Icosapent Ethyl’s CV Benefit Closely Tied to Serum EPA Levels: REDUCE-IT

Icosapent ethyl (Vascepa; Amarin) led to substantial reductions in cardiovascular events in the REDUCE-IT trial, but questions remained about how the prescription-grade omega-3 fatty acid formulation was working. Now, a prespecified substudy indicates that the benefits were strongly related to serum levels of eicosapentaenoic acid (EPA).

As on-treatment EPA levels increased, significant reductions were seen in a variety of different outcomes, including the primary MACE endpoint and the key secondary endpoint of CV death, MI, or stroke (P < 0.001 for both), Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), reported at the virtual American College of Cardiology (ACC) 2020 Scientific Session.

“These data provide a mechanistic underpinning for the large risk reductions seen in multiple endpoints with icosapent ethyl in REDUCE-IT,” he concluded.

Martha Gulati, MD (Banner – University Medicine Heart Institute, Phoenix, AZ), said the findings won’t have a big impact how she uses icosapent ethyl in practice, because there was already a lot of excitement about the main results when they were released in full in November 2018.

“It was a pretty exciting trial from the minute it came out, meaning that there was a group of people based on the population enrolled in REDUCE-IT that would benefit from this as an addition to optimal medical therapy,” she told TCTMD. “So from that standpoint, [the EPA analysis] doesn’t really change my practice, but I guess it helps me better explain to my patients how this drug works.”

EPA Levels in REDUCE-IT

REDUCE-IT included 8,179 statin-treated patients who had controlled LDL cholesterol, persistently elevated triglycerides, and either established CVD or diabetes plus at least one additional risk factor; its results showed that treatment with icosapent ethyl at a dose of 4 grams per day reduced the occurrence of MACE (CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina) by a relative 25% and the composite of CV death, MI, or stroke by a relative 26% versus placebo. A subsequent analysis of total events showed a 31% relative reduction with icosapent ethyl (RR 0.69; 95% CI 0.61-0.77). The findings supported an expanded indication from the US Food and Drug Administration.

The reduction in CV events could not be explained by the change in triglyceride levels, as some had hypothesized, leaving open the question about the mechanism of benefit.

With this new EPA analysis, the REDUCE-IT investigators explored that issue. They first showed that the reductions in events were consistent across baseline serum EPA tertiles for both the primary endpoint (P = 0.91) and the key secondary endpoint (P = 0.90).

Then Bhatt et al examined on-treatment serum EPA levels. Treatment with icosapent ethyl resulted in a median 363.9% increase in EPA levels—from 26.1 to 135.2 µg/mL. That change accounted for the majority of the improvement in CV outcomes seen in the trial, the researchers found, with limited contributions from other biomarkers, including triglycerides.

“The cardiovascular benefit observed in REDUCE-IT appears to be highly correlated with the observed increase in serum EPA levels,” Bhatt said.

When looking at serum EPA level as a continuous variable, they also showed that as the on-treatment level increased, risks of a wide range of adverse clinical outcomes decreased, including the primary endpoint, the key secondary endpoint, CV death, total mortality, any MI, any stroke, coronary revascularization, hospitalization for unstable angina, sudden cardiac death, cardiac arrest, hospitalization for new heart failure, and new heart failure (P < 0.001 for all).

The rate of the primary endpoint declined as on-treatment serum EPA levels increased both in patients who qualified for the trial on the basis of established CVD and in those who had diabetes with risk factors (P < 0.001 for both).

Analyses for any bleeding, serious bleeding, and atrial fibrillation or flutter are not yet available, Bhatt said.

Not Just Any Old Fish Oil

Bhatt noted that these results apply only to this specific formulation of EPA. Other omega-3 fatty acid products contain a mix of EPA and docosahexaenoic acid (DHA), which is important because EPA and DHA have been shown to have different biological effects in clinical and experimental studies, with DHA perhaps counterbalancing some of the positive effects of EPA. That could explain the lack of benefit seen in trials of other omega-3 fatty acid formulations, Bhatt said.

He additionally pointed out that it is unlikely that people could achieve the serum EPA levels observed in REDUCE-IT either by eating fish or taking over-the-counter fish oil supplements, and added that he discourages his patients from using such products.

Gulati was on the same page, saying that there remains a concern that patients will attempt to gain the benefits seen in REDUCE-IT using over-the-counter supplements, perhaps to avoid the cost of the prescription.

“There is something unique to Vascepa in and of itself, and we don’t want patients to think that you just need to add up some version of fish oil to make it the 4 grams a day of EPA that people got [in REDUCE-IT],  because you would be spending your whole day swallowing drugs,” Gulati said, adding that other components of the supplements potentially could be harmful or counteract the effects of the EPA. “We do go through a lot of education about it.”

Some questions remain, however, about why there was such a wide range of achieved serum EPA levels in the trial when everyone was receiving the same dose of icosapent ethyl, she said, opening the door to the possibility that future studies will explore whether some patients need more than 4 grams per day to obtain sufficient EPA levels.

Bhatt said that genetics could come into play, but that the issue hasn’t yet been explored. Further analyses from REDUCE-IT may provide some answers.