Hello, everyone, and it is my pleasure to have an esteemed group of experts as we are going to be talking about coronary artery disease and peripheral arterial disease as the state-of-the-art antithrombotic therapies for both coronary and peripheral atherosclerosis. I'm Professor Kelly Branch from the University of Washington, and it is my pleasure to have wonderful colleagues that are really going to be talking about this field, which, of course, we've known about for many years, but we have many new treatments, many exciting changes within this field, and we're going to be outlining those today. First, I have Professor Mark Benaca, who's at the University of Colorado. I have Professor Jeff Barnes from the University of Michigan, and Professor Roxanna Maran from Mount Sinai in New York, and it's a pleasure to have all three of you here to talk about this very interesting topic today. So, let me go ahead and start off, and we're going to be using first names because we're friends and colleagues here, but I wanted to start off to get kind of an introduction to really bring us into the topic. So, when we talk about coronary artery disease and peripheral arterial disease, we're talking about atherosclerosis, but is this really the same disease, and how do these patients differ? What is our current understanding? Jeff, I'm going to ask you first. Can you give us just a little bit of an outline about kind of atherosclerosis within these different patient populations? Well, you know, Kelly, I think it's a really good question, and at the core, yes, these diseases stem from the same pathologic process, which is atherosclerotic buildup of plaque in an arterial bed, but they also have really important differences that I think are essential for us to understand. Now, both of them build up cholesterol, and at a certain point, there's a thrombotic process that occurs, but in the coronary arteries, that tends to be a very sudden and severe event. That's what we think of as a non-ST elevation MI, or even an ST elevation MI in the most extreme form, whereas in the peripheral artery disease beds, so those are often what we're talking about as the lower extremity, this tends to be much more of a chronic thrombotic process sitting on top of atherosclerosis. Now, there can be acute thrombotic events, what we would call acute limb ischemia, but far and away, what the presentation we see most often is a buildup of chronic obstruction, which is a combination of both lipid buildup and chronic thrombus, as well as sort of artery to artery embolization. So, the thrombotic process is a perhaps even more important part of the chronic nature of peripheral artery disease as compared to coronary artery disease, where it's much more about the chronic lipid buildup. So, Jeff, I think you make a really good point, but when we're talking about really atherosclerosis, you know, we think about this more of a systemic disease, a polyvascular disease, and the neurologists are constantly reminding me that actually the carotids really are not a peripheral, but it really is a central artery as well, right? And sometimes we forget about that, but how do we tie this in as far as when we're trying to figure out what's the risk of our patients, we're talking about patients with coronary disease versus cerebrovascular disease versus peripheral arterial disease? Well, I think there's a couple elements for us to look at, and the first is what is the risk of those major adverse cardiovascular events, the MACE events that we talk about all the time. And of course, a patient with coronary artery disease is at risk for MACE events, but it's really important to understand that a patient with peripheral artery disease, I'm talking mostly about the lower extremities, but we can also include cerebrovascular disease, the disease of the carotid arteries, they're also at risk for major cardiovascular events. So, heart attack, stroke, things like that. Where I think there is potentially a difference is that if you have lower extremity peripheral artery disease, not only are you at risk for those MACE events, the stroke and MI events, but you're also at risk for major adverse limb events. So, risk of amputation, risk of having wounds and ulcers on the feet, needing revascularization. So, there's sort of two different sets of adverse events we have to think about. And in many studies, we've seen that patients who have peripheral artery disease are actually at higher risk of both MACE, major adverse cardiovascular events, and MAIL, major adverse limb events, than their corresponding patients who only have diagnosed coronary artery disease. So, great, great points, Jeff. Let me focus a little bit on peripheral arterial disease if we can. Because right now, really, the mainstay of treatment is how we treat coronary artery disease. So, we're using aspirins, we're using statins, risk factor modification, depending on whether or not they have diabetes or other risk factors for atherosclerosis. But if these patients are really at higher risk, then what are the treatments not really more aggressive? What should we be doing differently? And Mark, I'm going to send this one to you. What should we be doing differently for these patients, both conceptually, as well as really how we're going to treat and address these patients? Yeah, Kelly, that's a great question. And I agree with what Jeff said. I mean, first of all, there's nothing peripheral about peripheral artery disease. You could call it lower extremity artery disease, but it is central to what these patients suffer. And I think that most of the therapies that have driven our guidelines have been driven by small subgroups of cardiovascular trials looking for MACE benefits. So, if you look at the history of development in PAD, there are very few agents that have been studied specifically for these patients or for lower extremity events. And so, you're right. The core therapies, like aspirin and statins, have been studied and are labeled or at least recommended in guidelines, but we don't know a lot about what they do for limb outcomes. And that's really a gap in the research. And I think we could talk about specific therapies. One issue with peripheral artery disease is that it's not one disease. It's actually quite heterogeneous. We know that there are patients that are heavily calcified, those that have end-stage kidney disease or renal disease. We know that there's a difference between below the knee and above the knee disease. We know that the limb outcomes are driven by things like the large distribution of artery disease, the role of thrombin, and then also things like grafts, prosthetic grafts we saw in best CLI. And then there's microvascular disease. So, I think we are in the early days of therapeutic decision-making for patients with PAD and for development. But to answer your question, I think we just don't know how to risk stratify patients very well in PAD. Who are the ones that are going to get the amputation? Who are the ones that are going to get major adverse limb events? And how do we intensify therapies? So, I think it's an area where we need more research. Excellent. Well, let's talk a little bit about that, because I think a lot of what is guiding us are clearly the guidelines, right? They're giving us an idea about where we need to go. And peripheral artery disease guidelines from the AHA and ACC are actually in development. I hear they're in an advanced stage of development. And maybe you can tell us, maybe you can't. You might have to kill everyone that's listening here. But without opening up too much, tell us about what you think is missing and about what could be coming down the pipe that could help us treat these patients better. Well, I'll make a few comments. One, I think that we have more data now around therapies and their activity in PAD that I think will lead to enhanced guidelines. But there are sort of challenges, I think, as we think about treating our patients. One is, as Jeff said, what do we give for mace reduction? So, antiplatelet monotherapy. We know aspirin or clopidogrel have been class one in the guidelines, but neither of those therapies have any activity for preventing major adverse limb events. We know that dual antiplatelet therapy, so aspirin and a P2Y12 inhibitor, have been broadly utilized after PAD intervention, but there's actually no data to support efficacy for that. And we know that it increases bleeding. And so, how do we grapple with something we've done for a long time that may not be as supported by data? And we do know that some of the novel lipid lowering therapies, like the PCSK9 inhibitors, have profound benefits for preventing major adverse limb events, things like amputation or acute limb ischemia, as well as some of the newer diabetes drugs, where it's not really about A1C reduction anymore, but GLP-1 agonists have been shown to reduce amputations. And so, I think the guidelines will have to grapple with what are the benefits for mace, what are the benefits for major adverse limb events, and then I think particularly for therapies where there are safety questions, like bleeding, how to risk stratify, both for bleeding, how do you pick the patients who are less likely to bleed, but also for risk, so that you know you're picking the patients who are going to get a greater benefit from more intensive therapy. That's great. Jeff, as a vascular medicine specialist, what do you think is missing? Anything else you wanted to add on to what Mark was saying? Well, I think Mark really summarized it well. And the last iteration of the guidelines that we have were sort of state-of-the-art when they came out in 2016, but there have been several advances that have come out since then, and Mark really highlighted them. How do we intensify antithrombotic therapy and select the right patient to receive something beyond aspirin monotherapy? How do we think about better lipid management? How do we think about some of these novel drugs, like the SGLT2 inhibitors, the GLP-1 agonists, things like that? And then, of course, how do we do all of the other things we're supposed to do better? Tobacco cestation, blood pressure control, wound care, weight loss. I mean, there's a whole host of things that we really need to do, and that's all just in the patient who's been diagnosed with PAD. There's an entire separate group of folks with undiagnosed or unrealized PAD that we really have to think about. So I'm excited to see what these new guidelines are going to bring forward. There's a big opportunity to move the field in a really positive direction. That's a great point. Thanks, Jeff. And Roxanna, you've been very quiet, which I know is maybe slightly unusual for you. So I'm going to open this up to you, because we want to hear from you. Because I think one of the things that trials and sometimes physicians, we really don't consider the more nuanced approach of what about differences in ethnicity? What about differences between genders? When we think about peripheral arteriosclerosis, what are some of those concepts that we really should have in mind, which we sometimes don't? Thanks, Kelly, for including that in the conversation. But just to add a little bit to the discussion between Jeff and Mark, I want to say wholeheartedly, thanks to the COMPASS trial that finally looked at limb events as a major outcome for our patients. And I think the lack of evidence for all the things that we've previously used is the fact that we never used major adverse limb events as an important outcome measure in our clinical trials. It was missing. And it's really, really important now that we see it, we are starting to see other trials look for it, adjudicate those events. And hey, by the way, you know, PCSK9 inhibitors have an impact there. And I know that Mark is doing an unbelievable job in actually making sure that we are looking at all limb events in the same way, in a standardized way, so that we have some standardization. I know the Academic Research Consortium tried to do that, but I think Mark and his group are going to do a lot of great work there because of their incredible approach there. But I also think it's really important that every time we look at our clinical trials, we also say, well, we never looked at major adverse limb events in the past. We now do. We're enriching the criteria so that we get more of these events in patients who have peripheral arterial disease, recognizing that these patients have more ischemic and bleeding events. And very importantly, when you do that and you enrich for those, you will start to see more non-white patients because they're inflicted by this. And we have to do a lot of work to actually enhance and improve trial in terms of ethnicity, diversity in both ethnicity, race, and sex. And so, and I think that's what we're doing. But also then in the clinical application of products that are now approved is not to forget about those patients who are at the highest risk, which would be our African-American, Hispanic population in different regions, as well as women. And I think that's the part that we need to always continue to have a discussion over. I think it's a great point. I mean, we talk about these areas of places where we have much higher rates of amputation and much higher rates of revascularization, places like the South, where you have that amputation belt, just a huge swath. Could we be doing something earlier rather to try to prevent that? So, you make some wonderful points. So, Mark, I'm going to come back to you for a second because you really spearheaded, you know, one of the major trials, of course, within this field. So, can you tell us a little bit about Voyager PED and about how you think that's going to fit in both before when it was done, but now as we move forward into our new era? Yeah. Thanks, Kai. I appreciate that. And Roxanne, I appreciate your comments. It's been wonderful collaborating with you. And I think PED research has lagged behind coronary research, but we knew in the coronary space that the highest risk period, most vulnerable period for patients with coronary disease after an acute coronary syndrome and after revascularization, and we didn't really have much research in the way of what happens to patients after lower extremity revascularization for symptomatic PED, that sort of acute period afterwards, especially because of the degree of disruption that happens after lower extremity revascularization of the size of the conduits that go in, the amount of prosthetic material, we'll get to that as we talk about, you know, promising agents like factor XI. And so Voyager sort of brought together a couple of concepts. One was we need to escalate major adverse limb events to the primary endpoint, that it's as bad or worse to have an acute limb ischemia event as it is to have an MI. World War I stroke, when you look at disability, cost, hospitalization, mortality, all of those things. So they deserve a place in the primary endpoint. Voyager was the first trial to have a five-point composite primary endpoint, including acute limb ischemia and major amputation. And so this was the relevant endpoint for the population. And it studied patients in that really fragile or vulnerable post-revascularization period where we know that major adverse limb events are frequent. Now, a lot of people may not think that way. I trained in cardiology and, you know, my initial, before I started studying vascular medicine, I thought major adverse limb events were really rare and that especially patients with claudication were low risk. But what we've learned now is that actually these events are more frequent than MACE events. And in patients with claudication after revascularization, very high risk. So in Voyager, it was taking that population, that place in time, this primary endpoint, and then studying a novel therapy, which had been shown to be efficacious in ACS and chronic PD in the COMPASS trial. And then looking at adding low-dose ribaroxaban and inhibiting thrombin generation added to an antiplatelet in that acute period. Now, you know, I think a lot of people worry about bleeding with these agents and that's exactly what was studied to make sure it's safe to add this early on and looking at procedural bleeding, but most important efficacy. And as we can talk about, when added to aspirin, statins, and over 80% P2Y12 inhibition, which really did very little in the study, there were dramatic reductions in that primary endpoint with a number needed to treat of less than 40 at three years in a six to one benefit-risk ratio. And so I think we learned from that study that we can modify these outcomes and that we can do so with a net benefit in that thrombin is a key bad actor after lower extremity revascularization. Yeah, this is a great point. Let me just drill down a little bit on a couple of those things, one of which you talked about kind of the net benefit, if you will, the ratio, right, of bleeding versus events. So how does that work for PD? I mean, when we talk about, you know, the risk of mace or male, and then we talk about bleeding, what's the differential there? You said it was six to one, is that right? Yeah, so we did, you know, net benefit, or we did benefit-risk using an apples to apples comparison. And you look at the events, the mace or male events, and these are just revats. I'm talking about acute lymphoschemia or major vascular amputation, not even minor amputations. These are bad outcomes. And you weigh that against TIMI major bleeding, because there was no excess in fatal bleeding or ICH, but TIMI major bleeding, which are bad bleeds. And Roxanna will tell us even bleeds that are of lesser magnitude or are linked to mortality. But when you do that, you get a six to one benefit-risk ratio. And the pattern is one that we've seen in Roxanna and Mike Gibson and others have described this very well in the coronary population, where you have that sort of bleeding stress test early, but after that, the bleeding risk is quite flat, and the benefits then accrue over time. And so this is an acute therapy that transitions to a long-term therapy. We know over the long-term from COMPASS that that translates into reductions in all-cause mortality, and even in COMPASS, a 70% reduction in amputation. All right. Great point. So one final comment, and that is within Voyager PED, there was a substantial number of patients that were actually on PGY-12, on clopidogrel, something that was, you know, people had talked about COMPASS, maybe, you know, the comparator should have been clopidogrel, even though most people were using aspirin. But how did that stack up? How did clopidogrel work within that patient population? Yeah, it's a great question, Kelly. So, you know, when you look at the subgroup that got DAPT, that's over 3,300 patients. I mean, it's bigger than almost all the PAD post-intervention studies. And what we see is that actually the VET rate for major adverse limit VETs, even in the first 90 days, are extremely high on top of DAPT. You know, it kind of reminds me of the early days of the coronary literature for coronary stent thrombosis, before taclocodine came on the scene, and we saw VET rates on aspirin or aspiroworfen. It was about the same. And I think that just tells us that DAPT isn't particularly effective in the lower extremities, at least at the doses we give, and it doesn't interrupt thrombin. When you add rivaroxaban to that, you get over a 50% reduction in those acute sort of stent thrombosis type events, like acute limb ischemia, even in the first 90 days. And there's no interaction for DAPT. It just doesn't matter whether you use DAPT or not. They don't modify those outcomes. Now, what you do see is that for patients who receive DAPT for longer periods of time, for more than a month, you see more bleeding. And we saw a sort of borderline effect modification. The interaction term was 0.06, meaning you logarithm clopidogrel what was an interaction or borderline interaction for about a threefold excess in bleeding. And so what we learned there is that DAPT's not enough to prevent these bad events, that Rivaroxaban at an early does, but that triple therapy long-term isn't a good idea for bleeding. Today, I wanna just highlight something that Mark just said, which is in the coronary space, we really had this overwhelming body of evidence to tell us that dual antiplatelet therapy was the most important thing we could do after we placed a stat. Now, of course, how long and all that's sort of what we're gonna discuss, I think, a little bit more later. But in the peripheral artery space, we didn't have that. We just extrapolated from the coronary space. And I think what Voyager PED did for us was say, oh, it's not DAPT in the lower extremities, it's dual pathway inhibition, right? It's getting that single antiplatelet, probably aspirin, and combining it with that thrombin inhibition agent, in this case, a very low dose of Rivaroxaban. And that's the evidence-based therapy we should be using when we're doing lower extremity interventions, pulling back on the P2Y12 so that we're not adding unnecessary bleeding risk. And so we finally have an evidence-based antithrombotic therapy like we've had for decades in the coronary space. Fantastic. So wonderful points. I'm gonna pivot just a little bit. We're gonna go to coronary artery disease. We're gonna move up, and I will say, I couldn't echo enough that cardiologists, we really don't think enough about peripheral vascular disease, cerebral vascular disease. The joke is that you go below the diaphragm, go above the neck, and everybody kind of gets lost. And I did have a very well-meaning APP that came up and when we were talking about major adverse limb events are male, and she said, what about the females? And I said, I think we have a long way to go to educate because we're just not used to thinking about it in that space. But let's come back to coronary artery disease and talk about these patients. So we've heard a lot about these very high-risk polyvascular disease patients prefer arterial disease to river vascular disease. Now, people with coronary disease can or cannot be lower, but the risk, of course, isn't zero, and we should be treating our patients appropriately. So Jeff, I'm gonna come to you again. Tell us a little bit about what we consider appropriate when we're thinking about antithrombotics for coronary disease and maybe even in contradistinction to peripheral arterial disease. Well, I think this is an area that's probably evolving. I mean, I remember going through training and it was just ingrained in our thought process that any patient who was getting an intervention for coronary artery disease had to be on dual antiplatelet therapy for a year because the most feared complication was that stent thrombosis event, right? Yes, we needed to think about the other therapies, smoking cessation, tobacco control, lipid control, but they had to be on dual antiplatelet therapy. And the debate, of course, is which of the P2Y12 inhibitors you might choose. And I think that in the last decade, that conversation has started to shift a bit, right? We know that antiplatelet therapy is important, but with newer stents that are being placed and better control of other risk factors, how much and how long patients need to be on single versus dual antiplatelet therapy, what's the right antiplatelet agent for them to be put on is something that we're kind of grappling with. And I'm hoping that we'll have a discussion. And I'm sure Roxanna will have a lot of thoughts about that because she's been leading a lot of those efforts. Yeah, couldn't, perfect segue, because I really wanted to get to Roxanna, who is really our local expert on how do we treat these people? Obviously, we're all experts, but I mean, Roxanna has done so much work about how long we should be treating, how we should be risk stratifying, when should we pull back, when should we advance? So Roxanna, I'm gonna give this to you. There's so much confusion in this space. How do you approach some of these decisions for how we should be treating patients for secondary prevention? Yeah, so here's the thing, right? I mean, we just heard from Jeff so beautifully that it really is becoming extremely confusing. One minute we want long duration of dual antiplatelet therapies, and that's what we're taught, and we have some class one indications for that. And then the next minute we're hearing, well, you know, bleeding is bad for you, and what are you gonna do about that? And oh, by the way, 40% of our patients who undergo stenting have high bleeding risk. And oh, well, now we have to do shorter, but then maybe there's aspirin, but maybe we just drop the aspirin. Maybe we don't know. I mean, it just is a lot of confusion. And I think it's created, I mean, I think for me, it's created a 1-800-what-to-do-adapt number here where people are calling me all the time. But I think you're all experts. Everyone who's listening here is an expert only if they listen to their patients. Talk to them. Don't be on the computer while they're telling you about, by the way, I bump into things and I have black and blue bruises everywhere. Take a look at their frailty. Take a look at, ask them about what else they're taking at home that is not listed on the medication list, like how much NSAIDs they're taking or things like this and what's contributing to what. And I think that, to me, is one of the most important things, assessing the risk of the patient. And sometimes the eyeball test, actually looking at the patient, is better than any risk score that I ever made or anyone else has ever made. And I think we're going to come up now, I mean, I'm working on a project where we're going to use deep learning because we just had, like, literally it's 22 million permutations between duration type of antiplatelet therapies in whom and when and which scenario. And I think it really does have to do with risk assessment. I think what you could do best for your patients is do no harm, right? And as a clinician, when you're giving, you're saying, I'm giving you dual antiplatelet therapies and you feel good about it because you're protecting them against myocardial infarction, but you also, if you're not careful, might be causing them to bleed, a catastrophic bleed, like an intracranial hemorrhage for which you will never be forgiven for yourself. And I think in so many ways, what we're seeing now in clinical trials, that in most cases, especially when there's an overlap of bleeding and ischemic risk, less is more because bleeding is actually more prevalent in the complex, higher risk patient populations. We've gotten really, really good with our STAT technology. It's not when, you know, you're worried about that stent thrombosis. It's now like a 0.3% per year if you do a good job in your stent procedures. And of course, with intravascular imaging and physiology and enhancement of our interventional techniques, we've gotten so much better. Bleeding though, is a gift that keeps on giving. So early after an intervention, we intensify therapies and we should, but then we should peel back and think about that patient's presentation and then at least address some of the innovative approaches like dropping aspirin or platelet function testing, even though it's just a to-be recommendation in our guidelines, when you are dropping aspirin, putting someone on clopidogrel monotherapy, well, you better make sure they're responding to clopidogrel. Otherwise they're gonna be on nothing and they're not responding if they're not responding. And then of course, the dual inhibition, again, coming back to that, something we were never taught. When do we introduce that? Like the COMPASS strategy was never really incorporated in our work sort of process. And so therefore it's gotten lost, even though there was a mortality benefit. So at the end, I really think we just have to do better for our patients in terms of the antithrombotic regimens, look at the risks, assess them and think about some of these novel strategies. I think it's a great point, really wonderful point. Let me ask, when we're talking about risk, how do we, you talked about frailty, you talked about the eyeball test, you talked about getting stalled, something that we don't really do very well ever other than something easy like a CHADS-2-VASc, but how many times are we actually calculating risk based on some kind of score? And what are, people don't do that. I can tell you that in, I've put it into our database, into the EPIC. I've put it in so that when they're doing their cath lab reporting system, it, they have to put in these, the parameters and it says, well, it's a high bleeding risk patient, consider shortening the duration of DAP, make sure your, was imaging used, you know, et cetera. And these kinds of things that are really important so that the referring physician also has an idea of the fact that this was a high bleeding risk patient. But I do think the risk assessment in terms of ischemic events does have to do with the presentation of the patient, STEMI, non-STEMI patients, all MI patients who have diabetes and chronic kidney disease, they're really at an extravascular, extracardiac, peripheral vascular disease, cerebrovascular disease. They're just at high risk or they're rich in ischemic events. And we've got to, we can't ration because we're worried about bleeding. There, we have to think about that. On the bleeding side, I think it's more simpler, right? They've had a previous bleeding episode, they're old, they're frail, mostly women. And of course there is an AHRQ HBR criteria that actually works very well where you could predict a 4% AHRQ three to five bleed if they meet those criteria. So that's actually a really easy one. There's an app for it, it's very, very simple. But if you find that high bleeding risk who happens to also have ACS, you've got to be thinking about some of the novel strategies you can't keep them on dap forever and keep piling on more anti-platelet, anti-thrombotic regimens. So that's what I think, that's what I do in my practice and that's what I'm hoping I'm preaching here to everybody else. I don't know what you think about that but I wonder what Mark thinks. Do you use a risk calculator, Mark? It's a great question, Roxy. I've learned so much from you and there's been so much active research in that but I have to say, I don't really use a calculator either. And I think to your point, the eyeball test, the clinicians are good at spotting sort of high bleeding risk patients. We did an analysis from another trial where we looked at two factors, just a history of bleeding requiring hospitalization or anemia. I do think there's a lot of GI bleeding that it's unmasked when you put on these potent anti-thrombotic reagents. So unexplained anemia is a good flag that somebody may be high risk for bleeding but actually those two predictors perform pretty well. So yeah, I think there's sort of calculator fatigue sometimes in clinical practice. Jeff, what do you think? Well, I would agree. I also don't use a formal risk score because we don't have something that's as easy to apply and stands alone for bleeding risk. So many of those bleeding risk elements are also thrombotic risk elements, right? We think about CKD, we think about older age and those are things that sort of go hand in hand. I also always remembering in the back of my mind that bleeding is a thrombotic risk factor. So when somebody bleeds, they're then at risk for having a thrombotic event either because of the body's natural response to stop bleeding or because we as their clinicians or the patients pull back on their anti-thrombotic agents. And so avoiding the bleed in the first place is a great way to prevent a thrombotic event. And Roxanna, I want to come back to something you said earlier, which really I think is one of the most powerful things we can say. Just because somebody had a stent or an acute coronary syndrome event doesn't mean that they are mandated to have 12 months of dual antiplatelet therapy. And I know that's what I was taught when I went through training, but we really have to sit and listen to that patient, right? And so, as you said, the patient who tells you that they're bruising, tells you that they're falling, tells you that they're having concerns with bleeding in their gums, we need to know that we have permission to peel off or back off on some of those anti-thrombotic agents. Maybe it's one month, maybe it's three months, maybe it's six months after their stent or their acute coronary event, but we no longer have to force them to live through 12 months of dual antiplatelet therapy and all those minor or nuisance bleeding events that put them at risk for something bigger. And I think that's such an important message that needs to get out. Yeah, that's great. Let's delve into this a little bit because I think this is really interesting and so much work has been done by this group talking about the duration. And we talk about this really in two different concepts, one of which is the idea of shortening DAPT, so decreasing the amount of time from that, what we always thought was the obligatory 12 months. And then, of course, there's the de-escalation of therapy, and that is removing it from DAPT maybe to single or less potent agents. So when we're defining that, so let's talk a little bit about that. Give me some really good definitions about that. And then when we would consider both, either, what were the patients that are gonna benefit from short DAPT and or de-escalation? Roxanne, I'm gonna start with you because you've really done so much work, but I want everybody to chime in as well. No, I think this is a really, really good question. I mean, I think there is ample evidence that in a patient in whom high bleeding risk prevails, and it's a very, very high risk, less is more. So meaning you either have to de-escalate or you have to shorten the duration of DAPT to a single antiplatelet therapy. But also, I think it's evaluating those patients before they go to the cath lab is even more important because in the cath lab, the interventionist should be using judicious use of stents with intravascular imaging and physiology. And then absolutely having a conversation with the interventionist. Was there bifurcation stenting? And understanding what took place in the cath lab is really, really important. And a picture speaks a thousand words. You should all review the angiograms. You learn a lot and you kind of, it's sort of a signature for that patient's ischemic events going down the line. If you look there and you see small vessels, calcified disease everywhere, and then by the way, they have prophovascular disease and they just put in six stents. I hope they didn't, but maybe they put in three stents. You're still very worried about that patient's ischemic events on top of their bleeding events. But we know now in an all comer study, one month versus six months in high bleeding risk patients, with even in complex setting, when you shorten or modulate DAPT, they do better. Because when they bleed, when these patients bleed such, remember they had high ischemic burden, but they bleed, we stop everything. And since they end up with a life-threatening event, that's ischemic on top of the bleeding event. So we've got to avoid that first bleed so that we don't go into this spiral situation of just physicians acting on different things. So how do we do that is by modulating DAPT and surveying that patient closer. This is not a patient you only see once a year. This is a patient you would see every three months and working on their non-antiplatelet therapy issues. Like their LDL should be in the basement somewhere, honestly, and their SGLT2 inhibitors should be on board. And those are the kinds of things, if we do those, we know we're gonna enhance their ischemic events on top of what we're doing in modulating their antithrombotic events, so antithrombotic therapies. On the other spectrum, if you have a really, really young patient who comes in, who's a smoker, who's got clot everywhere, and by the way, is a diabetic woman maybe, and has just received a bifurcation left main stent, well, that patient who doesn't have ischemic, I mean, bleeding issues, that patient should get her lung gapped, and at some point, he or she will be aging and getting into a bleeding arena where you would have to modulate that. So it's not like this snapshot of seeing the patient as a Polaroid camera once and assigning their lifetime treatment. That's why I think this whole thing with the guidelines, lifetime therapy with aspirin, to me, is wrong, it's a wrong message, because it says, oh, you never have to see them again, just give them aspirin, say goodbye, and I don't think that's the way we should be caring for these patients. Okay, Jeff, what do you say? What comments do you have? Well, I love Roxanne's comment that it all starts before the intervention and thinking about what happens in the cath lab and understanding where those stents are placed and how they're placed, that's critical. But for me, I'm a non-interventional cardiologist, so I'm often picking up that patient afterwards, right? And let's be frank, most patients after a stent, be it acute coronary syndrome or chronic coronary disease, they're coming out with a more potent P2Y12 inhibitor and aspirin. And so I really have three options ahead of me if I'm concerned about bleeding risk. The first two have to do with shortening the duration of that, right? So rather than that standard 12 months, I can use dual antiplatelet therapy for one, three, or six months. And after that, I'll drop either to aspirin monotherapy or to a P2Y12 inhibitor monotherapy. And Roxanne has led some of the studies that have really helped us understand that those can be effective strategies to use. But I also have the option to do de-escalation. And when we say de-escalation, what we mean is going from that DAPT with the more potent P2Y12 inhibitor, I'm thinking paracegrel and ticabrelor, and de-escalating the P2Y12 inhibitor down to clopidogrel, which may have less bleeding risk associated with it. And that's another strategy if I think you still need to have dual antiplatelet therapy on board. So we can shorten the duration and go to monotherapy with aspirin or a single P2Y12, or we can de-escalate from our more potent P2Y12s down to clopidogrel plus aspirin and maintain dual antiplatelet therapy. So really a lot of options that we have to reduce bleeding risk. So Mark, what about you? what are your thoughts? Yeah, I think a lot of great points. I mean, a couple of things. One, I think what Roxanna said is right. I mean, it's not one size fits all. And we do have to realize that dual antiplatelet therapy does reduce risk, ischemic risk, even in 12 months. I mean, there's a mortality benefit in the PLATO trial. And that was a head-to-head with two DAP strategies. But I totally agree that we have to prevent that first bleeding event. I think de-escalation, to me, has become particularly attractive from what I learned from Twilight, because I do think that aspirin is a bad actor for bleeding. It has direct GI toxicity. We know that enteric-coated aspirin isn't well-absorbed, so we don't even know the benefit, really, people are getting. And that P2Y12 is really important for preventing coronary events. And so DAPT is, I still think, the standard after ACS for patients who have real-deal athero and aren't at high risk for bleeding, but the ability to drop aspirin and use P2Y12 monotherapy, I think, is quite attractive. I personally do not de-escalate to clopidogrel, just knowing that the effect of clopidogrel on any individual patient is quite variable. And there's some patients that actually have very robust effects. Some have almost no effect. We know from Paul Gerbel's work and others. And so, you know, sort of like I prefer DOACs to Warfarin, because you know that each patient that's getting it is getting the same effect, and you don't need to check. I think with clopidogrel, it's just not a good drug. And we actually know from trials like PLAIDO that the bleeding advantage from clopidogrel is almost nil. When you looked at multiple bleeding definitions in PLAIDO, sort of the head-to-head of ticagrelor versus clopidogrel, there was no difference in transfusions, no difference in PLAIDO major bleeding, no difference in a bunch of different measures. There were some that were slightly different, but I'm not sure there's a big advantage to using, you know, a more variable P2Y12 inhibitor. So I tend to favor ticagrelor and prazugrel and just drop the aspirin. Does everyone agree? Jeff, Roxanna? I'll still often use a lot of dual antiplatelet with clopidogrel and aspirin, especially if I'd gotten a month or more out. So out of that high-risk sort of post-intervention period, I'll also let it be driven kind of by patient choice and access to meds, affordability, once a day versus twice a day. So there's a lot of other factors that will sometimes go in. But I have found myself in recent years moving more towards this shorter-duration DAPT and then moving to a single P2Y12 monotherapy, because I'm now starting to see evidence that that's effective, whereas before, when I was trained, aspirin was the given, and then you picked which of your P2Y12s you're going to have. So I'm having to change my practice pattern a bit now. Yeah, thank you, Jeff, for talking about the P2Y12 monotherapy inhibitor, inhibitor monotherapy. But I also would say I still see there is this very nervous group of physicians who just don't want to peel away the aspirin. And I think that in certain, some scenarios for those patients would be to, at the very least, reduce the dose of your P2Y12 inhibitor or go from the potent to the less potent. So de-escalation in dose and in the potency can be done in certain scenarios. But if you are going to do that, I really do think, especially if you have a very high ischemic patient, like, for example, why would you want to de-escalate the ticagrelor dose to 60 and keep the aspirin going, where we know in Pegasus and that Mark was very involved in, there was a major reduction in death in my stroke, but there was a bleeding price. We never had a ticagrelor monotherapy, and the dose of ticagrelor was a full dose of 90 milligrams BID. So again, it becomes a little bit more confusing. Do I de-escalate in terms of going to a single antiplatelet therapy, shortening the duration of DAB, or do I de-escalate in dosing and potency? And I think you can do both, but it depends on how smart you are in terms of figuring out in whom and how to do that and how to manage that. Roxanna, I'd like to throw another potential wrinkle at you, which is, is there a situation in which you would actually change therapy from your standard dual antiplatelet over to dual pathway? I'm thinking perhaps that patient who has a coronary intervention, but has known peripheral artery disease, maybe has some moderate CKD or CHF rates, some of these risk factors that we've seen have shown benefit with dual pathway inhibition. Might you drop the P2Y12, keep them on that low-dose aspirin, and switch over to a very low dose of riboroxaban, and in whom would you think about that after coronary intervention? To be honest, if I'm really worried about their coronary disease, I keep them on the ticagrelor monotherapy. I feel like I can give that for a longer period of time, at least up to two years, in fact, based on the Global Leaders data, and feel good that I'm protecting this patient against ischemic complications. And then at the same time, I have two years to work on their LDL and their weight, their exercise, all these other things, as they are being protected with that. Now, who do I give the COMPASS strategy to? It really is in that patient who's very, who's got all of these other ischemic risk, for example, diabetic CKD, but then with peripheral arterial disease. And if they're getting both coronary and peripheral intervention, that's an easy thing. You just go straight over to ARIVA because of the Voyager data, and feel very, very good that you're actually enhancing patency, as well as major adverse limb events, on top of hopefully reducing major adverse cardiovascular events, like we saw in COMPASS. So that's who I choose. So, but we'll see what the computer says we should be using in a room, but that's how I do it. So I'm gonna say something a little bit provocative. So based on what we're hearing, there's a reluctance, there's a bias, towards aspirin, and especially as aspirin monotherapy. And so based on some of the discussions here, based on the data, and especially some emerging data, I'm gonna say, I'm gonna ask Jeff directly, is aspirin debt? Should we just be moving away from aspirin monotherapy, or should it still have a role? And then how do we mix and match? Yeah, I think it's a really challenging question. So thanks for coming to me first. Aspirin is by no means dead. I think aspirin is a really important part of certain treatment strategies. Where I think we have to be much more thoughtful is the idea that aspirin as monotherapy should be used for everyone with a history of atherosclerotic disease. To me, that concept is absolutely dead. But for instance, my patients with peripheral artery disease and coronary disease, my patients who have PAD and have diabetes, or CKD, I'm absolutely going after that dual pathway inhibition of which aspirin is a critical element. So aspirin isn't dead, it just has to be used in the right combinations for the- It's retired, it's retiring. It's getting more selective. Yeah, aspirin in certain scenarios. No, I think it's a really, it's a provocative question, Kelly. I gave a talk on time to retire aspirin. That's why I brought that up, because it's received a lot of online, many people ask me for those slides. And because I was provocative in terms of, why do we think like aspirin should be in the running, like upfront as like our VIP, if you were to like, let's say, as our CEO, so to speak. And I think we need to kind of think about aspirin and in its wisdom for all of its years in the making, appreciate what it has done in complementing some of our treatment modalities, but it shouldn't be the number one first place that we go to. And we certainly shouldn't be scared of withdrawing aspirin, especially in some of the patients that in select patients where we have so much ample evidence that they do just fine without. I, for example, I'm not sure that any of these potent agents need aspirin anytime. I'm not sure based on the pharmacokinetic. Now we don't have clinical data on this. So don't stop your aspirin, but we still give chewable aspirin 325 milligrams every time someone comes in with a myocardial infarction, whether they're taking aspirin at home or not. But I think in certain, and now there will be clinical trials that are ongoing in STEMI patients who are just going home on Ticagrelor and one on just Prasugrel. So it is the data on pharmacokinetic and blood thrombogenicity does not suggest at all that aspirin is doing anything on top of these potent P2Y12 inhibitors, Prasugrel and Ticagrelor. So let's rethink that for those patients, for example. Mark? Yeah, I agree with all of the comments. I think we just have to get smarter about the biology that we're trying to interrupt. I think as Roxanna said, with a potent P2Y12 inhibitor, we just learned that P2Y12 inhibition is really important for coronary events, especially in patients in the acute setting. And so that having a potent P2Y12 inhibitor on board may be enough and that you can reduce bleeding without a big ischemic price to pay. I'm not sure the same is true of peripheral artery disease, to be quite honest. There, I think the data for P2Y12 monotherapy is a little bit more sparse. There's the CAPRETE trial, which is very old trial now. And it did show a modest benefit of clopidogrel versus aspirin. Looked bigger in the PAD patients, but that interaction actually was driven because it looked worse in MI patients. We know that's not true now. We know that P2Y12 monotherapy looks just fine for coronary patients. So that's probably just a play of chance in that one old trial. And so I think aspirin is cheap, it's effective, and it will be around for the long-term. I think that it has utility in PAD, and I don't think we have the same confidence that, for example, Factor Xa inhibition as monotherapy is a secure option. I think P2Y12 for coronary patients is one thing, but unfortunately, because the COMPASS trial, well, I shouldn't say unfortunately. Fortunately, it was overwhelmingly efficacious and reduced mortality. But because the trial ended early, we don't really know whether Rivaroxaban 5 twice daily as monotherapy is an effective option. It's not labeled for that, and we just never got enough data. So I think that we have to be more nuanced about what we're targeting and what patient population and when. Excellent, excellent. Well, this is a wonderful conversation. In the last couple of minutes here, I'm going to throw out some quick cases to you, and then you're going to tell me how I'm going to be approaching this patient from antithrombotics, okay? So we're going to take a patient who's going to be in their 80s, going to have, came in with acute coronary syndrome, other notable risk factors include diabetes, include anemia, include some liver disease, which is low-level cirrhosis. How are you going to treat that particular patient who just came in, seeing you at three months, has gotten two stents for their ACS? How do you treat that 80-year-old with those risk factors? Roxanne, I'm going to start with you. Yeah, so this is, for me, just what you just pointed out. This is a high-bleeding risk patient, 100%, 81 years old. You didn't tell us the sex, if it's a woman. Female, female. And then liver disease was one of the, and anemia both, really, really put this patient over the top for, and then if there's AFib or a need for an oral anticoagulant, even more. But in this particular scenario that you're telling me, and depending on what they're on, were they on clopidogrel for these first three months, or were they on a potenegut? I'd like to know that. Because then, if you gave them aspirin and ticagrelor, for example, because you're also the same patient, is at a very high risk for ischemic events. So if they actually pass that stress test with no bleeding, no issue, at three months, it's an easier decision because there, this patient fits into a perfect example of a patient who, it meets the twilight criteria. No, after three months, no ischemic events, even though they are old, even though, I wanna keep that agent going, and I'd probably give them ticagrelor. If I'm really worried about bleeding, even though there's no data on this, I might reduce the dose of ticagrelor to 60B, I guess, and then maybe do a, after a week or two, just make sure that the responsiveness is there. I promise you it will be. That 60 milligrams in the 60 milligram dose, and I guess this worked beautifully, but it was in presence of aspirin. So because we're going to a monotherapy and we don't have clinical data, I might do that. So I just assume the patient received ticagrelor. If they only received aspirin and clopidogrel, here's another chance for me to reduce the duration of that. And what would I do now? I might just 100% go to clopidogrel monotherapy, but test the patient that they are responding to that. Because of the anemia, and I'm worried about gastro toxicity, especially if they had a prior GI bleed. And of course, I'd be very careful about their GI. I give them gastric protection with APIs. Okay, all right. How about a 65-year-old male? Comes in with unstable angina, has a history of diabetes and HEF-PEF with a hospitalization a couple of months ago. Comes to your office now, has now achieved his first stent, congratulations. And now you are approaching this patient from an antithrombotic standpoint. So Jeff, what would you do for this particular patient? Well, this is a gentleman who probably left on ticagrelor plus aspirin. That's probably where he's coming out after his stent. And I think the question is going to be, has he had any bleeding issues since then? Or is this somebody in whom we can safely continue him on dual antiplatelet therapy? But at the same time, I'm looking for some of those other risk factors, right? This is a great opportunity to ask him, has he gotten into cardiac rehab? Is he walking? Is he having claudication-like symptoms? Have we looked for PAD so that I can understand whether this is a polyvascular patient or is this a guy who has isolated coronary disease with a HEF-PEF? And that's going to change the way I would then approach his antithrombotic therapy, be it at six months or at 12 months, whenever. But what I'm hearing so far is this is not somebody who's had major bleeding risk factors. I may continue him on that dual antiplatelet therapy for a while longer. All right. And how about the 55-year-old who comes in, has very, very high lipids. That's been something that has been troubling him for many years. Comes in with some non-obstructive coronary disease in spite of having some chest discomfort seen on an angiogram, but at the same time was noted to have some peripheral arterial disease during the groin shot, subsequently worked up, found to have an abnormal but asymptomatic ABI. What are you going to do for this patient? How do we approach this patient? Coming back to you, it's going to be an aspirin monotherapy. Mark, what are you going to do for this particular patient? Yeah, that's a great question. So, you know, here we're not facing an acute coronary syndrome like the prior two cases, but we have unmasked in a relatively young patient, what the late Alan Hirsch used to call metastatic atherosclerosis. So this is a patient who's got both coronary disease and peripheral artery disease and a clear driver for that, which is hyperlipidemia. So looking at this patient, you know, the first thing I would recognize is there's no one therapy that's going to reduce this patient's risk. There are multiple axes of risk that we have to address and that, you know, at 55 over the next decades, his risk of having a bad outcome is extremely high. So clearly you said he had hyperlipidemia. I would, I'd probably check an LP little a given his age and the fact he has polyvascular disease. I try to get his LDL as close to zero as possible. And then I think, you know, I would recognize that thrombin is playing a bad role in this patient, particularly because of low extremity disease. And I would use aspirin and low-dose rivaroxaban so that I'm covering thrombotic risk and I'm covering lipid risk. Now, all the stuff that Jeff said earlier is critical too, right? So this, you know, healthy diet, is he smoking, smoking cessation, you know, exercise, all of the other factors that we need to think about, I would think there, and I would make sure that we keep a close eye in terms of pre-diabetes or diabetes and foot hygiene. I think there's a very much a holistic approach, but I think I probably have this patient on very intensive lipid lowering in one step, not titrated, I'd sort of just kitchen sink for lipid lowering and aspirin and low-dose rivaroxaban. Fantastic. So thank you to the three of you for really giving what I think is an enlightening and actually very compelling case for really rethinking how we approach antithrombotics in our patients. It's still a complex space, but there's a lot of room and maneuvering, but really it's all coming down to individualizing and personalizing antithrombotics for the patient sitting in front of you to achieve the best possible outcome. So to Mark Bonacca, Jeff Barnes, Roxanna Maran, thank you so much for joining me today and for giving such a wonderful conversation. So with that, we will go ahead and end and thanks to everyone for listening in and we hope we find this beneficial. Happy, best of health to everyone. Thank you.

antithrombotic therapies

coronary artery disease

peripheral arterial disease

atherosclerotic diseases

acute events

chronic condition

limb events

risk stratification

personalized approach