John Moscona, MD, FACC, Austin Heart Interventional Cardiologist, discusses DAPT after PCI.
briefly before I get started. Just wanna introduce myself. I'm from New Orleans, Louisiana. Just moved to your toe Austin a couple of months ago with my wife and two kids. Um, interventional cardiologist. A Z you can see there. Yes, so But I'm training coronary structural peripheral interventions. E think the focus for today, though, is really more of my coronary hat I have on here is well, chip cto Just Teoh. You know, I'm not sure. Sort of Who's on the call exactly. But just people may already know this, but to explain Chip and is kind of a term used for complex coronary interventions on CTO interventions on really covers sort of what my patients might need after rectum Me left Main PC, I buy application P C. I, which really has sort of an important focus for the topic here today because there's been a lot of evidence, a lot of data coming in the past, really about the past three or four years, about understanding how best to use anti platelet therapy after p c. I, and there's sort of two large focus areas for this one is on patients with really high bleeding risk but then also patients that have really complex coronary disease and have, ultimately a lot of stents placed. And so balancing the ischemic burden and management of that with the bleeding is so I'll sort of talk about that theme multiple times here this morning. I'm also just on here is my email, my cell phone number. At any point, if anybody wants to reach out to me for any questions about this, and I am at the essential practice for Austin Heart of the our hospital in Boston all right, I have no disclosures, All right? So before we start with contemporary dual anti platelet therapy, anti platelet therapy, I just wanted toe give a very brief historical background on aspirin. So the so we know that aspirin reduces death in acute M. I. And this is data that actually comes from the eighties. So the first real paper about this it was published in 1983 and see there the VA cooperative study, which is sort of funny because there's only you can see there, you know, 100 patients, uh, you know, with events and maybe 600 patients in each arm, which are much smaller thin the studies we have today. But this was really the first one of the Isis to sort of the other so that these studies really form the backbone of using anti platelet therapy in the setting of acute M I. Now, in terms of dual anti platelet therapy, cure is the big trial. But I think probably most people know so cure is a trial of using gapped on specifically clopidogrel and aspirin and showed that this reduced adverse cardiac events in the setting of acute my butt. One of the things to focus on here about the cure trial I just kind of highlight here in the bottom, right is that most of the absolute risk reduction of using depth this really occurs sort of up front. And in the first three months, I'm up therapy use after that am I. So keep that in mind that the benefit is within the first three months where this curves really separated and it's continued out. PC cure is sort of a sub study of the cure trial that that ends up being the basis of using gapped after stenting. Um, but again kind of see similar data, But again really This landmark analysis. This was published in Lancet in 2000, and one again shows that the benefit here really seeing even within the first sort of 40 days of use where those curves really separate. So that was seen again back even 20 years ago, that the benefit is really in the first month or couple of months. So there's a lot of anti platelet data adapt data, uh, that was published kind of in the early two thousands and then thes air. Just kind of a flow chart here of the most recent a c c H A and European Society cardiology DAP guidelines Which essentially, if you were to look him up today for stable ischemic heart disease, you used APP for six months, Um, at least and then for anybody that has an acute coronary syndrome you would used apt for at least a year. And there is an option, according to these sort of previous guidelines, to extend this therapy out for more than 12 months, sort of where deemed appropriate. Uh, the other thing on this sort of flow sheet to look at is for patients that have kind of high bleeding risk There's always sort of this option that's been there that, you know, maybe use a bare metal stent for just a month or something. Um, you know, Thio, sort of maybe pre surgery or something like that. But there is some options to shorten dept when needed. That really highlights the questions about adapt in general. So So these air just, uh I think kind of the three big questions about dap that we've sort of researchers were trying to answer in the past few years. So first. So how does more than 12 months of adapt affect these adverse cardiac commands? Mortality, stent thrombosis and bleeding, but also how to short dap durations? Now compare with that kind of 12 month treatment period and really with newer generation drug eluting stents. So I think that's kind of the focus as well. To kind. Understand, here this morning is that the stent technology has changed dramatically from now compared to where it was 20 years ago and even where it was five years ago, this means currently sort of thinner. Sh stench, drugs. Um, you know the device companies really do some interesting things with sort of where the coatings are on their stents. And really, this is all thought to help promote better and ethereal healing and sort of why that this is now kind of a contemporary focus of research studies. A lot of people think with better stents, could we get away with shorter debt? Um, the other question is about aspirin. So you know, the first slide show that, you know, aspirin obviously, is the cornerstone of coronary artery disease, medical therapy. But is it the best monotherapy you know, after cessation of that? And there's a lot of data that has been published toe maybe suggests that we should rethink that. All right, so adapt. Try Eliza. Very well known trial. I'm not gonna spend too much time on this, but just sort of suffice to say that you know this trial, looking at standard 12 month adapt or much longer duration. Adapt. 30 months after PC, I sort of demonstrated a couple of things. Uh, first that the longer you keep a patient on depth, then you can reduce sort of these ischemic events, um, stent thrombosis or, you know, some adverse cardiac events. But this study was also done with more than 50%. 1st generation drug eluting stents did have a combination of acute coronary syndrome stable ischemic heart disease, but lots of first generation stents. But then on the flip side, we adapt. Kind of showed us was even though you could reduce ischemic events with longer duration do anti platelet therapy. There was this sort of cost that occurred of increased bleeding aan den. This kind of interesting finding that basically, if you were gonna bleed sort of farther out, you know, more than a year out while adapt that was associated with an increased mortality. So, you know, this is really kind of a sub study type analysis, but at least gives a hint that, well, maybe there's there's a problem there with bleeding and mortality, which which really has probably been echoed. And other studies not just related to do anti platelet therapy. If we if you believe it, Zen a really bad. So so then the backbone for understanding. Well, what about shorter dual anti platelet regiments? You know what happens if you do three or six months 1st 12 months. So, um, there wasn't really a lot of great data. Maybe before the past four or five years in terms of really randomized data. But some studies Ah, lot of these air industry sponsored, but kind of get a signal that probably three or six months of gap 1st 12 months for most patients is probably pretty similar in terms off rates of stent thrombosis rates of them I and also possibly some reduced bleeding, but similar all all cause mortality. And I think that that kind of intuitively makes sense that, you know, if you're on a shorter regiment, adapt versa longer regiment probably will have reduced bleeding. But the question is what happens to the ischemic events? This is another, uh, study. This is called Prodigy. So this was actually included in that this meta analysis I just showed the previous slide. But the interesting thing about Prodigy is probably trying to separate out. Well, what about the types of stents being used to the types of stents effect the scheme IQ events, the ischemic endpoints, um, you know, in in terms of you know, how the adapt was used or the DAP strategy selected and what was found is that essentially the newer generation stents at that time were associated with the lowest ischemic events. So, you know, bare metal stents on the flip side seem to be associated with higher risk of events. So as the stent technology improved, it seemed that some of the ischemic endpoints were also improved, and you could really allowed for the use of a shorter depth duration. This is true even in some high risk populations. This is a more recent paper, but looking at six first 12 months adapt after stemming. This was just a non inferiority trial. But at least on this mostly was with this is aspirin. Plavix, for the most part but similar all cause mortality, Am I? You see that revascularization rate stroke and even Timmy Major bleeding a 24 hours. But this is with at the time, a newer generation, drug eluting stents. So six months at least, seemed to be non inferior to a 12 month strategy. Now there's other papers, though, where we'll maybe we didn't see that exactly. There was some. This is a non inferiority trial that didn't meet the primary endpoint, but a subgroup analysis. At least there was some increased M I with a shorter duration. So again, it's just it's the same question again, you know, can we shorten this without increasing the ischemic events and eso? This was kind of the backbone for the most recent randomized trials that they'll show here in a couple of minutes, but I think we hopefully everyone has a sense of what we're dealing with. So again, it's, you know, what's the ischemic burden and managing the ischemic Chris Post PC versus the bleeding risk in the overall state eso before getting into the randomized trials and talk a little bit about high bleeding risk. Because this is, I think, what you'll hear about. Or maybe you have heard about already if you get, you know, kind of emails about late breaking T C T trials or things like that. But there's a lot about shortening. Adapt for high bleeding risk patients. And so what does it mean to be a high bleeding risk? This is a table that probably covers really what you would think a high bleeding risk patient is. Um, major categories would be somebody who's already on long term oral anti coagulation patients with chronic kidney disease patients that have baseline anemia as need to be hospitalized for their anemia, get blood transfusion, liver disease, cancer, any kind of previous intracranial hemorrhage or stroke. So I think you know these air the without having to memorize sort of criteria patients that, you know you may see and say, You know what? I'm a little worried about their bleeding risk because of their other medical co morbidity is there are few sort of scoring schema or calculators that you can use toe really quantify the risk. Um, this is this is just an example, one called precise DAP that I think is pretty good data behind its use. But it allows you to look at the patient's baseline hemoglobin, white count age Granton in previous bleeding history to determine if they're high bleeding risk or not. Now what's important about this score, though, is really sort of validation of the score and just some kind of interesting observations about it. Eso this waas a paper based on the precise depth score, and it's validation in complex PC I patients. So patients at high bleeding risk based on this score and what happened to them if they were on a short backed regimen or a long doctor regimen. And looking at this, the bar graph kind of chart here. The big take away is that the shorter, adapt sort of side, which is this right side here, really favored in high bleeding risk patients, especially the setting of non complex disease. So I think that again kind of intuitively make sense. If you have a patient that that, you know, has bled before it had to be hospitalized for G. I bleed. Andre have maybe a straightforward right coronary artery lesion that needs to be stinted. And that's it. You know, those patients are probably going to be fine with, you know, a few months adapt rather than having to go out for a year. And if you were to go out for your longer and longer, probably were just increasing their bleeding risk without getting a lot of ischemic benefit. Where is on the flip side? The long DAP duration, which is on the, uh, this left here, is gonna favor patients that don't have a high bleeding risk, but in in in particular, those that have a lot of complex coronary disease, requiring what is gonna be complex P. C I, which may be multiple stents having to be placed or multiple vessels having to be treated multiple lesions and in this paper, a total stent length of over 60 millimeters, which is quite a bit. That's sort of a lot of stench. Dread a lot of metal in the artery there, along with patients requiring bifurcation, stenting to stand strategies and C t o p. C I. So again, intuitively, I think, makes sense to say, you know, if you have a patient that has very complex coronary disease requires, you know, a complex intervention, but they're they're bleeding. Risk is very, very low, and you probably do want to keep those patients on a longer duration adapt. And you're not gonna really have any concern about their bleeding risk, especially if they're a little bit yeah, all right. So hopefully I'm starting to kind of really just beat this horse to death. But the depth dilemma so extend adapt, prevents ischemic events, but at the cost of increased risk of bleeding and perhaps an associate increased mortality. So that's that's sort of what we're worried about extending it and does the shorter duration adapt? Uh, however, even though it may reduce the bleeding, we have increased ischemic events once I'm on it there and then, particularly patients that have had a stem e and n stemming any kind of a CS or complex P C I. And also looking at this through the lens of contemporary drug eluting stent in PC I practices. So just to remind again that that study there was so many patients and their more than 50% with first generation steps, So, um not really applicable to what we do every day in the lab. And then finally, what's the best model therapy strategy? Okay, so now we can move mawr into the sort of the basis for the most recent randomized controlled trials. So, um, the first aspect that I understand is a lot of the more recent trials Twilight, for example, which I think is the biggest one and maybe the one people have heard of the most. I'll show here in a minute. Um, a lot of these shorter adapt randomized trials have used the P two i 12 inhibitor monotherapy as theme the, uh, the mono therapy. After transition from depth, so important to understand a little bit, why on dis could it's ah whole talk on its own, but really? I'm just gonna highlight a few points first, is that some things to be aware of? That the mechanism of p two i 12 inhibition still involves kind of the aspirin from boxing pathway. Okay, so this is some of the bench lab data That sort of suggested that this might be a safe strategy to drop aspirin, but instead keep the Plavix or keep the Berlin tha, for example. And there's platelet aggregation data that that also kind of suggests that aspirin really doesn't have, ah, a lot of impact when added to the P to 12. In addition, in terms of of, you know, kind of reducing traumas, there is some clinical data as well. I'm not showing it here, but actually in the kind of the stroke realm that p two by 12 inhibition may be as effective is aspirin for secondary prevention of of events and really again that the combination of aspirin, p T. Y. 12 and ambition may end up on Lee really increasing the bleeding risk long term without really reducing the risk of the scheme equipments. So, to sum it up, the P two i 12 inhibitor mono therapy after a short duration adapt may provide at least similar efficacy and improve safety profile compared with current standard adapt and aspirin regiments. So this is kind of the conclusion of many investigators that has resulted in some of the most recent randomized trial design. Okay, so all right, so now talk about those randomized trials. So there's There's a few to kind of be aware of, because I think now that there's there's sort of four of these that will likely influence guideline recommendations in the near future, here is the first one. This is one called smart choice, so so presented first in 2019. This was a three month, 1st 12 month adapt study after PC, after PC I, where you can see here the after adapt to the patients were kept on the P T by 12, never not on aspirin. So in this sort of investigation, alarmed three months of aspirin plus the P. T. Y 12 and then dropped the aspirin. And in this study, they used clopidogrel, prasugrel, taika galore. These were current generation drug eluting stents is a non inferiority trial. Um, but the primary endpoint there is really this kind of all cause mortality and my stroke in 12 months after PC I. This composite and point and about 3000 patients total and he's also included acute coronary syndrome patients or stable ischemic heart disease patients. This was done in Korea. Here is a flow sheet or sorry flow chart. Justo visualized the trial design So the patients undergo PC I with a drug eluting stent. These air three types of the newest generation drug eluting stents and then random when the highlight here again is look at the percentages because I think this is important of who you know, how many patients had stable ischemic heart disease and how many had acute coronary syndrome and see here about 58% in both arms. So this is over almost 1500 patients in both arms, but a lot. A lot of patients with acute coronary syndrome, so not stable disease. Uh, the other thing is, most patients got clopidogrel Plavix. Okay, so not Berlin tha or athletes. And for the primary outcome, basically, this met the non inferiority input. So patients whether on adapt for the 12 months or patients who are adapt for three months and then transition to the P T Y 12 inhibitor, basically, just, you know, similar numbers in terms of that primary input for a subgroup analysis on the bleeding again, this was not the primary endpoint, but just another secondary outcome. There was less bleeding, and this was statistically significant in the P two I 12 inhibitor monotherapy group. Okay, so I think, you know, based on what sort of we mentioned the first half of this talk, this was You know, one of the things that you know the investigators were looking at is what would happen with the bleeding. Would it Would it be better? And at least in this trial, there was a suggestion that there was less bleeding. Hello again. That was not the primary outcome. Okay, so their conclusion was that peak to a 12 inhibitor monotherapy after three months. So this is a three month study. Her death was non inferior to the 12 month adapt strategy. All right, the next trial to know about a stopgap to so went from smart choice to stop that too. Very similar to the smart choice. But this was actually one month. So one month adapt after PC I on Ben transition to the P. T Y 12 inhibitor. So this is S O Japan. They used mostly clopidogrel and prasugrel and I don't know if this has changed, but I think the reason Tike a gorilla is not used at the time is that is not available in Japan during this time. But in a lot of patients, 3000 patients total a. C s or stable ischemic heart disease. Here is the flow chart here and to look at the clinical characteristics getting these patients. So one thing here stem e patients. About 20% of the patients in each arm also had stemming so in about 40% a CS for the procedural characteristics. And I haven't talked about this too much yet, but I think it's an important point. And again it would be a talk all on its own. But in Japan, very interesting is they use intravascular image ing almost like 100% of the time. So I mean and we don't do this in this country. Uh, most countries don't and, you know, the utilization of intravascular imaging is actually a big point. It's sort of an issue here in the United States of people using it. But in Japan, when they did this study for one month, adapt 100% of the time of Ivy Soros et not performs, which we really think probably enhances our ability to place against, um, but similarly here, So for the non inferiority of points. So it met that and also met up at any point for superiority at one month. Um, and that's sort of the blue line here for the one month adapt. Now they used as their primary outcome, which shut isn't used often in clinical trials but sometimes comes up this net adverse clinical event. What that is, really is a combination of a scheme IQ endpoints plus bleeding and point composite as the primary endpoint. So they they were trying to sort of define all of the questions together that we've mentioned this morning about a scheme IQ endpoints versus bleeding into one composite endpoint and demonstrated in this trial one month adapt. Then transition to the PT 12 was both not inferior. Andi. I also met a superiority had point. There's a bar graph chart, just kind of showing this again, and then the final conclusions. So one month adapt. Uh, using PT 12 inhibitor monotherapy was non inferior to the 12 months of death. All right, so two more to talk about and they're also kind of designed. Similarly, this is one called global leaders and focus here. Now, we've got so many patients, almost 8000 patients now in each arm. Okay, So so many so many patients here being treated with either one month of DAP, followed by Taika Galore for 23 months versus one year of that, followed by aspirin for 12 months and really global leaders was interesting. They were trying to demonstrate superiority of the strategy. Um, at least that's how the trial was designed. So the trial did not meet superiority, meaning that the strategy of one month adapt and then transitioning to tie kagle or after that one month and keeping the patient on for 23 months. It wasn't superior to kind of a standard 12 month adapt regimen followed by aspirin, but when you look at the overall number of events, they're actually fewer total events. Here. You can see this in the experimental group versus the control, meaning that short adapt group. So, you know, based on the way the trials designed, you know, they didn't meet the superiority endpoint. But, you know, I think when you look at 8000 patients in each arm being treated, you know, with this kind of one month strategy, you know, in terms of safety, things, at least to me, looks pretty safe. So the last one here to know and this, I think, is the most important one. This is probably the trial that's likely to move the needle in terms of guideline updates. Maybe next year. This is done by Roxana Miran. Um, I think probably most people know. It's obviously sort of, you know, famous and cardiology fantastic clinical researcher. A Mount Sinai. So the twilight study is also a tie kagle or study in, you know, over 7000 patients, really, and these air patients at high risk for bleeding, Um, but also at high risk for ischemic event, because there's a lot of complex PC I done in these patients and I'll show you that in a second. But also a study of random izing. You know, this, uh, do anti platelet strategy and then switching to Taika galore alone versus Taika Galore with aspirin and a taika galore alone page arm. The patient's also got a placebo, their primary endpoint and twilight that was really looking at the clinically relevant bleeding over the course of the year and demonstrated that with the shorter duration. Um, basically, uh, that there be three months and then go to tie Kagle or alone rather than keep the patient on Takagi Lauren aspirin, much less bleeding. And that was statistically as secondary endpoint. That casual or monotherapy, was also not inferior and preventing sort of the ischemic endpoints on that was the composite of death. Am I airstrip for complex PC? I So these this is kind of, you know, these are things that end up being kind of in my questions, you know? Well, you know where these just sort of patients that just got simple PC item. They didn't really have bad corner disease. They didn't need a lot of stents. They weren't CTO s. They didn't need a threat to me or by implication, stenting so in the twilight study. So these, you know, patients here. So also a lot of patients getting, you know, again, kind of a lot of metal, you know, over 1200 patients more than 60 millimeters of total stent length. Three vessels treated more than three lesions treated at the rectory. Used 10% of the time over 200 patients by application stenting CTO um, even left main. So another question there is, you know, would you feel really safe about, you know, putting a stent in the left main and then only doing DAP for maybe three months, but 350 patients with left main lesions included in this twilight trial. This is the number of events. Then that kind of occurred, um, in the sort of complex PC I patients first, the non complex PC I patients and on the side here again, I think you see that the number of events the event rates really are just very similar completely across the board. So really low event rates. And no, no real signal here that somehow there's a There's a big safety problem with doing three months adapt and then putting the patient on, you know, the P two i 12 inhibitor after the after the third month as monotherapy. So no real safety signal to be concerned about in terms of the esteem again points from this trial again, it's It's thousands of patients since a lot of patients Soto kind of some of those trials. So post P C I p two i 12 inhibitor monotherapy trials So early transition transitioning from adapt to P to 12 in addition alone s So this is sort of 123 months after p. C. I, I think, really have demonstrated that there's at least similar efficacy and limiting the ischemic events on death compared to the longer duration events. And it seems like we see that even in the acute coronary syndrome patients in some of these randomized trials and it's associated with reduced bleeding overall. So then the question is, Why do we see this now? And we didn't see this, you know, six years ago, eight years ago. You know what's changed, and I do think that there's been a lot of change. You know, those adapt The Adapts Trial, which was published in over 66 years ago, include a lot of bare metal stents, first generation drug eluting stents and second generation drug eluting stents. Even I mean, if you wanna I don't even know what generation exactly the industry would say we're on. But there's been many, many newer iterations of the way the most recent stents air designed within streets in particular. Whereas these global leaders trials Twilight trial smart choice stopped up to really include the newest generation drug eluting stents. So that probably makes a big difference. The other thing, Um, that is also sort of in the background is how we place this did. There is a lot of emerging data as well that the use of intravascular imaging to guide PC I results in reduced sort of adverse events. Meeting ischemic events, post PC I and A. Z mentioned to stop that to try allow almost 100% of the time, um, in Japan and even in smart choice, the Korean study 25% of the time, which is much higher than our utilization overall here in the United States. So this is just one last slide that I want to put in here because I think you may hear from some of the companies about their stents. They have some, whether it's registry data or some other data, their own kind of data that sort of supports a short dap duration on X one you might be familiar with is a Medtronic tri als the Science 90 Zions 28. Some of the registry data here, um, it evolves short baptism is a Boston scientific registry, but basically, the industry now the big companies will kind of you may hear will sort of promote this sort of short gaps or just kind of give some names to some of the studies they may talk about. All right, so Final Conclusion. So, uh, the foundation of a short DAP duration, I think again is really based on the fact that we have the newest generation sort of thin strut, drug eluting stents, often guided by intravascular imaging, really has sort of led to this evolution where the data now suggests that we can do a short dept. You know, maybe, you know, one of three months and in transition of P. T. Y 12 and ambition and and the patients will actually do really well, it seems that it's a safe and effective as the longer duration. And I do think that likely the guidelines will change. That's what you have conferences. And, um, you know, I think just in different papers. It seems that most people sort of sort of think that we're ready, toe, make a shift now, whether or not truly the recommendation is for all patients Or maybe this is more of a sort of default strategy that, you know, maybe three months adapt and then transition to maybe, you know, p to 12 inhibitor or even aspirin. Um, they sort of be the thing to start with and then figure out how to individualize that risk after maybe the recommendation. But, you know, you could still consider longer, uh, operations. I think when there's kind of back to a really high ischemic burden but very low bleeding risk. But I think that would probably have to be really individualized, because the data at this point really strongly supports what we we kind of mentioned about going Teoh a shorter depth. And then, lastly, I think bare metal stents will have an even more limited role in contemporary P. C. I, um, it's idea that well, let me put a put a bare metal stent in so that we can treat a patient for a month with that and then take the patient off and have their surgery or or whatever. I e think at this point, I don't even know if I would do that. I think I feel very comfortable. Uh, the place, you know, drug eluting stent and newest generation stent with intravascular imaging. Treat that patient for a month, adapt and then kind of go to the single anti platelet agent afterward. All right, so hopefully we're reasonable with time s. So that's it for this morning. So thank you very much. I put my email here. A the end, my cell phone number. Um, you know, I'm two months in here in Austin, so very available, you know, accept all referrals, anything. Coronary chip CTO, structural peripheral. I'm really happy to be here and and looking forward to working with everyone. Yeah.