OK. Hi, everyone. I'd like to welcome you to the session. This is a new era in stroke prevention, temporal evolution of left atrial appendage closure. So we're going to start with Dr. Jonathan Suh's presentation, a patient-centric approach to left atrial appendage closure from past to present. Thank you, Dr. Islam, for that kind introduction. Welcome to San Diego. I was telling other people that this meeting in San Diego is kind of how I knew San Diego was a thing, because just the way people talk about this city, our city here, is I could tell during previous heart rhythms that this was a place that I wanted to call home. So I have the luxury of talking to you about a patient-centric approach to left atrial appendage inclusion, summarizing some of the past to the present. And note that our other two esteemed presenters will be talking more about the further the present, but I get to tell you a little bit about the past. So the objectives of my talk are to describe the watch and early approval studies in the context of modern-day practice. Obviously, that entails discussing the randomized controlled trials, protect, prevail. And I'd like to focus on adverse events, not because it's very important to highlight that, but I just think we need to be aware of what the major concerns are in our evolution of this product to know where we came from and to reduce these adverse events, not necessarily to highlight them, but to address some of the initial aspects of adverse events. And I'd like to talk about the initial patient population studies so that we can understand how this has evolved in our implantation techniques and early populations, some comorbid conditions that we see with our patients, and some high bleeding risk opportunities. And then I'd like to talk in relation to that about the post-implant drug regimen and our evolution in early practice in Watchmen. So we know this depiction, and this is just to show Watchmen 2.5, the first generation Watchmen, so that our esteemed colleagues can talk a little bit more about the Flex and the Flex Pro and how this improved. But as we know, this generation device is now legacy. And this is what, when we talk about adverse events in relation to the early studies, and remember, when you talk about some of the registry studies, including work that we do, a lot of that data that is presented in regards to the adverse events were derived from this cohort of thousands of patients that were implanted with the first generation device. And we know that the next generation devices are safer. Let me present some of you some of that data later on in regards to where we're getting these numbers in regards to adverse events and what has been improved upon. But we know Boston Scientific manufactures this device. It was FDA approved in 2015. Obviously, the goal is to occlude the left atrial appendage with transseptal puncture and TEE guidance, as in the early randomized controlled trials. And all the way back to 2015, remember, these studies that derived this were started in 2005. So we have over 20 years of experience with implanting this device. But FDA approval already has been 10 years. And that historical aspect of the legacy devices, remember that comparator group was Warfarin anticoagulation. We are all using DOACs. What was that first trial? It was the PROTECT study with 2.3 years of follow-up, looking at the Watchman 2.5 first generation device, comparing that in patients to a comparator group of Warfarin anticoagulation. This was a non-inferiority trial, 700 patients, two to one more device than long-term anticoagulation. Despite our reimbursement cutoffs for CHADS-VASc score, this study did include those with a CHADS-2 score that was used back then. That's how long ago this data was used, of one or greater. And the device implantation was only successful in 91% of patients, which means 9% of patients were aborted or canceled, as we define now in the Left Atrial Appendage Occlusion Registry, that is nowhere near our rates of abortion or cancellation of procedure during the procedure nowadays. But this was the legacy data, and where the comparator and the compositive primary efficacy endpoint was stroke, systemic embolism, cardiovascular death. And our primary safety endpoint was a composite of major bleeding, pericardial effusion, the procedure related to stroke and device embolization. And when we look at the PROTECT-AF endpoints, the efficacy was non-inferior. You can see it from the Kaplan-Meier curves. Stroke was non-inferior, and all-cause mortality was no different. And what we see here in regards to the safety is that certainly there were adverse events from the device itself. And those adverse events, you can see with the curve on the bottom, were up front from the procedure-related aspects, but was non-inferiority over the long-term in regards to comparing that with bleeding. So when we look at some of these legacy Washman trials, the early data, we have PROTECT, which I just presented to you. The enrollment was 2005 to 2008, and then a cap registry, a registry of those implants after that. And then the FDA with three panels. Part of that was to do another study, which was PREVAIL in 2010 to 2012, looking at the comparison of Washman to Warfarin. So another randomized study needed to be performed, and then the CAP2 registry with even more implants that were studied or captured in order to really make sure that this device was safe and efficacious in regards to FDA approval. Now, when we take this data in aggregate and meta-analysis-type data in regards to PROTECT and PREVAIL at five years, what we clearly see from this forest plot of looking at both efficacy and safety, we see that Washman clearly, in aggregate, reduced hemorrhagic stroke because patients are coming off their anticoagulation, and was non-inferior in other aspects, including all-cause death or major bleeding. But what we really care about with this comparative group being anticoagulation, because that's really the only alternative in these individuals, is are there less bleeding events? And when you look at bleeding outcomes after left atrial appendage occlusion compared with long-term Warfarin, clearly there's less post-procedural bleeding in this population. And in aggregate data, we look at some of these first-generation device studies. Remember, the pericardial tamponade, so our most feared complication, I would argue, this is historical data, was 1.3% in patients that were studied with the first-generation Washman 2.5 product. Procedurally-related stroke was 0.2% about. Device embolization was 0.25%. And procedural-related mortality was 0.06%. What has that success been subsequently? And I would say the best way that this is studied, and I'm so glad that this has been done, part of the mandate in order to do left atrial appendage occlusion is to enroll the study in a registry. And by allowing this, we've really been able to study this device, including the early-generation device and subsequent generations of device across the spectrum in the United States. So Dr. Freeman et al. has looked at this in the NCDR, left atrial appendage occlusion registry, because remember, this registry captures almost every implant with these devices because it's mandated for reimbursement. Let's be honest, reimbursement is very important. And by demanding reimbursement, the patient to be enrolled in the registry really allows us to study this device, including its success and adverse events. So the success in the NCDR LAO registry, remember, I'm talking about some of the legacy or the previous-generation device. That's what this data is focusing on, is over 38,000 patients, 495 hospitals, 1,300 physicians with this early-generation device. And remember, it's 2016 to 2018 that I'm presenting. Other esteemed leaders will talk about some of the more recent device data and how they compare. But this was a sick population, right? Well, we historically were implanting patients that were 76 years old with a mean CHA2DS2-VASc score of 4.5 and a Hasblet of three. And procedures were canceled or aborted in 7% of cases. That's what was happening with the Washman 2.5 first-generation device. Not every procedure was successful, no doubt. And among cases where a device was deployed, 98% were implanted, thankfully with not much leak. But major adverse, in-hospital adverse events were 2.16% of patients. I remember this timeframe in 2016, 2018. I started implanting in 2016. I was not part of the randomized control trial. And I was, one year later from device approval from FDA before I started implanting. And we remember the most common complication, which is pericardial effusion requiring intervention of 1.39%. That's a distinct, and we all remember that device. That's accurate. 1.39% of pericardial effusion require intervention in the early-generation device. Our colleagues will talk to you about how that has decreased. I'd like to focus on that specific adverse event because it really is what kept me up at night in the early-generation implantation. Whereas stroke of 0.17% and death from the procedure were quite low. But the pericardial effusion requiring intervention was something that really has changed in newer generations of device. But I'm, again, tasked with talking to you about the sobering aspects of the first-generation device. And in this left atrial appendage occlusion registry between 2016 and 2018 with patients, how does that compare to the previous randomized controlled trials that allowed for FDA indication? Now, if you look at this, you can see that it is a more comorbid patient than what was involved in the randomized controlled trials and the people that we were planning early on with this device. And that potentially allowed for some of these pericardial effusion rates that are at least 1.4 to probably 1.9% in our early studies of left atrial appendage occlusion with the Washington 2.5 design. But this is an older population than the randomized controlled trials with a higher mean CHA2DS2-VASc score and a higher mean HAZBLED score, if you were to make that assumption knowing that the CHA2DS2-VASc and the HAZBLED seem to track. So just know that the people that we are implanting are sicker than those original randomized controlled trials. So again, not to focus on adverse events, but I think we need to be honest that the early-generation device was associated with adverse events. The most feared one for me personally was pericardial effusion. And we studied this and published this in Heart Rhythm looking at this rate with, again, their legacy device in Washington 2.5 and over 17,000 procedures in the national inpatient sample. And that rate was, again, tracked with this first-generation device of at least 1.24%. And other registry studies would show that with, again, the first-generation device of at least 1.4% in the NCDR registry. But when you did have a pericardial effusion, it was associated with a higher rate of mortality and a longer length of stay. And so this and a higher cost of the procedure and the procedural inpatient hospitalization. And when we looked at predictors of pericardial effusion from these adverse events from those early-generation device advanced age and a higher CHA2DS2-VASc score and obesity were associated with a higher risk of adverse events. The other thing that burdened me, I think, initially on the first-generation device and data in that regard was this aspect of, well, is my patient coming in with a readmission? They just seem to be hospitalized afterwards. And so we wanted to answer this question of, was it the sick population? Was it the actual Washington procedure itself? I was concerned that it was that. And what I like about this analysis is that I think we did a really good way of trying to match patients to really answer that question, which is looking at readmission rates of patients with atrial fibrillation. Obviously, patients had to have atrial fibrillation to have a left atrial appendage occlusion procedure in the United States. But also then comparing that to a comorbid population of matched, propensity-matched patients to see if they were getting admitted as well just with atrial fibrillation. Was it the device itself that's causing admissions or was it the actual atrial fibrillation? So when we did this propensity-score-matched analysis of over 14,000 patients, again, you see the mean age here of 76, which is very much like the LAO registry-type patients, 9.4% were readmitted in 30 days and 0.2% died. Now, when we talk about death after Watchman implantation, and I remember my first patient that I heard had died within the one year after Watchman, I was concerned maybe it was the procedure. We know now from studies that that rate of death within the first year of this very comorbid patient population is anywhere from seven to 9%. So it's just a very comorbid patient population. But going back to this readmission issue, when we propensity-matched these to patients with just atrial fibrillation that were not implanted with left atrial appendage occlusion, we definitely saw that essentially, compared to the non-LAO AF cohort, LAO patients had a lower 30-day readmission rate and all caused hospital mortality. So when you have a population of patients with atrial fibrillation that were matched, they're a sick population, it's not the LAO that's causing readmission or death. So that's what I really appreciated from this analysis is that it's just a highly comorbid population that is getting readmitted with LAO. So as far as the timeframe for pharmacotherapy, we know historically it was warfarin and aspirin, clopidogrel and aspirin in the randomized controlled trial. And when we talk about antithrombotic data in regards to what we treated patients between 2016 and 2018, these discharge medications were oftentimes warfarin and aspirin, then DOAC and aspirin being the next most common, and then warfarin only, DOAC only, and DAP being what was seen in these early studies in regards to post-procedural antithrombotic strategy. I will harp on this, which is some of the data that Dr. Freeman presented, and we had subsequent data to show that if you anticoagulate them with warfarin alone and drop the aspirin or DOAC alone, that these patients were less likely to bleed after initial Watchman device implantation. So in order to give it to my colleagues in regards to early approval Watchman studies, that hopefully they help us contextualize a comorbid population that I just presented to you with some of our data in regards to those going to the initial left atrial appendage occlusion, including adverse events, and ways to reduce bleeding after with antithrombotic therapy, and then hopefully we can improve the device design, that we have improved the device design to make these adverse events and thromboembolic events less prevalent. So thank you very much for your attention. Thank you for that great summary. I know it was a lot of data to get through, and in that era. Yeah, we publish in case reports, I've had a couple of initially, you're saying in the acute setting, yeah. We published a thrombotic event that we had in the initial aspect. I think we learned a lot from chief management and other aspects and ways to reduce that. So I did have two acute intraprocedural thrombotic type events that was very early in the Watchman 2.5 era and have had really none subsequent within the Flex and Flex Pro era. Thanks for that. Very nice presentation. Our second presentation is going to be safety and numbers from clinical trials to everyday practice by Dr. Mohamed Khanj. I'll hand it over to you. Thank you very much for being here. I'm not from San Diego. I'm from Cleveland and Cleveland is sunnier than San Diego. Please come and visit with us. Do you agree with that, Tyler? Nope. Okay. So I was asked to talk about the present, okay, and the present is what we're dealing with right now and the devices that we have right now and tell you that the present is good, slightly better than the past and I think we can live with what we have right now. You know, this is a case that I've done where I implanted a Watchman 2.5 and we call it as a legacy device, but actually it did help so many of my patients. Yes, the success rate of implantation was around 95% or so, 92%, but it was a really revolutionary device. This is one of the things that actually really advanced medicine. Look what happened in this individual. We completely obliterated the left ATL appendage. It saves a lot of people's life, but in life we like revolution, but we also like evolution and this is what happened with these devices. We started with the Watchman 2.5, but soon after that we got the Watchman Flex and then soon after that we got the Watchman Flex Pro and soon after that, hopefully David will talk about any future devices, they may add Pro, Pro, Pro, Pro, Pro after that and then I'm here to try to convince you that this field is only going forward and by forward, when we look at medicine forward, we look at two main things is safety and efficacy. I want my device to be really safe. I want to put my device and make sure that I'm not going to end up with any complication and I want to make sure that my device works, but also I want to make sure that it's applicable to all my patients. I'm not happy with the 91 to 95% success rate. I want to go to the 99, I want to go to the 100%. So what do these devices offer and can I address safety, efficacy, applicability and all these issues that we're dealing with? So this is a comparison between the legacy devices that we've had, the 2.5 and the Watchman Flex device, which was an intermediary device. What they did is they tried to make it slightly larger that they can offer more occlusion with slightly larger devices up to 35 millimeter. They got rid of the distal tines and they fold them inside so that we can be, this procedure could be a little bit safer and we don't have to worry about Dr. Seuss' complaints about pericardial effusion, not necessarily complaint, but findings that he saw in clinical trials. They added more struts and by doing that, they guaranteed more opposition to the wall of the left atrial appendage and by doing that, what we expect that we're going to see less per device leak and more stable devices. They added two layers of anchors and they got rid of that, they tried to minimize the amount of metal that's exposed and that would hopefully result in less DRTs than what we saw. So they tried to address three main things in healthcare, is safety, efficacy and eligibility. I want to deliver this therapy to more patients, I want to be more efficacious and more importantly than everything, I want to be very safe. So let's see, did we achieve any of these options? So this is what started in the pinnacle clinical trial, which was 400 patients, it was probably one of the fastest enrolling clinical trials here. We closed so very fast, pretty much everybody was enrolling in this clinical trial and there were implanting single arm study, implanting flex device and look what we saw. We saw the success rate of implanting this procedure is almost 99% and what we see in the bottom left of the screen, this is the complication rate. We went from 2.2 where Dr. Su and I and everybody else were worried about our patients to aggregate complication rate, aggregate of 0.5% and now with more experience with this device, we're seeing even much lower down to 0.3% or so. And the top right part of this slide, this is we were able to discontinue anticoagulation in the vast majority of our patients up to 96.2% so this therapy does work. But also, is it as efficacious as blood thinner, is it as efficacious as the old devices? So this is a very complicated slide, what you see is that risk of stroke and systemic embolization, the first at one year and at two year. And the black bar is the risk of stroke that we saw in the pinnacle clinical trial. At two years, we saw with the blue line. And what we see at two years is the risk of stroke was 3.4%, the estimated risk of stroke in this individual was 8.7% due to their CHADS VAS. So we got almost 62% reduction in stroke by implanting this device. So we know that this device does work and it is safe and I can apply it to most of my patients. So we're moving towards a perfect therapy for this structure. And one of my colleagues, Samir Kapatia, looked at the SURPASS database, where they look at the NCDR database and trying to see in real world where I don't have Dr. Sue, I don't have Dr. Islam, I don't have Dr. Deirazzo. Can we achieve a good success rate? Can we achieve a low complication rate? And look what we see. Complication rate was less than 0.5% even if I performed this procedure, not the esteemed colleagues around me. So we know that this is a very safe and effective procedure. Success rate was almost 98% for this procedure. So despite a high risk patients where their age is 76% and their CHADS VAS is almost 4.6%. What about event rate in this population? Well you see the same thing in real world data that the risk of stroke in these individuals, all stroke is 1.6% and ischemic stroke is 1.2%. So we know in real life, in real patients, while me and you are implanting this device, that this device works and it can decrease the risk of stroke because we went down, this population was 4.6 has blood score and we were able to cut the risk of stroke down to 1.2%. That's very, very, very low. And the 45 day key clinical events at discharge, this is what we see. This is our electrophysiologist. I just want to compare it to a procedure that our interventional colleagues walk around and say how wonderful this procedure is, which is PCI without ST elevation MI, where this procedure is not known to do anything. It doesn't improve life longevity. It doesn't cause less stroke. It doesn't do anything. It just makes you walk a little bit with less shortness of breath, chest pain. And if you compare the right screen versus the left screen, all it needs is probably first grade mathematics here, and you see that the safety of a Watchman device is much safer than PCI without ST elevation MI. Much safer when it comes to death, stroke, embolization, bleeding, complication, everything. So that tells you that this device is really, really, really safe. And then we started an option clinical trial where Dr. Wozni, one of my colleagues, actually my boss, presented it at AHA where they compared patients who had gone for an ablation, half of them got DOAC, and half of them got a Watchman device flex. The importance of this clinical trial is to try to address the complaints or we don't have enough data to compare this Watchman device versus DOAC. Well, guess what? This is the largest randomized clinical trial, 800 patients in each arm, comparing DOAC to a left atrial ependigial occlusion. Yes, it was at the time of an ablation, but so what? And what we see from this clinical trial is, guess what? When we implanted these devices, we were able to discontinue anticoagulation in the vast majority of patients, 90%. The other 10% is because we were working on further ablation in these individuals. But when we look at the risk of stroke in these individuals, guess what? It performed as good, mathematically maybe slightly better, but at least it was not power to study superiority, but from a non-inferiority clinical trial, risk of stroke with the Watchman group was 5.3% at three years. Risk of stroke with oral anticoagulation was 5.8%. So we know that it works when it comes to efficacy. What about safety? And we're talking about individual who has very low HASBLED score. And actually, I was shocked. When we looked at the HASBLED score in the optional clinical trial, it was 1.2 per 1.2. This means somebody is 65 years of age. And what we noticed in these very low risk individuals, that we were able to cut the risk of major bleeding or clinically significant bleeding by 54%. So that's also a very good strategy. And then we got better, and we introduced the Watchman FlexPro device. And they did a lot of things. They coded with a homocode coding. They enlarged the device up to 40 millimeter. They still worked on the same Watchman protocol. They added a little bit of radio-opaque markers for our colleagues on interventional cardiology. And let's see what we did. This is a clinical thing. This is an animal study that we did. I love our interventional colleagues, by the way. Some of them are probably present here right now. So this is an animal canine study that we did. And we implanted this device in canines, FlexPro versus regular Flex. And we did not put any anticoagulation, no antiplatelet therapy. And in the right screen, you see the FlexPro. On the left screen, you see the regular Flex. And what you see is two things. The first thing, when we implanted the FlexPro, there was less clot than with the Flex. And the other thing, we see more endothelialization. You see that layer that's pretty much all covering that left atrial appendage. So we know that this is less clots and more endothelialization. And currently, we're studying that in the HEAL-LAA. And we have a poster on Sunday. So I'd like you guys to come and visit with us. But what we saw with the HEAL-LAA clinical trial when we were trying to do this newer, broader version of this device, that we were able to achieve a complete seal up to 92% at implant. And there was no significant, large leak with these devices. And we added to this device, shortly after the introduction, the TruSteer sheath. And I hope that a lot of people use it, because I'm a big fan of it. Because what we noticed from the clinical trial is when we've used TruSteer sheath, we increased the success rate of implanting this device from the 96%. And that's what we've seen with pretty much all the previous clinical trial, the pinnacle, 97%. So we increased it to up to 99.5%. And that's what I'm here for. I don't want to deal with the patients like, hey, I took him for a procedure. I could not implant your device. So we were able to achieve a better success rate. And we achieved a better success rate, fortunately, with less complication. Because even with the use of a larger TruSteer sheath, we did not see any increase of vascular complication. And we were very happy with the results. So what are we dealing with right now? We started with a therapy that we used to use it as an absolute last resort. We're getting to a therapy right now, use it as an alternative. And I think David is going to try to convince us that it should be used as a first-line therapy. And with that, thank you very much for your attention. And we're open for questions. Thank you for a great presentation and bringing us up to current state. If there was one thing that you still find is lacking in product design, what would that be? What other things would you be looking for? I still would like to push towards 100%. I'm pretty sure David probably will be discussing future devices that I think we'll be able hopefully to address it. One of the things that I was a big believer of the Watchman 2.5. And I think that Watchman 2.5 addressed some anatomies that some devices cannot and did not address. But I think with the future devices that we're going to be lined up in the near future, I think we may be able to address that 100%. Great. So our last talk is going to be Contemporary Evidence in Future Directions, More Than a Bleeding Solution. Dr. David DiLugio. Thank you very much. I really enjoyed the first two presentations. The Watchman device, for those of you who don't realize it, is just what I consider a modern medical story that started with a napkin drawing with a concept of closing the appendage. And then a startup company to try to bring this to fruition, eventually clinical trials in human studies and an acquisition by Boston Scientific to really put a lot of money and research behind it. And the things that happened along the way were just nothing short of miraculous. Everything from being able to show a positive trial from the first in-human trial done, to iterate new devices, to develop a training team, and then to continue to pour money into improving the product over time, even now, and it hasn't stopped. And I had the pleasure of participating in Protect AF. So my first Watchman device was in 2005. There was absolutely no training. I mean, it was like very few devices had been done, and we kind of played with it on the back table and then did the case. And it was very interesting, and we didn't really understand it. We were just learning, learning, learning about the appendage. So take it to now, where we can do these procedures very readily with incredibly high success rate and excellent safety. It's just amazing to me. The question about what can really help, if I was to ask, I love the work that's ongoing at Boston Scientific to give us what they call proximal and distal independence. Because almost any case that I really have trouble with, it's because I needed the depth in a very narrow space, and the device cannot open properly. It can't conform because of the very small distal pinching of the device. And a device that can handle that and can do the same thing in reverse proximally, I think is going to be the next iteration that really makes a difference. So my topic was, this is the title I was given, Contemporary Evidence and Future Directions. More than just a bleeding solution. So I thought about it for a little while, and I decided to take it in a slightly different direction and get you to think about left atrial appendage closure as not just something that we do for people who are bleeding with their oral anticoagulant. I think that's a really important thing. It's an educational point that we have to bring to the community. And of course, we need data and experience to show that we're correct in this assumption that we can use the device for other things. These are my disclosures. So my objectives are to explore the other benefits of left atrial appendage closure beyond bleeding reduction. I think it's incredibly well established that the device, compared to any blood thinner that has ever been tried, is going to result in less bleeding over time. And it's an incredibly important development, and it ties into many of the positive outcomes of the device. But there is more. There's improved quality of life, which I think is very important, because it's a hell of a thing to tell a patient to take a blood thinner for their entire life, if you stop and think about it. We do it every day to thousands and thousands of patients. But to be able to eliminate that for our patients is a major improvement in quality of life. We're going to be able to show that we reduce stroke incidence with the device, even compared to oral anticoagulants, and severity of any strokes that do occur compared to anticoagulants. That's very important as well. I think that mortality reduction has been shown, not in all the major trials, but this is something that I think will flow naturally over time. And there's a long-term cost reduction of use of the Watchman device. In this day and age, this is very important. It's a little hard for our hospitals to get their arms around it, because they're thinking about the short-term costs. But in a system, a national system, a global system, the long-term cost reductions can be very important. And then something that we haven't really been able to do yet is to show a real impact on public health. We know that Watchman does good things. There's over 500,000 Watchman devices implanted so far in the world, and that number is going up very rapidly. And we're having positive impact. But we have to move the needle to show that we're actually, for example, reducing the incidence of stroke in the U.S. And when you have a public health impact with any medical therapy, I think you can really be proud of yourself. And then we will touch on some of the trials briefly. We've really seen them, and I'll mention a couple more that can have impact and help us along this pathway, this journey that we're on. So quality of life was a natural question that came out even in the very early stages. So the PROTECT-AF trial did an analysis of quality of life. And for those of us who implant the device and follow up these patients, it's kind of a non-question question. We know it's improving people's quality of life, but there needed to be some sort of analysis. And this is a good one. This is a good one in the very early stages. So it is regarding Watchman early device compared to Warfarin, which was what the scenario was in PROTECT-AF, as you heard earlier. And as you can see from the red bars, both the mental and physical component of the quality of life score was improved compared to Warfarin in all of the patients in the PROTECT trial shown here. And more people would have improved quality of life, and fewer people would report any detriment in quality of life when they received a Watchman device, both mental and physical scores. This is all comers. And also within the Watchman trial were patients who had been naive to Warfarin. And this is the same data with the Warfarin naive patients, and the differences are even bigger in terms of the magnitude of patients who experience an improvement in their quality of life. And this is, again, I mean, none of us probably takes Warfarin unless we have a mechanical valve. And the idea that we were giving Warfarin to these people for their whole life is just amazing to me. Of course, it makes you miserable. So this was something that we had to show, and we were able to show it, and it's very important. And I think that we are thinking now, and all you have to do is think about what's going on in the world with left atrial appendage closure, and you're going to have younger patients receiving Watchman device than ever before. And this impact on quality of life, I think, is something that can really be measured in future studies as well and show benefit. Now, we've learned from other clinical trials that the very elderly often end up with a Watchman device, because as you get older, the bleeding complications go up, and they're looking for an alternative therapy. We've also learned that that can often be associated with increased frailness, and these patients don't have a very long horizon, perhaps. But I do think it's important to realize that people live a long time these days. And in this study, they looked at octogenarians and nonagenarians with regard to quality of life. Anyone here implanted a nonagenarian, a person in their 90s? Yeah, I certainly have. I mean, sometimes these people come into your office, and you're like, you're 92 years old? You look great. They talk to you. They haven't lost a step mentally. I mean, it's a different world out there, and we just don't really use age as a cutoff. We try to think about what's it going to do for them. Is it going to prevent future bleeds? Of course, that's always in our consideration. But also, is it going to improve quality of life, decrease the risk of other complications? And so the print is very small, and I apologize. But very clearly, the differences in quality of life indexed to a control group of patients after Watchman was significant. Now, let's move to this issue of stroke reduction. We know we can reduce bleeding. It's been shown very clearly, and it's a primary goal, and it's built into sort of the indications that we're doing it for these reasons that are related to bleeding, primarily. But in this analysis, which is a very large analysis, they looked at patients who were on either DOACs or Warfarin, they had atrial fibrillation, and then who had a bleeding response. This is from a very large US database. It's not NCDR. It's actually a claims-based database. So you had a lot of patients who were on anticoagulant and had a major bleeding, 102,000 patients. And then what happened? Well, some were restarted on DOAC, which would be the general recommendation in most cases. You've had some GI bleeding. It kind of settles down. We've got to get you back on your DOAC so you don't have a stroke. And then you had some who went on to get a Watchman. And these groups were compared. So it's actually a fairly large database of patients, and they did matching to provide about 4,500 patients who could be really compared to each other. And what they found was that the rates of TIA and ischemic stroke were lower in patients who bled and got a—this is non-hemorrhagic strokes—who bled and then were moved on to get a Watchman device compared to those who went back to their oral anticoagulant. So it's one of the—it's a large database, and it's actually a good analysis for me because it really emphasizes the point that there is more to ischemic strokes than we think. And we have sometimes assumed that we are compromising with ischemic strokes when we use the Watchman because we're only really dealing with the appendage, and maybe there's an ischemic stroke that's going to be from a clot that originated somewhere else. But this trial actually provided very good information about actual reduction in embolic events. And of course, major bleeding was better as well. These graphs show the survival free of those endpoints, whether it's a major bleeding event, TIA stroke, or hemorrhagic stroke. Now if you recall from the early studies, an analysis was done in the Protect Prevail era that showed that the modified Rankin score of patients who did have an ischemic stroke after Watchman was less than patients who had ischemic strokes and were on Warfarin. This is another study that showed the same thing. It looked at discharge three months, 12 months. What are the modified Rankin scores of patients with left atrial appendage closure versus Warfarin? And what's remarkable is that, and we have to think about why this is, but you seem to have a residual risk of embolic strokes no matter how you're treated, whether it's a blood thinner or whether it's left atrial appendage closure. This is a fact of life. We don't prevent all ischemic strokes. The magnitude of prevention is obviously very significant, but we don't completely eliminate ischemic strokes. And what this study showed is that compared to Warfarin, strokes were much less severe when an ischemic stroke occurred in a patient with left atrial appendage versus Watchman. So this is actually a second trial that backed up the similar findings from the early Protect Prevail database. And then bring it to the modern era of DOACs. And this is a recent analysis of severity of ischemic stroke after left atrial appendage closure versus non-Warfarin oral anticoagulants, which is how we practice now. And what they did was they looked very hard in these centers to find people who presented with ischemic stroke. And you can see sort of the flow chart there. So they had a cohort of patients who had left atrial appendage closure and a cohort who were on DOACs. And then they propensity score matched to get a very similar group for comparison and looked at the primary endpoint of disabling ischemic stroke at discharge in three months. And as you can see, the modified ranking score, again, much higher in patients who are on a blood thinner, even our best modern blood thinners. And it is when the left atrial appendage has been closed. And whether or not they had a disabling or fatal stroke, also substantially less in patients who have left atrial appendage closure. So in my simple mind, it's because the clots I see in the left atrial appendage, they're big. And they produce major artery embolism and a lot of disability. And I think that's likely a safe kind of assumption. There may be some other reasons as well. For example, hemorrhagic transformation even on a small scale in the patients who embolize and then are still on a blood thinner. So this difference is really substantial and it's held up in the modern era of DOACs, which I think is really important for us. Because we just can't say, well, the original trials used Warfarin. I don't use Warfarin. I don't like the data. Now cost effectiveness, I mentioned that as one of my objectives to address here. And Vivek Reddy et al. looked at this in a sort of pooled analysis of five-year data with the Watchmen. So that took us through all of the initial trial, PROTECT, CONTINUING ACCESS, CAP, CONTINUING ACCESS, PREVAIL, CONTINUING ACCESS, all those trials, and then the five-year follow-up. And they tried to iterate every possible complication that these patients had or could have. So they developed this very complex chart showing, like, if you're on a blood thinner, what happens? And if you get a Watchmen, what happens? And all the different things that happen to patients and looked at cost. And what they found is that it doesn't take very long for the Watchmen to pay for itself, so to speak, compared to DOACs. DOACs are expensive. They have, like all blood thinners, there's complications. And when you look at Watchmen, with all its faults in the early days, it still had a very good performance with regard to cost effectiveness versus DOACs. It takes a little longer to reach parity with Warfarin, because Warfarin, of course, is dirt cheap. But the same concept is that it doesn't take very long before that cost effectiveness bar is crossed for us. And this is not the only study that's looked at this in detail. Out of Europe, a similar study. And what was done here is that they stratified by different CHADS-VASc scores, as you can see. They used the PROTECT data as a rubric. And then they looked at their own data at the Royal Brompton Hospital System in London. And what we should remember is that mortality is improved with PROTECT-AF. And that's shown here. There is a mortality benefit to left atrial pennis closure, shown even in that early trial. And they also showed the same thing regarding Warfarin therapy, not so much with DOAC. And then from a cost analysis, it was actually a very similar endpoint. It doesn't take too long. In their example, about six years before the costs of an anticoagulant are the same as the cost of a left atrial pennis closure device and all its follow-up. So let's move on to this concept of trying to get at public health impacts. I think it's really important for us to realize that there is an opportunity there. And all of our therapies are tailored towards individuals. But it is really important that we look at our country as a whole, the world as a whole, and how our therapies are impacting each other. So I wanted to bring up this thing called the Neuro-AFib Study. It's actually sponsored by Boston Scientific. It's a large-scale trial looking at strokes in patients with non-valvular AFib in stroke centers across the country, 25 stroke centers. And they gave us some retrospective data to kind of tease us. And I'll just show you a little bit of it right here. And the reason is because I want you to start to think of, where are the unmet needs? And where can we have an impact with our therapies? So here you have 6,195 strokes in patients with non-valvular AFib, either known or diagnosed at that time that they presented. Over 5,000 of these, 83%, were ischemic strokes. OK, so here you have your ischemic strokes. Well, 77% of them had AFib known. So they were known to have atrial fibrillation. But look at this. Only 46% of them were on oral anticoagulant and went on to have a stroke. So when you come in, it happens. It's a real thing. People are going to have ischemic strokes. That's a failure of the anticoagulant drug. So OK, aha, that's a pretty high rate. That's a substantial number of the strokes that present in these patients with AFib. We have to start to think of, is oral anticoagulant really that good? Look at this. More than half of the patients weren't on any sort of protective mechanism. They weren't on a drug, oral anticoagulant. They did not have a left atrial appendage closure. Interesting in this analysis, no one had a left atrial appendage closure. That's interesting, too. But the system fails so much. How did all these people come in with known atrial fibrillation, and they didn't have anything to protect them against an ischemic stroke? It happens. It still happens. New data. Some of the patients were actually diagnosed with AFib when they came in, about a quarter of them. So they had ischemic stroke. Oh, you have AFib. That probably caused your stroke. Some of them were on oral anticoagulants. I'm not sure why, but then it failed them anyways. But many of them, it's just, again, it's a system failure. How did we not know? Isn't there a way we should know that patients are at high risk of atrial fibrillation and could be at high risk of stroke? This is another end met need. The current guidelines are trying to help us with this question. They're saying there's something called pre-AFib. So now every time I read all these Holter monitors and everything, I'm like, this guy is at high risk for AFib. Look at the PAC count. There's brief atrial runs. That's something they want us to think about in their wisdom. And I think it is wise that we're always reacting to atrial fibrillation. So there's a lot to think about there as well. What about the patients who had intracerebral hemorrhages? Well, those patients were all on OACs, or at least most of them. And that is, again, the issue with OAC, is that there's a high risk of intracranial hemorrhage. And it's a system failure the way I look at it. How do we not know? We should know that a patient's at a higher risk of intracranial hemorrhage. Not everyone's at a risk of intracranial hemorrhage on Eliquis or Xarelto. Some people are. But we need to be identifying those patients. So this kind of really, to me, is very thought-provoking, and it helps us think about where we're trying to go and how can we have an impact. So they're, of course, very morbid, and this just shows you how death and disability of any stroke, particularly hemorrhagic strokes, is a major issue. Let's show the next slide here. Good. I think that as we move along with the clinical trials that are underway, we can address some of these issues. Now, remember LAOS 3. What LAOS 3 showed was that in patients getting surgery who had their left atrial appendage clipped and were treated with oral anticoagulant, they had a substantial 33% reduction in their risk of embolic stroke or systemic embolism over the follow-up period of this study. So better than oral anticoagulant alone, addition of left atrial appendage closure. And it's sort of like what they like to call the belt and suspenders. You know, I thought you only needed one, a belt or suspenders. Well, in this study, a belt and suspenders really keeps your pants up. It works better. That naturally led to the concept of the LAOS 4 trial, which is currently enrolling. And this is looking at high-risk patients, high risk of stroke, so high CHADS-VASc and ongoing AFib, either persistent or long-standing persistent, or paroxysmal atrial fibrillation with a prior history of stroke. So high risk of stroke, and they're going to be randomized to the Watchman with oral anticoagulant drug or oral anticoagulant drug alone, which is the control. I think this is very important. This gets to the concept of what we saw in LAOS 3, because we might be able to have a even more dramatic effect on stroke risk reduction overall. And this could really get to my goal of being able to get up here one day and say, look, we have actually reduced the number of strokes worldwide. The SIMPLIFY trial also goes in a somewhat different direction. And it really emphasizes diversity, which I think I'm allowed to say here, but nowhere else. Because as you know, many clinical trials are really all the conclusions are based on who's in the trial, and it's often just people who look a little bit like me. And so we need diversity to know that our data is widely applicable. And what we do in SIMPLIFY is we randomize patients who are getting the FlexPro device, the coded device, to one of three lesser anticoagulant regimen, either aspirin alone or a reduced dose, DOAC, in the trial that's emphasized on half-dose Eliquis, or DAPT, dual antiplatelet therapy. And this is kind of what it looks like on the anticoagulant arm. The idea is that the device, based on what you saw from Mo's work at Cleveland Clinic, that it is hemo-compatible, and we may be able to use much less anticoagulant initially, and perhaps even long-term, and still get the desired outcome. So that gets a little bit to the reducing of bleeding. Now also think about Champion AF and the impact it's potentially going to have. This is ongoing trials, of course enrolled, has a long-term follow-up. And the idea here is to get back to what PROTECT wanted to do. Few people realize that PROTECT was designed to create a product that could be held next to Warfarin, and you could say, which one do you want? Do you want PROTECT, do you want Watchmen, or do you want Warfarin? That was the idea behind it, and it was a non-inferiority trial. We just wanted to show it wasn't inferior, it was an equal choice. The FDA didn't look at it that way, so we ended up having all this gobbledygook about, oh, do they have to have a compelling reason? So for years and years and years, all we could put it into is people who were bleeding to death all the time. But we're trying to move back to what are the benefits of the device, and how can it be more broadly applied? So Champion is just putting it up, what's behind door one, and what's behind door two, try to create this equal choice. It's a 4,000 patient trial, or 3,000, it's a big trial. It's going to answer this question about whether we can straight up offer this device as an alternative to oral anticoagulant, in other words, the potential for first-line therapy. And you saw option, and the only reason I show the same slide again is just to remind you, we're not compromising on stroke or systemic embolism or mortality after AF ablation when we use the Watchman. We're not compromising. We're not giving up something. And in fact, over the long term, which is why we're doing AFib ablation anyways is to get better lives for these patients, we're adding another therapy that dramatically reduces long-term bleeding and all the things we talked about with quality of life and everything else that goes with it. So it's a winning thing, and for us, certainly, it's been a real breakthrough. So just to summarize, the benefit of left atrial appendage closure with regard to reduced long-term bleeding is established, but remember, there's been excellent research that shows very clearly improved quality of life, reduction in incidence of severity of ischemic events, reduced mortality, cost reduction, safe and effective use in conjunction with ablation. That's something we've learned from option. And I think a strong potential to positively impact stroke and bleeding on a global scale, which is what I really hope to see. Thanks very much. Thank you for an excellent presentation, and I think when you talk about system failure, it also sort of So, what are your thoughts there? Yes, you know, in this day and age, acceptance of the Watchman device is very high. We've crossed a point where almost every patient knows someone else who has a Watchman. And so, it's just a reality. You know, I see patients and they come in and towards the end of the thing they say, you know, you put a Watchman in my neighbor, you know, kind of thing. Or you're seeing family members, spouses of people you've treated before. I think that we've done a lot to really show that it can be done safely. And that's really what patients wanna know, that it's a legitimate therapy, it's safe. You know, they're not gonna, in our case, they go home the same day. I mean, I think that's very common in many institutions. It's just a very easy thing for them to go through. I think the other recurrent theme seems to be that blood thinners are not a benign therapy. Either they're gonna be in. So thank you, everybody, for your attention. We have very. Thank you. It was a very nice talk. Just a quick question because I've come across this recently in patients that failed anticoagulation and then you want to try Watchman plus NOAC. Have you had issues with insurance paying for the procedure if you're doing it outside of a clinical trial? Because, I mean, it's not one of the listed indications, so it's kind of an off-label use. I know there's some decent data behind it, but how would you get, you know, insurance approval for this case? Well, in my experience, the guidelines have changed, and so insurance approval really is not been a big issue for us in the last eight months. What the guidelines now say is that a 2A indication for the device for sort of your traditional bleeding issues and compelling reason to consider an alternative, but also 2B for people who need it for reasons that are not included in that, which could be things even like patient preference or difficulty being adherent to a drug, for example. And I think that would include an example like yours. To me, that's a strong indication you have to consider what to do in addition to the blood thinner. So we don't really see so much a problem. I think for those of you who are concerned about that, there's really one step that is very helpful to get devices approved by third-party payers, and that is to make sure that there's been a shared decision-making process between the patient and someone else, some other physician who cares for that patient and has discussed it with them. Maybe it's whoever referred the patient to you. Maybe it's their primary care, because it's very important that all things have been considered and the patient has a chance to really think about it outside of the consultation room with me. I can obviously tell them I think it's great. Here's the reasons I think it's great. But a physician who's involved in their day-to-day care can be very helpful. And if they document that they've had discussions and considered all the alternatives, we almost never see pushback. Thank you. Sorry, if I could ask one quick question also. Do you know if there's any data available on, you know, you're switching to Pradaxa for patients that have failed NOACs that are a factor XA inhibitor, since it's a direct thrombin inhibitor, I mean, a different mechanism? So there's a lot of data. The U.S. data actually keeps it very vague. The European data tells you do not jump. And actually, the most recent guidelines from Europe tells you do not jump from one to another. If one fails, it does not mean that another one should succeed. However, if you really look at DOAC versus Warfarin, just DOAC versus Warfarin, not between each other. And two drugs actually that have been shown to be superior, or actually the one drug that's been shown to be superior to Warfarin with respect to ischemic stroke is Pradaxone. Okay. So I think I've used that. There's some data, old, very old data with high-dose Warfarin. But the problem with that is much higher risk of bleeding that you cannot afford. In the U.S., because we deal with that, actually, unfortunately, when you're on a TE and there's a clot, and there's a clot on one factor XA inhibitor, there's no clinical trial to tell you what happened. But a lot of times what you see U.S. physicians doing is a transition from antithrombin to factor XA inhibitors, and we've seen some resolutions. We don't know the actual mechanism. At least from Europe, they have not suggested actually. They told us not to jump. In the U.S., we like to jump from one another. My personal practice has actually I've seen people, what I've done is I move to Pradaxa. Sometimes I've actually moved to Heparin that I am able to dissolve the clot. And sometimes what I've off-label used, off-label used, and a lot of operators have done that, is to close the appendage by jailing a clot, for example. And that's, again, off-label use. Thank you. Thanks so much.

left atrial appendage closure

LAA devices

stroke prevention

atrial fibrillation

Watchman Flex

procedural complications

anticoagulation therapy

quality of life

stroke reduction

insurance challenges