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RESPECT-EPA misses primary endpoint but hints towards improvements in CV outcomes by EPA

Presented by
Dr Hiroyuki Daida, Juntendo University, Japan
AHA 2022
The RESPECT-EPA trial did not demonstrate a statistically significant effect of highly purified eicosapentaenoic acid (EPA) on top of statins for the reduction of adverse cardiovascular (CV) events compared with statins alone in patients with chronic coronary artery disease (CAD) and low EPA/arachidonic acid (AA) ratio.

The Japanese JELIS trial (NCT00231738) displayed clinical benefits of highly purified EPA in individuals with and without CAD [1]. “However, other, more recent, trials have delivered conflicting results concerning the clinical benefits of EPA on top of optimal medical therapy in patients with CAD,” said Dr Hiroyuki Daida (Juntendo University, Japan). The current open-label RESPECT-EPA trial (UMIN000012069) assessed the safety and efficacy of EPA on top of statins in patients with chronic CAD and an EPA/AA ratio <0.4 [2]. The included participants (n=2,506) were randomised 1:1 to statin therapy plus 1,800 mg highly purified EPA per day or standard statin therapy. The primary endpoint was the occurrence of any of the following CV events: CV death, nonfatal myocardial infarction, nonfatal cerebral infarction, unstable angina pectoris requiring emergency hospitalisation plus a coronary revascularisation procedure, and revascularisation procedure based on clinical findings.

After 6 years of follow-up, participants in the EPA group had a numerically lower risk of CV events than participants in the control group, but the difference was not statistically significant (10.9% vs 14.9%; HR 0.79; 95% CI 0.62-1.00; P=0.055. Notably, the cumulative event curve was the same across the EPA and control groups at 2 years follow-up (both arms at 4.7%), with data slightly in favour of EPA at 4 years (8.6% vs 8.8%), but the curves diverged by 6 years (10.9% vs 14.9%), suggestive of long-term effects. Similar results occurred with the secondary composite endpoint of sudden cardiac death, myocardial infarction, unstable angina, and coronary revascularisation endpoint, with a significant difference occurring at 6 years (8.0% in the EPA group vs 11.3% with the control group; HR 0.73; P=0.031). There was no significant difference in all-cause mortality between the 2 groups at any time point. Dr Daida added that a posthoc analysis, excluding participants in the control group who displayed an EPA increase from baseline of > 30 μg/mL (n=182), did show a significant effect of additional EPA on the primary endpoint (HR 0.73; P=0.020). Finally, the safety analysis showed a higher rate of gastrointestinal disorders (3.4% vs 1.2%; P<0.001) and atrial fibrillation (3.1% vs 1.6%; P=0.017) in the EPA compared with the control group. Other safety outcomes, such as bleeding risk, were comparable between the 2 study groups.

Prof. Pam Taub (University of San Diego, CA, USA) commented on the results of the RESPECT-EPA trial in the context of other EPA trials. “There appears to be a benefit with EPA in terms of risk reduction for adverse CV events, but the magnitude of this benefit is unclear,” she said. “The largest effect of EPA was reported in the REDUCE-IT trial (NCT01492361), in which participants had the lowest baseline EPA levels and displayed the largest increase in EPA after therapy [3]. Next to that, the baseline high-sensitive (hs) CRP was higher in the study population of the REDUCE-IT trial, with larger reductions after EPA therapy, compared with the study population of the RESPECT EPA and JELIS trials.” Therefore, lower baseline EPA levels and higher baseline hsCRP levels may be indicative of a good response to EPA therapy. “However, more clinical and mechanistic data is needed to resolve this issue,” Prof. Taub concluded.

    1. UMIN000012069
    2. Daida H, et al. Randomized trial for evaluating secondary prevention efficacy of combination therapy - statin and eicosapentaenoic acid (RESPECT-EPA). LBS.05, AHA Scientific Sessions 2022, 05–07 November, Chicago, USA.
    3. Bhatt DL, et al. N Engl J Med 2019;380:11–22.


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