BBA - Biomembranes 2016;1858:3131-40.
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;369:1090-98.
17. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
18. Nissen SE, Lincoff AM, Wolski K, et al. Association between achieved ω-3 fatty acid levels and major adverse cardiovascular outcomes in patients with high cardiovascular risk: a secondary analysis of the STRENGTH trial. JAMA Cardiol 2021;6:910-17.
19. Budoff MJ, Bhatt DL, Kinninger A, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J 2020;41:3925-32.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), SCD/Ventricular Arrhythmias, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Computed Tomography, Nuclear Imaging, Diet

Keywords: Eicosapentaenoic Acid, Docosahexaenoic Acids, Tuna, Pravastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiovascular Diseases, Numbers Needed To Treat, Mineral Oil, Cholesterol, LDL, Fish Oils, Fatty Acids, Omega-3, Triglycerides, Phospholipids, Coronary Artery Disease, Coronary Angiography, Simvastatin, American Heart Association, Salmon, Secondary Prevention, United States Food and Drug Administration, Consensus, Medical Futility, Inuits, Risk Factors, Dietary Supplements, Myocardial Infarction, Risk Reduction Behavior, Diabetes Mellitus, Death, Sudden, Cardiac, Tomography, X-Ray Computed, Physicians, Prescriptions, Heart Disease Risk Factors, Tomography

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