All right, good morning everyone. Thanks again for joining us. Gives me great pleasure this morning to have one of my trusted colleagues on. This is Dr. Al Lin. Dr. Lin is Associate Professor of Medicine at Northwestern University, where he also serves as the Associate Director of Electrophysiology. He's either the PI or the co-PI on all of our studies involving left atrial appendage exclusion. He has extensive experience with both Watchman and Amulet, as well as the Lariat system. So he's gonna talk about left atrial appendage closure for AFib. I'd like to thank him for being here and we'll turn it over to him. Thanks so much, Al. Great, thanks. Thanks, Nishant. And thanks everybody for joining this morning. I, again, apologize for the dress. I haven't really worn a tie since March and when I saw Nishant in a T-shirt, I didn't feel so bad. So I'd like to spend most of this morning talking a little bit about left atrial appendage closure. And these are my, let's see here, if I can get this going, disclosures. I'm gonna spend most of the talk talking a little bit about left atrial appendage closure and its role in stroke reduction. Although I would like to also spend some time talking about left atrial appendage closure and its role in rhythm management of atrial fibrillation. But the first couple of slides here are just to remind us of the sort of high bar that we're gonna have to cross or at least meet with left atrial appendage closure in the reduction of stroke associated with atrial fibrillation. So this is just a quick slide of most of the Warfarin trials. This is stuff that we don't oftentimes take a look at anymore. But again, what it shows is a really remarkable reduction in the risk of stroke associated with the use of a drug that's relatively problematic in the sense that the dosing difficulties and drug-to-drug and food-drug interactions. You can see that the relative risk reduction in stroke was remarkable. And there was actually a relative risk reduction of all-cause mortality of 26% with Warfarin. And that, again, is a very remarkable reduction in all-cause mortality. If you sort of remember, if you look at the SCUDEP trial, for instance, with total mortality reduction, relative risk reduction, use of ICDs and heart failure, it was only about 23%. So we have a very high bar that we're gonna have to meet with left atrial appendage closure to be at least equivalent to that of Warfarin. And of course, that also raises the issue of how we're gonna compare the left atrial appendage closure devices to that of the direct oral anticoagulants. Of course, everybody's seen slides of variations like this. This, again, shows, despite the very large reduction in stroke risk and also large reduction in overall all-cause mortality associated with Warfarin, we just don't use Warfarin very much, right? And so that the overall use in eligible patients hovers between about 50 and 60% across all age cohorts. And so that the overall use in these age cohorts was right around 55%. Of course, that brings us up to the DOACs, right? So this is an old slide. And so we're actually over 80,000 patients enrolled now in the DOAC trial. So a remarkable amount of data and very strong data for the use of direct oral anticoagulants versus that Warfarin. It's either non-inferior or superior to Warfarin for stroke prevention. There are four commercially available medications now in the United States. There's no need for routine monitoring and there's little drug-to-drug interaction. So really a much better medication than Warfarin, both by compliance and ease of use. But again, we have issues, right, with the direct oral anticoagulants. So this is just a list of three of the direct oral anticoagulants in large clinical trials. And the overall discontinuation rate of the study drug was right around one in four, right? So one in four patients, despite the ease of these medications to use, again, about one in four individuals will stop the use of these particular medicines. Again, the overall discontinuation rate of Warfarin in these control arms of these trials was between 18 and 28%. And again, pointing to the major issue with the direct oral anticoagulants is the risk of bleeding. So again, the risk of major bleeding amongst all the direct oral anticoagulants was reasonably similar to that of Warfarin. And so we still, despite the fact that they're much easier to use, they may be slightly more effective than Warfarin. They certainly probably give a better time of therapeutic range than Warfarin, given the dosing regimens. We continue to have the issue that we have, which is that of major bleeding. That also raises the issue that we end up having individuals that end up getting underdosed with direct oral anticoagulants. This is actually a registry of non-valvular atrial fibrillation patients in Israel, looking at 8,425 newly diagnosed patients. And they found that about 40% of these individuals were being given off-label reduced doses. And when you sort of look at the outcomes of these individuals, you can sort of see that in terms of their major bleeding, major bleeding risk, we really didn't sort of prevent major bleeding by dose reducing them. In fact, what we may be just showing with this is that clinicians are actually relatively good at selecting out patients that are a high risk for bleeding. So there really wasn't a major reduction in bleeding with use of a lower dose, but we certainly saw a much higher risk of death. And the composite efficacy of death, stroke, and myocardial infarction was significantly higher with individuals on low dose direct oral anticoagulants. Now, again, this is just a registry of patients and this may just very well reflect that the individuals that were given lower dose DOACs were just sicker patients in general, but certainly raises the issue that giving individuals dose reduced direct oral anticoagulants may not be effectively treating these folks. Or again, just that we're good at selecting out individuals that are going to be at a higher risk. So that brings us up to the use of left atrial appendage closure for stroke prevention. I've not listed the TE trials and the data regarding the left atrial appendage as a source of thrombus in either stroke or systemic embolism. But again, most of the TE autopsy studies have all demonstrated approximately 90% of the thrombi associated with stroke and systemic embolism and atrial fibrillation come from the left atrial appendage. And so that fact was leveraged in designing this Watchman device, which is a device that is made up of a self-expanding nitinol frame with anchors that you see here on the legs. There is a permeable fabric cap that's placed over the nitinol frame. There are five devices and the idea was to deliver this device into the left atrial appendage and block the left atrial appendage and any thrombus exiting from that area. So if this is actually an older slide, you can see it's an older slide because we used a J-wire to enter the left atrial appendage here. We now use a pigtail, which gives us a little bit better safety. But as you can see, the idea behind placing the Watchman device, and again, this talk is going to mostly focus on some of the clinical data associated with Watchman, certainly can come back and give another lecture on sort of tips and tricks of implanting these types of devices. But in general, we now use a pigtail to enter the left atrial appendage. We then deep-seat this particular guide in the left atrial appendage and then uncover the Watchman device, which you can see here, and then blocking up the left atrial appendage. So again, a transeptal approach, entering the left atrial appendage with a traumatic pigtail, deep-seating that guide within the left atrial appendage, guided by the marker that we see here for different sizes, release the device by withdrawing the catheter and unsheathing the device, and then hopefully with a reasonable result here, demonstrating occlusion of the appendage. So I'm going to spend a little bit of time talking about the Protect and Prevail trial. There are issues with these two trials that have caused some consternation amongst individuals in terms of whether or not we really have equipoise between Watchman and Warfarin. I sort of fall on the side that we definitely have demonstrated equipoise, and I feel fairly confident that we have equipoise between the device, the Watchman device and Warfarin, although I'm just going to go through some of the issues and you can sort of make decisions for yourself. So this was the original trial looking at efficacy and safety of this device. It was a study centered at about 60 sites across the United States and Europe. It involved 707 patients randomized in a two-to-one fashion to left atrial appendage closure versus Warfarin. As you can see, all the individuals that were enrolled in the trial were Warfarin eligible. So they were maintained on Warfarin for 45 days. The TE was done at 45 days, six months, and 12 months. Dual antiplatelet therapy was then continued until the six-month follow-up after the 45-day TEE, which really reflects sort of the anticoagulation regimen and antiplatelet regimen that we currently use, or at least is based on the labeling from the manufacturer. So the primary efficacy endpoint was a non-infurity to that of Warfarin. It also looked at a combined endpoint of stroke, of stroke occurrence, CVR, explained death, or systemic embolization. And there was a primary safety endpoint looked at in terms of excessive bleeding and procedure-related complications. So these are the platformers of Bayesian analysis looking at patient years. And so the primary efficacy endpoint, you can clearly see that, although the curve starts separating right around one year's time, such that the posterior probability based upon this Bayesian analysis was about 96%, or I should say greater than 99% for non-infurity and 96% for superiority. The issue with the PROTECT trial was that the primary safety endpoint, you can clearly see here that there was a sort of unacceptably high overall complication rate during the initial implant. And it continued on and stayed higher than the Warfarin arm, such that the initial complications was concerning. The issue about this finding of the primary efficacy endpoint being superior to that of Warfarin between Watchman and the Warfarin arm was primarily driven by this fact, which was that the hemorrhagic stroke risk in the Watchman group was about 0.2% per year versus 1.1% per year for Warfarin. And that's been called into question quite a bit because this 1.1% incidence of hemorrhagic stroke for Warfarin is substantially higher than what we've seen in anticoagulation trials in the past with Warfarin, particularly in the modern DOAC trials. When you look at the Warfarin arms of those particular trials, we see that the overall incidence of hemorrhagic stroke in those trials is between 0.3 and 0.5%. So you see a nearly doubling of the overall hemorrhagic stroke risk seen in the Warfarin arm of the PROTECT trial. And this has been suggested as one of the reasons why we have to be a little bit careful about the superiority difference that we saw between Watchman and Warfarin, driven mainly by this finding. In an arm that had relatively small number of patients that were on Warfarin, remember it was a 2-1 randomization. So what the PROTECT trial really showed was that it achieved its non-inferiority goal. It looked that it was superior for the hemorrhagic stroke. Although again, there was a very high rate of hemorrhagic stroke in the Warfarin arm, nearly double that we see in larger trials with much larger groups of, larger number of patients in those trials. The primary safety ending point was significantly worse, especially in the first seven days. And the other main issue here was that the overall successful implant rate was right around 91%. So almost 10% of individuals did not undergo a successful implant. And then at the end of the trial, about 92% of individuals had discontinued their Warfarin, suggesting that there was a sort of an 8% failure to try to get these individuals off of Warfarin. One issue that did show itself as time went on, there were less events as operators gained experience, which you would sort of expect with a novel technology like Watchman and a sort of a newer technique of sort of implanting these type of devices. So that went to the FDA and the FDA was a little bit concerned about the overall safety profile of the device. And there was also some questions about adjudication of some of the hemorrhagic strokes and the counting of subdural hematomas as a hemorrhagic stroke in the Warfarin arm, but not in the Watchman arm. And so therefore, given all the questions that were raised regarding the PROTECT trial, they requested a second trial be done, which ended up being the PREVAIL trial. So the PREVAIL trial took a slightly sicker group of patients that overall enrolled about 400 patients. And one of the issues about the PREVAIL trial was that even though the entry criteria was slightly different in the sense that it was a CHADS-VASc score of one, I'm sorry, not a CHADS-VASc score of one, a CHADS score of one plus additional risk factors. So this was a slightly sicker group of patients that were enrolled in PREVAIL. What they decided to do was to borrow, since they were gonna reanalyze things by patient years, they decided to borrow some data from the PROTECT trial to add into the PREVAIL trial of patients that fit the profile in PROTECT that will qualify for PREVAIL. So again, it drew on some data from PROTECT. Again, used basically the same overall endpoints, although it added a secondary endpoint, which is a late efficacy endpoint, looking at a positive ischemic stroke and systemic embolism greater than seven days after randomization. So in an effort to try and look at proof and concept that the idea that plugging the left atrial appendage would actually reduce stroke and systemic embolism regardless of the original, or I should say procedurally related complications. And again, the most important part of this in many ways was the third co-primary endpoint, which is an early safety endpoint, looking at all-cause death, ischemic stroke, systemic embolism, device and procedure related events requiring open cardiovascular surgery or major endovascular interventions. And this was, again, looking at early safety by looking at these events occurring before, less than seven days from the procedure or index hospitalization. Interestingly, they excluded individual, sorry, excluded pericardiocentesis-resolved effusions that did not have to go to surgery. Another mandate from the FDA was that they wanted to see what would happen if this device was released into the wider world and requested that 20% of the centers participating in PREVAIL had not participated previously in the Watchman trial, and that at least 25% of the patients had to be treated by new operators. So looking at what would be the overall treatment efficacy and complication rate with newer implanters. So we clearly see that as time goes on, that the overall implant success rates continue to climb as there gets to be sort of a fund of knowledge and institutional knowledge of how to place these devices. This was the original success rate seen in PROTECT-AF, which is right around 91%. And then if you look at CAP, the overall success rate, which this was a continued access protocol in between that PROTECT and PREVAIL, went up to about 94% and then PREVAIL was over 95%. So as time goes on, we get better at putting this device in place. This is sort of the bottom line slide, which individuals have sort of pointed at as difficult data to reconcile at times. I sort of just focus in here on the final five-year analysis. So remember, this is the primary efficacy endpoint. If you sort of see the 18-month rate seen in the device arm was 6.6%, and then the control arm was 5.1%. This led to a rate ratio of 1.33, although it crossed the bar line of unity, the upper bound was 2.13, suggesting that there could be at least a twofold increase in the risk of an event occurring in the primary efficacy endpoint. And that was above the upper bound that was set at the beginning of the PREVAIL trial of 1.75. And so that the posterior probability of non-inferiority, which they wanted to be greater than 97.5% to achieve statistical, what they wanted to achieve statistical significance was only 88.4% at the final five-year analysis. If you sort of look at their secondary endpoint, which again was proof in concept of late stroke after greater than seven days of the procedure index hospitalization, you can see here that the overall rate was 2.5, basically 2.6, and the control arm was 1.4. And that led to a rate ratio of 2.2, which did not meet their overall goal, but they also had looked at a 18-month difference. And this particular difference did reach statistical significance based upon an upper bound of less than 0.0275. And again, here, probable non-inferiority of 97.5% in terms of their late secondary efficacy endpoint. This was the most important part of PREVAIL, which again demonstrated that the overall early safety endpoint was met. Their 95% upper bound in the credibility interval they wanted to be less than was 2.65%, and then they came in at 2.2%. And you can sort of see here that the overall instance of major complications early on was relatively small. There was two device immobilizations and one AV fistula, one cardiac perforation requiring surgery, one pericardial infusion, and tamponade requiring surgical intervention and one major bleed. So one of the questions came up is why did PREVAIL not achieve its primary efficacy endpoint significance? And one of the issues that came up, in many ways sort of opposite of what was seen in PROTECT, was that the warfarin arm in the PREVAIL trial did remarkably well. We actually, instead of seeing the high incidence of hemorrhagic stroke in the PROTECT arm, and I should say the warfarin PROTECT arm, we see that the overall incidence of ischemic stroke per 100 years in the PREVAIL warfarin arm was 0.3%, which is remarkably lower than the overall risk of ischemic stroke seen per 100 patient years in all the DOAC trials. And so this may have driven part of the reason why we see such a large range in the credibility interval at the upper bound, and that it may have also partially driven that particular result. Again, this is probably, again, not a real thing, right? Because the overall PREVAIL trial is relatively smaller numbers and the overall number of patients in the warfarin arm of the PREVAIL trial is reasonably small. So what did we end up with? We ended up with a PROTECT trial that had a very good efficacy signal, although, again, difficult to know whether or not the device truly is superior to that warfarin, but we certainly, I think, have pretty good evidence that the warfarin device is not inferior to Coumadin, but there were some safety concerns. And so what did we get with the PREVAIL trial? Well, we saw that we overall got a high degree of success in new incentors and new implanters. The safety endpoint was met, but the non-inferiority endpoints were not met. So this led then to analysis by looking at a patient-level meta-analysis. This was combining the PROTECT and PREVAIL trials together in a patient-level meta-analysis and looking at the overall efficacy endpoints. You can clearly see here that the all-cause death was a significant decrease when you combined the individuals in PROTECT and PREVAIL. You can see that the efficacy endpoint here, again, is strongly suggestive that equipoises met and that the Watchman was at least equivalent to that of Coumadin in the PROTECTION against stroke. And then this is plotting the overall incidence of stroke along multiple different registries and clinical trials, looking at the Watchman arm. And this is what you would expect as a stroke risk based upon overall CHADS-VASc score in that looking at the mean CHADS-VASc score, we see that the overall incidence of ischemic stroke for 100 years is sort of seen on the range that we would expect with individuals treated with Warfarin. So I think that overall, we see that the Watchman device, while there are issues about these clinical trials that you can pick at, I'm relatively confident at this point in time that the device has demonstrated that at least is not inferior to that of Warfarin. That led to this weird sort of phenomenon that we're in right now, right? Which is that the PROTECT trial and the PREVAIL trial both enrolled patients that were Warfarin eligible, right? Because you had to be Warfarin eligible to go under the anticoagulation arm following device implantation. But what CMS decided to decide for coverage was that it took individuals that had CHADS-VASc score of two or greater, or CHADS-VASc score of three, I should say, or greater, or CHADS score of two, the patient had to be suitable for a short-term Warfarin, but deemed unable to take long-term oral anticoagulation. So again, what we're doing is we're implanting this device in a group of individuals that were not really exactly studied in the PREVAIL and PROTECT trial. So what do we have in terms of real-world data then given the fact that we are probably implanting this device in a group of patients that were not exactly studied? We don't really have a ton of randomized control data, but we do have some registry data. This is one of the largest registries coming out of Europe, which is the Evolution Registry, looking at over 2,000, or I should say 1,000 patients. And what they did was they looked at a group of individuals here, about almost 500 patients that either had hemorrhagic stroke or a history of major bleeding. And so this is, again, more aligned with the group of individuals that we are implanting here in the United States with the Watchman device. And interestingly enough, they also left it to the individuals implanting the device on what type of post-device anticoagulation these individuals would receive. And you can see that in the individuals that had hemorrhagic stroke or major bleeding, that the overall individuals placed on either oral anticoagulation with either a DOAC or Warfarin was relatively low. Most of the individuals were placed on dual antiplatelet therapy immediately after implant. And some individuals were placed on just a single antiplatelet agent or nothing. And again, this is sort of a waterfall plot looking at the post-implant, first discontinuation of any medication and two-year follow-up of what these individuals were on. And you can see that the vast majority of these individuals were either on dual antiplatelet therapy, single antiplatelet therapy, or nothing following their initial implant. That raised the risk of whether or not you're gonna see an increased risk of device-related thrombus. That's the whole reason why for 45 days after the implant, we placed these individuals on oral anticoagulation. And again, this is a look at the overall risk of device-related thrombus over the various regimens. And again, you really see no statistical significant difference. Although again, a relatively high, you know, right around 5% incidence of device-related thrombus of the 45-day TEE, but really no difference between all three groups. Interestingly enough, the no anticoagulation or antiplatelet therapy showed around a 2% device-related thrombus. But again, really no statistical difference though amongst all three, suggesting that maybe we can have a regimen that does not require individuals to be anticoagulated for 45 days. And if you sort of again, look at the expected risk of stroke versus what was seen in the individuals that underwent Watchman implantation, again, not nearly as sort of statistically potent as a randomized trial, but you can clearly see here, even in the group of individuals that we are sort of implanting at this point in time, right, mainly in the United States, which are these individuals that have a contraindication or a relative contraindication to long-term anticoagulation. We can see that these individuals have a relatively high or what we would expect with the benefit that we would see with anticoagulation, we're seeing also with individuals that undergo the Watchman device. A couple of quick slides, I'm gonna skip ahead a little bit since I'm spending a little too much time on this stuff, but just a couple of quick slides about the WatchmanFlex. As you know, the WatchmanFlex is now commercially available in the United States, it's being rolled out somewhat more slowly, so not every center has the availability of placing the WatchmanFlex. There are some major significant design differences between Watchman 2.5, which is the current device that we see versus WatchmanFlex. The main benefits that are seen with this newer device is that there's a closed distal end. And what that closed distal end allows us to do is to form what we call this ball shape. And then when you have this ball shape, and because this one's closed, it's a very soft atraumatic shape at this point in time, in which you can push the device into the left atrial appendage. This allows us to implant the device without the guide of deep seated, and allows for us to place the device in individuals that have an appendage that has less depth. The other thing that helps with the less depth is that you can sort of see here that the original Watchman device is as deep as it is wide, right, in a sense. So this is sort of almost in a cube type dimensions, while the device with the WatchmanFlex device is it has a depth that's significantly less than that of the width of the device. The overall number of struts is also increased from 10 to 18, and you can sort of see here a little bit of scalloping that you can see in between the struts. And here on this fully expanded device, you see less of that scalloping. There also is less hardware exposed from where the attachment cable is placed between that of the Watchman and the WatchmanFlex. Again, there's a dual set of anchors versus the single set of anchors that you see. These anchors are here towards the back end of the WatchmanFlex device. And you also see that the fabric cap extends deeper down versus that of the original Watchman device, so that more of the device is actually covered by the fabric cap. It comes in five different sizes, although, again, there's more overlap between the sizes, which makes sizing a little bit easier. And this was the PinnacleFlex IDE trial, which again, sort of looked at the overall implant success rate of the device. You can see that the overall implant success rate is extremely high. It's right around 99%. Again, the safety endpoint or the performance goal here was to have a safety endpoint of less than 4.2%. It was seen at 0.5%. Interestingly enough, these two ischemic strokes, one was an individual that underwent a failed implant that had a TIA. So overall, a device that has a high degree of success of implant, substantially higher than even we saw it prevail, right? So going from about 95% to almost 99%, and overall, a very safe device to implant. Again, here is the primary efficacy endpoint, which is defined as effective closure at 12 months with a jet less than five millimeters. And again, while they expected to reach a 97% goal, they reached 100%. These individuals had a closure of the left atrial appendage with a jet less than five millimeters. And then if you look at oral anticoagulation discontinuation in patients, you can see that 96% of these individuals were off anticoagulation after their regimen, which in this Watchman FLEX trial, used DOAC rather than Warfarin. So I wanna spend a little bit of time also talking about another device, which is obviously only an investigation in the United States. If the amulet IDE trial has not been closed, but it's a different design. The idea behind the, you can sort of see here, the Watchman device is a single device, single unit device, I should say, with a fabric cap. Again, the Amplotzer device is a little bit different. It has a lobe here that engages the left atrial appendage, and then it has a disc that's designed to occlude the entire orifice of the left atrial appendage in a more proximal location. And again, here, this is more of a cartoonish view of what the idea of the amulet device is, is a device with a lobe implanted slightly deeper, but then a disc that covers the entire orifice of the left atrial appendage. And that may have some theoretical benefit. As you can sort of see here, in these anatomic models of the left atrial appendage, you can see that there are these crevices that you see relatively proximal in the left atrial appendage versus the area where you would probably place the Watchman device. All of us that have implanted the Watchman device have seen these sort of divots, in a sense, seen mainly on the limbus side, or the Coumadin Ridge side of the Watchman device that are proximal to where you've actually placed the device. And since this lobe goes in about 2 3rds past the circumflex, this disc then would remain here at the orifice, which may cover some of these little divots that we can sort of see here very proximally. It's not clear what the overall risk of thromboembolism is from these particular anatomic locations, but it certainly raises a theoretical possibility that the amulet device may be slightly better at protecting against these areas. Again, this is just a cartoon of the idea behind the amulet device. You can sort of see that there's a disc here that seals the orifice of the left atrial appendage. There is a waist and a sort of anchor here that attaches it to the lobe. The lobe conforms to the left atrial anatomy, and there are stabilizing wires along the lobe that engage the left atrial wall and allows the device to stay in place. Because this little connecting rod, in a sense, is flexible, the lobe and the disc don't necessarily always remain exactly completely aligned, and you can have the disc and the lobe maneuver itself somewhat independently of one another in order to create a better closure. This is actually a video of one of the amulet devices that we have implanted in the IDE trial. Again, here, the difference behind the amulet device is that while we placed the device in here with a pigtail, you can see that what we can do is the same sort of thing with the Watchman device, which is create a ball and then push the lobe out into the left atrial appendage without having to deep-seat the guide as much, because when we form the ball, again, you have a relatively soft atriumatic portion of that device. So what we've done is pushed out the lobe here and then pushed out the disc. This is actually trying to form what they call the football shape in an effort to see whether or not the device is firmly implanted and stable within the left atrial appendage. And you can see here that we've released the cable now and that this is the final position of the amulet device. No, we don't tend to have a lot of randomized data. In fact, we don't have any randomized control trials against anticoagulation with amulet device. We have some certain registries looking at the overall efficacy. And we see that the, again, looking at the overall risk of stroke in some of these registries, this is a registry from Europe, the ACP registry of about a thousand patients. We can see that given the overall CHADS-BASC score, we would expect a annual stroke risk of 5.62%, but we see 2.3% in the amulet patients. Again, suggesting a decrease in overall clinical efficacy in the reduction of stroke. The amulet observational study, again, was another study that was not a randomized trial looking at the overall efficacy of the amulet device. And again, here you see that the overall ischemic stroke rate is a 2.2%, suggesting, again, based upon what you would have expected based upon CHADS-BASC score, around a 70% reduction in the use of the amulet device. So again, we clearly see here a consistent theme that left atrial appendage closure with any plug, Watchman or amulet, has at least a near equivalency of what we would have expected with Warfarin and the DOACs. So in terms of future clinical trials and left atrial appendage plugs, the amulet IDE is the large trial in the United States looking for FDA approval. It's a randomized trial of amulet versus Watchman. And so this is now finalized enrollment. We are all, I want to say almost 1,000 patients are enrolled in this trial. And now we're just in the clinical follow-up phase. Hopefully we'll get more data early next year, and then hopefully maybe even commercial release of device based upon that data by latter part of 2021. There will be LAA plug trials versus DOACs. So both amulet and Watchman Flex are going to be involved in these trials. So Catalyst is the trial that's going to look at amulet versus DOAC, and Champion AF is going to look at Watchman Flex versus DOAC. And again, important trials looking for non-inferiority of these devices versus the sort of more contemporary means of anticoagulating individuals, particularly given the concerns over the benefit associated with Watchman and the Warfarin arms being related to the reasonably high risk of hemorrhagic strokes seen in those particular trials. The option Flex is another trial looking at DOAC versus Watchman Flex implantation, post-AID fibrillation. And the ASAP2 trial is ongoing, although enrollment is extremely slow. The ASAP2 trial is looking at anticoagulation in eligible patients, contraindicated patients, and randomizing them to a standard of care, which is basically nothing, versus that of a Watchman device. One of the reasons why obviously ASAP2 has been enrolling relatively slowly is that it's a randomized trial of a commercially available device. And so it's been particularly difficult to enroll in this trial. I have some major fears that this trial is not going to finish enrollment. So I want to spend the last 15 minutes or so talking a little bit more, rather than about stroke prevention with the left atrial appendage closure devices, is the role of left atrial appendage closure in rhythm management of atrial fibrillation. And one of the things that comes up a lot is what's the overall risk or possibilities of performing cardioversions in individuals that had a Watchman device. And we don't have a ton of data. We do have one published manuscript and study looking at this, was a multi-center retrospective review of 148 patients. And they came up with a sort of algorithm that they used. All 148 patients underwent a pre-procedure TE. And there was a small number, I think four, that ended up with device-related thrombus that was seen. Those four individuals then treated with, all were treated with a direct oral anticoagulant and a successful resolution of their device-related thrombus, and they proceeded to a cardioversion. If there were, so that the pre-procedure TE was an important part of the workup for these individuals undergoing cardioversions after Watchman. They then proceeded to go to cardioversion, and they found that there was no device-related, or should I say, no cardioversion-related thromboembolic events in either individuals that were started on anticoagulation after their cardioversion, versus those individuals that were left off of anticoagulation after the cardioversion. The main difference between the group of individuals that were started on oral anticoagulation was that they were relatively fresh from their implant. So the overall mean of time from implant in the individuals that were started on oral anticoagulation was 3.6 months, versus the 8.6 months of individuals that were left off of anticoagulation following their cardioversion, following their pre-procedure TE, which kind of makes a little bit of sense, right? So in the anticoagulation antiplatelet regimen that we use following Watchman implantation extends out to six months, right? So 45 days of oral anticoagulation followed by four and a half months of direct sort of dual antiplatelet therapy. And that's sort of the timeframe that we think the endothelialization of the device occurs. And so if individuals undergoing, or I should say, undergoing cardioversion, there is a reasonable expectation that they are not fully endothelialized, that that's probably what drove these individuals to start anticoagulation after cardioversion. So again, nothing really ironclad. This is just observational data, but there at least is some data that suggests that it's reasonably safe to undergo cardioversion. There were certainly no device, devices that dislodged from the left atrial appendage following cardioversion, and that there were no device-related, I should say, no cardioversion-related events occurring immediately around the cardioversion or the four weeks after. One of the other ways of closing the left atrial appendage, rather than using a plug, is to use the lariat system. And I'll go into the lariat system in a little bit, but one of the interesting aspects of the left atrial appendage is its role in maintaining or triggering atrial fibrillation outside that of obviously the pulmonary veins. I mean, this has sort of been data that has accumulated as we've looked at trials looking at left atrial appendage electrical isolation by catheter ablation. So this is a plot of the BELIEF trial, which was 173 patients with longstanding persistent atrial fibrillation. There was a group that underwent left atrial appendage, sorry, left atrial appendage, yeah, electrical isolation and left atrial ablation with PVI and other triggers versus left atrial ablation alone. And demonstrating that there was a significant difference in freedom from atrial fibrillation or atrial tachycardia in the groups that underwent left atrial appendage electrical isolation. That didn't just also extend to individuals that underwent RF ablation, there was a smaller observational trial looking at the use of cryo-balloon ablation with, or I should say cryo-balloon PVI and left atrial appendage electrical isolation using the cryo-balloon. And again, demonstrating a significant freedom from atrial fibrillation associated with left atrial appendage electrical isolation versus that just PVI alone. However, there's difficulties, right? So everybody that's tried ablating the left atrial appendage and doing that logically with either an RF catheter or a cryo-balloon has run into these particular issues, right, one is that it's difficult. So 13% of the patients could not achieve a left atrial appendage electrical isolation. Under the individuals that underwent repeat ablation, 37% of these individuals had reconnection. And interestingly enough, of the individuals that underwent left atrial appendage electrical isolation in sinus rhythm, when they had a TE at follow-up, almost half of these individuals had normal left atrial appendage function, which suggests at least that they have had at least some degree of electrical recovery if they have mechanical systole within their left atrial appendage. The complication rate is also a little bit of a concern. In the belief trial, however, there did not appear to be significant increases in overall complications. But the one issue that has come up is that if you ablate and isolate the left atrial appendage, is it possible that you're gonna overall increase the risk of thromboembolism from that left atrial appendage? And while the belief trial certainly suggested that there was no stroke or no TIA seen in about 60% of individuals that had impaired left atrial appendage function, there are definitely other trials that have demonstrated a higher risk of stroke and TIA regardless of left atrial flow velocities in individuals that underwent left atrial appendage electrical isolation. And even in another group of individuals, a relatively high risk of thromboembolism seen from left atrial appendage, even in those individuals that underwent oral anticoagulation. So suggesting that some of these folks may have to undergo left atrial appendage closure and not just anticoagulation following their electrical isolation. This brings up sort of the possibility of using the lariat system as a means of trying to electrically isolate the left atrial appendage and also exclude the left atrial appendage perhaps for the benefit of stroke prevention. Again, here the lariat system is a hybrid system in which there is a magnet wire that's placed within the left atrial appendage endovascularly through a transeptal puncture, epicardial punctures made in the pericardial space, another magnet wire is placed, these align up. And then from the pericardial space, we advance this ligature, which goes over the left atrial appendage and then ligates it. The main reason why this technique works is the advent of the use of sort of a much more anterior stick in the pericardial space. You can sort of see here, this is a lateral view of the pericardial stick that we have. And you can see that we've placed the wire in a much more anterior location. This is a little bit different than we do for VT ablation, epicardial VT ablation, where it's not necessarily as important. But since the left atrial appendage is an anterior structure, we have to get in more anteriorly in order to be able to connect those wires and achieve the magnet wires attaching and the ability for us to engage the left atrial appendage and place that ligature over it. This is just a couple of views of the system. Once we placed it again here, the magnet wires are attached here within the left atrial appendage. I've advanced the larynx system over this rail and then are tying or should I say, ligating the left atrial appendage here leading to the closure of the left atrial appendage. Again, no randomized controlled data on the risk of stroke prevention. This is from a single series looking, single center series, or should I say a multi-centered series looking at the incidence of stroke at the end of a year, demonstrating that, again, you would expect a 6% risk of stroke given the CHADS-VASc score and that the observed event rate of stroke was 1%, suggesting an overall reduction of 80%. But again, just really observational data. But more importantly, for the purposes of this aspect of it, we see that once we ligate the left atrial appendage, we see an immediate drop in both unipolar and bipolar voltages, probably from ischemic damage to the ischemic destruction of the left atrial appendage itself. Interestingly enough, this was a look at 50 patients that underwent left atrial appendage ligation with a device in place. So this is individuals that either had a defibrillator or a pacemaker. And again, looking at their overall incidence, this is each individual, this is a weird graph, but this is each individual patient. And you can sort of see here the sort of orange line is the AF burden at three months and the gray line is AF burden at 12 months. And this is for each individual patient. You can see here that there was a certain group of patients that had a relatively large reduction in overall AF burden at three months, some of which persisted out to almost a year's time, suggesting that the left atrial appendage does play some role in either maintenance of atrial fibrillation or initiation of atrial fibrillation. This was a multi-center observational study looking at individuals that underwent left atrial appendage ligation versus catheter ablation only that were case controlled. Again, demonstrating that there appear to be a substantial improvement in overall AF burden associated with combining left atrial appendage ligation to that of pulmonary vein isolation. We can clearly see that individuals that undergo left atrial appendage ligation have significant remodeling of their left atrium. As you can see that the overall volumes after you ligate the left atrial appendage dropped substantially. And this may also play some role in the overall potential efficacy of adding left atrial appendage ligation to pulmonary vein isolation or other AF ablation in maintenance of sinus rhythm. Just going to skip ahead here. Sort of to the final slide. So what that series of studies has generated the AMAZE trial, which is now finished enrollment. This is going to be a trial comparing staged left atrial appendage ligation to and then pulmonary vein isolation comparing to pulmonary vein isolation alone. This was only using RF. There were 600 patients enrolled that had persisted or long-staying persistent atrial fibrillation. And the primary endpoint again is a freedom from atrial tachycardia atrial fibrillation of greater than 30 seconds, which is a standard endpoint. This is now in follow-up. So hopefully we'll get a little more data as time goes on in early 2021. There is a continued access registry that is continuing on with the AMAZE trial, which is now going to include cryo balloon pulmonary vein isolation. So this continued access registry is continuing to proceed. So I think that's my last slide. Thanks. All right. Thanks, Al. That was great. Maybe I could just ask a couple of questions. What's your current management to patients that can't take anticoagulation, particularly since you said it was difficult to enroll in ASAP2. What do you currently do with those patients? Are you comfortable implanting a plug and just using dual antiplatelets outside of the trial? So it just is extremely patient dependent. So for the individual that has a relative contraindication, say for instance, they had a subdural hematoma from trauma, for instance, those individuals, we would probably still encourage that they go on the 45-day worth of anticoagulation. And in the individuals that have a real contraindication like that of a hemorrhagic stroke or spontaneous hemorrhagic intracranial bleeding or something like that, we have definitely just placed those individuals on dual antiplatelet therapy afterwards. I have thus far not put anybody, any of the patients I've implanted on single antiplatelet therapy or nothing at all, which was seen in the EWILLUSION trial, which is the EWILLUSION registry. And so I just take a very, very individualized approach that just sort of balancing the overall risks of essentially just hopefully a 45-day course of anticoagulation versus that of device-related thrombus that has been seen. Okay, thanks. And one other question. A lot of people are advocating for left atrial appendage exclusion as comprehensive AFib management, post-PBI in everybody. I'm wondering what your thoughts are on that and how you think we should use it as we go forward. Well, I'm not... So the question is, I think it's a little too soon to know what approach to take. I certainly think that implanting a left atrial plug in everybody post-AF ablation probably is not worthwhile as there is little evidence that left atrial plugs will improve the overall efficacy of the AF ablation. And in large amount of patients that we are doing AF ablation, and particularly those with paroxysmal atrial fibrillation, many of them don't really even have that high of a risk of stroke to begin with as their transverse scores are reasonably low. It does, it is sort of attractive for them perhaps to implant a device at the same time since you already have left atrial axis for your AF ablation. I'm not totally convinced at this point in time that we should be doing that routinely in everybody. Certainly, I don't think we should be doing it routinely in individuals that have a lower CHADS-VASc score. I mean, one of the issues that we have, right, is that we're not totally sure of the overall efficacy of the device for late stroke and TIA prevention. I mean, we do have five-year data coming from Protect and Prevail, but you sort of go back and look at the point estimates for ischemic stroke in those folks, right? And you can see that the device clearly is not as good as anticoagulation, it appears, in the prevention of ischemic stroke. And so, and that's at the five-year mark. So it's hard to know what's gonna happen at the seven-year mark and 10-year mark. Now, it may be balanced by the fact that we really are reducing the risk of hemorrhagic stroke and all the other sort of difficulties and dangers of remaining on oral anticoagulation for the long-term, but it's a little bit unclear at this point. And so I would encourage individuals not to consider routine placement of a plug. I do think where it's gonna be extremely helpful is to get the AMAZE data, right? So if the AMAZE data demonstrates that left atrial appendage ligation is really associated with an improvement in overall AF freedom in combination with that of a catheter ablation, I assume it's gonna be based upon the absolute benefit, so if it's a relatively small with statistically significant relative risk reduction, but it's relatively small, I don't know how applicable it is as the technique can be a little bit harder to universalize as the technique is a little bit more difficult than placing the plug. But if it's a substantial improvement in AF burden, then that does raise the possibility of whether or not this should be a routine part of the management of AF patients that have either persistent or long-staying persistent AF.

left atrial appendage closure

stroke prevention

atrial fibrillation

warfarin

Watchman

Amulet

direct oral anticoagulants

rhythm management

clinical trials