In this discussion Antonio Abbate, MD, PhD highlights anti-inflammatory therapies in cardiovascular diseases. Dr. Abbate specializes in cardio-immunology and cardio-oncology, evaluating and treating people with heart inflammation (pericarditis and myocarditis), and those at risk for heart complications due to cancer treatment.
Antonio, we'll give everyone a couple of minutes to, to join and then we'll get started here. Absolutely good morning. All right. Well, as people are, are joining in um, good morning, everybody. Welcome to cardiology grand rounds today. Hopefully everyone has dug out of the snow and staying warm out there today. The CME code today is 89780. Again, that's 89780. And Doctor Abate will have that on his slides in just a moment and we'll be sure to keep it in the uh in the chat box at the bottom as well. So, as per our usual routine, please feel free to leave any questions or comments in the chat or the Q and A tabs at the bottom. We're going to save the last 10 minutes or so, uh for a Q and A session with uh Doctor Abate. All right. So it's my pleasure to announce our speaker today. Doctor Antonio Abbate, he's from a small town outside of Rome, Italy. He did his medical training in Italy, followed by some of his training in Virginia. He's been a long believer in the connection between inflammation and cardiovascular disease. In fact, his phd thesis was even on IL one blockade and acute M I few years ago, he moved from the Medical College of Virginia to University of Virginia where he is now the Ruth C Heed endowed professor of cardiology. Doctor Abate continues to focus his interest on the connection of inflammation and cardiovascular disease. He currently has several research grants looking at the effects of Il one blockade on the prevention and treatment of systolic heart failure, as well as coronary disease. Over the past several years, there's really been a uh a renewed interest in in growth and the idea that there's a strong connection between inflammation and heart disease. We've seen results of studies looking at methotrexate and colchicine and it's with that in mind that we invited Doctor Abate today for grand rounds to really learn more about this connection between inflammation and heart disease. So with that, I will turn it over to you Antonio. Thank you for joining us. Good morning. I hope you guys can hear me. OK. Uh It's a pleasure to be talking in the video to you. Uh I wish I was there in person, but today is a really particularly cold day. So maybe uh easier to do it uh by Zoom. Thank you, Doctor Kanar. Thank you, Miss Lafferty for this uh um invitation and coordinating this. Uh I do have some uh I wanted to show this uh uh CME slide uh to get credit for this presentation. I'll show it again in the end and I think, uh, uh, Miss Lafferty will put it in the chat box. Uh, I do have some disclosures. Uh, I do, uh, work in bringing new drugs to patients. So I like to do work in drug development and in, uh, um, clinical trials. So I partner with some of these companies, I'll keep my, uh, presentations, uh, objective. If you have any questions about this, please uh ask me. So, um I'd like to start with uh uh with a quote as Doctor Kanar pointed out, uh I trained in Rome Italy. I was lucky enough to train with the, the late Atilio Masi and uh he was uh certainly a, a pioneer in the world of inflammation. And uh he taught us a lot of different things, but the one of the most quote important quote for Dr Mai was to look at the hidden side of the moon and sometimes, you know, paradigm don't fit everybody. Uh And we need to look at those cases that fit less and try to understand the mechanism. And uh uh there's one term that we used to um uh rehearse frequently in our meeting was a sign of clinical observation trying to understand what's different in different subgroups. How can you treat to the responders and not responders? I'm gonna give credit to uh Professor Mazri whos unfortunately, no longer with us. Um as we um you know, we're II, I can't see who is on the call. I can't see your faces. I suspect that it is. A lot of you are uh, clinical providers. Uh, physician nurses, pharmacists, uh A PPS. So I, I tried to keep this, uh, a mix of basic science and clinical applications. So, uh, if you would like to use the chat, uh, and I'm trying to try to, uh, monitor here some, um, but I'll tell you there's no price, no awards. So don't worry if you can't uh if you're driving in, don't bother with the chat. Of course. Uh which one of the following biomarkers predict aro thrombotic complications in patients with suspected acute coronary syndrome. So these are patients that are have either chest pain in the emergency room or they are admitted to the hospital. So, low density lipoprotein cholesterol, LDL troponins C reactive protein or all of the above. Can you please put that in the chat? A for LDLB for Troponin, C for CRPD for all of the above. Let me see if I can get a couple of you to respond. I, I see one for Doctor Kar. OK. And I'm the interest I I'm gonna go forward but if you have, if you are still putting it in, please do. Uh So I have a follow up question for Doctor Kandar since he's the one who responded is how many of you and Doctor Kandar, do you measure c reactive protein? In patients with acute coronary syndrome. Uh Unfortunately, at this point in my presentation live, I, I get ie a resounding. No, we're not checking it. Meaning that we know that c reactive protein is predictive like troponin and like LDL. But it's just not commonly checked and there may be a reason for that and that's what we were gonna cover in the next uh uh 30 to 40 minutes. Let me go to uh another question. Let me see if I can get more response here. So this is a clinical case. It's a 55 year old patients with ischemic cardiomyopathy had bypass and stents. He's now in the M I clinic. He just had another cat probably the 10th of his life uh has diffused coronary disease. The interventionist says, you know, Antonio, please don't send this guy anymore. Uh However, he is now in clinic. He's a symptom hematic. His blood pressure is controlled. He on good medical therapy including dual antiplatelet therapy is LDL cholesterol is 50. Now uh hemoglobin one C is 5.6 you know, I didn't put the normal value, but these are things that you guys are all familiar with. So these are very normal and the CRP is 0.5 mg per deciliter or 5 mg per liter. So the question for you as we try to further reduce the risk of this individual, what should we add? Should we add uh Apixaban Eliquis, should we add that's option. A. Should we add uh a Lyrica Ma uh prole injectable P CS K nine inhibitor? It's B should we add jargons and pho seems we can add jargons to anything. Uh Should we add colchicine uh an LRP three and chromosome inhibitor or should we just add a mole four and try to reduce this risk to the max? So let's see if I can get someone to respond. Antonio, I think some folks are having a little bit of trouble with the chat. So we're gonna try to Q and A and Q and A. OK. So we put in there as well. Yeah, I appreciate it. Thank you for bringing it up. I'm gonna close the chat and I see here that Doctor Malik is telling me you're asking me to put it to chat but is disabled. I'm sorry, my friend. Uh So we get the colchicine col. Great. So uh a at least some are uh kind of uh uh following the new trend of anti-inflammatory therapies. And I would like to uh show the data behind this decision. I would do the same. I would do d for this patient. So, what are we gonna review here? We're gonna review the concept that inflammation is a modifiable factor in cardiovascular disease. This is not new at all. This was not even new when I started medical school, which is almost 30 years ago now. Uh However, at some point, it seemed like it had died. You know. So when I, when I was doing my research in this field, uh many years ago, some of my senior uh attendings and the faculty and mentors to tell me that inflammation is dead. Well, I don't know, maybe it's not that maybe we can revive it. Um We'd like to review what are the anti-inflammatory therapies that we can use today? And I'd like to tell you a little bit of what's on the, in the pipeline for anti-inflammatory uh drugs. That's part of the major part of what I do in my time, develop new drugs or new applications. So I'll try to cover that as well. Uh I have some historical uh slides here. Um You know, again, iii I would not want to se send a message. This is a new topic. This may be a new rere uh This is an article that has been quoted many, many times. I've put here more than 33,000 times. It's probably much more uh Russell Ross. I never met him personally. Those who have met him, um recognized him as a true uh genius and pioneer in the field of atherosclerosis. I was completing a medical school at that time and I remember reading this review article in New England Journal of Medicine and how systematically he made the argument that atherosclerosis was not just a simple uh metabolic disorder of accumulation of cholesterol uh in the plaques, but it was actually inflammatory disease. You know, the review is beautiful to read. And if you go uh in one of the tables he characterized it says several condition that he says nobody would argue that these are inflammatory uh chronic inflammatory diseases. And he, and he shows how the atherosclerosis have the same characteristic, the same cells involved the same molecules. And he references that and I think that was maybe a turning point is, you know that, that we stopped teaching or learning that the plaques would just become permeable to cholesterol, cholesterol would deposit there. And then too much cholesterol deposit will have a a physical burst of of the of the plaque that was incomplete inflammation definitely had a role. Um I would uh I have to uh quote this article, this came out again when I was in medical school you may recognize again, uh Professor Masri here in the middle. Uh This is the original team from Rome, including uh uh Philippo CRE who followed him from London. Uh And that this team did one of the many observations that uh in patients with unstable Angina or acute Coronary syndrome, the levels of inflammatory biomarkers like c reactive protein predicted adverse outcomes. I'm not gonna go into detail of this article, but this was definitely one of the articles that uh brought back inflammation as a clinical uh uh experiment or a clinical uh uh talk. Um I need to give credit to Peter Libby Libby is known to uh II, I assume uh most of you all of you in the audience, he has been a physician scientist that bring him uh in Boston and he's done the molecular studies for how inflammation works in the plaques and some of the clinical trials that I'm gonna cover. There's so many beautiful reviews for Peter Levy and the images are outstanding. I recommend to you read one of those and then, you know, I would be remiss if I don't. And I quote, uh Paul Ridker who is also a Brigham, he's more of an epidemiologist and clinical trialist. He's done most of the trials that have changed practice in uh prevention, primary and secondary prevention for cardiovascular disease. And he's also a great presenter and a writer and I'm gonna borrow he one of his release, the latest review with a graph that I think explains really well what uh what the issue with inflammation is in this review. He has two represented uh patients, the one here shown on the right and the one shown on the left. If I had done the review, I've probably flipped them and on the left and the patient two and the right patient one. But again, it's, it doesn't matter. The patient uh two is, let's say healthier individual individual who has a normal response at rest. He has no enhanced or uh increased inflammation. Uh We're gonna talk more about c reactive protein as a biomarker but the c reactive protein is normal. He has an insult of some sort. In this case, could be an MRI, there is a rise and fall of inflammatory biomarkers and this of course, doesn't have to be just the CRP, it can be any biomarker, even white blood cell counts. And then he recovers down to normal below the normal level. So he had a good inflammatory response and resolution of inflammation. This is probably not the patient that we need to worry about for inflammation because some inflammation is probably good for you a little bit. Uh on the left is a problem. Uh Patient, this patient if you see starts with enhanced inflammatory signal, uh before the event occurs during the the event, the inflammatory response is increased is exuberant is too much and importantly, it doesn't resolve, it doesn't go back to normal, it may take a long time. And so what we're really seeing is that in this patient on the left inflammation can be the trigger of acute coronary syndrome can cause complication of acute M I can pro uh including heart failure and can remain as a residual risk. These are concepts, we're gonna cover a little bit more in the next few slides. Uh I wanna talk to you. Uh Also about a uh relatively new concept. Certainly, I did not learn this when I was in medical school. Uh is the concept of the inflamma Zoe. I've been lucky enough to uh learn and train with Charles de Noo who uh discovered uh the uh interleukin one protein and then cloned the gene. And he had uh already described how the uh processing of interleukin one beta, uh a key cytokine in inflammatory cascade was tightly regulated. However, the concept of inflamma zom came several decades later and, and it's this concept of having a macromolecular complex that senses injury or, or um pathogens. In this case, even cholesterol crystals can be the injury and amplifies the response to produce I one beta in a very regulated way. This is important because in vitro studies and animal studies have shown that the inflamma Zoe and interleukin one beta may be the link between atherosclerosis and hypercholesterolemia. As we all know that elevated levels of LDL OX LDL are a trigger for events. The the one of the mechanisms immediate to this would be the recognition of cholesterol crystals from the inflamma and expansion of the response this person feature here uh in the middle of the picture is Stefano to do. He's an associate professor at the University of Virginia. He is part of uh my team and uh he works on the this uh preclinical model of uh of disease related to inflamma. So, so uh this again, I believe this is uh again called richer slide here on the left, you see the inflamma zom in the middle, again, you see how this can respond to cholesterol crystals. One of the key characteristics to the inflamma. Zoe is a response to multiple stimuli at the same time. It's not specific, it's not an antibody against a specific antigen from uh uh a virus but more of the debris caused by viruses. The cholesterol crystals, the new Neurotropy extracellular traps, even epoxy can trigger defamation in flamas when the inflam osume is formed in the cell prone to leuk one beta is released in its active form. Al one beta is a very powerful cytokine is also known as the fever molecule. If you give a lot, uh if you give a dose of L one beta to patients to induce fever, you can induce shock al one beta, then induces thousands of secondary mediator. The one that's probably most uh important for the systemic effects. Interleukin six, we're gonna come back to interleukin six. Interleukin six has a very powerful effect on the liver and induces um the acute face reactant or secondary mediators including CRP, which we're gonna measure Paul richer and many others have shown that c reactive protein uh is a stable marker of inflammatory status and predicts outcomes in a dose dependent way, not very, not different at all or maybe even more powerful than other uh risk factors like uh hypertension, upper cholesterolemia. And uh again, uh there are multiple studies on this. This is the most recent one. It's a me analysis of a very large number of patients from three clinical trials. And in this, in this uh analysis, uh doctor uh Rer and colleagues show that there is a dose dependent increase in mace cardiac debt, no cause that with the c reactive protein. And also when we look at clinically relevant way to stratify the patients with LDL and C reactive protein. On the right here, you have four groups, whether your LDL is at goal, less than 70 your c reactive protein is a goal less than 2 mg per liter. And you show that if you have elevated c reactive protein, more than two, your risk is increased. It's probably more remarkable than the uh residual uh lipid risk. And so this is where when you, when I asked earlier, um what to do with the patient, you, you would likely identify the c reactive protein being more than two as a risk factor. Um Where does this data come from? Again, I showed you the, the, the latest uh data on sac protein. Very nice publication. But you know, this goes back, you know, more than 20 years, I was looking at my slides here uh on the top left is actually a uh um chapter in a book edited by David Morrow. Uh that I worked on as when I was a trainee and fellow. These are uh studies from the 98 and 2000. Uh you can see that when your c reactive protein is elevated, uh more than three on the left or more than 10 on the, on the right. Uh You have an increased uh adverse uh risk that is uh additive to the uh prediction of troponin T. In this case. And here on the right, you see some K meer curves again, if you have abnormal troponin, you do worse. But if you have abnormal cac protein, you do worse as well. This is not to say the cac protein is a better marker in a way, but it's a complementary marker to uh markers of necrosis like troponin. Uh Again, this is AAA different study. This was uh uh in patients with stemi. The prior one was patient with acute coronary syndrome. Inpatient with stemi. As we showed earlier, there is a ra rise and fall of c reactive protein. There's of course a rice and fall of troponins. There's an increase in B MP. All of these biomarkers predict adverse outcomes in patients with ST. So what do we do with these um uh with these biomarkers is CRP. The best one is CRP, the only one. Well, not really CRP is not specific. And uh there are a lot of different biomarkers that can be used to uh track risk uh in this review that is now um you know, almost uh 10 years old, we reviewed all the different inflammatory biomarkers in patient with M I and we came with a very long list uh and some of them are immediately avail to you in the practice, like the white blood cell count, the neutrophil, the neutrophil to lymphocyte ratio. So we we we've known this for probably um you know, 50 years. If a patient comes in with an acute illness and the white count is elevated, that's a bad sign. There's actually a a study more than 100 years ago that if someone came with chest pain and had a low grade fever, they would do worse. These are all markers of inflammation, but the c reactive protein is probably the preferred one began. This was a consensus paper uh that was put together by the A H A and the CDC 2003 more than 20 years ago. Uh I remember I was completing my training back then. Uh And uh it was um clear already back then. If you read all the data that if you measure c reactive protein, you could identify patients at increased risk. And this panel recommended that to consider c reactive protein. The patient is an intermediate risk where you wanted a little bit of additional risk certification did not recommend any other inflammatory bone markers. And back then said you shouldn't really treat patients based on your c reactive protein because we don't really have clinical trials. Maybe we'll have a little bit more, you know, fast forward. 10 years later, there's a new uh consensus uh paper from the European Society of Cardiology again. Uh Also here, uh there is in endorsing the use of c reactive protein in some cases, including some cases of primary prevention, some cases of secondary prevention, some cases of stemi and most important identify your patients at greater risk in whom you would want to intensify your treatment. Again, some patients are clearly high risk, you know need c active protein. Some patients are clearly low risk, you might not need it, but intermediate risk may help you stratify these patients. So I think with this, we cover the bullet number one. I hope I convinced you that ao thrombosis is an inflammatory disease. Of course, there's much more literature to review. I hope that I uh convinced you that I showed you that the inflammatory response follows injury. And uh uh the inflamma has a role in this uh when you don't resolve inflammation, you have an increased risk and c reactive protein as of today's preferred inflammatory biomarker for cardiovascular primary and secondary prevention has a, a long half life. It's standardized and it's probably the one that we're gonna use. We find uh better data. So what do we do if we find patients with elevated uh inflammatory risk or elevated risk, what are the available anti inflammatory drugs until recently? There weren't any. And so patients say I'm not gonna check CAC protein if there's nothing I can do. But I'll show you that some of our uh routinely used drugs have a clear anti-inflammatory effect and there are some targeted drugs. So again, back in 1997 you know, back again when I was in medical school, uh a very informative editorial from Attilio Masse at that point with the hidden side of the moon, this was a study done again by Paul Ritger. It was a um a retrospective analysis uh of a a trial that randomized uh uh physicians to uh either aspirin or placebo for primary prevention. The overall uh trial showed some benefit for aspirin. But when he went back and stratified patients, according to c reactive protein, he found that patients who have elevated c active protein at time of enrollment in the study so long before the events occurred, uh The uh the uh benefit of aspirin was remarkable. Again, this was not a randomized trial in patients with LB DC Act probably most but, but rather a secondary analysis. But I thought this was very informative as you're deciding aspirin for primary or second uh provider prevention. You could take this into account knowing that there's not a targeted trial. What was very informative of this analysis here is that your, your predictive level of c reactive protein was not only for the immediate events, the one that occurred within one year but also for events occurred six years later. So likely this elevated c reactive protein in this patient population in primary prevention is look, is uh showing what we think. It's the um the vulnerable patient with a proinflammatory phenotype rather than an acute illness or an acute injury. Uh What can we do about it? Ok. This on the left is the graph that I showed you earlier from Paul Ridker. I added here some uh drugs that we could uh target. Uh I will talk to you in a bit about how we can inhibit the inflamma zom and cal colchicine. I'll show you how we can inhibit directly io one beta with an Ara Roon set. Oops, right. Two, sorry, with an Ein relo seal kind of kome. I'll show you how we can reduce IL six directly. But let's focus here on statins. We all use statins every day. I hope we do and statins definitely reduce LDDL cholesterol, but they have other effects, what we call pleo tropic effects, which I'm not sure we know exactly how they work. But what we know is that reduces c reactive protein patients and it reduces inflammation in an animal model. So along these lines, this trial again by Paul Ridker is very, very informative. This is in the jupiter trial again. Now it's 2008. So talk about 15, uh years ago, uh and more, almost 16 years ago, a very clever trial. So these are patients that were in uh uh primary prevention. So they didn't have, have never had an a thrombotic event. There were at increased risk because of age and other cofactors. They had an LDL that was considered normal back then. 108 between 94 and 119. So it's considered not an indication for statin back then. And they all had an elevated C reactor protein. It had to be more than two. Uh And uh it was a median of 4.2. So it was by default elevated. So it's just was looking at the inflammatory risk in primary prevention. I'm gonna go forward. I suspect that many of you have seen this result already. But sometimes we forget all the older trials in this trial. What we see is that treatment with resumes statin uh dramatically reduce the primary endpoint of uh uh mace and uh and all the the secondary endpoint in a pretty, in a very remarkable way. And so what this is and I'm not gonna show you uh I mean, it was highly well tolerated as we expect. We know statins, this is the break for the primary and all the different end points you can see here very quickly looking at hazard ratio, they are all very favorable. The P value are all incredibly favorable. And you know, fast forward. This led to an indication of rosuvastatin, not only to reduce uh cholesterol in patient with hypercholesterolemia, but to reduce risk in patients who are intermediate cardiovascular risk because of age or other risk factor and have an elevated c reactive protein. More than two shown to reduce the risk of stroke and I arterial vascularization. And I think this was remarkable. Uh It, it proved the concept again that aosis was uh likely an inflammatory disease. Uh like it being proposed by Russell Ross. Uh of course, in this study, also LDL was reduced. So Kostin was reducing LDL and C reactive protein, but clinically important was reducing event. Let's go back here to our drawing board here. And as I mentioned, uh the um the inflamma zom is kind of central to this uh event because it senses uh injury that can be tissue injury, it can be cholesterol crystals and then produces inter one beta. And so there are multiple ways that we can intervene this cascade. We can go with colchicine on the in flamas or with KK one beta. And uh uh this is another schematic um you know, for those who have not had a chance to familiarize with the inflamma zom, but it's a relatively um recent concept. Um I I, you know, I mentioned earlier is highly regulated process. And you know, if you want to memorize this, to understand it's kind of a bump that needs to be primed first. The priming comes from uh chronic in stimulation with proinflammatory stimuli like danger associated molecular patterns. This can come from viruses like COVID, for example, can come from bacteria can come from diet. This might explain why patients after COVID have an increased cardiovascular risk, but then needs a trigger, needs something that sets it off an individual cell. And usually this trigger is either a direct insult to the cell uh or uh extracellular damps like extracellular A TP. At that point in chromosome is formed, you can actually see it on the microscope. It produces a large quantity of one beta and other cytokines like ile and then the cell dies and when it dies, it releases all the uh internal uh content outside is a very pro inflammatory form of that. So it's kind of an explosion. Um I mentioned earlier that uh the, the inflamma Zoe is kind of the link between hypercholesterolemia and atherothrombosis. I'm gonna go a little fast here and I wanna talk to you about KAB. The clinical trials with KO Kin KAB is a medication that goes under the name of Ilaris. It's already FD approved for uh some chronic inflammatory diseases like uh um uh congenital genetic uh based disease in Children and adults. And uh in this case, uh again, Paul Ridker and PL used this uh molecule that blocks specific L one beta in a clinical trial that I'm sure most of you have heard about, which is the cantus trial. So in this patients in secondary prevention, all of them had an M I had to be at least 30 days from the most recent M I then randomized to one or more arms of kokino versus placebo. Uh The study designed and there went several different modification. It started with a description of 7000 patients with two doses, then it became 17,000 patients with three doses and four year follow up and then modified again in 10,000 patients uh for five years. And this was based on decisions to add another dose and actually a higher number of events than predicted. Um who are these patients? These are our our typical patients that we see in our uh secondary prevention clinic like post M I post re vascularization, you know, 60 years of age, uh about a third female. Uh diabetes was very prominent in this uh in this study because it likely associates with EV C reactive protein. All these patients needed to have ac reactive protein of more than two LDL was pretty good. I mean 8083 different groups, you know, maybe not perfect but pretty good. Especially considering when the study started, c reactive protein was elevated as I showed earlier. That was an inclusion criteria. Uh What did this study show? Well, Koum showed a a, you know, a dose dependent response on sac protein. It might not be a strong, statistically differences between the group you can see here on the top right um panel that, you know, 50 mg 100 5300 mg all dramatically reduced CAC protein. It may be a 300 mg every three months, did a little bit more, but there's no clinically significant effect on LDLHDL triglycerides or blood pressure. None that would explain any clinical benefit. So you know, when you hear Paul Ridker presented, this is like this is a ideal to uh setting to test an anti inflammatory drug that has no cholesterol lowering effect. What, what did the study find? Well, uh it was a little bit of a complex statistical analysis because it had three different uh treatment groups. Uh There was a hierarchical um uh path to the analysis of the data. And so the 1 50 mg was the uh preferred uh um dose. The one is actually clinically approved for other conditions. And when you see here on the bottom left, this panel is enlarged, there was in hazard ratio of 0.85 that met statistically significant. So the study did meet the primary endpoint kit of 150 every three months reduced adverse cardiovascular events. If you look at the other doses, the 50 mg didn't quite do anything. The, the 300 mg had a similar hazard ratio, a similar P value. But by the way, they analyze the statistics was not considered statistically significant. Um These are the uh the primary endpoint event rate. There was an absolute 0.64% reduction uh with Kenne Kno versus placebo. Uh This study has been analyzed in multiple different ways. Uh The, the uh the trial had a very strict DS MB that looked at all of the events. There was a concern this would cause uh cancer and infection and there was a small but significant uh increase um in fetal infection. The signal. Now, if you look at the numbers, they're pretty small numbers and it only becomes significant when you trend different groups together. But I don't want to absolutely uh neglect this. It's, it is a signal that it's there. It's not surprising. Il One blockers are um many affect your response to uh infection. They likely don't um cause immunosuppression. They don't impede your way to fight infection but may delay your recognition of infection, meaning you can have an infection. Not realize. And by that point, the infection is, has grown out uh to uh uh much larger burden than you would. Otherwise, of note, if you have someone with infection on treatment like COVID-19 and you give uh one blocker like kin or another. Uh one blocker, you actually don't do worse at all. You actually do better. So the probably the problem here is not the the effectiveness of the infection fighting but directly condition of the infection. When you look at the type of infection. Also, there's no signal for increased opportunistic infection. This is different from other cytokines like TNF blockers, for example. And the the increased risk was really seen in the more common form of infection like cellulitis, pneumonia, uh not quite for urinary tract infection. And so in this study, they also sorry, I went, went too far. Yeah, they also looked at the risk of cancer when we use biologics. We're always concerned about the risk of cancer. There was really no increase in cancer with the kind of kno I treated for up to five years. And there was uh you know, unexpected reduction of uh uh lung cancer mortality in this study. Again, this study was not shown to uh uh was not designed to uh look at cancer effects, but it was an unexpected uh finding that was quite assuring and these old patients did not have cancer diagnosis at time of enrollment. Uh There's been a lot of publications with the cantus. There was a, you know, about a 52 to 60% reduction in gout attacks, 27% of reduction in knee and hip joint replacement, an increase in 1.3 g deciliter with hemoglobin. This should not come to surprise to us because these are all inflammatory complications that we have with aging and they all seem to be at least in part related to il one signaling. But uh Kakuma is not approved uh not available to use for cardiovascular disease uh reduction. But that was the first trial that showed that going after a target molecule like uh one would reduce uh thrombotic risk without changing cholesterol blood pressure and other uh let's move upstream here from kin on the colchicine, the LP three inflamma inhibitor. Now, colchicine has been known for millennia um and it was used as roots for different diseases as powerful anti-inflammatory drug. Most of us have used at some point or another to treat gout. Uh It's routinely uh for um familiar Mediterranean fever. Uh More recently, we found that by inhibiting the microtubules, that is what we have learned um decades ago. Uh it also inhibits the assembly of macromolecular structures in the cell including the inflamma om. So we would call this as a non-specific inflam masom inhibitor. And uh experimental studies in the lab have shown that consistently that you can trigger cholesterol crystals. So you can inhibit that with colchicine. So let's move on to the clinical trials and support the use of colchicine. Uh This one here is a uh trial of patients with a recent mi A colt trial was published a few years ago. Uh All patients had an M I uh I think the median time was about 14 days uh after the mis some earlier, some a little later. Um typical patients, we expect, you know, a, a minority of female, about 20% of diabetes. 61 years of age patients were randomized to colchicine or placebo. And you can see this, I'm sure you've seen it across the different um platforms, social media or other colchicine led to a statistically significant reduction of a thrombotic events. And that is a ratio 077. The P value was significant again and again, if you look here at the absolute difference between the two groups, about 0.448 per year, uh, for, uh, culture, uh, compared to placebo. Uh, if we look at the, uh, we stay on this study here, we look at the adverse event verse events was actually, um, pretty, pretty favorable. There were some nausea flats G I, um, uh, intolerance with colchicine that we're all familiar with. There was a signal they were gonna talk a little bit more, uh, about pneumonia. There was a little bit more pneumonia in the patients with, uh, uh, with colchicine. Uh, overall infection rate may be a little higher but not statistically significant but no, uh, signal for uh adverse, um, major adverse event like mortality related to infection like we had seen with the cans. So we gotta stay tuned if we think about how colchicine works, uh, we might, should not be surprised if this one has also a potential warning, uh, regarding an increased risk of infection. Uh, follow up to low duco two trial. This is I study about, again, more than 5000 patients, uh, again, uh, 66 years of age, again, about 1/5 or sixth of females, then about 20% diabetes. Most of these, although they were stable at time of enrollment, most of these had a prior acute Coronary syndrome beforehand. And, uh, what we see here is that, uh, even, uh treating patients with stable chronic coronary disease, uh, adding, uh colchicine was, um, particularly beneficial in preventing long term event. And actually this was even more striking than the cold cot and an absolute difference of 2.8% per year, which is, uh, a number in a treat is pretty small. So, these two studies, I'm sorry. But they're saying on the, uh, lodo two, looking at the, uh, side effects and tolerance here, uh, if you look at non cardiovascular death, there's a little more in the colchicine doesn't quite cross the, uh, the uh the 1.0 burden here. Uh We look at pneumonia here. There is no signal. If you look at infection, there's no signal. Uh there are more discontinuation for gas intestinal uh tolerance as we can expect. Uh But since then, a lot of publications of culture, a lot of wonderful reviews. This is a pool of analysis that appeared a couple of years ago. Uh There's other trials that are smaller than the ones I just presented. They all consistently show that colchicine reduced the events, uh the uh mates mace events by about 25%. They also reduce coronary vascularization by about 23%. There's a reduction of M I in some trials, there's a reduction of stroke. Uh it doesn't quite reduce cardiovascular death and there may be a potential small signal for an increased uh infection in these, in these patients. Uh but not to the point that it's uh uh a lethal infection warning, the fast forward to June 2023. And uh uh we now have an FDA label approval for uh colchicine in the formulation of 0.5 mg. That was the one tested in these two trials. If you open the label and you read it, you'll find that actually the uh the um uh colchicine 0.5 has an indication. It's very similar to what we saw with rosuvastatin is reduced. The risk of M I stroke, coronary vascularization, cardiovascular death in patients with established eos cardial disease or multiple risk factors for cardiovascular disease. Uh The dosage it's recommended is 0.5 mg. There's another formulation, 0.6 is available in the United States. It's also generic. Um You have to remember that colchicine uh can have drug to drug interaction especially with strong C uh cyp three A four or uh uh glycoprotein P inhibitors. Uh But remember, statin is not a concern that comes up all the time. 95% of all these patients in trials were a statin. So don't worry if you are concerned with a low uh patient with a low GFR, you can switch to rosuvastatin which has lasted uh drug to drug interaction should not be used in patients with uh uh renal failure. GFR less than 60 or creatinine, more than two, not with severe liver dysfunction, blood dyre and uh biliary tract obstruction. Um And uh again, here's warning it's pretty well tolerated, but there are side effects G I side effects are the most common and it can suppress your bone marrow. It can give you neurotoxicity. So you wanna keep that in mind. If you have patients on treatment, you wanna follow them, make sure that they're not um having neutropenia or pyopen thrombocytopenia or they're having uh elevated CK or muscle weakness. Um So that is the only drug that we have in, in, in FDA education, specifically cardiovascular disease. I'm monitoring my time because I know I'm gonna, I'm gonna run out of time. Uh But let me just give you very quickly some interesting observations. This is a Bid acid if you haven't tuned in on bapa acid is another uh inhibitor of the cholesterol cascade showed here on the right. Um And likely like statins is also involved in inflammatory cascade. So, benic acid was tested in patients with statin intolerant here in the clear outcome trial. I'm not gonna review the trial in detail, but I'd like you to notice that the c reactive protein reduced dramatically in the clear uh uh outcome trials here on the right. You can see the c reactive protein is going down 22% uh 20% 19% in a highly statistical way, including the reduction of LDL. Of course, and there was a benefit of uh outcomes whether this can with some of the benefit can be related to the anti-inflammatory treatment. I'm not sure, but this is interesting uh drug that we may learn more in the future and certainly to consider in patients who are, um, statin intolerant. Um, here we go. Um, do all drugs work. Do, is this something that whatever we give these patients, they make it better? Not really. Uh, I can, uh, we can see here that this is a, a trial done with the methotrexate. Uh, Paul Ritger was the P I of this trial as well. It's called Cert, uh, methotrexate is a drug that we use all the time for a, a long list of uh uh rheumatologic diseases. Um And in this trial, if you look at the left here, methotrexate did not reduce c reactive protein. Uh it likely affect the more the lymphocytes more than the innate immunity and there was no difference, no effect on the clinical outcome. So, not all anti-inflammatory uh uh drugs are, are the same and we have some examples like TNF blockers, I'm not gonna cover today. We actually increase the risk of heart failure. Uh One more trial, one more drug that is on their radar. Uh You cannot really be uh alive now, not have heard about Ozempic or other G LP one receptor agonists. They were all over the news. Uh This is definitely an important clinical outcome trial. The select trial with SELU goes P one receptor agonist. This drug works on metabolism, weight loss and interesting enough, it also reduced the c reactive protein by about 40%. The exact mechanism is not known or at least, I don't know for sure. But it, it's intriguing to me that this may be another way to reduce inflammation. Uh As I mentioned, that drug uh leads to weight loss reduction and weight loss itself is anti-inflammatory or on the opposite, Aitsu for inflammatory. So maybe that's one of the mechanisms, maybe one of the things we need to keep in mind. So to wrap up the second part here, now when we're gonna run out of time, I'll be very quick. On the third one, rosuvastatin is, you know, approved for LDL cholesterol reduction and to reduce cardiovascular risk in patients who have c reactive protein more than two at an intermediate risk. Uh colchicine, he also approved to reduce cardiovascular risk in patient established coronary disease, kin is shown to do that in a clinical trial, but it's not approved beed acid and semaglutide are approved for other indication, but they also reduce cardiovascular risk and inflammation. So that will be uh interesting on our radar. Um I'm gonna skip this one here. Uh I do have a quick question here at this point. I need to get a sip of water and see if people are still awake here. So, uh which of the following treatments target the inflamma pathway and have shown to reduce pericarditis complication and randomized clinical trial. So I'm going a little bit away from anthro thrombosis, but I do want to cover this topic if we have time So A nsaids and colchicine B, nates colchicine and steroids, C colchicine steroids in an all one blocker D colchicine and all one blocker. E all of the combination. Remember, I wanna know that they target the insome and they've shown in randomized clinical trials. Ok. You got an anonymous that I agree with Josh West is great doctor Nagra is going for AC uh Well, we don't really have good clinical trials on steroids unfortunately, or maybe we should have. But um the answer is D col DL ones uh blocker. Let me show you some data here. These are old data that um they were done. Most of these were done in Italy actually from the mass and mazzio, but they're just remarkable, impressive. And I really think it's worth spending a few minutes on it. This is the colchicine for the treatment of acute pericarditis here, the cope trial. Now, 2005 here on the right. 2013, the A a trial uh these were um uh uh again, uh many, many years ago, patients with a first episode of acute pericarditis, they all receive some sort of nsaids, either aspirin or something else and dramatically reduction of recurrences with colchicine II. I wanna spend this couple a minute here to say pericarditis is not as benign as one thinks, not just chest pain, it goes away and at least 25% of of cases becomes recurrent or refer or complicates as we can see in these graphs here. Colchicine is absolutely important here. Um I'm gonna go to next slide here. These are Corp trial Corp two trial again, published some years ago, uh prominent journals. These are patients with recurrent pericarditis. So higher risk you can see a higher number of events recurring, a significant impact of culture symp. Uh This is an image that actually Mao Mao sent me to the right, the number needed to treat to prevent a complication of pericarditis. We're talking about 3 to 5. So don't forget that colchicine should be in your Armamentarium to treat colchicine uh pericarditis. What if colchicine is not enough? And we use something else. These are three separate trials that I'm not gonna be able to go in details, but they all use a different I one blocker and a kind right here which is a recompete uh um agonist uh RLO SEP which is an L one trapped. Uh Golf cleva is an L one trap. The only one is FDA approved right now is rhapsody for pericarditis. He's an old patient with severe pericarditis, uh re uh refer to standard treatment and they were um treated with the I one blocker, they all went in remission, then they were randomized to withdraw to placebo. And you can see that when you have these patients in remission, you take the one blocker away after the acute phase, they all the most of them or all of them have recurrences and this drug keeps them out of recurrence and this steroid sparing. So keep that in mind, as I mentioned, Roon is approved for this syndication at this point. Um What are other anti-inflammatory trials going on? We're gonna run out of time. I'm gonna be very, very brief on this. I'll be happy to take any questions or email me directly afterwards. You should know about ill six IL six is uh downstream from IL one and there are drugs that are available already like docile climb for other indications. There are drugs being investigated in clinical trial like Zyl Vab. That is they are a different way of blocking dial six, but they uh both are effective. There's a wealth of preclinical data that suggests a potential benefit. There's a large phase two trial with Zab in the rescue. Again, Paul rer dramatic reduction of CRP more up to 92%. And this is now being tested in uh um in three different clinical trial. The Zeus trial when patients with prior mi a prior cardiovascular event and renal impairment in the Hermes trial, which there are patients with uh elevated c active protein as well, heart failure uh and uh elevated an T PRO B MP. And in the artemis trial, which is still being defined the details by patient with an ongoing acute myocardial infarction. Uh They're all sponsored study by the no, no disc and they're all looking at this drug, Zil Vim me where they can prevent event in the treatment of trial. This is the outline of the research we do in virgin. Uh We are um mostly focused on interleukin. One. We participated in the cantus trial, we participated in the pericarditis trial. Uh We had some trials of our own in pericarditis. We have some trials in a QM. I uh looking at whether all one block kid can prevent heart failure. We have trials in patients with established heart failure to see if we can improve uh cardiorespiratory fitness and uh prevent readmission. We have some trials in cardiac sarcoidosis. We're starting some trials in the acute myocarditis. I don't think I'm gonna have time to show you these uh slides. You can, you're gonna have access to the slides and the recording. You can look at our uh publication for the sty trials where we, we show a beneficial effect in patient with semi. You, you can look at our trial uh for patients who recently decompensated heart failure. How uh and it can, may improve uh peak vo two. There's another trial going right now. Um You can look at our um early phase studies with the uh new uh uh inflame inhibitors. I think stay tuned. There are gonna be more inflame inhibitors. These are some advertisement from a Novartis and rush to show these are in development. So, uh these will be um something we have to be stay tuned. And I think I wrap it up by telling you that the pipeline is target inhibitors of IL six. They're already in phase three target inhibitors of IO one, there's many phase two trials including many of our hours and flamas inhibitors is more of an early stage. We're kind of in a phase one area. These are a long list of collaborators, trainees, friends, mentors and you know, there's too many to uh to list uh my partner in crime for the IO. One research is Ben Van Tassel at BC U. We have a, a collaboration of UB NBC U that's very strong still. Uh And I'm gonna, with this, I think I'm gonna go you to CME and so we can leave some time for questions. All right, Antonio, thank you very much for joining us today. You make a very compelling argument for inflammation and cardiovascular disease, uh a compelling argument for the importance of the connection as well as a compelling argument for the treatment of this. Um I'll let folks start to please feel free to submit questions in the Q and A tab or in the chat, but I'm gonna get it started with uh with a question or two here as folks are typing uh theirs. Where do we go from here with, with the role of inflammation? You know, when we look at other groups, the heart failure group has done a great job of focusing on GDMT and, and poor medicines. The, the lipid folks have really got us very focused on an LDL of 50 in people with cardiovascular disease, the, the coronary or the interventionalist that was focused on antiplatelet medicine. So, where do we go from here? Antonio on the inflammation side? And I tie that back to your first patient who had multiple stents now has diffused atherosclerosis. I, is that the right time to intervene or, or do we need to intervene even sooner on some of these patients? Yeah, that's, that's a great question. Uh You know, the case that I presented earlier, I think that's the low hanging fruit. I think this would be a, a very good case. I'm gonna try to go back to it, but that's a patient who's had multiple acute events. Uh It had multiple revascularization is coming back to the hospital. Uh You, you must address what are the residual risk for that patient. And if you um if you uh read uh reviews from uh Paul Rer, he tries to divide uh residual risk in residual lipid risk. Uh This is the patient we're talking about, you know, residual lipid risk, residual metabolic risk, residual thrombotic risk and let's add the residual inflammatory risk. So, you know, we could go ahead and target all of those at the same time and maybe we should. But what I'd, what I'd say is if this patient comes to your hospital and leaves the hospital with the same treatment, they were on when they came in. You're missing an opportunity because this patient is unstable. He has, he's gonna have more event, we know his data. So we should be looking at all of these aspects. And what can we do? Is there something that needs to be rerecord acutely? Are there symptoms that are driving reesor organization that certainly should be taken care of? Are we doing a dual anti therapy? And there's multiple ways of doing that as we now. Uh But if we don't, I think we should integrate c reactive protein and uh and consider either adding intensifying the treatment that we know already reduced c reactive protein or adding uh colchicine for um for secondary prevention in this population. That's what I'm doing as a standard care. One key question that comes all the time is, do you need to check sac protein? Can you just prescribe colchicine? Uh That's a, that's a, that's a like a common question. And I'll say in the trials for colchicine c reactive protein elevation was not necessary. So you could go ahead and just start it uh in other trials, it was necessary like in the jupiter and the cantus. And so the way I see it, it helps me stratify the patient and explain to the patient what I'm targeting. So I tend to test it. Uh but if you were to do it without testing, you certainly could do it. That's not a problem. Great. So walk us through I if a patient, if you're attending in, in the hospital or the, the CCU service and somebody does come in with an acute M I. Are you checking CRP routinely? And then how, how do you use that information to adjust therapy? Right. So we, as you, as you um as you heard me, they say there's limited a approved uh strategies right now that have been testing clinical trials. So acutely right now, we don't really have a uh a strategy to reduce inflammation upfront during the acute phase. Uh This is kind of undergoing clinical trials. We have a semi trial that we're enrolling in uh uh in Charles and Richmond where we're giving an I one blocker acutely. But the most practical aspect right now would be to check c reactive protein at discharge or in clinic on the first visit and look at the residual inflammatory risk. This is what has been tested in the uh Callcott trial if it's with low dole two, although those were more stable patients, this is what been done with the cantos trial was more than 30 days. You wanna see how they quiet down and target that residual inflammatory risk. Now, I also tested uh many times in the uh acute setting like stemi uh or even heart failure, but that's not, not really the target treatment. I don't really have any treatment that I can give in patient. Not yet, but it does tell me which of the patients are more likely to have complications. For example, in stemi elevated siac protein correlates with cardiac rupture with acute heart failure. And so that can be a predictor. Ok, not alone. I mean, you would look at the EKG, you look at the ejection fracture, you look at the my biomarkers of necrosis. You look at the angiographic results but someone who has ac reactive protein up to 100 uh milligram per deciliter doing the M I, they're in a bad shape. All right, we have a couple of questions that came through our Q and A um tab here. The first is, can you use colchicine with carvedilol? Oftentimes this pops up as a warning. Yeah, I, but I, I think honestly that the pharmacists are getting better now and they're not kind of, you know, calling us with all the statin uh questions. So, uh the answer is yes. Uh you can, um the, the uh the only concern would be the patients who has low GFR or has some liver injury. So colchicine will accumulate and uh uh and it can give, it can become toxic. There's a possibility it's even toxic to the kidneys. So, if there's a normal GFR, uh Carvet has no problem if your GFR is around 60 you're or you're on other medications that are moderate uh uh inhibitors that can be an issue. Um But in, in general, both of these drugs are a pretty wide therapeutic range, meaning that if your, if your uh Coreg is giving you trouble, you're gonna have more uh bradycardia have more blood pressure. You can adjust the dose. If colchicine is accumulating, uh you may have more side effects like G I um I and that's comes up a lot about side effects of colchicine. And uh in many case, we reduce the dose, we can go to 0.3. If we're using 0.6 we can go in every other day with colchicine as well. But I would say Carvet is really not a concern, more concerned like drugs like fluconazole, amiodarone has some concerns as well but not Carvet and not and no statins either. All right. Next question has to do what percent of patients with coronary disease who have very well controlled lipid levels have AC RP greater than two. And are those patients candidates for colchicine then? Great, great question. So, you know, we know this only from the uh screening process of uh of trials because we, I I don't, I haven't seen a population wide study where we are measuring this in every single uh individual. It's estimated that in secondary prevention, it's about 30 to 40% that have elevated CAC protein. We're talking about patients that are stable on optimal therapy with LDL reduction and those are I think were the low hanging fruit because really you have done everything else, everything is perfect. And that CAC protein is a little bit of your signal that something is still lingering under there. If you take patients with diabetes that are uncontrolled cacti protein is almost always high. But in that case, again, I would say colchicine may be, but you do want to intensify their diabetes regimen because if you can make diabetes better, the c active protein may go down at the same time. Uh I uh also, uh just for, you know, those who are getting familiar with CAC protein, I did put in this slide, you know, there are two tests that can be used for CAC protein, one that we call high sensitivity or cardiac CRP that's much more sensitive. Uh I it's virtually uh detective in everybody and the normal value is considered less than 2 mg per liter. What's confusing is that the standard CRP that's available in every hospital that's not as sensitive, you cannot detect it less than 0.3. But the uh it's milligram per deciliter. So if you have 0.3 of a standard CRP, you actually have three of milligram per liter, although you may not convert them, you know, linearly. But uh that's what it's uh so it's important to keep that in mind. All right. Well, Antonio, it's uh um 830 I, we on behalf of sort of pen cardiology. We thank you um for coming to speak to us today remotely uh in, in this format. Uh I certainly learned a lot. And I thank you and your team for all the work that you've done over the years, really leading the field of inflammation and cardiovascular disease. And as we continue to learn more, I think will be an important pathway um for us to all treat patients um even better, hopefully prevent uh primary and secondary prevention purposes for, for ongoing heart disease. So thank you for all the work you've done and thank you for joining us. It's an honor and the work you guys do is inspiring. So thank you for having me. All right, take care. Have a nice day. Thank you everybody.
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