RESPECT-EPA: Missed Primary Endpoint but Hints of Benefit With Icosapent Ethyl

CHICAGO, IL—When added to statin therapy, icosapent ethyl, a pharmaceutical-grade omega-3 fatty acid formulation, did not reduce major cardiovascular events among patients with chronic CAD in the randomized RESPECT-EPA trial conducted in Japan.

RESPECT-EPA, which randomized patients to icosapent ethyl or to standard care without a placebo, is unlikely to resolve any of the controversy around the mineral oil control used in the REDUCE-IT trial and questions about the magnitude of benefit it reported.

Though there was a numerical difference in favor of icosapent ethyl plus statins versus statins alone for the primary composite endpoint in RESPECT-EPA, the difference fell just shy of significance (10.9% vs 14.9%; HR 0.785; 95% CI 0.616-1.001), according to Hiroyuki Daida, MD, PhD (Juntendo University, Tokyo, Japan).

However, a secondary composite outcome of sudden cardiac death, MI, unstable angina, or coronary revascularization—similar to the primary endpoint of the positive JELIS trial—revealed a significant advantage for icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), he reported here at the recent American Heart Association 2022 Scientific Sessions.

“We believe these findings indicate a possible prognostic benefit of EPA in chronic coronary artery disease patients [on] statins whose EPA/AA ratio was low,” Daida concluded. A low EPA/ arachidonic acid [AA] ratio, used to select patients for the trial, is a marker of increased inflammation.

Controversy Around Icosapent Ethyl

Previously, the REDUCE-IT trial demonstrated a 25% relative reduction in the risk of major adverse cardiovascular events with icosapent ethyl among statin-treated patients with high triglyceride levels, consistent with the positive results of the prior JELIS trial in a similar population. Ever since the findings came out, however, a debate about whether the mineral oil placebo used in REDUCE-IT inflated the observed benefit has persisted.

The open-label RESPECT-EPA, which enrolled patients with chronic CAD who were being treated with statins and who had an EPA/AA ratio below 0.4, adds more fodder for the discussion. Investigators randomized 2,506 patients (mean age 68 years; 83% men) to icosapent ethyl 1,800 mg/day or no additional treatment on top of statins. Most patients (54%) had a history of MI, whereas nearly all had undergone coronary revascularization with either PCI (88%) or CABG (11%).

At baseline, median LDL-cholesterol level was 81 mg/dL and median triglyceride concentration was about 119 mg/dL. The median EPA level was 46 µg/mL, which is higher than in REDUCE-IT (26 µg/mL) but lower than in JELIS (97 µg/mL).

In the icosapent ethyl group, there was a significant increase in EPA concentration and declines in LDL cholesterol, triglycerides, and AA, but no changes in high-sensitivity C-reactive protein or HDL cholesterol.

In addition to the lack of a significant difference for the primary endpoint, and a significant difference for the secondary composite endpoint, rates of all-cause mortality, CV death, MI, ischemic and hemorrhagic stroke, coronary revascularization, and unstable angina requiring emergency hospitalization were statistically similar in the two trial arms.

A post hoc analysis that excluded patients who failed to have an increase in EPA levels in the treatment arm and those who had a large increase in EPA levels in the control arm demonstrated a significant advantage for icosapent ethyl on the primary composite endpoint (HR 0.725; 95% CI 0.553-0.951).

I think in terms of our patients with residual risk, we should still consider EPA as a molecule to institute for these patients. Pam Taub

In terms of safety, GI disorders were more frequent in the icosapent ethyl arm (3.4% vs 1.2%; P < 0.001), but there were no differences in TIMI major or minor/minimal bleeding. Consistent with prior trials of omega-3 fatty acid supplementation, new-onset atrial fibrillation (AF) was increased with icosapent ethyl (3.1% vs 1.6%; P = 0.017).

Cost, AF Risk Come Into Play

Commenting for TCTMD, Amit Khera, MD (UT Southwestern Medical Center, Dallas, TX), one of the moderators of the late-breaking science session at which Daida presented the results, said the trial provides some insights into what has become a controversial area while leaving other questions unresolved.

On one hand, though RESPECT-EPA was a negative trial, having missed its primary endpoint, there was a signal of benefit consistent with what was seen in JELIS and REDUCE-IT, Khera said. And that comes in a trial that enrolled a broader secondary prevention population without inclusion criteria related to triglycerides.

On the other hand, the trial was underpowered and any suggestion of benefit did not start to emerge until about 3 or 4 years into follow-up, a finding without a clear explanation. Moreover, if icosapent ethyl is having a positive effect, it’s at least somewhat offset by the increased AF risk, Khera said.

“I think we have to pay attention to that, because . . . if there is some benefit, there is the trade-off with A-fib and we may have to select our patients a little more carefully,” he said.

Putting RESPECT-EPA into the context of prior trials, Khera said it “does go in the positive column because now we have three studies that at least have some signal towards improvements with cardiovascular outcomes with icosapent ethyl, but the flip side is, I think this still leaves questions.”

Khera, director of preventive cardiology at his institution, said that when considering icosapent ethyl for his patients, he weighs the signals of benefit against cost and the AF risk. The latter is particularly important among patients already on dual antiplatelet therapy, because a diagnosis of AF often comes with a prescription for anticoagulation, heightening bleeding concerns. And generally, he added, he makes sure he’s aggressive about managing his patients with other proven approaches—like lifestyle measures, LDL cholesterol-lowering, and sodium-glucose cotransporter 2 (SGLT2) inhibitors—before considering icosapent ethyl.

Pam Taub, MD (UC San Diego Health, La Jolla, CA), who was the discussant following Daida’s presentation, described EPA as a molecule with demonstrated benefits that include decreased inflammation and improved endothelial function.

She addressed the controversy around the impact of the mineral oil placebo used in REDUCE-IT, saying that its effects on certain biomarkers calls into question the magnitude of the benefit seen in the trial. “The truth is probably that relative risk reduction is somewhat less, so the magnitude of benefit is uncertain,” Taub commented.

There is a need for more research to identify the patients most likely to benefit from icosapent ethyl, she said, agreeing that the small increased risk of AF warrants attention.

Ultimately, though, “I think in terms of our patients with residual risk, we should still consider EPA as a molecule to institute for these patients,” Taub said.