 Well, thank you very much, Dr. Wilson. That was a very kind introduction and it's a privilege to be back here again, speaking to all of you. It's been a while since I've been here, and it's amazing to just see all the growth. And I want to thank the fellows last night for really a wonderful dinner, Dr. Kulture as well for her hospitality. I had a wonderful session at sort of a brunch this morning, again with some of the fellows and faculty. And it's just heartening to see how much excitement and enthusiasm there is here at this historic institution. So thank you for letting me be a part of it for a couple of days. I'm going to be speaking about the reducer trial before I get into the specifics, just in case I go too fast or people want more, much of what I say is summarized in a couple of pages in a recent perspective in the European Heart Journal. Before I get started, though, with this grand rounds by way of disclosure, I should mention relevant to this talk is research funding from Amarin Pharma. That research funding goes to Brigham and Women's Hospital for my role as the study chair and principal investigator of the reducer trial, which was sponsored by Amarin Pharma. They make icosapentethyl, a prescription medication. That drug is FDA-approved in patients with triglycerides greater than or equal to 500 milligrams per deciliter. What I'll be speaking about, the reducer indication would be considered off-label. So let me just make that clear. All right. So as far as cardiovascular risk, you're probably familiar with the terms of secondary and primary prevention, perhaps also primordial prevention. That refers to the prevention, not just of disease, but of the development of risk factors. And I'm going to be speaking a lot about a particular drug we studied in a trial. But it's important to give due respect to the basics. That is diet, exercise, healthy lifestyle. And really, when it comes to cardiovascular risk prevention, risk reduction, especially in people where we're talking about high triglycerides, diet is probably the most important thing they can do. And the best diet, as far as I can tell from the data, is a plant-based diet, high in fruit and vegetable intake, high in whole grain intake. The best exercise is anything you can get a person or patient to do, regular daily physical activity, even if it isn't structured exercise, is better than nothing. And weight control and trying to prevent weight gain is one age is particularly important to keep cardiovascular risk in check, and especially when one is talking about triglycerides. Speaking of triglycerides, this is a slide borrowed from Dr. Peter Libby. It shows that the weight of evidence now supports that they are, in fact, causal risk factors. And not triglycerides, per se, but really triglyceride-rich lipoproteins. Not just markers of risk, but causally involved on the pathway to atherosclerosis, the weight of evidence, the weight of epidemiologic evidence, genetic evidence. And now I'll say even trial evidence supports the causal role of triglycerides and atherosclerosis. So in years past, triglycerides were in, and they were out. And I think they're back in again. This is one example of why I made that statement about triglycerides being on the causal pathway. This is work by Brian Ferenc from the University of Cambridge. He presented it as a late-breaking clinical trial a couple years ago with the ESC in Munich in 2018. It was subsequently published in JAMA earlier this year. And what was done in this analysis was an examination of genes that are associated with higher or lower levels of LDL cholesterol and triglycerides. And what we found in this analysis was that genes associated with lower levels of LDL or lower levels of triglyceride were independently associated with lower rates of lifetime cardiovascular disease. And it's a Mendelian randomization study, meaning that nature has done the randomization to either genes that are associated with higher or lower levels of cholesterol or triglycerides. So that certainly supports, suggests strongly that these are both on the causal pathway. Now the degree of, if you believe these sort of studies, the degree of LDL reduction or triglyceride reduction needed to reduce atherosclerotic events over the course of lifetime are different. That is you need to lower triglycerides by a lot to get a similar degree of risk reduction seen with a lesser degree of LDL cholesterol lowering. But still showing that both are likely on the causal pathway. And of course, no one's debating that about LDL anymore. And I imagine in the future, that won't be debated about triglyceride rich lipoproteins either. Now there are lots of different therapies for hyper triglyceridemia. For the sake of time, I'm not gonna go through everything out there, I'm not gonna review the older data, say for fibrates or niacins or that sort of thing. And there's a lot of new therapies for hyper triglyceridemia as well. Very exciting. Our approach is targeting RNA to lower triglycerides. These compounds in various stages of early investigation can lower triglycerides by 50%, 80%, 90%. So large reductions beyond anything we have right now in terms of oral medications to reduce triglycerides. And these of course need to be studied in large, long cardiovascular outcome trials. But assuming that there's no offsetting cardiovascular toxicity, potentially this could be a really useful therapeutic. Now let me speak a bit about omega-3 fatty acids, sometimes called fish oils. And the omega-3 fatty acids have been studied pretty extensively. This is a meta-analysis from JAMA cardiology that pulled together a number of the trials over the years looking at omega-3 fatty acids, largely low dose omega fatty acids. So I'm talking about a gram a day. Largely mixtures of EPA and DHA. And overall, what we see is neutrality. That is no significant benefit, the rate ratio right around 1.97 to be precise. So no significant benefit, no harm in terms of cardiovascular events, but no benefit of low dose omega-3 fatty acids studied and randomized clinical trials. From the time of that meta-analysis, there have been a couple of other studies that are worth highlighting. One is the ASCEND trial. This was a trial led by professors Armitage and Bowman from Oxford University, consisted of 15,000 patients with diabetes, but without known atherosclerosis, who were randomized to a gram a day of an omega-3 fatty acid, a mixture of EPA and DHA, or to a placebo. And over the course of this large, long-term randomized clinical trial, no significant difference between the omega-3 fatty acid or placebo. Now, if you're a believer and are willing to go beyond that and delve deeply into the data, there were some positive signals with the usual caveats of a trial that was overall neutral, but examining vascular death as an isolated endpoint, there was a nominally significant reduction in vascular death with the omega-3 versus placebo. Again, need to be cautious because the overall composite event rates, it was a rate ratio of one, no difference at all, but maybe something that are worth investigating further. Not actionable, I wouldn't actually recommend this sort of omega-3 to a patient. In fact, I would actually actively prescribe these types of agents, but something maybe suggesting further investigations warranted. So that was the ascend trial. This is the vital trial led by one of my colleagues at Brigham Women's Hospital, Dr. Manson. And the vital trial took 25,000 or so primary prevention patients and randomized them again to a low dose of an omega-3 fatty acid, a gram a day of EPA and DHA, a mixture. And found overall in this large, long-term primary prevention trial, no significant difference between the two treatment arms. A hazard ratio of 0.92 p-value is not significant. Now, again, if you're a believer, maybe these curves are separating after several years, so much like, say, a statin in a low-risk primary prevention population takes a few years for the curves to diverge. So maybe something was going on here, but again, with a p-value that's negative you have to be cautious. Though if you're willing to go further than that neutral primary endpoint as Dr. Manson was and delve a bit deeper, if one looks at the isolated endpoint of total myocardial infarction, excluding the first two years of follow-up, there was a significant reduction or nominally significant reduction in MI, a hazard ratio of 0.72. So once more, need to be cautious. Hypothesis generating, not actionable, want to actually treat a patient based on this, but once more signals, maybe there's something going on here. Now, before talking more about omega-3 fatty acids or prescription medications, it's important to mention that there are a lot of fish oil supplements out there. Your patients are taking them, even if you don't know it. And one thing about supplements in general, not just fish oil supplements, is that many physicians and pharmacists don't understand how these are regulated. These aren't regulated by the FDA as a prescription medicine is. Prescription medicines are very tightly regulated in the US and you might not always agree with the FDA in terms of labeling for drugs, what's approved, what isn't approved, but in terms of guaranteeing the purity and safety of drugs, there's no other agency, in my opinion, in the world that does that better. And the supplements are regulated by the FDA, but as a food. So a much less rigorous oversight of say the production quality or the purity of various supplements or the food supply for that matter, very different from how prescription medicines are regulated. So when patients are getting these supplements, when they're taking them, and these are typically expensive supplements if you've ever gone to the drug store, you never really know what you're getting. The purity can vary from batch to batch and there's really a little evidence supporting their use. That's true of fish oil supplements, that's true of vitamins, et cetera. And how many patients are actually on fish oil supplements? It's a little hard to get at the numbers, but these are some data from the Gould Registry. This is an ongoing registry of patients with dyslipidemia in the United States. This particular analysis published in circulation, we were describing the diabetic patients, but one interesting thing relevant to this talk was the percentage of patients, these are diabetic patients with atherosclerosis in the US that are taking fish oil. 20% of the patients were taking fish oil. I should say 20% admitted to taking fish oil was probably a higher percentage. So even if you're not aware, a lot of your patients are taking these medications or supplements, they're not medications. Now this is some work by a colleague of mine, a scientist at Harvard Medical School and at the Brigham, Preston Mason. And he's a basic researcher and he examined the fatty acid content in the leading US fish oil supplement. And it says, leading US fish oil supplement, you'll have to take his word that this is the leading supplement. He didn't put the name of the supplement there because he was afraid of getting sued. So you've got to trust me that it is the leading supplement. And what he found when he analyzed it was that there was EPA and DHA in the supplement. That's what people thought they were taking. That's what they were paying for. But there was also a bunch of saturated and other fats there. In fact, over half of the supplement was other things than what the person was thinking they were getting or paying for. And these saturated fats potentially are subject to oxidation and other things such that even if there was some benefit afforded by these doses of EPA and DHA, they might be masked by the other stuff that's in these including fatty acid subject to oxidation. So a potential reason to avoid these supplements. Let me shift gears now from official supplements to the Jealous Trial. Now, before I speak about the Jealous Trial, let me just ask and get a show of hands. Who here has heard of the Jealous Trial? Raise your hands if you've heard about it. Okay, so I counted a total of four people. So this was a trial done in the early 2000s published in the Lancet in 2007. So one of the world's leading medical journals publishes this, but so few people seem to actually know about it. Why is it? Well, first let me tell you what it is. The Jealous Trial was a randomized trial of Japanese hypercholesterolemic patients receiving randomized to receive either 1.8 grams a day of EPA, icosapentenoic acid, or to a control followed for several years. And the overall trial was positive, a significant 19% relative risk reduction favoring EPA versus no EPA with consistent benefits in the primary prevention and secondary prevention cohorts enrolled in the study. So a positive trial. And the average triglycerides at baseline of this trial were about 156 milligrams per deciliter. So half the patients had normal triglycerides by current guideline standards. So the drug at that dose, EPA at 1.8 grams a day seemed to reduce cardiovascular events by a substantial amount. Why did this trial have virtually no impact on clinical practice globally? I don't know, but I have three reasons that I'll cite. One is that it was only done in Japanese patients and therefore some doctors said, well, is it generalizable to a Western population? That's a legitimate critique in terms of generalizability, but it doesn't affect the validity of the trial and the population in which it was conducted. And if anything, I'm generalizing now, in general Japanese people in Japan would have higher fish intake and have higher baseline levels of EPA in their blood. And therefore you would think supplementation of EPA would have an even greater benefit in people with low EPA levels, such as from the West. So I wasn't sure that the critique of it being Japanese patients was such a major critique. The second critique was that these hypercholesterolymic patients were treated with provostatin 10 milligrams a day. So sort of low doses of low potency statins. Now I'm not sure that that's such a fair critique either because at the time these patients were enrolled in the 2000s, the early 2000s, that wasn't such an uncommon practice anywhere. And in particular in East Asia, even now, there's sometimes hesitancy to use higher doses of statins or anti-platelet agents or anti-quagglings because of fear, perceived fear, and sometimes even data backing it of a higher rate of side effects. So I'm not sure that's such a fair critique in any way. There's no reason to think that LDL reduction and EPA supplementation would compete with one another. Those are entirely complementary pathways, maybe even synergistic pathways. So I'm not sure that's such a valid critique in the end. And the final critique, perhaps the most serious one, at least from a trialist's perspective, is that this trial, despite being a randomized trial, was a so-called open-label trial. That means patients were randomized to receive EPA or they didn't, there's no placebo control here. And it was a probe design, but still there's always a little concern about bias creeping into trials where there isn't a placebo in there. Not sure what bias would creep in in this particular trial, but that's the problem with open-label trials. You never know what the bias might be. So that's, I guess, a legitimate critique. At any rate, good science, but really no effect on clinical practice, perhaps viewed best as a hypothesis-generating study. That is the jealous trial of 18,000 people. Now I'm going to talk about cherry, which is a small study, 193 Japanese patients. Everybody got a reasonable dose of a pretty good statin, four milligrams a day of petavastatin, and then were randomized to receive 1.8 grams a day of EPA or not. So much like jealous, the same dose of the same drug, but the same limitation of an open-label trial, no placebo. They were followed for only six to eight months. An intravascular ultrasound was done at baseline, done in follow-up. And what was found was a significant difference in the rates of plaque progression, favoring the addition of EPA to statin versus statin alone. So potentially mechanistic support of the same drug, same dose used in the jealous trial, and sort of perhaps providing further support that what they saw was real. Now this is a really small study. Again, Japanese patients 241 randomized in an open-label fashion to the same dose of EPA or not on the same background of sort of moderate intensity statin. And what was found here was a significant reduction in major adverse cardiac events, including a significant reduction in CV death, reduced from 4% to 0.8% with a p-value of 0.04. Now obviously the trial is small with 240 patients. Obviously it's underpowered. The effect size is enormous, a little bit hard to believe, but still provocative findings. Now why might it be that these results using EPA are so different from the meta-analysis that I showed you are those two other large randomized clinical trials as send and vital? Well it might have to do with what is in the pill. And EPA or icosapentenoic acid may have benefits on the cardiovascular system that are different than DH. And this is more work from Preston Mason, the scientist I mentioned earlier from Harvard and the Brigham. And what he's done in cell membrane preparations is show that EPA integrates into the cell membrane in a much more orderly fashion. See these nice straight, well-behaving blue lines. Then does DHA, which integrates into cell membranes in a much more chaotic, potentially disruptive fashion. And that might explain some of the differences in trials that we've seen through the years. Of course, it's not proof of that, but it's certainly provocative. And that's not to say that DHA is bad. In fact, in human health, DHA does seem to have an important role, as you might know or might not know, an infant formula in the US. DHA is mandated to be in there because it's believed to be important for infant neuronal development. So it's not that DHA isn't without potential value, but at least for adult cardiovascular health, it seems like EPA might be where the action is. And there's a bunch of other research he's done showing the potentially beneficial effects on cell membrane preparations of EPA, not shared by DHA. Also, properties not shared by fibrates or niacin, which are known to lower triglycerides, but at least in the statin era, haven't clearly shown cardiovascular benefits. So maybe these differences explain the results. This is a slide from Dr. Mason's. Well, and I think it puts into perspective an important concept. We all like things that are derived from nature. Patients love things that are quote unquote natural. And that's fine. If you think about heart failure, the joxen after all is derived from purple fox glove, penicillin from penicillin mold, pachytaxel from the Pacific U, but and icosapentethyl prescription medicine I'm going to focus on now is ultimately derived from marine products, but much like you wouldn't tell a cancer patient to go chew on Pacific U bark, I think telling patients go eat more fish and maybe it's okay advice, but it still doesn't reproduce what we can and what we've done in the lab, which is create a prescription grade medication, icosapentethyl. And that's what I'm going to focus on now. So if you haven't heard about it, now this is something that's been studied quite a bit in the marine trial. This was a study that took 229 patients with triglycerides between 500 and 2000 and randomized them to icosapentethyl or placebo and found a significant reduction in triglycerides. This trial led to the FDA approval of icosapentethyl for patients with trig graven 500, presumably to prevent pancreatitis. Now after that came the anchor trial, which was led by a Dr. Ballantine who I think just walked in the room. I saw him here a minute or two ago. There he is in the front row. And what this important study did was examine icosapentethyl, not in folks with super high triglycerides, but in a range between 200 and 500 on top of statins and showed even there, it significantly reduced triglyceride levels and did so safely. And since that time, there have been many prescriptions of icosapentethyl. So there's lots of safety data for many years and it seems to be a really safe drug. Now, while this was happening, there were plans to see if icosapentethyl wouldn't just reduce triglycerides, but reduce cardiovascular risk. And that's what the reducer trials about 8,000 patients on statins with triglycerides above somewhere around 150 or so who were randomized icosapentethyl or placebo. So this is a whole development program. Now, let me get a bit into the specifics of the reducer design. And this is the overall concept here. Patients were statin treated and there was a statin lead-in phase where patients had to be stabilized on a statin dose. Their LDL had to be between 40 and 100. We wanted patients with well-controlled LDL. We didn't want patients with poorly controlled LDL in our trial. So we wanted folks that are maximized on their generic statin. And then patients with either established cardiovascular disease, which was 70% of the population or high-risk primary prevention diabetes plus one additional cardiovascular risk factor or more were enrolled into the trial. So a hybrid secondary primary prevention trial. Inclusion criteria were largely modeled on the Charisma trial if it seems familiar to some of you. So that's basically what the trial inclusion criteria were. And for triglycerides, the intent was for them to be somewhere between 150 and 500. But we allowed a 10% variation because triglycerides can be a bit all over the place. So the inclusion criteria that you'll see in the papers is 135 to 500 or so. But in fact, there were patients about 10% or so who had triglycerides between 100 and 150, which are by the current guidelines, normal triglycerides. So that's how that came in. Patients were randomized to icosapentethyl four grams a day or more specifically two grams twice a day with meals or to a matching placebo. And it had to be a matching placebo, something that was colorless, odorless, the same consistency as icosapentethyl. So that ended up being mineral oil. And then patients were followed for several years, up to 6.2 years and an average, a median follow-up of 4.9 or you could say five years average follow-up. The primary endpoint was five point MACE or major adverse cardiovascular events. Cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization or hospitalization for unstable engines. So that's the primary endpoint. Here are the key baseline characteristics of the trial. The average age was 64, about 30% were female, about 70% as I mentioned were secondary prevention, about 30% high risk primary prevention. Of the secondary prevention patients, consisted of those with stable CAD, cerebral vascular disease or PAD. The average LDL at baseline 75, so not particularly high, well controlled even by current standards and registries. And here's the distribution of triglycerides. The median triglyceride on entry was about 216. So not super high triglycerides, but actually triglycerides that are elevated but not totally out of control. Here is the background medical therapy. It was excellent, 80% were on anti-platelets, 20% were on dual anti-platelet therapy, 10% on anti-quaggulants, 78% on ACE inhibitors or ARBs, 71% on beta blockers and by protocol, essentially everyone was supposed to be on a statin. So really what I'm presenting here is incremental benefit beyond excellent background therapy with generic medications. And before I get into the actual results, we did examine biomarkers. This is a cardiovascular outcome trial. It wasn't a biomarker study. Dr. Valentino already shown the drug was effective for lowering triglycerides. So we confirmed what was already known as significant reduction in triglycerides and changes in other biomarkers as well that were significant. But the biggest change in biomarkers was in levels of EPA, icosapentanolic acid, a 350% increase in EPA. And personally I think that's what drove a lot of the benefit more so than changes in other biomarkers. Now not that surprising, these were patients with relatively low EPA, largely from Western regions of the world. We gave them four grams a day of EPA and the EPA levels went up by a lot. So really not that surprising, but I think that's what explains the benefit. I hear the main results published in the New England Journal of Medicine. Dr. Valentino was the senior author on this report in NEJM. And what we found for five point MACE was a significant reduction over an average of five years from 28% to 23%, a hazard ratio of 0.75. So 25% relative risk reduction, about a 5% absolute risk reduction, relatively low number needed to treat of only 21, statistically significant findings. So that's the primary endpoint of the study. Now we also pre-specified a key secondary endpoint of hard events, cardiovascular death MI stroke, which was reduced from 20% to 16% over that average of five years, 26% or so relative risk reduction, a 4% absolute risk reduction again, a highly statistically significant. So overall, the trial was positive. What about subgroups? Well, these are pre-specified subgroups that we've examined to date. You can see a remarkable consistency of benefit favoring icosapentethyl versus placebo. This includes across the full range of LDL cholesterol, includes people with higher or lower HDL. Basically, any way you slice the pie, consistent benefits, shown here, for example, consistent benefits in the US and non-US patients. And in fact, at AHA, I'll be presenting as featured science on behalf of the Reducent Steering Committee, the USA subgroup, the 3000 patients from the US. So we'll see what that shows. So that's the primary endpoint and subgroup here is the key secondary endpoint, CV death MI stroke, once more consistent benefits across these subgroups. And particularly interesting, I thought, is this consistent finding of reduction in CV death MI stroke in those with baseline trades above 150, but also below 150 in that 10% of the population, suggesting that maybe part of the benefit here goes beyond just the triglyceride part of the story. So this is a pre-specified hierarchical testing sequence. This is really more for regulatory purposes. What this means is you can legitimately keep going down from row one to two to three, as long as the row above it is statistically significant in clinical trials. And as physicians, of course, we would look at all the data you'd never throw out data from a trial. But for regulatory purposes, if one line's not significant, you're really not allowed to go further down. Here, we were fortunate in as much as everything in green was statistically significantly reduced. The primary and secondary endpoints that I already shared with you, but also significant reductions in fatal or non-fatal MI, 31% reduction, in fatal or non-fatal stroke, a 28% reduction, a 32% reduction in hospitalization for unstable angina, a 35% reduction in urgent or emergent revascularization, and a 20% reduction in death from cardiovascular causes. And at the bottom here in blue is all-cause mortality, where we see a trend with a p-value of 0.09 to a 13% lower rate. My own feeling is if we had kept the trial going longer as the Academic Steering Committee wanted to, that would have been a significant finding because there was a significant reduction in CV death, not shown here as a hazard ratio for non-cardiovascular death, which was one, so no offsetting toxicity. So I think that would have actually hit. But the company funding, this was a small company, they didn't have a lot of money and we couldn't keep the trial going any longer. So those are the primary sorts of end points and key secondary end points and the individual components. Now let me share with you some tertiary end points, all pre-specified, all adjudicated in blinded fashion by an independent Clinical Events Committee, Mike Gibson's group in Boston. And what we see here is a 50% reduction in cardiac arrest and a 30% reduction in sudden cardiac death, both statistically significant. I mentioned the significant reduction in revasque, but this also consistent of significant reductions in emergent, urgent and even elective revasque was significantly reduced. So that's all I'm gonna say about efficacy. Let me shift gears now to safety. And this table describes treatment emergent adverse events or TEAEs and the top row shows subjects with at least one TAE, the bottom row shows serious TAEs leading to death. And as you can see the P values for all these rows non-significant, but more importantly, look at the actual event rates, 81%, 81%, 2%, 2%. So the actual event rates are virtually identical. So basically here, overall in the trial, the drug was as well tolerated and as safe as a placebo. That's true if we use a very, very sensitive definition of adverse events, 81%, or a very specific definition of adverse events, 2% down here. So across the range of sensitivity for adverse events, nothing overall in the trial. So the 30,000 foot view is that it was very well tolerated and safe. Now, if you've ever been involved in these large clinical trials, there's hundreds and hundreds and thousands of rows of adverse event tables. We were combing through all of them actually trying to find something negative to say. And this is what we found. We did find a trend with a p5.06 to an increase in serious bleeding from 2.1% to 2.7%. Though fortunately no significant excess in GI bleeding, central nervous system bleeding, other serious forms of bleeding, no significant excess in fatal bleeding, and no significant difference in hemorrhagic stroke, which was actually an adjudicated endpoint. So really the only difference here is this trend, which personally I think if we had studied more patients or followed them longer, that would have likely been statistically significant. And in fact, if we look at the overall trial for minor bleeding, there is a significant excess, goes from about 10% to 12%. The other thing we found was a significant difference in hospitalization for atrial fibrillation or flutter, which was an adjudicated endpoint, pre-specified adjudicated and blinded fashion, increasing from 2.1 to 3.1% with a p-value of .004. Importantly though, as you may recall, stroke in the trial overall was not increased. In fact, in the trial overall, it was significantly decreased by 28%. So the most feared complication of AFib didn't seem to be occurring in excess in the trial, and as I mentioned, was significantly reduced. And if we look at the subgroup of patients who had a history of atrial fibrillation at baseline, or who developed it during the trial, even in those subgroups, there is a consistent benefit directionally favoring icosapentethyl versus placebo for stroke, but for that matter, for the composite primary and secondary endpoints for cardiovascular death and so forth. So that subgroup looks like all the other subgroups I showed you, a consistent benefit favoring icosapentethyl versus placebo. Let me share with you now some post-randomization data. These are patients categorized by whether they achieve triglycerides at a year, so post-randomization, less than 150 or greater than or equal to 150. The primary endpoint in this panel, the key secondary endpoint in this panel, in red is placebo, in blue is icosapentethyl with achieved triglycerides greater than 150, in green icosapentethyl with triglycerides at one year achieved less than 150. And in either case, a similar and significant reduction in the primary endpoint and in the key secondary endpoint. Again, suggesting but not proving that there might be more going on to this drug than just triglyceride reduction. And of course, this doesn't look at Delta triglycerides, it doesn't look at multiple cut points, it doesn't look at triglycerides in a linear or a cubic spline fashion. These are all things we plan to do, just haven't had the time to do yet. And in the accompanying editorial in New England Journal of Medicine, the editorialist called this the miracle of EPA, so unusual for the New England Journal of Medicine to allow that type of flowery titling of an editorial. But I think the authors and editorialists felt that the data really were paradigm shifting. And the Discussant for the AHA late breaker, Dr. Carl Ornger put together this slide and has published it since. And in his mind, this is a new paradigm for cardiovascular risk reduction, obviously diet and other things up top. But then in patients that are at cardiovascular risk, either secondary or high risk primary prevention, they ought to be on a maximally tolerated dose of a generic statin. That's just the background. And then therapies that potentially should be considered are azetamide, PCSK9 inhibitor each if the LDL is high or if the triglycerides are high, icosapentanoic acid, EPA or what we studied, icosapentethyl. So I think that's a good sort of summary. So that is the primary trial results, primary publication. But now let me shift gears a little bit to this secondary publication published in the Journal of the American College of Cardiology a bit earlier this year. And what this did was examine not just first ischemic events, that's the conventional conservative way of examining data, but also examining subsequent or recurrent events and adding them together, that's total events. So what do I mean by this? Well, of course a patient might have a non-fatal myocardial infarction that would count as their endpoint in a trial, but that patient assuming it wasn't a fatal MI could go on then to have a recurrent ischemic event, maybe a non-fatal MI again, or a non-fatal stroke or a cardiovascular death. So what we're counting now is not just the first event, but recurrent events. And viewed in this light, first are the first events here in green, a 25% risk reduction as I already shared with you. But now we see significant reductions in second ischemic events, third events, and even fourth or more events significantly reduced such that in total, a 31% reduction in total events. Again, a highly significant P value. So beyond though the large relative risk reduction here, look at the absolute rate of events in this population of 8,000 patients, events reduced from 1700 to 1100, about 500 fewer events occurring, ischemic events occurring in those patients randomized to icosapentethyl versus placebo. Now here's the adherence in the trial. First of all, blue and red, icosapentethyl versus placebo, no significant difference in adherence. But over time, as is the case in all these long-term studies, it was true and improve it, et cetera, adherence goes down. But despite the fact that adherence to drug and placebo are going down in this trial, still there was that large reduction in ischemic events I showed you. So you can only imagine if you had patients who were actually adherent to the therapy, the risk reduction would be even larger than what I've shown you. Depicted here in graphical form is basically the data I just shared with you. But now over time, the 25% reduction in first events, but here the 30% reduction in total events, the curves are continuing to separate with longer durations of follow-up. In a statin-like way, the curves start to diverge in about a year. So very statin-like if you took stable patients and randomized them to statin or placebo. The other thing I'll point out here though, look at this red line, the placebo line, five years, look at the proportion of patients who've had an ischemic event. So this patient population is really high risk and I should really point out this isn't a STEMI population. These are people being rolled into the ED with an ACS. These aren't patients with an ischemic stroke today. These are stable outpatients, largely enrolled in their doctor's office, identified as being at high risk just by virtue of being hopefully on a good diet, on a good dose of a good statin, but still having modestly elevated triglycerides. That demarcated substantial subsequent cardiovascular risk. So elevated triglycerides are a potent marker of risk. That was the primary endpoint I just showed you. This is the time to first event and total events for the key secondary endpoint, same story. Now we did a bunch of fancy statistics here in terms of recurrent and total events. Actually the person that did this is Professor Stuart Pocock at Imperial College, probably the world's expert on recurrent event analyses. So there are a lot of different pre-hoc and post-hoc analyses that we did. But let me just focus on the one pre-specified analysis for the FDA we had mentioned to them that we were gonna do the Anderson Gill methodology for recurrent events. And there we see a 32% reduction in ischemic events with a p-value of 3.4 to 10 to the minus 22. So a very large robust risk reduction. So that even if there are parts of the trial that you don't like, subgroups that you're unhappy with, various elements of the trial that displease you, you can throw out those subgroups and the trial still remains quite robustly positive. So what does this mean to a practicing physician? Well, moving away from the statistics, if we think about it, for every thousand patients treated with icosapendethyl for five years, 12 cardiovascular deaths would be averted, 42 fatal or non-fatal amyze would be avoided, 14 fatal or non-fatal strokes would be avoided, 76 coronary revascularizations would be avoided, 16 hospitalization for unstable angiomy prevented, such that 159 ischemic events would be prevented had the patient received icosapendethyl versus placebo. And in the accompanying editorial to this piece, Dr. Granger and colleagues from Duke University asked the risk of total events with icosapendethyl, can we reduce it? Their conclusion was that this secondary analysis of reduce it provides even more confidence in the importance of the effects of the icosapendethyl. Now, these are some very recent publications and Jack just come out in the past few weeks. This particular exam analysis examined patients by baseline tertiles of triglyceride and the effect of icosapendethyl versus placebo. And in the low, middle and highest tertiles we see a consistent benefit favoring icosapendethyl versus placebo. I've shown total events here, but it's the same thing if you looked at time to first event. And the interaction P value here is negative, meaning that these reductions are statistically speaking are all quite similar. Though that was a P interaction for relative risk reduction. If you look at the P interaction for absolute risk reduction, it's 0.03 nomally lower. So you could make the argument that you are in fact getting more bang for your buck as it visually appears in patients with higher degrees of triglycerides versus lower degrees of triglyceride within this range. So something for everybody, if you wanna say it is a triglyceride story, well that allows you to say it. And if you wanna say it's totally triglyceride independent can also make that argument. But the bottom line is the implication is within the full range of triglycerides we studied significant benefit of icosapendethyl versus placebo. This is an even more recent publication Jack just came out in the past 10 days or so examining patients by baseline triglycerides less than or greater than 200, less than or greater than 150 by baseline tertiles of triglycerides by achieved triglycerides greater than equal to 150 any way you slice the triglyceride pot a consistent reduction favoring icosapendethyl versus placebo. Now this is a slide from a recent review article also just came out in the past couple of weeks that was written with one of my medicine residents Dr. Patel, one of my cardiology fellows, Dr. Patel no relationship between those two Patels they just happened to share the same last name. And what we did was review all the data for triglyceride lowering trials some of which are shown here and there are a lot of different drugs and trials that show triglyceride reduction up top but relatively few where there's been a translation to reduction in cardiovascular events. Sure you can go back in time to VA hit and that well done trial in the VA system showed a significant reduction a 22% reduction in the schemic events with a fibrate but that largely predated the Staten Era and if you look at more contemporary trials like field and the Staten Era you know no clear benefit of fibrates when added to Staten Shore you can look at some subgroups, low HDL, high trig there's some signals there as I showed you before signals in the Omega-3 but nothing where I think you could say it's actionable and say I'm going to actually treat with a fibrate. A same story with Niacin, the contemporary era where on top of Staten no clear benefit maybe even some signals of harm and with Omega-3 fatty acids sure you can go back in time to trials like the Gissy trials and their modest benefits that we're seeing there but again that largely predated the Staten Era and in the Staten Era you've got trials like Jealous with the multiple limitations I mentioned of that trial but really in terms of the contemporary era patients that are well treated with Staten and other background medical therapy stands reduce it whether it was both a significant reduction in triglycerides but also a significant reduction in ischemic events. Why might it be that the drug seemed to be so effective could be the triglyceride reduction but it seemed like maybe there's more maybe benefits in terms of endothelial function perhaps altering the EPA to AA arachidonic acid ratio favorably maybe effects on different other pathways including maybe things like this observation now this was a letter to the editor in response to someone asking what happened to blood pressure reduce that we hadn't examined it initially big trial lots of data lots of things were still examining but for safety purposes blood pressures typically captured in large outcome trials and what we found were significant differences in both systolic and diastolic blood pressure favoring icosapentethyl versus placebo now these are small reductions in blood pressure I realized but still potentially suggesting maybe some other effects beyond what we had previously appreciated and in the slide borrowed from Peter Libby potentially omega-3 fatty acids including EPA having effects on various inflammatory pathways ultimately having an anti-inflammatory mechanism of action in years to come I think lots of smart basic scientists will try to decipher whether these pathways are or aren't at play and aren't clinically relevant but lots of provocative science potentially anti-platelet and anti-coagulant effects indeed in the trial we saw a significant increase in minor bleeding so that sure suggests that it does have some sort of antithrombotic effect but probably mild because we didn't see any increase in GI or CNS bleeding or something like that but it might account for a proportion of the reduction in MI that we saw for example potential effects on plaque directly and preventing plaque progression and along those lines Matt Boudoff is going to present in about a week at the AHA a late breaker called evaporate and we don't know what the results are at this point in time but what he's presenting is about 60 US patients who've been randomized to icosapentethyl four grams a day or matching placebo and followed for 18 months though he's presenting the nine month interim analysis where they've had a CT-angio a non-invasive CT-angio at baseline and at nine and 18 months so we'll see whether icosapentethyl had any effect on plaque progression or not if you recall the cherry trial in Japanese patients did show a significant reduction using IVIS what he's doing is using non-invasive CT-angio in American patients to see if those sorts of results can be reproduced if the trial shows reductions in plaque progression well then we've got another mechanism of benefit that's proved and might explain some of reduce it and if the trial is totally negative all that means is that the benefits we saw and reduce it aren't mediated by direct effects on plaque progression that's all I'm gonna say about reduce it and icosapentethyl but there are other important studies ongoing such as the strength trial this trial is fully enrolled with 13,000 or so patients secondary or high risk primary prevention the trig entry criteria is a little bit higher than reduce it 200 to 500 and unlike reduce it there's an HDL inclusion criteria patients needed to have low HDL we didn't require that but then they're being followed for many years that trial might report out in 2020 or so but the randomization is to four grams a day of a mixture of EPA, DHA versus placebo and another trial prominent being led by some of my colleagues at the Brigham doctors Rittger and Libby and Pradhan and Everett who are taking secondary and high risk primary prevention with trigs between 200, 500 low HDL and randomizing them to pema fibrate or placebo another way of lowering triglycerides it's a selective proxysome proliferator activated receptor alpha modulator so to see if this pathway separate from omega-3 fatty acids that reduces triglycerides might also reduce cardiovascular risk so when we're done three trials reduce it's completed of course but three trials that should help us figure out what's driving the benefit so if reduce it's the only positive trial of the three well that means the action is all high dose EPA if on the other hand strength is as positive reduce it it means it's high dose omega-3 could be EPA, could be DHA, any of the above and if prominence positive it suggests that any triglyceride lowering mechanism or at least the one by pema fibrate can also reduce cardiovascular risk and on the other hand let's say strength is somewhere in between that probably means it's the EPA that's contributing to cardiovascular risk reduction and if strength is totally negative it means it's the EPA but with a threshold effect that is you have to give the high dose and it's sort of a middling dose won't do the trick how does reduce it fit into the broader context of residual cardiovascular risk reduction while my colleagues Dr. Cannon and Bronwell proved it in the proof it study that lowers better with respect to LDL cholesterol and high intensity statin really should be the standard of care and high risk patients if they can tolerate it taking it one step further and prove it showing that azetamide and other LDL lowering mechanism of action could further reduce cardiovascular risk and now we've got reduce it showing a significant reduction in residual cardiovascular risk by a novel pathway. How generalizable are the results? Well this is one of many analyses that have come out looking at generalizability this is a clarify registry it's stable engine of patients in Europe and we found that about 15% of patients with very conservative estimates would be eligible for icosapentethylene a lot of the patients we said weren't eligible probably could have been about 34% of the ineligible patients were ineligible because their LDL cholesterol is greater than 100 which it shouldn't have been they should have been on something to get it lower so a proportion of these patients likely would have also been eligible and also this is just looking at CAD and stable CAD we enrolled in reduce it PAD and CVD and diabetes with at least one risk factor so this is probably an underestimate and Dr. Ballentine's VA analysis they saw about 20% or so were eligible and a European analysis a very recent one showed that about 50% of that population was eligible so it'll depend on sort of the geography the ethnic mix and so forth but bottom line is that this isn't something that's a niche application or drug it's a lot of patients are numbering in the millions in the US and tens of millions worldwide how does this fit into the even broader context of cardiovascular risk reduction? This is a slide I modified from Dr. Rickers looking at redefining residual risk so of course the foundation's got to be diet and lifestyle that should go without saying but then in patients that are at risk secondary or high risk primary prevention they should be on high intensity statin assuming they can tolerate it which a lot of patients feel they can't but we've got to do what we can do but then there might be residual cholesterol defined risk where the LDL is still elevated say above 100 where we know from trials I can prove it and Fourier and Odyssey that lowers better whether you deal with the Zetamide whether you do it with a PCSK9 inhibitor maybe based on some of Dr. Valentin's work Bempidolic acid who knows so if the LDL is really high I'd say focus on that on the other hand there might be residual inflammatory risk as evidenced by high CRP and there the Canto's trial has proven that at least with a very specific anti-inflammatory drug Canokinamab cardiovascular risk can be significantly reduced by 15% now for a variety of largely commercial reasons that drug isn't going to be commercialized for cardiovascular indications it's making too much money as an orphan drug so the company isn't going to commercialize it but there are other similar pathways that are being explored that I think ultimately some of them will pan out and actually be therapeutics that we can use in patients as far as specific anti-inflammatory drugs and there are also some ongoing trials a couple will be presented as late breakers at AHA looking at very non-specific targeting of inflammation such as with colchicine so we'll see whether that general approach works it didn't work with methotrexate but we'll see what happens with colchicine so keep your eyes open especially for the targeted approaches I think there's a lot to comment and Dr. Wilson shared with me some of the exciting work you all are doing along that pathway there's residual thrombotic risk that definitely exists in our patients but unfortunately no simple biomarker a lot of smart scientists working on different point of care assays global assays for thrombosis but right now nothing that really factors in everything yeah there are some point of care platelet function tests but nothing that's really perfect but there are targeted anti-thrombotic approaches based on the trials such as pegasus and compass and thymus showing that for example, ticagular or low dose riveroxaban in the right patients who are at low bleeding risk can confer additional cardiovascular protection and then we've got residual triglyceride defined risk, reduced it I think has moved the field forward in that regard and strengthen prominent whether they're positive or negative or somewhere in between will further help us understand whether triglycerides or indeed a modifiable target for therapy and then LP-Lidl-A risk is an important emerging field with a number of companies either planning or launching targeted LP-Lidl-A reduction and it might be that reduced it and icosapentethyl is really working through a variety of different pathways not just the triglyceride one at least that's what I think so before concluding just a few things to leave you with those are the data, some upcoming trials but I won't wait for upcoming trials I think the reduced data are immediately actionable and the American Diabetes Association agrees this is their 2019 guideline update this is verbatim from their guidelines I've put in the coloring in blue and red and what they state is that in patients with atherosclerotic cardiovascular disease or other cardiac risk factors on a statin with controlled LDL cholesterol but elevated trig between 135 and 499 the addition of icosapentethyl should be considered to reduce cardiovascular risk it's a level A recommendation which is our highest grade of recommendation importantly these guidelines also say that the results of reduced it should not be extrapolated to other products so those supplements and other things they're saying don't do it don't let your patients waste their money on those sorts of things they also go one step further and say statin, fibrate and statin, nice in combinations generally speaking are not recommended anymore as a level A recommendation really meaning don't do it the ESC European, Society of Cardiology European atherosclerosis society guidelines came out about a month ago and they said in high risk or above patients with trig between 135 and 499 despite statins, omega 3 fatty acids specifically icosapentethyl 2 grams twice a day should be considered in combination with a statin and that's a class 2A recommendation now this is in the guideline but this is the European Medicines Agency an advisory they put out a few months ago they're the European FDA and they said omega 3 fatty acids these one gram a day supplements or the prescription medicines that are a gram a day should no longer be considered effective in preventing heart disease so Europeans have been very clear they've just said don't use those agents ineffective and most recently has been the National Lipid Association I think this came out about a month ago came out in print earlier this week and with the NLA said with respect to icosapentethyl was basically our inclusion criteria for reduce it giving it a class 1 recommendation their highest level of recommendation and I didn't have time to make the slide but in the past couple of weeks the Brazilian Cardiology Society also gave icosapentethyl a class 1 recommendation for the reduce it like population the final point I'll make is one about cost effectiveness we've always got to consider this these days in medicine and this is ICER I don't know if you're familiar with that there's a term in cost effectiveness called ICER but that's not what this is this refers to a group the Institute for Clinical and Economic Review they're an independent not-for-profit based in Boston a bunch of internists mostly that are looking at cost effectiveness of things and I'm gonna say they're a very conservative group I don't mean politically concerned I mean just in terms of their estimates and everything they're kind of anti-pharma, anti-industry and in general I often disagree with the assumptions they make as I did here but nevertheless they did this and their final report was just published in the past few weeks and in 100% of their sensitivity analysis they found icosapentethyl to be cost effective that was true at the $100,000 per quality just a life year willingness to pay threshold which is the most commonly used one currently by health care economists it was true by the $150,000 metric which is what a lot of people say is the correct willingness to pay threshold in high income countries like the US and it was even true at the $50,000 per quality just a life year willingness to pay threshold that's the old fashioned dialysis number really we don't use that anymore but even by that 100% of their sensitivity analysis showed the drug to be cost effective and the reduced steering committee and Bill Weintraub will be presenting as a late breaker at the AHA our patient level cost effectiveness analysis this was a trial level one they didn't use total events they only used first events they didn't count revascularizations they didn't count the reductions in hospitalization for unstable energy we have access to all that data so I think it's a much more robust analysis but anyway even their conservative estimates showed the drug to be highly cost effective at its current pricing so to conclude then viewed now in the larger universe of risk reduction I think what we've demonstrated in the reduced trial is in high risk primary prevention and secondary and tertiary prevention a significant incremental benefit of adding icosapent ethyl to statin and diet and patients who despite statin and diet have modestly elevated triglyceride levels and that doesn't undercut from the importance of things like good diet and exercise that's always got to be the bedrock of what we do but despite that there are patients with residual cardiovascular risk and I believe icosapent ethyl is a useful addition to our momentarium to how to treat those patients and hopefully make a big impact on a patient level but even just a more global public health level well thank you very much for your attention really such a privilege and pleasure to be back here speaking to all of you thanks so much