11 Practical implications of REDUCE-IT

Hello colleagues. I'm Professor Subodh Verma from the University of Toronto at St. Michael's Hospital

where I'm a cardiac surgeon, and also hold the Canada Research Chair in Cardiovascular Surgery, in addition to co-directing the CardioLink trials program. I'm really delighted to be here to talk a bit about the practical implications of the REDUCE-IT trial, but before I get started, let me share with you my disclosures.

Now, I'm going to give today's presentation highlighting what I think are 10 important clinical implications of the REDUCE-IT trial. I would like to start with the first principle, and that is the principle of safety. In my opinion, REDUCE-IT confirms the safety of icosapent ethyl in people with established vascular disease or people at risk of cardiovascular events who have diabetes. As you've previously heard from Professor Bhatt in a previous presentation, the side effect profile of icosapent ethyl is actually quite benign.

In fact, when you look at the treatment-emergent adverse events between the placebo and the icosapent ethyl group, they actually are identical. There are two specific side effects of note.

One, there is an excess in minor bleeding. This is not central nervous system bleeding. This is minor gastrointestinal bleeding where there is a 0.6% excess.

There's also an increase in adjudicated atrial fibrillation hospitalizations of 1%. This is really interesting mechanistically, but clinically, is not really quite relevant because people who develop atrial fibrillation should be managed with rate control and anticoagulation. There's really no specific need for discontinuing therapy or avoiding therapy with icosapent ethyl in this population. That is exactly what was done in the context of the trial.

Now, with respect to the second clinical implication, I want to emphasize that icosapent ethyl was really compared to standard of care. Placebo is in quotation marks. What it really means is excellent background therapy.

To illustrate that, let me call your attention to the utilization of moderate to high-intensity statins at baseline, which was upward of 90%. That is reflected in the baseline LDL cholesterol prior to randomization of 1.9 millimoles per liter.

This translated into a very meaningful number needed to treat of 21, over a period of 4.9 years. Not only is this a statistically robust result, but it is clearly clinically applicable for the entire population studied in the trial.

The third point I'd like to make is that there is indeed a reduction in cardiovascular death. Reducing CV death is actually one of the most important outcomes in clinical trials, particularly cardiovascular clinical trials. It is exceedingly hard to demonstrate given how good background therapy is in these trials.

However, when you do look at the data from REDUCE-IT, and you go down the hierarchical sequence of analysis, you actually note that there is a 20% reduction in cardiovascular death, which achieved statistical significance.

The fourth implication for practitioners listening to today's program is that the benefits were observed really irrespective of baseline LDL cholesterol or baseline triglycerides within the range that we studied in the REDUCE-IT trial.

Shown here is that concept further illustrated. At the top, you see baseline triglycerides either expressed in milligrams per deciliter, or in millimoles per liter. You see that in people with a triglyceride at baseline that was either above or below 1.7 millimoles per liter, had an identical relative risk reduction. Likewise, if you look at the various tertiles of LDL cholesterol at baseline, you also see that people with an LDL cholesterol at baseline below 1.73 millimoles, between 1.73 millimoles and 2.17 millimoles, and greater than 2.17 millimoles per liter had an identical benefit of icosapent ethyl. This is important as we think about how to apply this evidence to people with cardiovascular disease or risk factors.

I'd now like to emphasize the fact that the benefits observed in the trial were seen consistently in the two cohorts of patients that were enrolled. As you will recall, there was a high-risk primary prevention cohort of people with diabetes and one risk factor, and then there was a secondary prevention cohort of people with established vascular disease.

There was really no heterogeneity seen between these two groups per se. An identical relative risk reduction from a statistical standpoint. Likewise, what about people with and without diabetes? They also derived a similar benefit and a consistent benefit of icosapent ethyl in this trial. That is illustrated here in the pink arrows.

Now, the next implication that I think is really important is that the benefits of this therapy are seen across all eGFR ranges. This is a very important clinical pearl because we're often worried about how to use drugs at low eGFR at baseline.

In this post hoc analysis from the REDUCE-IT trial, you can see in the encircled orange box that there is a consistent benefit of icosapent ethyl across the various eGFRs, including the groups of people who had a GFR between 50 and 30 ml per minute. That's really important and reassuring, and again, a practical tip for using this therapy in the clinic.

Now, we've talked a lot about the global cardiovascular risk reduction of this strategy, the reduction in MACE, and MACE plus, but may I, again, call your attention to one specific outcome that I think is of considerable interest, and that is the reduction in stroke.

What was observed in the REDUCE-IT trial was that when you look at first ischemic strokes, they were reduced by 36% with icosapent ethyl compared to placebo. What this is telling us is that the biology of this drug is that it reduces really atherosclerotic vascular disease and vascular events in all territories. Cerebrovascular, coronary, peripheral, need for CABG, need for PCI. It's quite impressive that the risk of an ischemic stroke is reduced by such a magnitude given that we have very few effective and safe therapies to reduce the rates of ischemic stroke in people with vascular disease.

Now, at the end of the day, when you and I go to the clinic, the question is, can you apply these data to the people we're seeing? Is it generalizable or not? That is something that has now been evaluated in many analyses.

I'm only going to share with you one that I was involved in from the Quebec Heart CABG database, where you can see that in people with a history of CABG who underwent CABG at the Quebec Heart Institute in Canada, that one-quarter of patients would be eligible for icosapent ethyl according to the label, or according to the REDUCE-IT, or FDA, or Health Canada criteria.

Likewise, in another analysis, also led by a Canadian, Dr. Patrick Lawler, a cardiologist at the Toronto General Hospital, he evaluated, with his colleagues, in about 2.5 million patients, the relationship between triglycerides and outcomes, and the proportion of patients with ASCVD, or vascular disease that would be eligible for icosapent ethyl.

They found on the right, that even low levels of triglycerides demonstrate an increasing relationship to vascular events. On the left, you see in dark blue that a quarter of ASCVD patients in Ontario, Canada, in this analysis would have qualified for the REDUCE-IT criteria. The REDUCE-IT trial results are truly applicable in the real world in this population.

Now, what about mechanism of action? There's a lot of discussion around how does this medication work? There's a lot of basic science, there's a lot of animal data, there's a lot of cell culture data, et cetera, but for me, what is quite reassuring is that there's human translational data in the context of a clinical trial.

This was the EVAPORATE trial looking at icosapent ethyl in people who had coronary artery disease who were followed for about 18 months with icosapent ethyl or placebo. Coronary plaque volume was assessed in the coronary arteries by coronary CT angiography. You can see, again, the primary endpoint, which is the low attenuation plaque, was reduced significantly with icosapent ethyl compared to placebo. All of the other indices also seem to really corroborate this primary outcome, suggesting that this therapy, irrespective of the exact molecular mechanism, actually does seem to regress atherosclerosis, which is quite important and meaningful to clinicians trying to understand the biology of this agent.

Now, we've talked a bit about the trial. We talked about some of the practical nuances and highlights. We've talked a bit about the mechanism, but what has the world said? What are the guideline writers actually said with respect to the use of this therapy?

The guideline writers have actually been quite favorable when you look at the REDUCE-IT trial. In fact, 28 global medical societies now recognize icosapent ethyl as an important treatment for ASCVD. This includes the American College of Cardiology, the American Heart Association, the Canadian Cardiovascular Society, endorsement from the ESC guidelines on cardiovascular prevention, and many others that are listed on this slide.

I would like to highlight that the 2021 Canadian lipid guidelines recommend the use of icosapent ethyl in people with ASCVD or in people with diabetes who have one additional risk factor, these are the two populations of patients that were enrolled in the trial, as long as they've been well treated with a statin at a maximum dose and their triglycerides are between 1.5 and 5.6. This recommendation in the CCS guidelines is a strong recommendation based on high-quality evidence.

In addition to that, this is an excerpt from the CCS 2021 guidelines that highlight the fact that really intensifying LDL cholesterol and using icosapent ethyl are really horizontal things that enter into the algorithm, or they're not really competing and do not have to follow one specific order sequentially. I think this is a very valuable diagram from which we've adapted this figure to illustrate the fact that these are complementary approaches to reducing vascular risk in people with ASCVD or at high risk of events with diabetes.

The 2021 ACC expert consensus decision pathway on the management of ASCVD risk in patients with persistent hypertriglyceridemia was also recently published in JACC, led by Dr. Salim Virani.

As you can see in this diagram, in adults with ASCVD and fasting triglycerides above 1.7 millimoles, or 150 milligrams per deciliter, or non-fasting triglycerides that exceed 175 milligrams per deciliter, and are below 500 milligrams per deciliter, clinicians are advised to rule out secondary causes, optimize diet and lifestyle, optimize glycemic control, and maximize statin therapy. After that, if the LDL cholesterol is now below 70 milligrams per deciliter, you should rule out secondary causes if patients are still persistently hypertriglyceridemic, and then consider icosapent ethyl according to this guidance.

Finally, I'd like to emphasize that the current science does not suggest that this is just any mere fish oil, that the same thing would happen if you took an over-the-counter fish oil, or you took another formulation because it appears that the benefits seem to be unique to this preparation.

Indeed, in that vein, the 2021 Canadian Lipid Guidelines have said explicitly that we do not recommend the use of over-the-counter omega-3 polyunsaturated fatty acid supplements to lower the risk of CV events. These are marketed as natural health products in Canada, and this is a strong recommendation with high-quality evidence.

Furthermore, we've said in the Canadian guidance that supplementation with OTC long chain PUFAs marketed as natural health products in Canada that include EPA alone, EPA and DHA mixtures, or fish oils from supplements or dietary sources, does not offer any clear advantage for cardiovascular risk reduction.

The American Diabetes Association has also echoed this sentiment, where they've said it should be noted that data are lacking with other omega-3 fatty acids, and the results of REDUCE-IT should not be extrapolated to other products per se.

Let me conclude, colleagues, by saying that in my evaluation of the REDUCE-IT trial and its various sub-analyses and having used this many times in patients with cardiovascular disease, I conclude that this is a lifesaving therapy. It is entirely safe. It has changed guidelines. I did not have a chance today to talk about the cost savings and the cost-effectiveness data that have been published to support it as well.

Therefore, when you and I, and other doctors listening to this program are trying to integrate contemporary, residual risk pathways into secondary prevention risk reduction, you can see there's many, many ways to think about how to target specific therapies. Right in the middle, you'll see residual triglyceride risk. I think that's really important after statin therapy, after optimizing LDL cholesterol, if there is residual or persistent triglyceride risk, that is a patient that should be appropriately targeted with icosapent ethyl.