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Omega-3 fatty acids and cardiovascular risk prevention

Stephanie Connaire

Take Home Messages
  • A number of observational studies have suggested that the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexanoid acid (DHA) reduce cardiovascular risk.
  • Two major studies investigating this include the STENGTH and REDUCE-IT trials, which appear to have conflicting results.
  • There are a number of theories as to why these trials may have conflicting results, including the effect of the choice of different placebos and the administration of both EPA and DHA in the STRENGTH trial compared to just EPA in the REDUCE-IT trial.
  • There is currently insufficient evidence to conclude whether omega-3 fatty acid supplementation reduces cardiovascular risk in patients already deemed to be at high risk. Therefore, I would not advocate that these patients are routinely recommended to take omega-3 supplements.
Introduction

Diet and nutrition have a significant impact on the risk of cardiovascular disease, often through influencing risk factors such as blood pressure, cholesterol levels and body weight. The impact of diet on cardiovascular disease has been studied on three different levels, including specific nutrients (such as fatty acids and vitamins), specific foods or food groups and specific dietary patterns (such as the Mediterranean diet).

The types of fatty acids consumed are particularly important when it comes to the prevention of cardiovascular disease. Polyunsaturated fatty acids consist of omega-6 fatty acids, which are mainly derived from plants, and omega-3 fatty acids from fish oils and fats1. Observational studies have demonstrated that the consumption of fatty fish or omega-3 fatty acids is associated with a lower incidence of cardiovascular events2,3. There has been particular interest in the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) which have also been associated with lower cardiovascular risk4, 5.

In 2018, Aung et al conducted a meta-analysis of all large clinic trials assessing the associations of omega 3 fatty acid supplements with the risk of coronary heart disease and major vascular events. The results of this meta-analysis of 10 trials involving 77 917 individuals provided no support for omega-3 fatty acids in the prevention of coronary heart disease or major vascular events. However, they concluded that the results of ongoing trials were needed to assess if higher doses of omega-3 fatty acids (3-4g per day) may have significant effects.

STRENGHTH Clinical Trial

The Long-term Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STENGTH)6, evaluated the effects of omega-3 CA (Epanova; AstraZeneca) in patients already on statin treatment with high cardiovascular risk, hypertriglyceridemia and low high-density lipoprotein (HDL) levels. Omega-3 CA is a carboxylic acid formulation of the omega-3 fatty acids EPA and DHA that does not require hydrolysis by pancreatic lipase, removing the need for consumption with a high fat meal and therefore resulting in greater bioavailability than the standard preparations.

In this randomized, double-blind trial, 13078 patients from 675 sites in 22 countries were enrolled between October 2014 and June 2017. They were randomized to receive either omega-3 CA at a dose of 4g per day or the placebo, corn oil, in addition to usual background therapies including statins. All patients were over 18 years old and considered at high risk of a future cardiovascular event. For inclusion into the trial they were all required to be treated with a statin for at least 4 weeks. They also had hypertriglyceridemia (levels 180-500 mg/dl) and low levels of high-density lipoprotein cholesterol (<42 mg/dl in men or <47 mg/dl in women).

The primary efficacy end point was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization and hospitalization for unstable angina. The study was terminated early in January 2020 when 1384 primary end points had been recorded based on the data crossing the pre-specified futility boundary with a low probability of demonstrating a clinical benefit of omega-3 CA. At study closure, the median patient follow-up was 42 months.

The primary end point occurred in 785 patients (12%) treated with omega-3 CA compared to 795 (12.2%) treated with corn oil (p=0.84). Additionally, drug-related adverse events were more common in the omega-3 CA group compared to the corn oil group (22.2% vs 12.9%). There was  a greater rate of adverse gastrointestinal events (24.7%) compared to the placebo group (14.7%), and a greater incidence of new-onset atrial fibrillation was noted (2.2% vs 1.3%; HR 1.69; 95% CI 1.29-2.21; p < 0.001).

The study concluded that, among patients treated with statins at high cardiovascular risk, the addition of omega-3 CA to usual therapies resulted in no significant difference in the composite outcome of major adverse cardiovascular events (MACE). However, it should be highlighted that it remains uncertain as to whether benefits might be observed in those at a lower cardiovascular risk. Additionally, as highlighted in the study’s limitations, the study participants received 4 g per day of Epanova, a combination of EPA and DHA, and the trial did not evaluate different doses or proportions of this preparation.

REDUCE-IT

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT)7 published in the New England Journal of Medicine in 2019 came however to a very different conclusion. This multicentre, randomised, double-blind and placebo-controlled trial recruited a total of 8179 patients with hypertriglyceridemia and a history of atherosclerosis or diabetes mellitus to icosapent ethyl (Vascepa; Amarin) 2 g twice daily or a mineral oil placebo. Mineral oil was chosen as a placebo as its colour and consistency is very similar to icosapent ethyl. Patients were followed up for a median duration of 4.9 years.

Similar to the STRENGTH trial, the primary composite end point of REDUCE-IT was also a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation or hospitalisation for unstable angina. A primary end point event was found to occur in 17.2% of the patients in the icosapent ethyl group, compared to 22% of the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001), leading the investigators to conclude that among statin-treated patients with hypertriglyceridemia, the risk of ischaemic events was significantly lower in those receiving icosapent ethyl.

The overall rates of adverse events were similar between the two groups, but with the rate of hospitalisation due to atrial fibrillation or flutter significantly higher in the icosapent ethyl group (3.1% vs. 2.1%, p=0.004) and there were numerically more patients with reported serious adverse bleeding events in the icosapent ethyl group (2.7% vs 2.1%, p=0.06).

Discussion

There has of course been discussion around why  the REDUCE-IT trial showed such positive results with an impressive 25% relative risk reduction in MACE and the similar STRENGTH trial concluded no such reduction.

One postulated theory is that the mineral oil placebo used in the REDUCE-IT trial in fact had pro-inflammatory effects which exaggerated the treatment benefit observed in the trial8.  However, this theory has been countered with the publication of a review article (by the principal investigator of REDUCE-IT) confirming that mineral oil is an inert substance with no significant systemic effects on the human body when taken orally other than acting as a laxative, and with “inconsistent and generally not statistically significant effects” on serum lipids9.

Another possible explanation is that there is an adverse effect associated with DHA, which was not used in the REDUCE-IT trial. However, this has not been proven or seen in any prior studies.

Furthermore, there were some differences in the trial populations. The REDUCE-IT trial included more patients with established coronary artery disease (71% vs 56%) and perhaps these omega-3 fatty acid therapies are more effective in these patients.

Table 1. Comparison of STRENGTH and REDUCE-IT baseline characteristics
 

STRENGTH

REDUCE-IT

Formulation

Omega-3 CA (EPA and DHA)

Icosapent ethyl (EPA ethyl ester)

Placebo

Corn oil

Mineral oil

Patient baseline characteristics of treatment group

Median age

62.3

64

Male vs female

65% vs 35%

71.6 vs 28.4%

White race

81.7%

90.3%

Diabetes

70.5%

58.6%

High intensity statin

49..8%

31.5%

Conclusions

The 2016 ESC Cardiovascular Disease Prevention Guidelines state that EPA and DHA are especially important omega-3 fatty acids, but it is debatable as to whether they actually have a favourable effect on all-cause mortality and mortality from coronary artery disease and stroke. The opposing conclusions from the STRENGTH and REDUCE-IT trials have not clarified this position any further and questions around the benefit of omega-3 fatty acids in the prevention of cardiovascular disease remain.

Further studies are needed to compare the EPA ethyl ester icosapent ethyl with the carboxylic formulation of EPA and DHA, omega-3 CA. This may provide clarity on whether there is an adverse effect associated with DHA. Comparing these against the same inert placebo would also eliminate any questions regarding additional confounding effects of the placebo.

In summary, given the lack of clear evidence of benefit in addition to the potential adverse effects associated with omega-3 fatty acid supplementation (including hospitalisation with atrial fibrillation or flutter and gastrointestinal side effects), I do not believe that we should be recommending omega-3 fatty acids routinely to patients with high cardiovascular risk.

Disclosures

None.

References
  1. 2016 European guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal (2016) 37, 2315–2381 doi:10.1093/eurheartj/ehw106
  2. DelGobbo LC,Imamura F ,Aslibekyan S,et al.; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCe). ω-3 Polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMA Intern Med. 2016;176(8):1155-1166. doi:10. 1001/jamainternmed.2016.2925
  3. Jayedi A,Shab-Bidar S.Fishconsumptionand the risk of chronic disease: an umbrella review of meta-analyses of prospective cohort studies. Adv Nutr. 2020;11(5):1123-1133. doi:10.1093/advances/ nmaa029
  4. Mozaffarian D, Lemaitre RN, King IB, et al. Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann Intern Med. 2013;158(7):515-525. doi:10. 7326/0003-4819-158-7-201304020-00003
  5. Valagussa F, Franzosi M G and Geraci E et al. Dietary supplementationwithn-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354(9177): 447-455. doi:10.1016/S0140-6736(99)07072-5
  6. Nicholls S, Licoff A, 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. JAMA. 202;324(22):2268-2280. Doi:10.1001/jama2020.22258.
  7. Bhatt D, Steg G, Miller M. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Eng J Med 2019; 380:11-22. DOI: 10.1056/NEJMoa1812792.
  8. Neale T. Fish Oil Tanks in STRENGTH, Making Waves for REDUCE-IT. 2020. https://www.tctmd.com/news/fish-oil-tanks-strength-making-waves-reduce-it
  9. Olshanky B, Ching M, Budoff M et al. Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies. European Heart Journal Supplements. 2022. 22: J34 - J48, https://doi.org/10.1093/eurheartj/suaa117