Introduction and methods

EPA Levels and Cardiovascular Outcomes in the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

Presented at ACC.20 by Deepak Bhatt (Boston, MA, USA)

The overall REDUCE-IT trial showed that use of 4 g icosapent ethyl was associated with a reduction in the primary endpoint, a composite of CV death, MI, stroke, coronary revascularization and unstable angina compared to placebo (HR 0.75, 95%CI:0.68-0.83, P<0.00000001). The key secondary endpoint of ‘hard endpoints’ CV death, MI and stroke was also reduced in the icosapent ethyl group compared to placebo (HR 0.74, 95%CI: 0.65-0.83). These results resulted in the question of what is driving this large risk reduction.

Main results

• Adjusting for EPA levels showed that risk of primary endpoint was not as much reduced with icosapent ethyl as in the main analysis (HR 1.03, 95%CI: 0.91-1.16, P<0.0001), suggesting that EPA levels account for a large portion in the risk reduction. A similar phenomenon was observed for secondary endpoint of CV death, MI and stroke (HR 0.98, 95%CI: 0.84-1.14, P<0.0001).
• Adjusting for time-varying triglycerides in the effect of icosapent ethyl on the primary endpoint showed that triglyceride levels only account for a small fraction (HR 0.77, 95%CI: 0.70-0.85, P<0.0001). Adjusting for other biomarkers showed a similar pattern.
• Higher on-treatment levels of EPA were associated with a lower risk of the primary outcome. This association was also observed for the key secondary outcome, CV death and total mortality (all P<0.001).
• Also, higher on-treatment levels of EPA were associated with lower risk of outcomes of any MI, any stroke, coronary revascularization and unstable angina (P<0.001).
• Tertiary outcomes in the REDUCE-IT trial of sudden cardiac death, cardiac arrest, new heart failure (HF) requiring hospitalization and new HF were also associated with EPA levels (higher EPA levels associated with lower risk of outcome) (P<0.001).
• When looking at two subgroups, patients with established CVD and diabetes patients with risk factors, both showed an association of higher EPA levels with lower risk of primary outcome (P<0.01).

Conclusion

This sub-analysis of the REDUCE-IT showed that higher on-treatment EPA levels were associated with lower risk of CV outcomes, including the primary endpoint, the key secondary endpoint, MI, stroke, revascularization, unstable angina, sudden cardiac death, cardiac arrest, new heart failure, and all-cause death.

Bhatt pointed out that the observed effects in the REDUCE-IT trial appear to be mediated by EPA levels. Basic science studies have suggested that these effects are specific and can not be generalized to other EPA formulations beyond icosapent ethyl or to DHA.

Discussion

This study validates the unique benefit of EPA, according to the discussant Eugene Yang, MD (Bellevue, WA, USA). Also in light of the STRENGTH CV trial that was terminated and evaluated a combination of EPA and DHA. There are different effects of EPA and DHA, as pointed out by prof. Bhatt and in combination may have unfavorable effects. A lower dose of EPA and DHA in the ASCEND trial published in 2018 also failed to show a CV benefit. It appears that EPA does not mediate its effects by lipid-lowering, but pleiotropic effects -anti-inflammatory effects or other targets that have yet to be elucidated- may be at play. Finally, he noted that better understanding of the increased risk of bleeding (although not significantly increased) observed with icosapent ethyl is necessary.

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Watch a video by prof. Bhatt