Dr. Kohli On The RESPECT-EPA Trial

The RESPECT-EPA study sought to assess if the use of eicosapentaenoic acid (EPA) reduces the risk of adverse cardiovascular events in Japanese patients with chronic coronary artery disease (CAD) who are also on statins. The study was presented at the 2022 American Heart Association (AHA) Scientific Sessions.

DocWire News Medical Leader Dr. Payal Kohli spoke in more depth about this study, and its clinical implications.

Dr. Payal Kohli: The RESPECT-EPA was another very interesting trial in preventive cardiology. So we knew from back in 2005 when we had the JELIS study, which was a Japanese study of EPA, it was a combination of patients in primary prevention and patients in secondary prevention. And their LDLs were not well controlled. There was a median LDL in that trial of 181 milligrams per deciliter, very low background intensity of statin. But that study showed maybe a signal for benefit in that secondary prevention population getting EPA, patients with existing atherosclerotic cardiovascular disease.

So this was sort of the verification arm of that study where they enrolled only patients with chronic CAD who are already on statin therapy. Now, we don’t know exactly what dose of statin therapy, but their LDLs in this trial were controlled, it was about an average LDL of 81 milligrams per deciliter, excuse me, median LDL of 81 milligrams per deciliter. But the triglycerides, interestingly, in the RESPECT-EPA trial were not elevated. So they didn’t have a triglyceride cutoff to get into the trial, like they did in REDUCE-IT, and so the average triglycerides or median triglycerides were about 117 to 120.

And they looked at a lower dose of EPA than what we used in REDUCE-IT. So they looked at 1.8 grams a day as opposed to four grams a day of what was used in REDUCE-IT. Now, interestingly enough, RESPECT-EPA was a Japanese study, in Japan they don’t believe in placebos. So it was an open label study with a high rate of crossover. So about 30% of patients during the course of the trial had kind of stopped, their EPA therapy are crossed over to nothing at all, and those were still counted in the EPA arm. As opposed to the REDUCE-IT study, which was of course a randomized double-blinded study, so much more rigorous in terms of its statistical design.

The population coming in from Japan tends to have a higher EPA level because of their diet. So even though they tried to enrich a population with low EPA levels at baseline based on the trial design, the EPA levels coming into the study were about twice what they were in REDUCE-IT, which was a worldwide trial with a big American cohort as well in REDUCE-IT. So it was a different population, it was a population with chronic CAD but lower triglycerides, higher EPA levels at baseline and they were getting a lower dose of EPA as well.

And then they looked to see whether it improved cardiovascular outcomes. And the primary endpoint was only borderline statistical significance, but you could see the curves diverging at about four years. And the secondary endpoint did meet statistical significance as well. So the results of the trial, I would say, are consistent with what we saw with REDUCE-IT, where you give a high risk population EPA and you can change their cardiovascular events and modulate their risk. But they were not as robust as what we saw in EPA, and I think that could have been partly because the trial was underpowered with a lot of crossover in patients, a low event rate overall in a lower risk population, and only 1200 or so patients per arm.

So to me, this trial kind of adds to what we already know about EPA and that it works. One of the criticisms of the REDUCE-IT trial in the past has been that there was an active placebo, that the mineral oil placebo that patients received in REDUCE-IT was actually doing harm and that’s why it made the treatment arm look better. But hopefully this trial, which didn’t have a placebo at all because it was an open label study, puts that kind of fear to rest because we did see some biological activity, we did see some benefit in some of the endpoints, even though it was not quite as robust as REDUCE-IT.

So very interesting study. It would’ve been great if it was a slam dunk, but it was kind of a borderline study, but I think very directionally consistent and I personally am going to keep using Icosapent Ethyl in my high risk patients, the ones with elevator triglycerides and ASCVD or diabetes. And the biological activity of having more AFib and a little bit more bleeding was in fact also seen in RESPECT-EPA, so we know that EPA is doing something. Maybe in the future, Rob, what we’ll see is that we’re actually checking people’s EPA levels coming in before they start IPE therapy and then we’re actually maybe titrating the medication to their on-treatment EPA levels, because that may be what helps determine which ones respond better and which ones don’t respond as robustly.