In this video, Deepak Bhatt, MD, MPH, overviews the findings from the eicosapentaenoic acid (EPA) analysis of the REDUCE-IT trial and what impact the results may have on the future of cardiovascular therapies.
Additional Resources:
1. Bhatt DL, Miller M, Steg PG, et al. EPA levels and cardiovascular outcomes in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial. Presented at the 2020 American College of Cardiology/World Congress of Cardiology. https://www.acc.org/education-and-meetings/image-and-slide-gallery/media-detail?id=062fc9e4b3a74a9fb1c196a35dad8f3b
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. doi:10.1056/NEJMoa1812792
Deepak L. Bhatt, MD, MPH, is the executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School in Boston, Massachusetts. He specializes in cardiovascular medicine and interventional cardiology.
TRANSCRIPT:
Deepak Bhatt: I’m Dr Deepak Bhatt from Brigham and Women’s Hospital and Harvard Medical School. It’s really a pleasure for me to present a recap of REDUCE-IT EPA, which I just presented as a late-breaking clinical trial at the American College of Cardiology Annual Sessions—I should say the virtual annual sessions—which was an exciting undertaking this year.
Before getting into REDUCE-IT EPA, let me quickly recap REDUCE-IT. This was a trial of over 8000 patients randomized to icosapent ethyl, which is a highly purified ethyl ester of EPA, or eicosapentaenoic acid in Omega-3 fatty acid, a prescription version, or to a placebo.
Patients all had either established atherosclerosis or diabetes plus multiple cardiovascular risk factors, at least one. In addition to those clinical inclusion criteria, patients had to have triglycerides greater than equal to 135 milligrams per deciliter. In fact, we had patients with triglycerides that were fasting, as well as 100, but the inclusion criteria actually 135 or greater. The overall trial showed a large and significant reduction in ischemic events. A 25% reduction in first ischemic events and a 30 or 31% reduction in total ischemic events that is first and recurrent ischemic events. Large in relative terms, large in absolute terms.
The primary results for first events were published in the New England Journal Medicine, the total events analysis was published in the Journal of the American College of Cardiology. And more recently, the USA subgroup data were published in Circulation, showing results consistent with the overall trial and if anything even greater degrees of benefit, including the 30% reduction in all-cause mortality that was significant.
What I presented at the American College of Cardiology was the EPA analysis—that is looking at serum levels of EPA or eicosapentaenoic acid. The first part of the analysis examined patients by their baseline levels of EPA to see what the effect of the drug versus placebo was, and there was a consistent benefit for the primary and key secondary ischemic endpoints across the full range of baseline EPA level, meaning that even in patients that had high baseline EPA levels—maybe from good genes or other factors we don’t know or from diet, such as a diet high in fish and seafood—even those patients with quote unquote naturally high EPA levels, it was still a substantial and significant benefit of giving icosapent ethyl vs a placebo.
The second part of the analysis, which I think is really quite scientifically interesting, is that we looked at these levels of attained on-treatment EPA levels. And what we found were highly statistically significant correlations between the level of on treatment EPA and reductions in the primary and key secondary endpoints of the trial and also in a number of the other secondary endpoints, including cardiovascular death, all-cause mortality fatal or nonfatal heart attacks, fatal or nonfatal strokes, urgent revascularization, hospitalization for unstable angina, sudden cardiac death, cardiac arrest—all significantly reduced. And these were also lower in the trial with the drug vs placebo, but here we see now that the mechanism of benefit that we observed on critical endpoints in the trial was translated through increases in EPA or eicosapentaenoic acid levels.
In the overall REDUCE-IT trial, there was a numerically lower rate of heart failure, but this wasn’t statistically significant. However, in these EPA analyses, we see that patients at the highest levels of on-treatment EPA, there was indeed a significant reduction in new heart failure and hospitalization for heart failure Thus, we see in REDUCE-IT EPA, the full extent of ischemic events and now also heart failure are significantly correlated with higher levels of on-treatment EPA.
I think this explains the bulk of benefit that we saw and changes say in triglycerides, or LDL, or CRP, while significant in the trial accounted forjust a fraction of the overall benefit. So it did appear that EPA is where the action is. And I think this is important, not only for understanding the benefits that we saw in REDUCE-IT, but also for the future in terms of opening up a whole new axis of cardiovascular risk reduction that mediated by EPA
Beyond the specific findings of reducing EPA and the relevance for icosapent ethyl, I do believe these findings will usher in a whole new era of EPA-based therapeutics. That is, much like statins were first developed for lowering LDL cholesterol and then found to reduce ischemic events and then a whole class of therapies arose, I think the same thing may happen in the field of EPA-based therapeutics. Obviously, we would need to do large, long-term trials to find the benefit of any novel EPA-based therapy, but I suspect in years to come, scientists and industry will develop different sorts of compounds that target risk reduction through the EPA axis. So I do hope that what we found here will be useful, and it might take a decade or two for all of that to manifest, but hopefully we will have made a major scientific contribution through reducing EPA.
Thank you very much for your attention.
