Omega-3 fatty acids in primary and secondary prevention of cardiovascular diseases

Abstract

Even with substantial progress in primary and secondary prevention, cardiovascular disease (CVD) persists as a major cause of mortality and morbidity globally. Omega-3 polyunsaturated fatty acids (Ω-3 PUFAs) have gained considerable attention for their ability to improve CV health and prognosis. Metanalyses of randomized controlled trials have demonstrated Ω-3 PUFAs’ positive impact on CVD outcomes for both primary and secondary prevention endpoints. Marine Ω-3 PUFAs also improve CVD risk factors including blood pressure, lipids, and inflammation; however, many physicians do not recommend Ω-3 PUFAs, largely due to inconsistent results in randomized trials. In this comprehensive review article, we evaluate both historic and current data concerning primary and secondary prevention of CVD with use of Ω-3 PUFAs, delve into the potential causes for the varied results, and examine the most current recommendations on the usage of Ω-3 PUFAs.

Introduction

Cardiovascular (CV) disease (CVD) remains a major cause of morbidity and mortality worldwide. Medications in common use, such as statins, along with more recent innovations like proprotein convertase subtilisin/kexin type 9 inhibitors, have made strides in reducing these CVD morbidity/mortality rates. However, the therapeutic benefits of omega-3 (Ω-3) polyunsaturated fatty acids (PUFAs) have also been demonstrated in numerous large-scale studies. The first evidence of this was documented in the 1970s after Bang and Dyerberg et al.¹ demonstrated considerably lower levels of plasma lipids in Greenlandic Eskimos compared to a similar population in Denmark. The investigators reported Eskimos who consumed a diet high in marine fish oils had low plasma levels of cholesterol and triglycerides (TG), prolonged bleeding times, and a low incidence of CVD. This ignited the initial curiosity about the potential CV advantages of a fish-rich diet and the contribution of Ω-3 PUFAs to CV health.

Following this initial epidemiological research on Eskimos, numerous studies have delved into the impact of Ω-3 PUFAs. These fatty acids have demonstrated beneficial effects on TG concentrations, blood pressure, inflammation, and immune function, as well as favorable alterations to endothelial function and platelet coagulability. A large amount of data suggests these effects have benefits for both primary and secondary prevention of CVD, as detailed further below. Yet, the use of Ω-3 for CVDs has sparked ongoing debate and controversy, with inconsistencies in research findings fueling discourse. This review examines in detail key research findings, the significance of doses and types of Ω-3, and the latest guidelines pertaining to Ω-3 PUFAs and CV health.

Overview of Ω-3 PUFAs

Ω-3 PUFAs, specifically eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA), exhibit unique structural characteristics and play vital roles in various physiological functions. EPA and DHA are long-chain fatty acids primarily derived from marine sources, while ALA is a short-chain fatty acid found in plant-based sources.

The structure of Ω-3 fatty acids is characterized by multiple double bonds, which confer their fluidity and flexibility. EPA and DHA contain longer carbon chains and more unsaturated bonds compared to ALA. This structural difference influences their functional properties. Table 1 summarizes the organic sources of PUFAs.

Table 1.

PUFA sources.

Fatty Fish	Fatty fish such as salmon, mackerel, sardines, trout, and tuna are excellent sources of EPA and DHA. These fish accumulate Ω-3 fatty acids by consuming algae and other marine organisms.
Fish Oil	Fish oil supplements, derived from fatty fish, provide a concentrated source of EPA and DHA. They are available in liquid form or as capsules and are a convenient way to increase Ω-3 intake.
Algae	Certain types of algae are rich in EPA and DHA. Algae-based supplements are available for those following a plant-based or vegetarian diet.
Flaxseeds and Chia Seeds	Flaxseeds and chia seeds are plant-based sources of Ω-3 fatty acids in the form of ALA. These seeds can be ground and added to smoothies, yogurt, or oatmeal to boost plant-based Ω-3 intake.
Walnuts	Walnuts are a good source of ALA and provide a plant-based option for obtaining Ω-3 fatty acids.
Hemp Seeds	Hemp seeds contain ALA and can be sprinkled on salads, added to smoothies, or used in baking for a nutritional Ω-3 boost.
Soybeans and Tofu	Soybeans and tofu contain ALA and can be incorporated into various dishes, providing Ω-3 for those following a vegetarian or vegan diet.

At the cellular level, Ω-3 fatty acids impact multiple biochemical pathways involved in cardiovascular health. Clinical studies consistently show EPA and DHA reduce TG levels in a dose-dependent manner. They achieve this effect through a decrease in hepatic production of very-low-density lipoprotein (VLDL), a particle rich in TGs, and an increase in lipoprotein lipase activity, an enzyme responsible for VLDL particle breakdown.^2,3 Additionally, these fatty acids stimulate beta-oxidation, a process that breaks down fatty acids, thereby reducing the raw materials available for hepatic TG synthesis.⁴ Lastly, Ω-3 PUFAs possess anti-inflammatory properties, and as inflammation is linked to high TG levels, this can indirectly contribute to lowering TGs.⁵

Regarding low- and high-density lipoprotein (LDL, HDL), Ω-3 PUFAs cause a complex set of changes. Although fatty acids may precipitate an incremental increase of LDL cholesterol in certain situations, they concurrently cause a shift in LDL particle subtype, transitioning from small, dense particles - a phenotype associated with augmented atherogenicity - to larger, buoyant particles, which reduces their overall atherosclerotic potential. Higher intake and levels of Ω-3 PUFAs correlate with increased HDL levels. HDL cholesterol plays a pivotal role in the reverse cholesterol transport pathway, aiding in the removal of other cholesterol forms from the bloodstream, including LDL cholesterol. Accordingly, it is generally accepted that a rise in HDL cholesterol levels generally signifies a decreased likelihood of CVD.⁶

Inflammation is also a driving mediator of CVD. Ω-3 PUFAs have potent anti-inflammatory properties in part by modulating the pro-inflammatory effects of immune cells. Ω-3 PUFAs suppress the activation of nuclear factor-kappa B (NF-κB), a transcription factor involved in the expression of inflammatory genes, thereby reducing the production of inflammatory cytokines like interleukin-1 beta (IL-1β) and interleukin-6 (IL-6).⁷ Furthermore, Ω-3 PUFAs promote the synthesis of specialized pro-resolving mediators, such as resolvins and protectins, which actively resolve inflammation and promote tissue repair.⁸ These anti-inflammatory actions help attenuate vascular inflammation, prevent the formation of atherosclerotic plaques, and maintain vascular integrity.⁹

Additionally, Ω-3 PUFAs have favorable effects on endothelial function and exhibit antithrombotic properties. Endothelial dysfunction, characterized by impaired nitric oxide (NO) production and increased oxidative stress, is a key event in the development of CVD. Ω-3 PUFAs can improve endothelial function by enhancing NO bioavailability and reducing oxidative stress. They promote the production of NO by endothelial cells, which leads to vasodilation, inhibition of platelet aggregation, and suppression of smooth muscle cell proliferation. Ω-3 PUFAs also possess antioxidant properties, which help counteract oxidative stress and protect endothelial cells from damage. These combined effects contribute to the maintenance of optimal vascular tone, blood flow, and overall CV health.¹⁰

Primary prevention

Many of the early epidemiological studies concluded high Ω-3 PUFA intake was associated with lower rates of CVD. For example, in 1985, Kromhout et al.¹¹ studied fish consumption among 852 middle-aged men without CHD in the 1960s. An inverse dose-response relationship was observed between fish consumption and death from CHD during 20 years of follow-up. This finding persisted after multiple logistic-regression analyses. Mortality from CHD was >50% lower among those who consumed at least 30 g of fish per day than among those who did not eat fish. This was followed by a randomized clinical trial (RCT) of 12,866 middle-aged men determined to be at high risk of CHD. Statistically significant inverse associations were found with CVD, all cause mortality, and CHD with the use of dietary PUFAs over a 10-year period.¹² Furthermore, a US retrospective study of 20,551 patients without CVD found the relative risk of sudden death was 0.48 (95% CI: 0.24–0.96; p = 0.04) in those who consumed fish at least once per week as compared to those who consumed fish less than once per month.¹³

Japan EPA Lipid Intervention Study (JELIS) evaluated the impact of about 2 g/d EPA on hypercholesterolemic patients who were on statintherapy at baseline. JELIS randomized 14,981 patients for primary prevention and a much smaller fraction of patients, 3664, for secondary prevention in a prospective open-label, blinded endpoint study with a 4.6-year mean follow-up. They found a 19% relative reduction in major CHD events (p = 0.011) when both primary and secondary prevention groups were combined. However, when the primary and secondary prevention subgroups were analyzed individually, they found non-significant risk reductions in major CHD events, CHD death or non-fatal myocardial infarction (MI), fatal or non-fatal MI, and non-fatal CHD events, ranging from 18 to 19%, 18–25%, 21–25%, 18–20%, respectively.¹⁴ Similarly, a RCT in 2013 of 12,513 Italian patients who were considered high risk for CHD but with no prior CHD found no significant difference in CVD outcomes between intervention (1 g daily of Ω-3) versus control (olive oil).¹⁵ Analogous results were found in the ORIGIN Trial (n–3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia), which included over 12,500 patients with type 2 diabetes and CVD risk factors. A daily dosage of 1 g of Ω-3 fatty acids did not show a statistically significant reduction in CVD death (HR: 0.98; 95% CI: 0.87–1.10; p = 0.72) compared to placebo.¹⁶

The findings of these JELIS and Italian trials suggest that PUFAs did not reduce primary prevention endpoints for CVD mortality and morbidity; however, there were many relevant limitations. First both were inadequately powered to analyze subgroups effectively. In the Japanese population of the JELIS trial, CHD related deaths were notably lower (around 22–26 per 100,000 person-years) compared to the USA and northern Europe. Also, with approximately two-thirds of participants of JELIS trial being women, whose CHD event incidence is 2.3 times lower than men, and considering the Japanese population’s characteristics, the overall low occurrence of CHD events, including deaths, was exceptionally low. Similarly, in the Italian trial, there were only 142 CVD deaths of the 12,513 patients included. The low event rate of both studies may also be related to dietary differences, including fish consumption. Japanese culture is known for a diet rich in fish/seafood, and in the Italian study approximately 70% of patients consumed ≥1 serving of fish per week. Also, a major limitation of these studies may be related to dosing given the fact that they used 1–2 g daily, which may not have been sufficient to reach therapeutic levels thus altering the trials results. A more detailed discussion of relevant primary prevention trials and Ω-3 dosing is reviewed below.

In 2019, the VITAL Trial (VITamin D and OmegA-3 TriaL), which included over 25,000 participants with no previous history of cancer or CVD, found no statistically significant reductions in Major Adverse Cardiovascular Events (MACE) (HR = 0.92; 95% CI: 0.80–1.06; p = 0.24) with Ω-3 fatty acid supplementation at a daily dosage of 1 g (capsule containing 840 mg of EPA + DHA). However, the combined daily dose produced statistically significant risk reductions in several key secondary CVD end points, including fatal MI, fatal/non-fatal MI, and total CHD (composite of MI, revascularization, or CAD death), by 50%, 28%, and 17%, respectively.¹⁷ The ASCEND trial (Effects of n − 3 Fatty Acid Supplements in Diabetes Mellitus) found similar results. This study randomized 15,480 patients with diabetes and no known CVD to 1 g of Ω-3 versus placebo; it found no statistically significant reduction in major CVD events (HR: 0.97; 95% CI: 0.87–1.08; p = 0.55).¹⁸ The ASCEND trial was initially perceived as negative due to finding only a 3% reduction in the primary composite endpoint of MI, stroke, or vascular death, which did not reach statistical significance. However, it is important to note that the low-dose Ω-3 product used in the ASCEND trial did demonstrate a statistically significant 18% reduction in the relative risk of CVD death, defined as death from CHD, stroke, or other vascular causes. Despite these findings the ASCEND investigators downplayed this finding and it was dismissed from conclusion. However, it seems unjustified to downplay the significance of reduction in vascular deaths in this study. In fact, a reduced risk of CVD death tends to be a recurring theme in many, though not all, large-scale studies of Ω-3 supplementation. Additionally, in 2020, the STENGTH trial reported findings consistent with those from the VITAL and ASCEND studies, as elaborated upon later. Given these are the only large-scale studies regarding primary prevention and Ω-3, there unfortunately remains a paucity of data on this topic. Regardless, as evidenced above, a significant amount of data suggests Ω-3 positively influences risk of CVD outcomes when used in people without existing CVD.

Secondary prevention

Much more data exists on the use of Ω-3 PUFAs in secondary prevention of CVD. The first large RCT to test the hypothesis that oily fish confers protection against CHD was the Diet and Reinfarction (DART) Trial, which enrolled over 2000 men with a history of MI. This study found a statistically significant 29% reduction in all-cause mortality (p < 0.05) in the group with approximately 400–800 g of fatty fish intake per week compared to the control group.¹⁹ These promising results were followed by a landmark study, the GISSI-P Trial (Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after MI) which included over 11,000 patients with recent MIs. In those randomized to Ω-3 supplementation at a daily dosage of 1 g, it demonstrated a 15% risk reduction in the composite primary end point (death, non-fatal MI, or stroke). This benefit was attributable to a risk reduction of death and CVD death by 20% and 17%, respectively (p-value <0.05).²⁰ Additionally, two large meta-analyses have reviewed data involving the use of Ω-3. These studies included both primary and secondary prevention although an overwhelming majority of patients had prior known CVD. In 2021, the analysis of 149,051 patients by Khan et al.²¹ found Ω-3 treatment significantly reduced CVD mortality (RR: 0.93; p = 0.01), non-fatal MI (RR: 0.87; p = 0.0001), CHD (RR: 0.91; p = 0.0002), MACE (RR: 0.95; p = 0.002), and revascularization (RR: 0.91; p = 0.0001). The meta-analysis showed a greater relative risk reduction (RRR) with EPA monotherapy of 0.82, than with EPA + DHA, 0.94. Similar findings were demonstrated by Bernasconi et al.²² who also performed a meta-analysis of Ω-3 RCTs. A total of 40 studies with a combined 135,267 participants were included in the analysis. Of note, only two studies included in the original meta-analysis involved subjects with no prior history of CVD. Bernasconi found use of EPA + DHA was associated with statistically significant (p < 0.001) lower risks of MI, CHD events, fatal MI, and CHD mortality of 13% (95% CI: 0.80–0.96), 10% (95% CI: 0.84–0.97), 35% (95% CI: 0.46–0.91), and 9% (95% CI: 0.85–0.98), respectively. The use of EPA + DHA was found to significantly reduce the risk of all outcomes considered in this study, except for CVD events (− 5%; p < 0.05 but borderline significant based on pre-specified rules for significance). For CVD events and nonfatal MI, the protective effect increased significantly with higher doses of EPA + DHA. These protective CHD effects are likely due to increased plaque stability. For instance, a RTC, including 188 patients, found those receiving fish oil prior to carotid endarterectomy had higher fractions of intraplaque EPA/DHA concentrations with a corresponding higher proportion of stable plaques (thick fibrous caps without signs of inflammation) as compared to the control group.²³ The culmination of these findings indicates that long chain marine Ω-3 s are not only an effective strategy for secondary prevention but also supports their use in primary prevention and are especially protective against CHD.

However, multiple other studies have failed to corroborate these findings which has sparked ongoing debate and controversy. Some studies have demonstrated that Ω-3 supplementation can reduce the risk of CVD-related events for secondary prevention, while others have found little to no benefit. For example, the OMEGA Trial, a randomized, placebo-controlled study, assessed the effects of highly purified Ω-3 fatty acids on top of modern guideline-adjusted therapy after MI. Participants were given 1 g of Ω-3 or a placebo. After a median follow-up of around one year, the results showed no significant reduction in the primary (CVD death) and secondary endpoints (total mortality, MACE, revascularization).²⁴

These contradictory results could possibly be due to several limitations. Since GISSI-P was published there have been several fundamental developments in CVD research; for example, how intervention study arms are treated with aggressive medical therapy. In the GISSI-P trial, which found Ω-3 benefit, only 5% of patients received statin therapy at baseline; in contrast to the OMEGA trial, which found no Ω-3 benefit, a much larger proportion of patients (81%) received statin therapy at baseline. Additionally, the lack of an Ω-3 benefit in the OMEGA trial may have been due to the low rate of sudden cardiac death, total mortality, and MACE within 1 year follow up after MI in those that received this improved optimal medical therapy. A more likely and potentially significant limitation of these studies includes the possibility that a daily dose of 1 g of Ω-3 fatty acids may have been too low and the trial duration too short.

Omega-3 dosing

Researchers have attempted to clarify the above findings by using meta-analyses to evaluate outcomes based on dosage. For example, Rizos et al.²⁵ conducted a systematic review and meta-analysis of RCTs to evaluate the effects of Ω-3 supplementation on MACE and effects of dosing. They did not find statistically significant difference with use of Ω-3 fatty acid supplementation on all-cause mortality, CVD death, sudden death, MI, or stroke. The mean Ω-3 dose was 1.51 g per day (0.77 g/d EPA, 0.60 g/d DHA). The authors concluded that there was also no evidence for an association between treatment effect and the Ω-3 PUFA dose.²⁶ However, Del Gobbo et al.²⁷ conducted a review of 19 cohort studies to evaluate the association between Ω-3 acid biomarkers and the risk of CHD in those with no prior history of CVD. The analysis demonstrated that each 1-standard deviation increase in Ω-3 fatty acid blood levels was associated with a 9% lower risk of fatal CHD. This was followed by the REDUCE-IT Trial, a RCT involving over 8000 patients with established CVD and high TG levels. It demonstrated a highly significant 25% reduction in MACE (HR: 0.75; 95% CI: 0.68–0.83; p < 0.001) with high-dose Ω-3 supplementation using icosapent ethyl (the ethyl ester of EPA) at a daily dosage of 4 g.²⁸ Although, protagonist concerns were raised due to the use of a mineral oil placebo in REDUCE-IT. This concern was substantiated by the observation of a >30% increase in C-reactive protein levels associated with the placebo, theoretically leading to the differences in CVD outcomes. However, it is noteworthy that the Food and Drug Administration granted icosapent ethyl (used in REDUCE-IT) a label claim for reducing CVD events based on an analysis which concluded the mineral oil alone could not fully account for the observed outcome differences.

Another consideration that may account for the inconsistent results is dosing and its relationship to the study population. For instance, trials such as GISSI-P and JELIS were conducted in Italian and Japanese populations, respectively, who have higher baseline Ω-3 levels due to diets with increased fish and seafood intake as compared to the typical diet of Western populations. One possibility is that there may exist a threshold effect regarding endogenous Ω-3 levels and CVD benefits, as some studies have shown that participants with lower baseline Ω-3 levels have more impactful results after supplementation. Therefore, populations such as those in GISSI-P and JELIS, who may consume more fish on a regular basis, likely have higher baseline Ω-3 levels and a lower dose of Ω-3 may be adequate to achieve a clinical benefit, as opposed to Western populations who on average consume less fish and likely require a higher Ω-3 dose to achieve the same therapeutic effect. Supporting this notion are the findings of the REDUCE-IT trial, in which higher Ω-3 doses (4 g/day of highly purified EPA) were associated with significant CVD benefits and, in particular, a more robust benefit in the US cohort, which likely had the lowest PUFAs diet compared to the other populations in the study.²⁸ Regardless, it is an axiom in medicine that if the dose of any agent is too low, the agent will be ineffective. Why would the same not be true for Ω-3 fatty acids?

The answer to this question may be related to the CVD outcome being studied. For example, in the Bernasconi meta-analysis²² the dosage of supplementary EPA + DHA in the treated groups varied from 400 mg/day to 5500 mg/day. Of the included studies, 5 (combined n = 8036) were conducted with dosages lower than 800 mg/day, 10 (n = 94,936) with dosages between 800 and 1200 mg/day, and 25 (n = 32,295) with higher dosages. The (weighted) average dosage received was 1.2 g/day of EPA + DHA. Supplementation with EPA + DHA was associated with significant reductions in the risk of CHD death of 9%, and fatal MI of 35%. Meta-regression found significant benefit was achieved with lower doses (less than the 800 to 1200 mg/day) with diminishing return with higher doses, suggesting a dose-response plateau. This evidence is consistent with previous data from Mozaffarian and Rimm et al.²⁹ which supported the hypothesis that CHD mortality reduction can be achieved with dosages as little as 250 mg/day. This contrasts with other CVD outcomes, such as nonfatal MI or CHD events, which seem to have a more linear benefit with use of higher doses. For instance, in the case of nonfatal MI, the Bernasconi study found the risk reduction was dose dependent, and each additional 1 g/day was associated with a further 9.0% significant risk reduction. Overall, the relationship of Ω-3 dose and its level of therapeutic benefit appear to be dependent on the study population and the particular CVD outcome of interest.

Recent data

To further add to the confusion, two RCTs published in late 2020, the STRENGTH Trial (Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk) and OMEMI Trial (Omega-3 Fatty Acids in Elderly With Myocardial Infarction) both found non-significant results.^{30; 31} The STRENGTH Trial, which enrolled over 13,000 patients at high CVD risk, did not show a statistically significant reduction in MACE (HR: 0.99; 95% CI: 0.90–1.09; p = 0.84) with high-dose Ω-3 supplementation using a combination of EPA + DHA at a daily dosage of 4 g. Similar to REDUCE-IT, some suggested the possibility of harm related to the DHA component in the STRENGTH intervention. However, this appears unlikely given that previous research has not shown adverse CVD events associated with DHA, and the DHA levels in the study were moderate and did not correlate with event rates.

The OMEMI Trial was an RCT which studied outcomes in patients aged 70 to 82 years with recent (2–8 weeks) acute MI after addition of 1.8 g n-3 PUFA (930 mg EPA, 660 mg DHA). Of 1014 people with follow up data, no significant reduction was found in treatment group for a composite outcome including nonfatal acute MI, unscheduled revascularization, stroke, all-cause death, or heart failure (HF) hospitalization after 2 years follow up.³⁰ However, this trial had notable limitations. It was underpowered largely due to lower-than-expected event rates. Also, the dosage used in OMEMI was about twice that used in comparable earlier trials, although considerably lower than the dosage used in REDUCE-IT and STRENGTH trials, which again underscores the importance of dosage to achieve therapeutic benefits.

Due to the conflicting data, the Mayo Clinic Proceedings editorial suggested that Bernasconi update their meta-analysis to include STRENGTH and OMEMI results.^22,32 The newly published results had minimal change on the meta-analysis and did not alter the conclusions. Now including 42 studies with almost 150,000 participants (Fig. 1), these investigators again found statistically significant reductions in fatal MI (35%), MI (13%), CHD events, and CHD mortality (both 9%).³³ This data supports the conclusion that EPA and DHA intake is an effective intervention for protection against CVD (Table 2).³⁴

Fig. 1.

Pooled results from the Bernasconi meta-analysis. Adapted from Mayo Clinic Proceedings, with permission.³³

Table 2.

Major studies on CV outcomes with Ω-3 supplementation.

Study (Author, Year)	Trial Design	Number of Subjects	Duration	Patient Population	Intervention vs. Control	Results	Limitations
DART (Burr et al., 1989)19	RCT	2033	2 years	Men with a history of MI	Fatty fish vs. Control diet	CHD event (RR: 0.91; 95% CI: 0.73–1.14); CHD death (RR: 0.71; 95% CI: 0.54–0.93)	Diet based. Prior to modern therapy.
GISSI-P (Marchioli et al., 1999)20	RCT	11,324	3.5 years	People with recent MI	Q-3 vs. Placebo	Overall mortality, nonfatal MI, and nonfatal stroke (RR: 0.85; 95% CI: 0.74–0.98); CVD death, nonfatal MI, and nonfatal stroke (RR: 0.80; 95% CI: 0.68–0.94)	Prior to modern therapy.
JELIS (Yokoyama et al., 2007)14	RCT	18,645	Mean 4.6 years	Japanese adults with dyslipidemia	EPA vs. No EPA	Major CHD event (combined SCD, fatal and nonfatal MI, unstable angina, coronary revascularization) (RR: 0.81; 95% CI: 0.69–0.95)	Limited to the Japanese population, potential for population-specific effects. EPA only.
OMEGA (Rauch et al., 2010)24	RCT	3851	1 year	Elderly individuals with history of MI	Ω-3 vs. Placebo	Sudden death or sudden cardiac arrest followed by successful resuscitation but death within 3 weeks (OR: 0.95: 95% CI: 0.56–1.60)	May not generalizable given elderly and female population. High background fish intake. Low power.
ORIGIN (Bosch et al., 2012)16	RCT	12,536	Median 6.2 years	People with dysglycemia and CV risk	Ω-3 vs. Placebo	CVD death (HR: 0.98; 95% CI: 0.87–1.10)	High background fatty acid intake.
ASCEND (Bowman et al., 2018)18	RCT	15,480	Mean 7.4 years	People with diabetes and no prior CVD	Ω-3 vs. Placebo	Nonfatal MI or stroke, transient ischemic attack, or vascular death (RR: 0.97; 95% CI: 0.87–1.08); Statistically significant 18% RRR in vascular death	Participants had diabetes and no prior CVD, limited generalizability.
VITAL (Manson et al., 2019)17	RCT	25,871	Median 5.3 years	Men aged 50+ and women aged 55+ with no history of CVD	Vitamin D and Ω-3 vs. Placebo	MACE (HR: 0.92; 95% CI: 0.80–1.06); Reduced risk of MI by 28%, and CHD death by 17%	Study population may not represent all age and gender groups.
REDUCE-IT (Bhatt et al., 2019)28	RCT	8179	Median 4.9 years	People with established CVD and dyslipidemia	Icosapent ethyl (highly purified EPA) vs. Placebo	Composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina (HR: 0.75; 95% CI: 0.68–0.83)	Limited to individuals with high TGs. Potential for selection bias.
STRENGTH (Nicholls et al., 2020)31	RCT	13,078	Median 3.4 years	People with high CV risk and dyslipidemia	Carboxylic acid formulation of EPA + DHA vs. Corn oil placebo	Composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization (HR: 0.99; 95% CI: 0.90–1.09)	Potential limitations in the choice of formulation and population characteristics.
OMEMI (Kalstad et al., 2020)30	RCT	1014	2 years	Patients post-MI	Ω-3 vs. Control	Composite of nonfatal acute MI, unscheduled revascularization, stroke, all-cause death, HF hospitalization (HR: 1.08; 95% CI: 0.82–1.41)	Limited sample size and short duration of follow-up. Low dosage.
Bernasconi study (Bernasconi et al., 2021)22,33	Meta Analysis	149,359	n/a	Primary and secondary prevention	Ω-3 vs. Control	MI (RR: 0.87; 95% CI: 0.80–0.96); CHD events (RR: 0.91; 95% CI: 0.85–0.97); fatal MI (RR: 0.65; 95% CI: 0.46–0.91); CHD mortality (RR: 0.91; 95% CI: 0.85–0.98)	Dependent on the quality and characteristics of included studies.

Omega-3 index

Given the above findings, the beneficial effects of Ω-3 appear to be dependent on therapeutic levels. EPA and DHA are present in every human being at unpredictable levels (even in the absence of intentional intake), and their bioavailability is complex; therefore, standardizing dosage may be difficult. The Ω-3 index is the EPA + DHA content of erythrocytes expressed as a percent of total identified fatty acids. It was originally suggested as a marker of increased risk for death from CHD, but it can also be viewed as an actual risk factor, playing a pathophysiologic role in the disease. A 10 cohort meta-analysis found each 1-SD rise in Ω-3 index was associated with 15% risk reduction for fatal CHD.³⁵ The optimal levels of Ω-3 index appear to be 8% or greater,³⁶ which has generally been accepted as the standard target for this risk factor. Furthermore, based on data evaluated in 2023 of a meta-analysis including 58 studies, practical recommendations to improve Ω-3 index to ≥8% are consumption of 1000–1500 mg/d EPA/DHA for at least 12 weeks.³⁷ The inconsistent results of prior Ω-3 studies were likely heavily influenced by the complexity of Ω-3 bioavailability and dosing issues, but also may be related to the specific CVD outcome being studied. As discussed previously, there is data suggesting a more linear relationship between dosing and benefit with nonfatal CHD events and a plateau effect when analyzing dosing benefits involving CVD mortality. Therefore, it is obvious that a significant amount of data is missing regarding this topic, and RCTs using the Ω-3 index to guide dosing would be helpful to rectify this limitation.

EPA compared with EPA + DHA

One important question is whether EPA, DHA, or some combination of both is more effective in preventing CVD outcomes. There is the belief that EPA is better for CVD prevention given observations that DHA supplementation can increase LDL-cholesterol levels. One study found high-dose DHA increases LDL turnover and contributes to larger LDL particles compared with EPA³⁸; however, large LDL particles are linked to lower risk of CVD as compared to small LDL particles.³⁹ Unfortunately, there is hardly any further data on this topic. Due to the concerns with DHA, much of the information available for larger dosages has been obtained using highly concentrated forms of EPA, and the range of DHA dosages across studies is minimal. Bernasconi attempted to study this relationship and noticed that the dose response curve of EPA was different compared to the EPA + DHA curve. However, after analysis there was a non-significant difference, thus the authors were unable to conclude that EPA alone is a more effective agent for CVD than the combination of EPA/DHA.²² Regardless, there is a more significant amount of data involving the benefits of Ω-3 PUFAs and atherosclerotic plaque stability with EPA versus EPA + DHA. EPA alone has been shown to have consistent anti-atherosclerotic effects in many imaging modalities including intravascular ultrasound, coronary computed tomography angiography, and optical coherence tomography. Furthermore, EPA combined with a statin was found to increase fibrous cap thickness, and decrease the amount of peri-plaque inflammation as evidenced by decreased inflammatory cytokines (pentraxin-3) and macrophage accumulation.⁴⁰ These findings suggest EPA may be more beneficial than DHA for CHD outcomes; although, this has yet to be validated.

Other omega-3 benefits

The benefits also appear to encompass HF. One of the initial retrospective studies was the Cardiovascular Health Study conducted by Mozaffarian et al.,⁴¹ which examined the incidence of both HF with reduced and preserved ejection fraction (HFrEF and HFpEF, respectively) in older adults in relation to circulating long-chain Ω-3 fatty acids. The study found that individuals with higher levels of Ω-3 fatty acids had a significantly lower risk of HF, with a HR of 0.48 for EPA (CI: 0.30–0.71; p = 0.005), 0.64 for DHA (CI: 0.40–1.04; p = 0.057), and 0.51 for total Ω-3 fatty acids (CI: 0.32–0.80; p = 0.003). These results were followed by a larger meta-analysis by Djoussé et al.⁴² which investigated the association between fish consumption, Ω-3 fatty acids, and the risk of HF. This analysis of multiple population-based studies revealed that each serving of fish consumed per week was associated with a 5% lower risk of HF. Moreover, each 0.1 g/day increase in Ω-3 fatty acid intake was associated with a 3% lower risk of HF. Of note, the classification of HF was not reported. To date, no published RCTs have assessed the effect of Ω-3 PUFA supplements on the primary prevention of HF. The only major RCT trial evaluating use of Ω-3 for secondary prevention of HF is GISSI-HF trial.⁴³ It found among patients with clinically diagnosed HF (91% were HFrEF), Ω-3 supplementation significantly reduced both the risk of total mortality by 9% (RR: 0.91; 95% CI: 0.83–0.99; p = 0.041) and the risk of CVD-related hospitalizations or death by 8% (RR: 0.92; 95% CI: 0.85–0.99; p = 0.009). These findings suggest that Ω-3 PUFA supplementation may reduce HF related hospitalizations and death in patients with HFrEF.

Additionally, others have found reduced stroke risk.⁴⁴ For example, one study reported that men who consumed fish 2–4 times per week had a 18% lower risk of stroke compared to those who rarely consumed fish.⁴⁵ More recently, the association between fish consumption, long-chain Ω-3 fatty acids, and the risk of cerebrovascular disease was examined in a systematic review and meta-analysis by Chowdhury et al.⁴⁶ which revealed that moderate fish consumption was associated with a significantly lower risk of cerebrovascular disease by 6–12%. Additionally, in a post hoc analysis of patients with a history of stroke from JELIS, recurrent stroke occurred in 33 of the 485 patients (6.8%) randomized to EPA versus 48 of 457 patients (10.5%) in the control group, for a risk reduction of recurrent stroke of 20% (RR: 0.80; 95% CI: 0.64–0.99).⁴⁷ Also, a large meta-analysis (n > 180,000 subjects) with harmonized statistical methodology found that being in the highest quintile of blood levels of Ω-3 fatty acids was associated with a highly significant 18% reduction in risk of ischemic stroke, and no association with hemorrhagic stroke.⁴⁸ Similarly, high-dose EPA in the REDUCE-IT trial, despite increasing relative risk of AF by 35%, reduced relative risk of stroke by 28%.²⁸

Omega-3 and AF

Some clinical trials have raised concerns about a potential association between Ω-3 intake and atrial fibrillation (AF), which could negatively impact the use of Ω-3 in clinical practice. Notably, increased AF incidence was observed in both the STRENGTH and REDUCE-IT trials. However, it is important to observe that this relationship seems to be influenced by dosage. For example, both the STRENGTH and REDUCE-IT trials administered high doses of PUFAs at 4 g daily. In contrast, lower doses of Ω-3 appear to have little to no association with an increased risk of AF. For instance, in a RCT involving over 25,000 patients, the comparison of low-dose Ω-3 (460 mg/d of EPA and 380 mg/d of DHA) to a placebo showed no significant difference between the two groups (HR: 1.09; 95% CI: 0.96–1.24; p = 0.19).⁴⁹ Furthermore, a meta-analysis conducted by Jia et al.,⁵⁰ which included data from over 83,000 patients, found a 51% increased risk of AF with higher doses of Ω-3 (>1 g daily) and a much smaller increased risk (12%) associated with lower doses (≤ 1 g daily). In light of these findings, it may be advisable to consider shared decision-making regarding AF risk for individuals at high risk. However, for most patients, the cumulative cardiovascular benefits of low-dose Ω-3 likely outweigh the associated risks.

Clinical recommendations

Various organizations and expert panels have provided specific recommendations regarding the consumption of Ω-3 fatty acids. Between 2017 and 2019, the American Heart Association (AHA) released three statements on Ω-3 supplementation. The AHA does not recommend Ω-3 supplements for those without high CVD risk; however, the AHA does recommend at least one to two servings of fish or seafood, such as salmon, mackerel, sardines, and trout, per week to reduce risk of CVD. The AHA also suggests considering other sources of Ω-3 fatty acids, such as walnuts, flaxseeds, and chia seeds, for those who do not consume fish. Regarding those with known CVD, the AHA recommends approximately 1 g/day of EPA plus DHA, preferably from oily fish. To manage high TG levels, the AHA concludes that 4 g/day prescription Ω-3 s (containing EPA plus DHA or EPA only) lower TG levels when used alone or as adjuncts to other lipid-lowering medications.⁵¹

Additionally, based on strong evidence from mostly prospective cohort studies but also some RCTs, the 2015–2020 Dietary Guidelines for Americans concluded that eating patterns incorporating seafood are associated with a reduced risk of CVD. Also, consuming about 8 oz per week of a variety of seafood that provides about 250 mg per day of EPA and DHA is associated with fewer CVD deaths in both healthy individuals and those with preexisting CVD.⁵² The more recent updated 2020–2025 guidelines did not specifically comment on supplementation but recommended 2 or more servings of seafood per week or other Ω-3 rich food sources for those who do not eat fish.⁵³

In summary, guidelines and recommendations for Ω-3 fatty acid intake emphasize the consumption of fatty fish as a primary source of EPA and DHA. Also, incorporating other plant-based sources of Ω-3 fatty acids into the diet can provide additional benefits. In general, current recommendations state prescription or over the counter supplementation should be reserved for those with high CVD risk or established CVD.

Conclusions

A robust and significant proportion of data supports the efficacy of Ω-3 at therapeutic levels in both the primary and secondary prevention of CVD. It appears the primary unanswered questions relate to the optimal mix of EPA and DHA and ideal target doses of these Ω-3 fatty acids. Research employing higher doses of Ω-3 typically results in more uniform CVD benefits, though these outcomes may vary according to the specific CVD endpoints assessed. The Ω-3 index has been proposed as a tool to navigate these dosage concerns, yet it has not gained widespread traction in clinical settings. It is evident an information gap exists on this topic, and RCTs utilizing the Ω-3 index could provide clarity. The AHA recommendations seem to align with current evidence, endorsing Ω-3 supplementation for individuals at elevated risk or established CVD and for those with elevated TG levels. Despite advancements in CVD treatment modalities, the medical community should consider the use of Ω-3 supplementation, especially when accounting for the solid empirical support it has demonstrated, rather than rejecting it based on neutral results from suboptimal trials that do not fully account for its complex bioavailability.

Abbreviations:

Ω-3

Omega-3

ALA

Alpha-linolenic Acid

AHA

American Heart Association

AF

Atrial Fibrillation

CV

Cardiovascular

CVD

Cardiovascular Disease

CI

Confidence Interval

CHF

Congestive Heart Failure

CHD

Coronary Heart Disease

DHA

Docosahexaenoic Acid

EPA

Eicosapentaenoic Acid

g

Grams (unit)

HR

Hazard Ratio

HF

Heart Failure

HFpEF

Heart Failure with preserved Ejection Fraction

HFrEF

Heart Failure with reduced Ejection Fraction

MACE

Major Adverse Cardiovascular Events

mg

Milligram (unit)

MI

Myocardial Infarction

Odds

ratio, OR

PUFA

Polyunsaturated Fatty Acids

RCT

Randomized Controlled Trial

RR

Relative Risk

RRR

Relative Risk Reduction

TG

Triglyceride

VLDL

Very-Low-Density-Lipoprotein