Icosapent Ethyl: Exploring the Remarkable Benefits of the REDUCE-IT Trial for Patients with Recent ACS Prof Philippe ...

Icosapent Ethyl: Exploring the Remarkable Benefits of the REDUCE-IT Trial for Patients with Recent ACS Prof Philippe Steg

By Professor Philippe Steg

That may be the most difficult question because, a clinical trial doesn't study this. A clinical trial tests, whether it's efficacious and whether it's safe and well tolerated, and those are the answers we have from REDUCE-IT. Outside of REDUCE-IT from prior experience and from studies that have been done since, there is evidence that, Icosapent Ethyl is efficacious in lowering triglycerides, reducing CRP to a moderate extent, improving endothelial function, probably has some genuine antiplatelet effects and increases the serum level of EPA. Efficacy appears to be quite correlated to the increase in EPA that's measured in the bloodstream of patients after a year.

Can the benefits of EPA be generalized to other patient populations beyond these included in the reduce it trial?  

I think it's a tantalizing question. We don't have a good answer to this until we've tested it.  I think until we test it, the safest bet is to use the drug in the population in which it was proven to be efficacious. So I would advise to stick to the REDUCE-IT patient population with the Icosapent Ethyl, although, I think it's a very reasonable proposition to test it in patients, for instance, who have high cardiovascular risk or established cardiovascular disease and do not have elevated triglycerides.

How does the use of EPA impact the incidents of fatal cardiovascular events in patients with recent ACS?  

So in the overall REDUCE-IT trial, which enrolled patients who were adults on statins with triglycerides between 135 and 500, were either in secondary prevention or diabetics with at least one additional risk factor. There was a marked and robust cardiovascular event prevention effect with Icosapent Ethyl, compared to placebo, approximately a 25% reduction in cardiovascular events. That reduction included the primary outcome, which was a quintal composite. But also the key secondary outcome, which was CVS, MI and stroke, the conventional triple composite MACE outcome. It included total events, it included a significant reduction in mi, a reduction in stroke, and a reduction in cardiovascular mortality. So there were really substantial and robust benefits overall in the trial. Now, we wondered whether the efficacy and safety would be different in patients with recent ACS, and there were a number of reasons to look at this. First the recent ACS patient population is a high risk patient population in whom thrombosis may play a more important role in inflammation and atherosclerosis in determining risk and benefit of interventions, and therefore we were not sure that the treatment would be as beneficial. On the flip side of the equation, we were also concerned that there might be more safety concerns with Icosapent Ethyl in that specific population who is often receiving intensive antithrombotic therapy and dual antiplatelet therapy than in the overall trial population. And what we found is actually the reverse. What we found is that this group of patients with recent ACS. Approximately 1500 patients with a median time since the index ACS of approximately 5 months had tremendous benefit from Icosapent Ethyl, in terms of reducing the primary outcome, they had a 37% ACS risk reduction, a 9%, 9.3% absolute risk reduction, and a number needed to treat to avoid one primary outcome event of only 11. So this is the population that has the highest risk and the greatest benefit from treatment. And in terms of safety, we were concerned with bleeding, in fact, there was no increase in bleeding,  in that population with Icosapent Ethyl. Numerically, if anything, there were fewer bleeds with Icosapent Ethyl with placebo, and that was also true in the subset of patients who were recent ACS on dual antiplatelet therapy, a population of particular concern.

Finally, as in the overall trial, there was a statistically significant increase in the risk of atrial fibrillation or flutter with Icosapent Ethyl. But I would like to point out that despite this increase, there were fewer strokes with Icosapent Ethyl, and fewer, CV deaths in the Icosapent Ethyl arm. So it seems to really that this is a high risk patient population that rise particular benefit. There is no reason to withhold treatment or deny treatment to these patients due to concerns of bleeding.

How does the efficacy of EPA compared to other medications commonly used in the management of ACS, such as aspirin and beta blockers? 

Well, we had a medium follow up, which I think was a little over 4 years. But when we look at the outcome event rates, in the REDUCE-IT trial, there are really straight lines. And so it seems that the longer you treat, the greater the benefit. And I don't see any particular reason why we would want to discontinue a therapy that is so effective. So I think we should, once we institute therapy on those patients who are eligible and if they tolerate it, I would continue it long term because probably, as with most secondary prevention therapies, they only work if you take them.

What is the recommended duration of treatment with EPA following ACS, and are there any considerations for discontinuing or tapering medications?

Well, it's really hard to give a formal answer to this because we haven't done the permutation trials that would really address this scientifically. Historically aspirin was tested, on its own Beta blockers quite a while ago then statins were introduced, ACE inhibitors in ARBs and more recently novel agents to lower LDL cholesterol, and then Icosapent Ethyl for hypertriglyceridemia patients. I think when we look at the magnitude of the benefit, this is one of the most potent preventive interventions we can use in patients with established thrombosis. The 25% relative risk reduction favorably compares with most interventions for secondary prevent.

What is the role of EPA and secondary prevention of ACS? And can it be used in combination with other preventative therapies?  

I think it has a strong role for patients who are eligible, which I'll remind our audience, our patients with a prior cardiovascular event or patients in primary prevention who have a another risk factor. But if we're talking about post ACS, so there are patients who've had an event and who have received statins, have LDL cholesterol that's reasonably controlled with statins and triglycerides between 135 and 500. I think this is the eligible patient population to which we should stick. Now, not only do I think that it should be used in combination, with other preventive measures, I think it's really important that patients receive full-fledged secondary prevention treatment. In fact, in REDUCE-IT, the rates of uses of evidence-based secondary prevention treatments was very high. This was a well-treated population as would be demand. By regulators and third party payers to evaluate properly this therapy and in REDUCE-IT, we were careful to enforce high rates of uses of secondary prevention treatments.

What are the potential cost savings associated with the use of EPA in the management of ACS?  

So, as you know, cost effectiveness studies are quite tricky, and they're largely based on modeling and hypotheses. We have done within the trial using trial data, a cost effectiveness study by Dr. Weintraub, which was published, I think last year, which showed that Icosapent Ethyl was quite cost effective, which isn't surprising given that, it's not that expensive and it's extremely effective. So when you have such a strong treatment effect, usually most treatments are gonna be cost effective and it is cost effective. But I will acknowledge that this is modeling and there's always an element of judgment in how you select the model and whether you believe the models or not, I think it's an extremely effective therapy and it's not a very expensive therapy.

What patient characteristics such as age or comorbidities, should be considered when determining the appropriate use of EPA in the management of ACS?

Well, you know, again, I, I think we have to come back to the inclusion criteria. I think that's the best way to apply the evidence is to use the treatment in the population that, which it was exactly tested, that was statin treated adult men and women, with established cardiovascular disease or diabetes mellitis, and at least one other risk factors with TGS between 135 and 500 and an LDL cholesterol between 40 and a 100 on a statin. So that's the target population. When we model how many patients with cardio coronary artery disease, that would represent, we found in several large scale registries that it represented approximately 15% of the patients, so 1 out of 8 coronary artery disease patients is eligible for Icosapent Ethyl.

Can you achieve the same benefit with diet enriched in fish or with over the calendar supplements? 

One last point I'd like to point out to our audience is that Icosapent Ethyl was remarkably effective in the REDUCE-IT trial. This corresponds to highly purified high dose EPA, eicosapentaenoic acid . Now, other combinations of omega-3 fatty acids haven't shown the same efficacy, whether it's combination of EPNDHA or lower dose EPA. I will also point out that supplements that can be routinely found over the counter and are widely used in certain countries, including the United States, omega-3 fatty acid acid supplements should not be used in substitution for EPA or Icosapent Ethyl because when we test them and there are labs such as Preston Mason's lab in Harvard that have tested them. What we find is that their content is unpredictable and can often be not as rich in omega-3. Fatty acid as expected, contained a variety of omega-3 fatty acid acids and contained oxidized omega-3 fatty acids, which are probably not beneficial and likely detrimental. Finally, although diet is important, if we wanted to reach the levels of plasma or serum EPA that are achieved with Icosapent Ethyl, we would need to eat, an enormous amount of fish, every day long term, which is probably not feasible. So I think it's good to eat some fish  but I don't think that we can reasonably expect to achieve the same clinical benefits with the amount of EPA that is in a fish rich diet.

In closing, what message would you like to convey to our cardiology viewers as a physician?  

 I think we have now one more tool in our preventive armamentarium. In addition to the existing, important therapies such as antiplatelet agents antianginal agents, ACE inhibitors. And statins, ezetimibe, and the like. We now have an agent to address the residual risk that's related to elevate triglycerides in that population. And given the magnitude of the benefit and the relative safety of the treatment, we should leverage this and use it widely in the eligible patients. We don't often have therapies that have established reductions in cardiovascular mortality and Icosapent Ethyl does have that. And I think it's important, and our most recent analysis in recent ACS patients found that the recent ACS patient population appears to be the one that derived the greatest benefit and no particular harm. So I think that's a good target audience for our treatment. 

What is Icosapent Ethyl and how is it used in Cardiology?

Icosapent ethyl is a prescription medication used to treat high triglyceride levels in the blood. It is a type of omega-3 fatty acid that is derived from fish oil. Specifically, icosapent ethyl is a purified form of eicosapentaenoic acid (EPA), which is one of the main types of omega-3 fatty acids found in fish oil.

High levels of triglycerides in the blood can increase the risk of heart disease, stroke, and other related health problems. Icosapent ethyl works by reducing the production and storage of triglycerides in the liver, which helps to lower triglyceride levels in the blood. It is usually taken orally as a capsule, and the dosage and length of treatment may vary depending on the individual's medical history and condition.

10 Key Takeaways from the REDUCE-IT trail on Icosapent Ethyl

1. The REDUCE-IT trial found that icosapent ethyl reduced the risk of major adverse cardiovascular events (MACE) by 25% compared to placebo.

2. MACE includes cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and hospitalization for unstable angina.

3. The benefit of icosapent ethyl was observed in patients who had elevated triglyceride levels (≥150 mg/dL) and were receiving statin therapy.

4. Icosapent ethyl was associated with a 20% reduction in the risk of cardiovascular death compared to placebo.

5. The trial also found that icosapent ethyl reduced the risk of myocardial infarction by 31% compared to placebo.

6. Icosapent ethyl was generally well-tolerated by patients in the trial, with no significant safety concerns identified.

7. The results of the REDUCE-IT trial suggest that icosapent ethyl has a different mechanism of action compared to other omega-3 fatty acid supplements.

8. The trial demonstrated that icosapent ethyl has significant anti-inflammatory effects, which may contribute to its cardioprotective effects.

9. The REDUCE-IT trial was a randomized, double-blind, placebo-controlled trial, which is considered the gold standard for clinical trials.

10. The results of the REDUCE-IT trial have been incorporated into clinical guidelines, and icosapent ethyl is now recommended as an adjunct therapy for patients with elevated triglyceride levels who are receiving statin therapy.

Professor Philippe Steg - About The Author, Credentials, and Affiliations

Professor Philippe Gabriel Steg is a renowned cardiologist and academic who has made significant contributions to the field of cardiovascular medicine. He was born on February 10, 1958, in Paris, France, and obtained his medical degree from the University of Paris.

Professor Steg is currently a professor of cardiology at the Université Paris-Diderot and the Head of the Cardiology Department at Hôpital Bichat in Paris. He is also a Senior Consultant at the Cardiology Department of the Hôpital Européen Georges Pompidou in Paris.

Throughout his career, Professor Steg has been at the forefront of research in the field of cardiovascular medicine, with a focus on the prevention and treatment of atherosclerosis and acute coronary syndrome. He has authored or co-authored over 700 scientific papers, and his research has been published in leading medical journals such as The Lancet, the New England Journal of Medicine, and Circulation.

Professor Steg has received numerous awards and honors for his contributions to cardiology, including the Grand Prix Scientifique of the French Academy of Medicine, the European Society of Cardiology Gold Medal, and the International Atherosclerosis Society Distinguished Leadership Award. He is also a Fellow of the European Society of Cardiology, the American College of Cardiology, and the American Heart Association.

In addition to his research and clinical work, Professor Steg is a dedicated teacher and mentor to many young cardiologists. He has supervised numerous doctoral theses and has served on the editorial boards of several medical journals, including the European Heart Journal and the Journal of the American College of Cardiology.

Overall, Professor Philippe Gabriel Steg is a highly respected and accomplished cardiologist who has made significant contributions to the field of cardiovascular medicine. His work has helped to improve our understanding of the prevention and treatment of heart disease, and his research continues to inspire and inform medical professionals around the world.