RESPECT-EPA– Randomized Trial for Evaluating Secondary Prevention Efficacy of Combination Therapy

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6 December 2022

RESPECT-EPA– Randomized Trial for Evaluating Secondary Prevention Efficacy of Combination Therapy - Statin and Eicosapentaenoic Acid

The RESPECT-EPA trial showed a marginally significant effect of highly purified eicosapentaenoic acid (EPA) on the primary outcome (a composite of cardiovascular death, nonfatal myocardial infarction [MI], nonfatal ischemic stroke, unstable angina pectoris, or coronary revascularization). The study did, however, have large dropout and protocol violation rates.

Daida H, et al. RESPECT-EPA – Randomized Trial for Evaluating Secondary Prevention Efficacy of Combination Therapy - Statin and Eicosapentaenoic Acid. Presented at the American Heart Association Scientific Sessions 2022.

STUDY SUMMARY

Objective

To evaluate the effects of EPA in combination with statin therapy on cardiovascular events in Japanese patients with chronic coronary artery disease (CAD).

Study design

Investigator-initiated, open-label, randomized trial conducted in Japan.

Study population

Patients with chronic CAD and a low EPA/arachidonic acid ratio (<0.4) on statin therapy.

Study Outcomes

• Primary outcome: a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization
• Secondary outcomes: composite events of CAD, composite events of stroke and events related to death

Methods

Eligible patients were randomly allocated to treatment with highly purified EPA (icosapent ethyl, 1800 mg/day) plus statin therapy or statin alone. The enrolment period was 4 years and the follow-up period was 4 years from the end of the enrollment period.

Results

The trial randomized 2,506 patients (1249 to the EPA group and 1257 to the control group). Overall, median low-density lipoprotein cholesterol was 80 mg/dL (2.1 mmol/L), triglyceride (TG) was 120 mg/dL (1.35 mmol/L) and EPA was 45 µg/mL. At 6 years from the start of randomization, there was a marginally statistically significant reduction in the primary outcome (10.9% versus 14.9%, hazard ratio 0.785, p=0.0547). There was a significant reduction in the composite secondary endpoint of sudden cardiac death, MI, unstable angina, and coronary revascularization (8.0% versus 11.3%, hazard ratio 0.734, p=0.0306).

Author conclusion

RESPECT-EPA showed a non-significant reduction in the primary endpoint with purified EPA in patients with chronic CAD on statin therapy. Purified EPA did significantly reduce the composite secondary endpoint of sudden cardiac death, MI, unstable angina, or coronary revascularization. Safety results showed that use of purified EPA was associated with a significant increase in gastrointestinal disorders and new-onset atrial fibrillation.

COMMENT

Results of the RESPECT-EPA trial add to ongoing controversy regarding the role of TG-lowering therapeutics in reducing residual cardiovascular risk. Although reduction in the primary outcome in the EPA group was not statistically significant, there was a significant reduction in the secondary cardiovascular outcome. However, the trial also has limitations that need to be considered. These include the open-label design, and the high rates of discontinuation and protocol violation in the study, both important sources of bias in the analysis. Moreover, unlike other recent trials of evaluating high-dose omega-3 fatty acid therapy, the trial specifically included patients with low EPA levels at baseline and thus tested a different hypothesis to that in REDUCE-IT and STRENGTH (1,2).

Full publication of the results is awaited.

References

1. 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.
2. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.

Key words

omega-3 fatty acids; eicosapentaenoic acid; RESPECT-EPA; residual cardiovascular risk