REDUCE-IT: CV Benefit of Icosapent Ethyl Directly Related to EPA Levels

April 02, 2020

The reduction in cardiovascular (CV) events seen in the REDUCE-IT trial with icosapent ethyl (Vascepa, Amarin), a high-strength formulation of purified eicosapentaenoic acid (EPA), were directly related to on-treatment serum levels of EPA, and not to a decrease in triglyceride levels as had originally been anticipated, a new analysis confirms.

"The benefits in the REDUCE-IT cannot be explained by the degree of changes to triglycerides or other biomarkers such as LDL cholesterol or CRP [C-reactive protein]. It is only on-treatment levels of EPA that correlates strongly with the benefits seen," lead investigator, Deepak Bhatt, MD, Brigham and Women's Hospital, Boston, Massachusetts, said.

Bhatt presented the latest findings from the trial earlier this week at the "virtual" American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).

The REDUCE-IT trial, reported in 2018, enrolled 8179 patients who had elevated cardiovascular risk already treated with statins. It found that a high dose of icosapent ethyl (4 g daily) reduced the rate of cardiovascular events by 25% over a median of 4.9 years of follow-up.

Prior to REDUCE-IT, icosapent ethyl was approved for the treatment of patients with triglycerides above 500 mg/dL, and it was anticipated that it would bring about benefits to a broader population of patients at cardiovascular risk primarily by lowering triglycerides, Bhatt explained.

"However, the current analysis found that the lion's share of the drug's large cardiovascular benefit is driven by achieved EPA levels, and not the lowering of triglycerides," he stated.

"Changes in triglycerides levels and other cardiovascular risk markers, including LDL, HDL, apoB, and CRP, appear to be responsible for a significantly lesser portion of the overall observed benefit," he said.

"The reduction in triglyceride levels contributed just 2 percentage points to the overall 25 percentage points reduction in clinical events seen in the study," Bhatt reported.

"The primary endpoint, the key secondary endpoint, cardiovascular death, and even all-cause mortality were all significantly reduced by higher levels of on-treatment EPA," he noted.

"Similarly, there was also a strong and significant relationship between on-treatment EPA levels and lower risk of fatal and non-fatal [myocardial infarction], fatal and non-fatal stroke, coronary revascularization, and hospitalization for unstable angina," he added.

"Tertiary endpoints saw significant correlation between on-treatment EPA levels and sudden cardiac death and cardiac arrest, as was noted in the overall trial. In addition, while heart failure was numerically lower in the icosapent ethyl group but not significantly so, now here for the first time we are seeing an association between higher on-treatment levels of EPA and lower risk for heart failure hospitalization," Bhatt commented.

The significant association between achieved EPA levels and lower risk of cardiovascular events was also seen in both major subgroups in the trial — those with established cardiovascular disease (the secondary prevention cohort) and those with diabetes and other risk factors (the high-risk primary prevention cohort).

He also reported that the risk of cardiovascular events was unrelated to baseline concentrations of serum EPA, and that icosapent ethyl raised serum EPA levels by approximately fourfold.

"It is important to point out that these benefits appear to be mediated through EPA levels, and as far as we can tell from basic science studies, these benefits are specific for EPA and can't be generalized to other EPA formulations beyond icosapent ethyl or to the other omega-3 fatty acid, docosahexaenoic acid (DHA)," Bhatt stated.

Greg Schwartz, MD, University of Colorado School of Medicine, Denver, said the association between benefit and EPA levels was expected since "EPA essentially is the active ingredient of the drug." Schwartz was a panelist at the ACC virtual session at which this latest analysis was presented.

He asked Bhatt why, if the benefit is related to the serum concentration of EPA, it would not apply to other products that can give these EPA levels.

"Baseline EPA was in a relatively narrow range and icosapent ethyl raised levels by 400%. You cannot achieve these sorts of levels by eating lots of fish," Bhatt replied. "And in terms of dietary supplements — the reality is the sort of pill burden you would have to take to get anywhere near these levels of EPA would be 20 to 30 supplement pills a day, and then there is the risk of all the other stuff in these pills, such as DHA, which may actually counteract the benefit of EPA, and other fats and saturated fats, and you still would be unlikely to achieve these types of levels of EPA."

Bhatt noted that the STRENGTH trial — which was testing a 4 g/day mixture of DHA and EPA — was stopped because it was unlikely to meet its primary endpoint. "It will not have achieved as high levels of EPA as occurred with icosapent ethyl in REDUCE-IT, and the DHA might have counterbalanced some of the benefits of EPA," he added.

Schwartz asked if even greater benefits could be expected with higher doses of EPA.

Bhatt said that was an "interesting and provocative" question. "But I have to default to what we studied — 4 g a day given as 2 g twice a day with meals," he said. "That was the winning dose that provided the large degree of risk reduction we saw in the trial. Is it possible that higher doses could cause even more CV benefit — maybe; it's certainly something that might be worthy of study."

Discussing the study at an ACC press conference, Eugene Yang, MD, University of Washington Medical Center, Seattle, said the latest analysis "validates the potential unique benefits of EPA, especially in the light of the results of the STRENGTH trial testing a high dose combination of EPA and DHA."

"I think we know that there are different potential effects of EPA and DHA, and in combination they may have unfavorable effects on certain lipid parameters such as increasing LDL levels, whereas EPA may be having a neutral effect or give slightly lower LDL levels," he commented.

He also noted that studies of lower dose combinations of EPA/DHA, such ASCEND and VITAL published in 2018 using a 1 g combination of the two omega 3 oils, failed to show a benefit in reducing cardiovascular events.

"We need to ask whether the EPA benefit is specifically related to lipid lowering effects, which does not seem to be the case based on these results, or whether it is other pleiotropic effects, possible anti-inflammatory effects, or its effect on other downstream targets that have yet to be elucidated. Those are areas that we need to try to understand better."

Bhatt told Medscape Medical News that the mechanism of benefit of EPA is a "fascinating and evolving story."

"There are several downstream effects EPA has, such as stabilization of cell membranes, that may explain some of what we saw in REDUCE-IT, including a significant reduction in cardiac arrest and sudden cardiac death," he said.

Bhatt has co-authored a review paper on potential EPA mechanisms just published in Arteriosclerosis, Thrombosis, and Vascular Biology.

The paper reports that "omega-3 fatty acids modulate T-cell differentiation and give rise to various prostaglandins and specialized pro-resolving lipid mediators that promote resolution of tissue injury and inflammation," but that "EPA and DHA differ in their effects on membrane structure, rates of lipid oxidation, inflammatory biomarkers, and endothelial function as well as tissue distributions."

One particularly interesting observation is that "human plaques readily incorporate EPA, which may render them less likely to trigger clinical events."

Schwartz also called for more exploration of the potential safety effects of higher doses of EPA. "We need to have a better understanding of the potential bleeding associated with higher EPA levels, as there were slightly higher rates of major bleeding with icosapent ethyl in REDUCE-IT, although this did not reach statistical significance," he noted.

To Medscape Medical News, Yang elaborated: "There have been concerns in the past about increased risk of bleeding with higher doses of omega-3 fatty acids and in the REDUCE-IT trial, patients randomized to EPA had higher rates of major bleeding (2.6% vs 2.1%) but this did not reach statistical significance.

"Since the safety data has not been released from this analysis, it will be important to see if higher EPA levels also signal a higher major bleeding event rate, so we may need to find a happy medium of a specific EPA level that does not increase risk of bleeding," Yang said.

Bhatt confirmed to Medscape Medical News that such further analyses are underway.

REDUCE-IT was sponsored by Amarin. Brigham and Women's Hospital receives research funding from Amarin for Bhatt's role as chair of the trial.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC): Abstract 20-LB-20501-ACC. Presented March 30, 2020.

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