High dose of omega-3 carboxylic acid has no effect on MACE outcomes

AHA 2020 The STRENGTH trial found that omega-3 carboxylic acid supplementation had no beneficiary MACE outcome in patients with established or high-risk of CVD compared to placebo.

Presented at the AHA Scientific Sessions 2020 by A. Michael Lincoff (Cleveland, OH, USA)

Introduction and methods

It remains incompletely defined whether supplementation of omega-3 fatty acids is beneficiary to CV outcomes. Omega-3 carboxylic acid (CA) does not require pancreatic lipase for absorption and can thus potentially achieve higher and more reliable concentrations in the blood, regardless of co-ingestion of fatty meals.

The STRENGTH trial assessed whether administration of omega-3 CA supplements (containing a combination of EPA and DHA) compared to placebo improved CV outcomes in patients with high vascular risk and atherogenic dyslipidemia.

STRENGTH was a multicentered, placebo-controlled, event-driven (1600 events to have 90% power to detect 15% reduction in MACE) trial that included statin-treated patients (n=13,078) with established or at high risk for CV disease with triglycerides (TG) levels of 180-500 mg/dL, HDL <42 mg/dL (men) and 47 mg/dL (woman) from October 2014 to June 2017. Participants were randomized to 4 g of omega-3 carboxylic acid (EPA and DHA dissolved in corn oil) daily or corn oil placebo. Primary MACE endpoint was a composite of CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial was stopped due to futility on January 2020 after review of 1384 primary endpoints. Median follow-up of patients was 42 months.

Main results

• Plasma EPA levels were increased in the omega-3 CA treated patients compared to patients on placebo (268.8% vs. -10.5%, respectively).
• In patients supplemented with omega-3 CA, TG levels were decreased by 19% compared to a reduction of 0.9% in individuals supplemented with corn oil. hsCRP was reduced by 20% in the group treated with omega-3 CA compared to 6.3% in the placebo group. There were minor differences in LDL-c and HDL-c concentrations between the groups.
• There was no difference in MACE outcome in patients supplemented with omega-3 CA compared to individuals on placebo (HR 0.99, 95% CI: 0.90-1.09, P=0.84).
• The risk for time to onset of atrial fibrillation (AF) was increased by 69% over the entire follow-up period in patients treated with omega-3 CA supplements compared to placebo (HR 1.69, 95% CI: 1.29-2.21).

Conclusion

High-dose omega-3 CA supplementation had no beneficiary MACE outcome in statin-treated patients diagnosed with or at high risk for CV disease compared to placebo. Furthermore, a higher prevalence of AF was observed in the group with omega-3 CA compared to placebo.

In the end, Michael Lincoff discussed possible explanations for the different findings in the STRENGTH trial and the REDUCE-IT trial [1]. First, in the REDUCE-IT trial, the increase in EPA levels from baseline to 12 months in patients receiving icosapent ethyl was 144 µg/mL compared to 89.6 µg/mL in patients in the STRENGTH trial receiving omega-3 CA supplements. These differences are unlikely the cause of the different end results in the two trials, according to Lincoff. Second, the STRENGTH trial used a combination of EPA and DHA, while the REDUCE-IT trial used purified EPA. Perhaps DHA has a neutralizing effect on EPA. However, DHA has never been associated with an increased risk of adverse CV events or atherosclerotic effects in preclinical models. In contrast, high levels of DHA have been associated with a CV protective effect in epidemiological studies, said Lincoff. Third, there were differences in the two trial populations. The REDUCE-IT trial included more patients with established CAD included compared to the STRENGTH trial (71% vs. 56%, respectively). However, there was, according to Lincoff, no interaction of disease status on treatment effect on MACE. Last, corn oil, compared to the mineral oil used in the REDUCE-IT trial, did not increase lipid (LDL-c and ApoB) and inflammation (hsCRP) markers in the placebo group, suggesting it was a neutral vehicle.

Discussion

Alberico L. Catapano (Milano, Italy) proposed several theories on why discrepancies were observed between the STRENGTH and OMEMI trials compared to the REDUCE-IT trial. Firstly, icosapent ethyl (pure EPA) produced higher EPA plasma levels. Secondly, Catapano raised the point that DHA might be less biologically active or could even counteract the benefits of EPA.

Thirdly, there could be a possibility, that the mineral oil led to an unfavorable effect in the placebo group and could have exaggerated the efficacy of icosapent ethyl in the treated group, he said. Furthermore, different patient populations were enrolled in the trials. There were less CV patients in the STRENGTH trial compared to the REDUCE-IT trial (56% vs 71% respectively), but since the OMEMI trial only included CAD patients, Catapano overruled this argument immediately. Lastly, the dose could make a difference, as the availability of EPA was less in the STRENGTH trial than in the REDUCE-IT trial.

What exactly the cause of the discrepancy is at this moment is unclear, he said, but we certainly have to address the points of doses, plasma levels, as well as the effect of placebo. And a comparative clinical trial is important, bearing in mind the dose effect, and would definitely provide more clarity.

References

1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019; 380:11-22.

- Our reporting is based on the information provided during the AHA Scientific Sessions 2020 –

The findings of this study were simultaneously published in JAMA Watch a video on the STRENGTH trial