Welcome, everyone, to this HRS-sponsored webinar on What the 2023 AFib Guidelines Tell Us About Anticoagulation, Stroke Prevention, and Non-Pharmacological Therapies. I'm Mina Chung. I'm a clinical cardiac electrophysiologist at the Cleveland Clinic, and I have the honor and pleasure of moderating this webinar, as well as having served as vice chair of the 2023 ACC, AHA, ACCP, and HRS Guidelines for the Diagnosis and Management of Atrial Fibrillation. The chair of that document was Dr. Jose Hoglar, and we're indebted to the writing group, some of whom have taken the time to join us this evening as speakers and panelists. So I'm going to ask them to introduce themselves at this time. First, Dr. Fred Kusumoto. Hi, Mina. Thank you very much for that kind introduction. Yeah, so my name is Fred Kusumoto. My day job is at Mayo Clinic here in Jacksonville, Florida, and I'm so excited for this next hour and a half to discuss these issues. Thank you, Fred. And then Dr. Neemesh Patel. Hi. Yeah. Nice to meet you all. My name is Neemesh Patel. I'm one of the EP faculty at UT Southwestern in Dallas. I was one of the junior faculty writer on the Atrial Fibrillation Guideline. Nice to meet you all. Thank you. You did a lot, including a lot of research. So thank you. Dr. Kristen Campbell. Hi, thanks, Mina. I'm Kristen Campbell. I'm a clinical pharmacist at Duke University and practice in electrophysiology. And I'm excited to be here tonight. Great, thanks to all three of you. To all of you on this, there's a Q&A site on this webinar, so please feel free to use it and we'll try to get to as many of your questions as possible. So without further ado, Fred, please kick us off and set the table. Great, let me go ahead into share. Okay, here we go. So I have no disclosures other than I do have to add an extra one. So I'm really old and slow. So please make sure that any important questions you ask Dr. Patel, all right? Because it'll take me a long time to answer. So my job is really just to set the table for the discussion that we're going to have for after Dr. Patel and I present. Really, that's going to be the fun and important part of this because as we all know, we can talk about all of this evidence, et cetera, but really our decisions when we take care of our patients are so nuanced and individual. So I'm going to divide my talk into two parts. I'm going to talk about the risk of stroke in patients with atrial fibrillation, and then I'm going to talk about the benefit and practical use of anticoagulation in patients with atrial fibrillation. So let's start with the first. What's the risk of stroke in patients with atrial fibrillation? Well, it's important for us to know that the risk is high and it's actually increasing relative to atrial fibrillation. This is wonderful work done from Canada, which suggested that in fact, that because of hypertension control, diabetes, things like that, that large artery strokes were actually decreasing, but over time in this period from 2008 to 2012, in fact, cardioembolic strokes began increasing very dramatically. This is Canadian work, but there's other work that I could have shown and chosen, which really does suggest in fact that the epidemiology, the pathophysiology of the stroke patients that we see in clinic every day, in fact, or who are at risk, it is in fact changing. So here's the recommendation. Patients with atrial fibrillation ought to be evaluated with some sort of validated clinical risk score, such as CHADS-VASC, and you'll notice that it says some type of validated risk score, because there've been a number of risk scores that have been developed. Now, clearly CHADS and CHADS-VASC are the ones that in fact, we will see the most common here, but in fact, you can see over the last five to six years, has been an increase in other types of risk scores that have been suggested as a possible better alternative to the CHADS and CHADS-VASC. And this is something that Jose and Mina really pushed upon the group, was really to think beyond the box, beyond sort of the CHADS-VASC score, and we'll talk a little bit about why that is. So is the CHADS-VASC no longer the one ring that rules them all? Well, in fact, yeah. So here's Garfield, and I'll go through a few of the others, which uses in fact, all of the CHADS-VASC components, but adds additional components. You can see prior bleeding, kidney disease, race and ethnicity, whether or not anticoagulation is being used, the presence of dementia and smoking. And you can see in fact, when you look at the C-statistic, not a lot of difference between the CHADS-VASC and also the Garfield score, but when you look at that group where you're really interested in thinking about whether or not to anticoagulate, because it is a either yay or nay type of decision that has long-term implications. In fact, perhaps the Garfield score, at least in this study, had better sensitivity without sacrificing specificity. And there are a host of other things. So I chose biomarkers for this, and here then are the multiple biomarkers that could be associated with thromboembolic risk. And in fact, in Engage AF-TIMI-48, they found that in fact, whether you use troponin T, BNP, GDF-15, in fact, you had a higher likelihood of having stroke or systemic embolism or major bleeding with increased levels of any of these biomarkers. Well, then you say, well, how does this help me differentiate between those patients who are at risk for bleeding and those patients who are at risk for systemic emboli? And the group really recognized that. And they suggested that in fact, perhaps pro-BNP was in fact valuable for predicting stroke, whereas GDF-15, perhaps more valuable in identifying those patients at higher risk for bleeding. So again, getting to a more nuanced level with regards to thinking about risk of stroke and risk of bleeding, because all of this group knows, and the listeners know, that in fact, one of the problems with the HASBLED score is that in fact, the CHADS-VASc and the HASBLED score had in fact, a lot of overlap. So someone who has a higher CHADS or CHADS-VASc score almost by definition has a higher HASBLED score. So here is the slide that I want you to remember. So in fact, looking at the clinical variables of the sort of the different risk schema that had been developed to date, and looking at them comparing to the CHADS-VASc components, you can see that all generally use age. Now some weight age. So instead of either having cutoffs at 65 or 75 as CHADS-VASc have, perhaps you have a continuous variable, right? Because does our risk for stroke suddenly change when we're 75, when we're really 74 in six months? Probably not. And so again, thinking about it in a more nuanced fashion, you can see that just about all of them use some amount of the CHADS-VASc component, and then others then use additional clinical variables. I reviewed Garfield for you, and then laboratory values, where there'd be biomarkers in the ABC and ABCD score, or the presence of proteinuria, or a reduced GFR in atrium. When you kind of look at the C statistics for all of them, in fact, you can see the CHADS and the CHADS-VASc in red, and if I then blow this up a little bit and take a look at some of these other scores, in fact, you can see that perhaps Garfield AF, that Subra ABC, increase that C statistic from that 0.6 level to 0.7. Now it's not quite as bad as flipping a coin, but nonetheless, one can see that these risk scores that we use on a day-to-day basis, and I'm telling people to use it for sure, again, thinking that in fact, there are some shortcomings to any of these scores individually. And perhaps it's going to be even more. This is something that just was published in Nature Medicine a few weeks ago. In fact, taking a huge cohort of patients who were deemed at lower risk for stroke, and then followed them for five years. And in fact, you can see even in these patients who were deemed at lower risk, those patients who had atrial fibrillation as shown in the orange circles, in fact, had a higher likelihood of a stroke, had a higher likelihood of ischemic heart disease, importantly, dementia, and even most important, all cause mortality. So again, gets to the fact that these are people who are thought to be low risk, but not without zero risk, and certainly did have higher risk than those patients who didn't have atrial fibrillation. So to summarize this section, risk of stroke is significant, and the percentage due to embolic strokes is increasing. No question about it. The data is very consistent about that. The second is that all of these risk tools, super valuable and helpful, but we have to acknowledge that none are perfect. So let's move on to the second part of this discussion, really thinking about the use of anticoagulation in patients with atrial fibrillation. The use of anticoagulation in atrial fibrillation has been around for a long time. It was, in fact, first suggested in JAMA in 1950 by two Los Angeles cardiologists looking at a mixed group of patients who had ischemic heart disease and also rheumatic heart disease. But there have been now multiple studies. Here, I've shown a number from the heart meta-analysis, which has, in fact, been used, suggesting that, in fact, there's a significant stroke reduction in just about all patients who have atrial fibrillation. And importantly, in fact, you can see this 60% reduction in stroke when you look at all of them collectively. Here, then, is a comparison of NOACs and left atrial appendage occlusion to sort of our standard therapy in Warfarin. You can see that there were differences, whether it be in RELY with the Bigatran, ROCKIT-AF, and rivaroxaban, epixaban. Remember, in the ROCKIT-AF, a lot of those patients had stroke. That's why they had a higher CHADS-2 score compared to the RELY and the Averroes study. In fact, you can then see, too, that here is LA occlusion, which Dr. Patel is going to cover sort of extensively in his talk. Here is then PROTECT-AF and PREVAIL so that you can see everything sort of all together. Here's the issue, though, right? Here's Yogi Berra. When you come to a fork in the road, you have to take it because you're either making a binary decision to anticoagulate that person or not, at least in the world that we live in today, and arguably for the near future. And here, then, are the recommendations put out by the U.S. guidelines, and actually also, really, by the most recently presented European guidelines. Anticoagulation for those patients who have an annual risk of stroke for 2%, which then translates into a CHADS-VASc score of 2 for men, a CHADS-VASc score of 3 for women, or if you're going to use the CHADS-VASc score, as was suggested in the European group, that then takes sex out of the CHADS-VASc score. But this was a big discussion, and I know that Mina will get into this during the discussion about whether or not to include a CHADS-VASc. We ultimately chose to do it because it's something that is used a lot, but it's really to emphasize that absolute risk of stroke of 2%, which is where you're going to think about anticoagulation, 1% to 2% where you're going to be thinking about it, but perhaps not sort of trying to mandate it, as it were, and importantly, reevaluation. Why these issues, right? And this comes from the AF guidelines document, which is really important. It's important to note that when we look at all of these studies that look at CHADS-VASc and then look to see what the stroke rates, in fact, are, it's really dramatically different. Now, let's take a look at this data in a different way. So here now, you can take a look at those patients who have a CHADS-VASc score of 0, 1, and 2 on the y-axis, and on the x-axis, you can see the differential stroke rates, the differential stroke rates in all of those studies using 2 sort of as our sort of number. You can, in fact, see, all right, 0 seems pretty good, right? I mean, you can see that all of those studies have a pretty doggone low stroke risk rate for those patients who had CHADS-VASc score of 0. 2 is also pretty good. You can see most of those kind of just graze 2%, et cetera, or perhaps even higher in the Taiwanese studies. The big issue is that CHADS-VASc score of 1, right, where you have really variable stroke rates in this group from extremely low, extremely low, as shown in the left, to fairly high in either Dan Pace's Denmark study or in the Taiwanese study. So what do you do for this? And so the guidelines say, okay, if you have that intermediate risk based on the CHADS-VASc score, think about other things, right? A nuanced evaluation, really thinking about the future because there are a whole host of different things that are coming up. A few things just to quickly go through in the last few minutes of my presentation. This is a lovely study from the Danish National Patient Registry. And so they looked at a number of patients who are not on anticoagulation. Now they got rid of the patients who had prior, you know, venous thromboembolism, mechanical heart valves, things like that, prior thromboembolisms. So in fact, you can then see their group of patients who had a CHADS-VASc score of zero, two, and one. And what they showed, in fact, is just this. You can see that when you had that CHADS-VASc score of one, you had appropriately this intermediate risk of stroke, but it kind of varied. And if you can see here to the right, in fact, there was significant overlap of the 95% confidence intervals. It really does emphasize that, you know, the discriminatory characteristics of the CHADS-VASc score, it's what we use. It's easy to remember, et cetera, but again, moderate at best. And it will be interesting to think, I hate to even say this, but think about the electronic health record. Maybe that's something that's going to be valuable for us, in fact, as opposed to the bane of our existence, which will then provide us with a more nuanced approach. What might it look like? Look at, well, it might look at hypertension control. This is a work from Aristotle looking at Pixivan versus Warford. I misspoke sort of before, my apologies, but looking at those patients who, in fact, had, quote, poor control of hypertension compared to those who had better control of hypertension. They had a pretty broad definition of what they considered poor control of hypertension. You can see it below in the orange, but in fact, importantly, you can see that those patients where the hypertension was poorly controlled had a higher risk of stroke or systemic embolism compared to those patients who had controlled blood pressure. How about the left atrial appendage morphology? Here's a recent meta-analysis. We all kind of know about the different morphologies. Generally, about half the people have the chicken wing, and the other half have all of these little nooks and crannies and really sort of these kind of odd little sort of areas, which might then be a nidus or a site for a clot. And in fact, the investigators found that in the meta-analysis, that if you had some type of anatomy other than the chicken wing, that in fact, you were going to be at higher risk for stroke that those patients who had a chicken wing, in fact, had a lower likelihood, lower risk for stroke. Like all meta-analysis, when you look then at the funnel plot, perhaps some publication bias, things like that, again, thought-provoking things that we can then use and talk to our patients in a very nuanced fashion. The last thing is thinking about AF burden. So I'm old, as I mentioned. So I was taught paroxysmal persistent doesn't make a difference. If you had AF, you were at higher risk for stroke. And this is from the heart meta-analysis, which showed that in fact, whether you had intermittent AF as shown in the hatch lines or sustained AF as shown in the solid lines, your risk for stroke was pretty similar. Well, now more recently, when you look at sort of larger meta-analyses with more studies, it's a bit more nuanced. There's no question that those patients who have non-paroxysmal atrial fibrillation, so persistent atrial fibrillation, appear generally to have a higher risk of stroke compared to those patients with paroxysmal atrial fibrillation. But we still have the recommendation, basically at this point in time, that if it's persistent, paroxysmal, or permanent, you're really kind of making a decision independent of AF burden. But we all know about the recent publication of Artesia and NOAA AFNet6, which in fact show a lower risk of stroke in those patients who in fact have subclinical atrial fibrillation. I'm sure we'll talk about that in the panel discussion because I think that this is really important. Remember, these are patients who did not have symptomatic atrial fibrillation, but they had three to four hours of atrial fibrillation, so they had card-carrying AFib. And here's what I'd like to emphasize. We as electrophysiologists, oh, someone has AF, we're gonna start them on anionic coagulation, then we kind of wash our hands and we're done. In fact, no. Just no, and Nimesh will talk about this a little bit more potentially. In fact, in those patients who are on appropriate anticoagulation, in fact, there is some presence or continued presence of left atrial appendage thrombus. In addition, in the SUAS-AF study where you had patients who were extremely well treated with excellent anticoagulation, you can in fact still see that there was an incidence of silent cerebral emboli as those patients were followed over time. So just because we put patients on anticoagulation doesn't mean we're done. There are other things that need to be addressed, whether it be risk factors, et cetera. So let me finish with this. We talked about risk of stroke in patients with atrial fibrillation that's significant. The percentage of embolic stroke is increasing. Stroke risk tools are helpful, but we have to understand that they're not perfect. We should use a stroke tool for sure, but we should think about annual stroke risk in an individualized basis and very nuanced. And so that then will finish my discussion here. I'll stop sharing, but really it's something that I'm sure we're going to discuss a lot in the panel discussion. Thank you very much. Thank you, Fred. That was fantastic. That was a wonderful overview and review of entire oral anticoagulation field. Let's move now to Dr. Patel and talk also about non-pharmacologic agents. Thank you. Thank you. And I think you can see the slides okay? Yes. Thank you. Perfect. So I'm going to touch on a few aspects of special populations as they pertain to pharmacologic therapy. So atrial fibrillation complicating acute coronary syndrome or percutaneous coronary intervention, atrial fibrillation in the setting of chronic coronary artery disease, atrial fibrillation in the setting of chronic kidney disease, including end-stage renal disease. And then I'll pivot to non-pharmacologic therapies for stroke risk mitigation and atrial fibrillation, including surgical left atrial appendage occlusion. And then I'll focus most of the time on percutaneous left atrial appendage occlusion. These are all areas where we had some updates in the guidelines and particularly the last one I think is probably the most new and controversial I would say. So I'll start with atrial fibrillation complicating acute coronary syndrome or PCI. So the updated recommendation gives a class one level of evidence study recommendation that in patients with atrial fibrillation and an increased risk for stroke who undergo percutaneous coronary intervention, direct oral anticoagulants are preferred over vitamin K antagonists in combination with antiplatelet therapy to reduce the risk of clinically relevant bleeding. And then the other recommendation, also class one, was that in most patients with atrial fibrillation who take oral anticoagulation and undergo PCI, early discontinuation of aspirin and continuation of dual antithrombotic therapy with an oral anticoagulant and a P2Y12 inhibitor is preferred over triple therapy, which is based on those two therapies plus aspirin to reduce the risk of clinically relevant bleeding. And this is all really based on three major randomized control trials, Pioneer AF, PCI, Redual PCI, and Augustus. And these were all trials that compared post-PCI regimens, either direct oral anticoagulant to warfarin or a dual antiplatelet therapy with oral anticoagulant or triple antithrombotic therapy versus dual antithrombotic therapy with a single antiplatelet agent. And a meta-analysis of all three of these major randomized trials basically showed that dual antithrombotic therapy, again, that's an anticoagulant with a single antiplatelet therapy was associated with a 40% relative risk reduction of major bleeding in multiple definitions, but the primary was the ISTH major bleeding. And also NOAC-based regimens, as opposed to warfarin-based regimens, were associated with a 42% relative risk reduction of major bleeding. Now this has to be weighed against a slight increase in risk of stent thrombosis with dual antithrombotic therapy regimens compared to triple antithrombotic therapy regimens. And so, you know, some leeway was given, especially in the text for the guideline that in patients who there is a perceived high risk of stent thrombosis, maybe complex PCI bifurcations at the discretion of the interventionist that a period of triple antithrombotic therapy may be reasonable for a longer period of time than just one week to a month. Pivoting to chronic coronary disease. So a class one level of evidence B recommendation was also given in patients with AFib and chronic coronary artery disease, which was defined in this recommendation as beyond one year after revascularization or coronary disease not requiring revascularization without any history of stent thrombosis, oral anticoagulant monotherapy is recommended over a combination of oral anticoagulant and single antiplatelet therapy, be that either aspirin or a P2Y12 inhibitor to decrease the risk of major bleeding. And this is primarily based on this randomized trial published in 2019, included about 2000 patients with coronary artery disease without revascularization in the prior year. And they were randomized to either rivaroxaban alone or rivaroxaban plus and antiplatelet therapy. And the primary efficacy endpoint was stroke, systemic embolism, MI, unstable angina requiring revascularization or death. There's a non-inferiority study with a margin at 1.46. And then the primary safety endpoint was major bleeding from the ISTH definition. And what you can see here looking at the event curves is that they were similar as they relate to the primary efficacy endpoint that met the non-inferiority endpoint. And for the primary safety endpoint, rivaroxaban monotherapy was associated with a much lower incidence or statistically significantly lower incidence of major bleeding than combination therapy. And then finally, I'll move on to atrial fibrillation and chronic kidney disease, which is a little bit more complex and controversial than I think the other two recommendations. I'll go through the recommendations and then go through the evidence, which is honestly limited to guide these recommendations. But a level one evidence B recommendation is that for patients with AFib at an elevated risk of stroke and chronic kidney disease stage three, treatment with warfarin or preferably an evidence-based dose of a direct thrombin or a factor Xa inhibitor is recommended to reduce the risk of stroke. A 2a recommendation is given that for patients with AFib at an elevated risk for stroke and chronic kidney disease stage four, treatment with warfarin or labeled doses of direct oral anticoagulants is reasonable to reduce the risk of stroke. And finally, a 2b recommendation, level evidence B, is that for patients with AFib at an elevated risk for stroke and who have end-stage renal disease or are on dialysis, it may be reasonable to prescribe warfarin or an evidence-based dose of apixaban for oral anticoagulation to reduce the risk of stroke. And these recommendations are largely based on the fact that chronic kidney disease is underrepresented in the major clinical trials that evaluated the performance of oral anticoagulations for stroke risk mitigation in atrial fibrillation. And they're largely based on observational data and pharmacokinetic studies as well. And I think the key thing to take from this recommendation is that the benefits in stroke risk reduction have to be offset, weighed against the increased risk of major bleeding that is inherent in kidney disease. And one example of this is the renal AF trial. This was a randomized trial published a couple of years ago that compared warfarin to apixaban for patients with atrial fibrillation and end-stage renal disease. And the study ultimately was underpowered to detect the difference in outcomes between the two groups. But the major observation from the study is that there were 10 times more major bleeding events than there were strokes in the study. And so clearly, the benefit of oral anticoagulation in patients with end-stage renal disease is much more nebulous than most of the population that we treat from a safety perspective. And this is reflected in the guidelines in terms of what the dosing recommendation should be. I won't go into this in detail. But obviously, the degree of renal dysfunction should be considered in deciding what the dose of the direct oral anticoagulant should be. For apixaban, the dosing is in part dependent on the patient's weight, their age, and their serum creatinine level. And then dabigatran and adoxaban are generally contraindicated in patients with end-stage renal disease. And rivaroxaban also has dose reductions on the basis of kidney dysfunction as well. So these should be considered in the context of the patient's renal dysfunction. And certainly, for patients who have end-stage renal disease, careful consideration must be given to the decision about anticoagulation altogether. So I'll pivot from there, those special populations for which we have special considerations for anticoagulation to non-pharmacologic therapies. I'll start with surgical left atrial appendage occlusion or excision. So in this recommendation, a class 1 level of A recommendation is given that in patients with AFib undergoing cardiac surgery with an elevated CHAZ2-VASc or equivalent stroke risk, surgical left atrial appendage exclusion, including to continued anticoagulation, is indicated to reduce the risk of stroke. I won't go into detail of the second recommendation. But this speaks to the quality of the left atrial appendage exclusion and why that would be important in terms of stroke risk reduction. And then I'll focus a bit on this recommendation here, number 3. It's a 2B recommendation that in patients with AF undergoing cardiac surgery with a high stroke risk, the benefit of surgical left atrial appendage exclusion in the absence of continued anticoagulation to reduce the risk of stroke and systemic embolism is uncertain. The major basis for these recommendations is the LAOS 3 study that was published three years ago. It's a randomized controlled trial of 5,000 patients who had atrial fibrillation and a high CHAZ2-VASc or who were undergoing cardiac surgery. They were randomized to either surgical left atrial appendage occlusion at the time of cardiac surgery or just routine care afterwards. And the primary outcome was stroke or systemic embolism. And looking here at the incidence curve over time, you can see that surgical left atrial appendage occlusion was associated with a much lower risk of stroke or systemic embolism and follow-up. Now, turning to the last recommendation that I mentioned about anticoagulation, in this study, the postoperative usual care actually included oral anticoagulation. So we cannot really make the assumption, at least based on this study, that undergoing surgical left atrial appendage occlusion would make it such that you don't necessarily need oral anticoagulation afterwards. That is a common thing that we get asked about in these patients that have undergone surgical left atrial appendage occlusion. But the best of our data still suggests that patients should receive oral anticoagulation in most cases, of course, unless they have some sort of contraindication otherwise to continue oral anticoagulation after surgical left atrial appendage occlusion. At this point, I'll pivot to percutaneous left atrial appendage occlusion. The 2019 FOCUS update on the management of atrial fibrillation gave a 2B indication to percutaneous left atrial appendage occlusion. It may be considered in patients with AF at an increased risk of stroke who have a contraindication to long-term anticoagulation. This guideline, which I'll go into some detail as to why this recommendation was upgraded, gives a 2A indication, level of evidence B, that in patients with atrial fibrillation a moderate to high risk of stroke and a contraindication to oral anticoagulation due to a non-reversible cause percutaneous left atrial appendage occlusion is reasonable. And a 2B recommendation, a weak recommendation, is given that in patients with AFib and a high risk, moderate to high risk of stroke and a high risk of major bleeding on oral anticoagulation, percutaneous left atrial appendage occlusion may be reasonable as an alternative to oral anticoagulation based on patient preference with the understanding that the evidence for oral anticoagulation is much more extensive. So for the next few minutes, I'll get into the details of the data that supported these recommendations. The first major randomized control trial evaluating the performance of percutaneous left atrial appendage occlusion was PROTECT-AF, published now 10 years ago. It was a non-inferiority randomized control trial that took 700 patients who had AFib and an increased risk for stroke. They randomized the percutaneous left atrial appendage occlusion, particularly the original Watchman device or Warfarin. It's important to note that these were patients that were considered candidates to continue Warfarin long-term. The non-inferiority margin was a relative risk of two, and the primary composite efficacy endpoint was stroke, systemic embolism, or cardiovascular unexplained death. And then the primary composite safety endpoint was procedure-related events like a pericardial effusion requiring intervention, procedure-related stroke or device embolization, and in major bleeding including intracranial or bleeding requiring transfusion. In follow-up for this study, this study met the non-inferiority for the primary efficacy and safety endpoints. So if you look at the primary efficacy endpoint, which again included stroke, systemic embolism, or cardiovascular death, the event curves were similar between groups and it met the standard for non-inferiority. For the primary safety endpoint, it also met the standard for non-inferiority between the two groups. So you can see that there were some early safety events that occurred with the device. And if you look at the non-inferiority, the margin for non-inferiority was two, and this just barely met that endpoint. And so this raised some concern and ultimately mandated a second randomized control trial. So this is just in table form, again, looking at the primary efficacy endpoint similar to between both groups, and in fact, a reduced risk of hemorrhagic or disabling stroke in patients underwent percutaneous left atrial appendage occlusion. And then again, there were numerically higher safety endpoints in the device group, but this did meet the endpoint for non-inferiority. The study did also show actually that there was a lower rate of cardiovascular and all-cause mortality in the percutaneous left atrial appendage group compared to the Warfarin group, which has been seen on meta-analyses comparing percutaneous left atrial appendage occlusion to Warfarin as well. Now as I mentioned, PREVAIL was another trial that was mandated because of the high rate of safety events in PROTECT-AF, and so second non-inferiority trial included 400 patients with non-valvular atrial fibrillation and an elevated CHADS-2 score, randomized to either percutaneous left atrial appendage occlusion or oral anticoagulation with Warfarin. This was the non-inferiority margin in this study, 1.75. Similar primary efficacy endpoints, stroke, systemic embolism, cardiovascular, unexplained death, and then a late ischemic endpoint of the composite of ischemic stroke or systemic embolism excluded after the first seven days after randomization. So looking at events that did not occur within the immediate period after the device implant. And then they looked at early safety events like all-cause death, ischemic stroke, systemic embolism within the first seven days of randomization, and then device-related serious complications requiring surgery or major endovascular interventions. Now the pre-specified criteria for non-inferiority was not met in this study, and the main reason why was there was just very few events in either group, and so it was underpowered to detect the difference between the two groups. So it did not meet the non-inferiority criteria. But the non-inferiority endpoint was meant for events not related to the immediate periprocedural period. So for those events that were not related to the immediate aspects of the procedure, the device was found to be non-inferior to oral anticoagulation for the primary endpoint. And in this study, they did find that the success rate for percutaneous left atrial appendage occlusion was higher than in the previous studies with a lower rate of complications as well compared to PROTECT-AF. Now a five-year meta-analysis of PROTECT-AF and PREVAIL was performed in 2017, and what the study found was that percutaneous left atrial appendage occlusion was associated with a lower risk of disabling stroke, as well as a lower risk of all-cause death, and then a lower risk of non-procedure-related major bleeding. And so this was offset by overall similar rates of major bleeding, but not accounting for the procedure-related bleeding. There was a lower rate of non-procedure-related major bleeding. And it's presumed, and we'll have to see as more data comes out, as this procedure has become safer, that this rate of major bleeding has become lower as well. Now we've talked a lot about comparing percutaneous left atrial appendage occlusion to warfarin. PROG-17 was the one randomized trial, to my knowledge to date, that has compared percutaneous left atrial appendage occlusion to direct oral anticoagulants. This was published in 2020. It's a randomized trial of 400 patients with non-falvular atrial fibrillation. They were randomized to either percutaneous left atrial appendage occlusion in this study, the majority of which were the amulet device or direct oral anticoagulants, in most cases a PIXABAN. The primary composite outcome was stroke, TIA, systemic embolism, cardiovascular death, clinically relevant bleeding, or procedure device-related complications, and the non-inferiority margin was 1.5. And in this study, percutaneous left atrial occlusion was found to be non-inferior compared to direct oral anticoagulants. Actually looking at the primary endpoint, there was actually numerically fewer events in the left atrial appendage occlusion group, and this was found to be non-inferior to direct oral anticoagulants. Now that's the available randomized data. Since that time, obviously a lot of these devices have been implanted, and registered data has informed us more about the safety and efficacy of this device. This is the EVOLUTION registry published in 2017. It's a prospective registry of 1,000 patients who underwent percutaneous left atrial appendage occlusion. They found, in general, a high rate of procedural success, 98.5%, with the caveats and the limitations of a registry. People have to enroll and submit data to a registry, so this may bias towards higher success rates than we're seeing in randomized data. In the one-year follow-up, what was interesting was found is that this overall was associated with a low risk of ischemic stroke. What is interesting about this EVOLUTION registry is that percutaneous left atrial appendage occlusion is associated with a lower than expected rate of ischemic stroke and major bleeding. What has been found in some of these studies is that the rate of stroke is actually dramatically lower than what would be expected by the CHADS-2-VASc score, which underscores some of the limitations that have been discussed about the CHADS-2-VASc score, that perhaps with contemporary medical therapy, the CHADS-2-VASc score may, in some senses, overestimate a patient's risk of stroke, which has relevance in our decision about whether or not someone should get a percutaneous left atrial appendage occlusion device in the first place. The EVOLUTION registry did show that there was a low rate of major adverse cardiac events after device placement and procedural complications, lower than had been previously described in either PROTECT-AF or Prevail randomized studies. And finally, the last study I'll highlight is the PinnacleFlex registry. Again, this is another prospective registry of the next-generation WatchmanFlex device. Again, a very high procedural success rate is reported, 98.8%, and a very low rate at the primary safety endpoint at one year's death. Ischemic stroke, systemic embolism, procedure-related events requiring open cardiac surgery are a major endovascular intervention. So again, the evolution of this device that it seems that it is becoming more successful in device implants with lower risk and may be, over time, a reasonable alternative to oral anticoagulation in some patients, especially those that are enriched with a high bleeding risk. So in summary, the randomized data demonstrated non-inferiority of percutaneous left atrial appendage occlusion to oral anticoagulation for the risk of stroke and major bleeding. Percutaneous left atrial appendage occlusion actually is associated with a lower risk of mortality compared to warfarin. There is improving success rates, lower complication rates over time. And based on that, our updates to the guidelines give a two-way recommendation that percutaneous left atrial appendage occlusion should be considered in patients with non-valvular atrial fibrillation and a contraindication to oral anticoagulation. And percutaneous left atrial appendage occlusion may be considered very carefully as an alternative to oral anticoagulation based on patient choice with important considerations. Now, these important considerations are number one, that we have an abundance of randomized data and clinical experience supporting oral anticoagulation. Several large randomized control trials showing that oral anticoagulation is safe and effective to reduce the risk of stroke as it pertains to atrial fibrillation. Not mentioned here, but we're all aware that strokes don't only come from the left atrial appendage. And so patients are not potentially protected from a stroke if it relates to causes that are not from the left atrial appendage in a way that oral anticoagulation may. And then the issue of device leaks and device-related thrombosis is an important one. There are several studies that now show that in a non-trivial percentage of patients that undergo percutaneous left atrial appendage closure that undergo follow-up imaging, device leaks and device-related thrombosis are seen. They are associated with an increased risk of stroke, but they haven't been directly compared to not being on anything, either not being on anticoagulation at all because you have a serious bleeding issue. And then I'll finally highlight this table that is from the guideline that, you know, when considering a bleeding contraindication that would warrant percutaneous left atrial appendage occlusion, we should really think about things that are irreversible and severe. So severe bleeding due to a non-reversible cause, either in the GI, pulmonary or general urinary system, spontaneous intracranial bleeding due to something that is clearly non-reversible, and then serious bleeding that is related to recurrent falls where the falls are not felt to be treatable. Beyond that, anything that could be conceivably reversible, oral anticoagulation is likely the better option in most of those patients at this point. So I'll stop here, thank you. Thank you, Nimesh. That was really an awesome overview as well of special considerations, special populations in anticoagulation as well as non-pharmacologic options. And it's really interesting with all the therapies that we have, oral anticoagulants and these percutaneous and surgical left atrial appendage occlusion devices. I was really intrigued, Fred. I'll just start us off with a question. I was intrigued by the data that you showed showing cardiombolic stroke is going up. Is it adjusted? Is it due to just a fib going up in our population? Or is it, you know, it seems like we would have made some difference by now because of the penetrance of anticoagulation and the appendage closure. Well, so that data is older. So, you know, 2012 was at least the date I showed. But it's interesting, that data, I just chose a Canadian study, but there have been multiple other studies that I could have chosen in the interest of time. I did not have it where it in fact does suggest that cardiombolic strokes are increasing sort of over time, really compared to sort of the other stroke risk, which I think we're doing better with hypertension, you know, things like that. Now, there are some differences as this group knows. There is a huge bias towards data and research that comes from European studies and North America. Now, better from Asia, things like that, a little bit from Africa, et cetera. But so nonetheless, let's think of, let's make sure that we understand that there are global differences in access to different types of drugs, care, et cetera. But yeah, you know, I think we are making some progress. Remember all the data, even the most recent data that I could have pulled here from a few years ago. In fact, the most recent sort of year that it looked at was 2016, 2017. So again, thinking about we're always behind. So my hope is, yes, that we are making progress. So I'm not the ultimate sort of pessimist, but I do think that, yes, I do think that we're making progress, but there's a lot of embolic stroke that's out there. We still don't know kind of this whole notion of atrial fibrillation. How does this happen? And I'm sure we'll talk about with atrial myopathy and other types of issues. And then what I emphasized sort of before with the Swiss AF, that in fact, we can put people on anticoagulation. We're not done. I mean, managing their diabetes, managing their high blood pressure, doing all of those other things to reduce the risk of stroke is absolutely critical. And maybe we can explore that a little bit. You know, the residual stroke risk, despite anticoagulation has been highlighted, by both of your talks. And I always thought, and have thought that oral anticoagulation is preferred over a left atrial appendage occlusion device, unless you had some contraindication to it. But the data that you showed mentioned, that you showed to Fred is having us change our thinking a little bit in that we are not done. And I used to think, and I was thinking, I'm thinking that, you know, you're only closing off the left atrial appendage and the rest of the atrial myopathy is still there. But this data that you showed about the different shapes, you know, the smoothness, I suppose, inside the left atrial appendage, maybe it really is due to the trabeculations, et cetera. Are you switching yourselves to maybe just go through our panel here in terms of, are you being more aggressive with left atrial appendage closure? Because now we have that indication that says if the patient prefers, you know, we can consider. I haven't really, to be honest with you. I still think, you know, those randomized trials are relatively small compared to the large body of evidence supporting oral anticoagulation. And I do think you brought up a good point about maybe oral anticoagulation may not be enough and that maybe there is some additive benefit to percutaneous left atrial appendage occlusion in some patients, but that has not yet been demonstrated. I think there are randomized trials that are evaluating just that very question along the lines of the Laos 3 study is that, you know, because in that study, most of the patients continued oral anticoagulation yet there was still a clear additive benefit to surgical left atrial appendage excision. But no, I would say for the most part, my practice is really only considering it in patients with serious bleeding issues at this point. I have to be honest, and I don't know about everyone else, most of the time patients ask about percutaneous left atrial appendage occlusion. For me, it doesn't have to do with bleeding issues. It has to do with cost of the drug, the oral anticoagulants. I mean, it's an unfortunate situation of our medical system in some senses that a patient is cheaper for them to get a invasive procedure than it is to continue oral anticoagulation. I'll just add a few points. And I have another disclosure with regards to left atrial appendage occlusion. So I'm the chair of this hearing committee for the NCDR and left atrial appendage occlusion. So for our listeners and viewers, please take that into account. But I agree with you, Nimesh. It's still anticoagulation really first, unless there are other types of issues. We have to wait for Catalyst and Champion to come out. And I still don't think it's going to be a clear answer at that point in time, because it's interesting thinking about Andre de Tau's work showing that device related to rhombus. And maybe what you do is you do the left atrial appendage, plus you give low dose anticoagulation. I'm not saying that for sure at all, but this is a complex issue. And the last thing I'll say before I stop talking is that we kind of stick everything all into the same sort of boat. It's kind of like persistent atrial fibrillation, which we all know has different types of mechanisms. I think the same thing here with stroke and AFib, that we kind of stick it into a single sort of bucket and hope that a single answer is going to solve this. But I think it's far more nuanced and way more complex than we appreciate. I can't add anything that is different to the practice, obviously as a pharmacist, I'm not implanting these devices, but I would say that our group's practice is very similar to what you've spoken of. And I haven't heard too much of patients asking for cost reasons specifically for the device itself, but they certainly come in with a lot of cost inhibitions asking for help. And it is an unfortunate state that we're in, but generally we're still reserving them for people with bleeding histories. And then the other issue that comes up now is we now have a code for being able to do concomitant AFiblation and left atrial appendage occlusion. Who do we do that? Who do we, where do we use that? What's the role of concomitant procedures there? Well, I'll take that first. I don't know what the others say. I don't do that. So there you go. I mean, it's just a lot of time in the left atrium. We don't know a lot. I personally think that code got way over its skis. And so I'll put on my health policy hat when I think about sort of things. I just don't, it's great to have it. And I know that people are spousing it, but I think it's way, way, way too early to do that as a more generalized things. Now, clearly there are gonna be some patients where there is a reason to do those procedures concomitantly, especially now that the boy, AFIblation is pretty doggone fast and left atrial appendage occlusion is pretty doggone fast and good hands, now with the flex and other types of devices. But still just because it's easy doesn't mean that we should do it together. Yeah. Just to add onto that, most of the patients that I consider for the percutaneous left atrial appendage occlusion are patients who I'm not really even making that much of an effort to maintain in sinus anymore. And I think this speaks to one of our biggest knowledge gaps along the lines of NOAA, AF and Artesia. Those are patients that without a previous history of clinical atrial fibrillation and asking the question, does oral anticoagulation benefit the subclinical AF? But a common question I get asked from patients about that I don't quite know the answer to is patients that have paroxysmal atrial fibrillation that undergo atrial fibrillation ablation or rhythm control that have from everything you can see pretty good control of their AFib. They have, if anything, very brief episodes do they need to be on oral anticoagulation? And if so, I mean, if they don't, then they may not need a percutaneous left atrial appendage occlusion either. So, you know, it's a gray area. I mean, I could tell you what I do for management but it would be completely, you know, not evidence-based. But in general, for patients that I'm sending for percutaneous left atrial appendage occlusion, it's usually patients with either a high burden of AFib or usually permanent AFib that I'm not really even considering rhythm control. All right, so I guess we have some randomized studies coming up. So I know OPTION is a randomized trial of ablation versus ablation plus left atrial appendage occlusion. And hopefully that'll get reported soon and might highlight, you know, give us some insights in terms of how to approach concomitant procedures. And Rod Passman's clinical trial REACT-AF for these rare episodes of AF. Can we do pill-in-the-pocket anticoagulation? Have you been using that or not using that? And Kristin, do you see that? Yeah, no. So this is something that we've definitely talked about. We're not comfortable with that yet. We have not moved towards that. We obviously do get a lot of patients that ask about that just with hesitations, but maybe depending on data that comes out, but right now we can't recommend it, I don't think. Yeah, I wouldn't say it's something I necessarily recommend, but, you know, I certainly see a lot of patients that have a strong desire not to be on oral anticoagulation where, you know, the decision is either they're not gonna take it at all, or at least they will take it if there's convincing evidence that they have atrial fibrillation. In those cases, it's kind of similar to the REACT-AF, at least protocol that it's kind of a la carte when they have episodes of AFib that are substantial, that are detected in some fashion, then they go back on anticoagulation. So REACT-AF may include a CHADS-2-VASc score cutoff. What about somebody that has PAF and it's really, you know, got a low CHADS-2-VASc score? You know, would you consider it at that point? Because they wouldn't necessarily be on oral anticoagulation. Well, I'll take that. I mean, I think we're all dancing around the thing that we don't know the mechanism for stroke in all patients. I mean, clearly there are cases where it's causal. I absolutely, there is good data, you know, back in the old days, oh, it was all atrial myopathy. No, when you look at AF burden, there is something there. I tried to show the permanent versus the paroxysmal. There's other data that I could have shown. Rod shows beautiful data with certain interpretations where in fact the AF seems to sort of mediate that risk for stroke and others where in fact there doesn't seem to be a temporal relationship between AF and stroke. I think those are patients with atrial myopathy. We've all done, you know, these sorts of procedures where, you know, we kind of do a quickie voltage map and my goodness, you know, they've not been touched before with ablation or whatever the case may be, but boy, the AF is, you know, the atria is just a desert. It's barren of EGMs. And so I think we're gonna get better. I really do, but I do think that what we're dancing around is causality versus association and really trying to tease that out. And just as a sort of a general guide, maybe wrong, I think that the older someone is, I'm thinking more likely it's gonna be association rather than causality. And the younger the patient is, I'm thinking a little bit more along the lines of causality, but that's just a Fred Kusumoto type of thing. And please don't, you know, sort of take it as something that comes from the guidelines, et cetera. It is a difficult decision and is moving. And that really gets to what Jose and you, Mina, we're getting at thinking about AF and risk of stroke in a more nuanced and more complex fashion where you're really thinking about the annual risk of stroke as opposed to their scores or whatever the case may be. And kudos to the both of you for leading us through that, because I think absolutely important as opposed to just saying, Chad's vast score or Chad's VA, who cares, blank. That means you get it. And it's blank, you don't get it. You know, it's just not that binary. Right, and it's everyone on the writing committee, we had some really robust discussions on that. And, you know, so I actually, let's go to that, because how do you do this practically in your practice now when, you know, you have these guidelines that say 2%, 1%, and as you showed the data, even on the different studies, it's sort of variable in there. Yeah, that was my question. I was interested to hear the interpretation and how you apply in those patients that are in between that have say a Chad's vast score of one or annual score of 1%. And then, you know, what things do you weigh? You talked about, is there hypertension controlled? Is there diabetes control? What do you give weight to each of you? Well, I'll go first, since it was my slide. So a couple of things, interesting, you know, when we think about the Chad's vast score, you know, I pulled out some slides looking at some of that Taiwanese data and the Hong Kong data, which are the real outliers. It really did show that the, in fact, that the Chad's vast score, the higher the Chad's vast score, the higher your risk for stroke. It's just that it started at such a high value and then got to a super high value, you know? So there are a host of things, cigarette smoking that we didn't talk about. We talked about, you know, I briefly mentioned the anatomy of the left atrium. Again, I think it gets back, at least for me, and I'll be curious to hear what the other panelists and the other speakers here say. It really gets down to me thinking about whether or not I think it's more likely causal versus association with AF burden. And then kind of going through some of the other discussions and then really talking to my patients. I mean, it is truly shared. It has to be shared decision-making. I mean, we have this big thing about that and appropriately so, because we tend to stick things into these big buckets and I just don't think it's necessarily applicable. Yeah, I think the only thing that I would add to that, I mean, out of the CHADS-VASc score, if I had to say which one, at least in my mind, seems like it's the most critical one, if they have, would probably be the prior history of stroke. I mean, I think that's the one that most predicts the risk of a future event. So, you know, but again, I guess that's really, that's already a CHADS, that's already a score of two then at that point. So, yeah, I don't have anything else other than that that Fred said in terms of, just consider them all almost equally, except for maybe stroke in my mind. There is a meta-analysis. I pulled this slide up. So, I showed this group instead, the Danish group that age also. So, not only stroke, but when you look at sort of age. So, I will often, the older someone is, the more I say, look, you don't want to have a stroke and I'm more concerned about you having an atrial myopathy. So, I put a lot of weight into that. So, if someone has, you know, is 73, you know, for example, I say, hey, look, man, you're going to be 75 in a few years and it's not going to suddenly, you know, your stroke risk isn't low now compared to two years. And the other thing we're dancing around is this is not giving warfarin, right? This is giving apixaban, which has the same bleeding risk in Averroes as aspirin. So, you know, that is, so that has changed that sort of risk benefit ratio. And I get to Neemesh's point about cost because I do have a lot of patients in my practice who, you know, think about that a lot and it's often in the donut hole. My hope is things like the health policy strategies of, you know, in a few years, being able to have Medicare negotiated, apixaban, rivaroxaban, et cetera. These are the kinds of things that are going to help us and make some of those barriers a little bit lower. And we didn't even talk about factor nine, you know? So again, it is evolving really, really rapidly. And so very exciting for the audience who doesn't, don't know, can we actually work higher in the coagulation cascade and get rid of that pesky factor seven bleeding there, but then actually then reduce risk of bleeding. The data's mixed, but fascinating that this is clearly a moving target. Right. So I think on a practical basis, what I intend to do is, you know, CHADS-2-VASC as you showed is the most studied score. And if they have a higher CHADS-VASC score, it's a no brainer. I will recommend the anticoagulation. But as you showed, it's in the lower risk groups that you use some of these other factors and it may be Garfield, it may be atria, it may be some other risk score, but we also have a table in the AF guidelines that show some of the factors that are associated with higher risk of stroke outside of CHADS-2-VASC. And they do account for things like the atrial myopathy, left atrial enlargement and AF burden. You pointed out that more persistent does have a higher risk. So there are features like that and what you also covered Fred about uncontrolled hypertension, et cetera. So there are things like that in there to cover. But yeah, thank you. A reminder to the audience to put in questions if you have any. But let's talk about subclinical AF because we were somewhat guessing when we were writing the guideline because it was before Artesia and NOAA-AF came out. So how do you think things have changed now with Artesia and NOAA-AF and are there different cut scores? Do you think about the subclinical AF a little bit differently? Yeah, I mean, maybe those trials made me feel more confused than anything else to be honest with you about how we should manage this. Before those two trials, I was probably basing most of my management off of, I think it's called the ASSERT study that looked at device detected atrial fibrillation and risk of stroke. Obviously it's not randomized data like NOAA-AF and Artesia, but essentially initially it found that, the initial study I think found that even short episodes were associated with the increased risk of stroke. But once it was, the post hoc analysis, kind of once it was stratified by various durations that it was really episodes greater than 24 hours with six to 24 hours being kind of this gray area, that had sort of framed my thinking on how I would manage patients with subclinical AF that are at least device detected atrial fibrillation. If they certainly had, if they had greater than episodes, lasting greater than 24 hours, in most cases I would prescribe oral anticoagulation. If it was between six and 24 hours, I would kind of consider their other risk factors as well. And then for the most part, if they had episodes less than six hours that were relatively infrequent, in many cases I would defer oral anticoagulation in those settings with the understanding and that's not based on any randomized data and with shared decision-making with the patient. Well, I'll add a little bit to that. So in the guidelines, in fact, there is this lovely sort of, I don't know, you can't really call it a table, but a figure showing that, you have to take in, what are the consequences, right, of atrial fibrillation? So it uses the CHADS-VASc score, but you could use anything, right? So that the more that there is a higher likelihood for sort of stroke risk, then you're going to think about sort of is, does that then make me pull the trigger at a lower level of atrial fibrillation? You're spot on. And again, it gets to this conflation that we have with atrial fibrillation, right? Because it's an EKG diagnosis when someone comes into the hospital. Well, these are all patients in ASSERT, which looked at this little atrial pacing protocols for reducing AFib, which didn't work. But anything, as Nimesh pointed out, greater than five minutes, six minutes, so you got rid of the artifact, et cetera. So they had AFib, it just wasn't clinical. Those were all patients with basically sinus node dysfunction or a large percentage of them, at least certainly in most and in ASSERT. With no AFNet6 and artesia, I mean, this is a different population potentially compared to sort of all patients. But the audience should know, these were patients that had high CHADS-VASc scores. Average was, as I recall, two to three. Certainly placed people that you would think about to anticoagulating. And they had long episodes. It was three to four hours is sort of the median. And this was significant. They were subclinical. And so is this subclinical AF something different in the patient who has sinus node dysfunction? But to get back to, you know, Kristen agreed with me sort of before, you know, it's not like we're telling people to go on anticoagulation with Coumadin, right? I mean, I get it that it's expensive, but we're talking about something that is reasonably easy to take and is not too difficult. So again, at least for my practice, it's made me sort of decrease sort of the bar, you know, a bit. So even in the setting of NOAA-FNet6 and Artesia, which in fact, although we can talk, argue about the nuances on sort of, we were at equipoise really, where one study suggested a benefit potentially and another sort of not, it really is one of those shared decision-making. I have so many of my patients who are just horribly afraid of stroke. Well, if that's the case, then we should think about this. On the other hand, I have other people who say, God, I can't stand this anticoagulation. You know, I do something where I work out a lot, that, you know, whatever the case may be, and if they're willing then to take on that risk, but it is a long discussion, that's for sure. Right, NOAA-AF6 was stopped early and the meta-analysis with the two of them did show a significant reduction in stroke with anticoagulation. So we have that data and our- Albo versus placebo versus aspirin, you know, which has some additional risk of bleeding. So it's not quite as clean that we can, you know, jump between those two. And I know you know that, Mina, but I do think that it's important for us to, you know, sort of, again, while I appreciate that Jeff and colleagues, they did that, it still doesn't change the fact that, like Dimesh, I'm really confused. Yeah, I mean, it was at the risk of higher bleeding, although they would argue that it was, you know, not serious or fatal bleeding. So I guess we'll see the, I think there are more sub-studies that are coming out that may be enlightening, maybe in terms of, you know, the actual, that we had written a certain CHADS-2 VASc score, you know, above, which we would anticoagulate. And, but hopefully we'll get a lot more enlightenment with some of their sub-studies coming out. So someone has a question about post-op AF. Yeah. Yeah, I was just going to introduce that. So what are your thoughts on stopping anticoagulation after like post-op AFib? And then as a separate question, also after AFib ablation? So let's take that. Yes. Yeah, I mean, I guess I'll tell you what, you know, my practice pattern is, I guess. For post-operative atrial fibrillation, you know, when I see them in follow-up, usually taking into consideration what their other risk factors for having atrial fibrillation are outside of the surgical event. Many of these patients are at increased risk and that I don't necessarily just assume that this was an event isolated to this surgical episode. And in most patients I discuss, you know, either remaining on oral anticoagulation if the patient has an increased risk for stroke based on these stroke risk scores, or if they have a strong desire to discontinue oral anticoagulation, some sort of close surveillance for recurrence. And, you know, again, it's all shared decision-making with the patient. Not every patient wants to have a loop recorder stuck into them. And not every patient wants to wear an Apple watch all the time or a smartwatch to detect for it. So I go through all the different options, either, you know, just close clinical monitoring if they were, you know, clearly symptomatic when they had the episode, or maybe a home ECG device, like the cardiac device or watch. I could kind of go through all those options with them. And then if the simplest option is just for them to continue to take oral anticoagulation, then I think that would be quite reasonable to do if a patient has a lot of risk factors for recurrent atrial fibrillation and also a high CHAS-VASc score. And then I guess the question is about post-ablation. And, you know, that is sort of what I brought up earlier and I think is just uncertain. I don't know the answer to that. I mean, again, I've had some patients who, frankly, their main reason for wanting to undergo a rhythm control strategy is in the hopes that they might not have AFib and thus may not need to take oral anticoagulation. Sometimes it's not just symptoms that patients bring that up and spend a lot of time highlighting the uncertainty of that strategy. But I have, in some cases, been willing to do that, that do an AFib ablation or anti-rhythmic agents with close surveillance for recurrent atrial fibrillation with obvious understandings of the limited data to support that strategy. So I have nothing more to add. What the questioner emphasized and what Nimesh just mentioned is that AF in the setting of cardiac surgery, very, very different natural history than those patients who don't have, who have AF in the setting of non-cardiac surgery. Remember, because of the inflammatory process, things like that, when you follow people who had AF after a mitral valve or whatever the case may be, even though they have cardiac issues, their future incidents of atrial fibrillation, once they've kind of gotten it corrected, lower, if you take everyone collectively. Now, obviously it's nuanced and it has to be individualized. So I wanted to emphasize that point that might be lost on the rest of the, sort of the audience. The second thing is there's a lot of studies, registry studies, looking at patients and their stroke risks after ablation. And at least there is one Chinese study to suggest that two is the cutoff. I don't buy into that. I think it really is something that, at least at this point, it's an independent decision. I do think that there is some help that we get from the AF study. I mean, from the EP study itself. And that's why I am a firm believer still, even with PFA and everything else, getting a feel for what does the atrium look like? I mean, we focus on the ablation, but it's important that it's a diagnostic and prognostic procedure also. Because again, as I just mentioned just briefly, there are some patients who have not been touched with prior AF ablation, whatever the case may be. And my God, their atria looks like a desert. And other patients where I think you're gonna have this horrible atrial myopathy, you've had 20 years of diabetes or whatever the case may be. And the atria look beautiful. And the voltages are great. And I can't change any of the conduction. Who knows what we're going to do down the line. But I think that we are going to get to a more nuanced decision-making by adding some of this additional information that we get at the EP study and other things that we think about clinically that Nimesh already brought up. Really Fred, in those if desert, the electrogram desert ones, you might want to consider genetic testing as we were recommending, have a recommendation for genetic testing for early onset AF and some of the cardiomyopathy. They have a higher rate of cardiomyopathy and ion channel mutations or variants. And some of those like Lamin A may have very low amplitude and there may come a day actually where that really influences our anticoagulation strategy as well. Yeah, and amyloid too, right? I mean, that's what you mentioned, I mean, my goodness. And so, and that's something that we can potentially do something about for ATTR. Yeah, I just wanted to mention, we do have a recommendation if there's for acutely ill patients that were septic or otherwise acutely ill and they have atrial fibrillation that we do recommend doing some sort of surveillance or follow-up because some of them really do have a higher rate of AFib recurrence. So, and it's probably worthwhile kind of looking at as well for post-op AF. But for ablation, I go into the ablation telling them, this is a separate question, that you shouldn't go for an ablation to think that you're gonna get off your oral anticoagulant, that it's a separate question. There's a, we have a ceiling of success for AFib ablation that it's not 100%. We see reconnections, not infrequently, we see it with PFA, similar to thermal ablation. And hopefully maybe that'll get better as we're mapping or retouching or whatever we're doing with PFA. But I tell people their bodies have an amazing way of growing across what we do to it. And so just like in Affirm way back when we were doing rate versus rhythm control and some people were getting taken off of their anticoagulants, the AFib would come back as a stroke. Well, a similar thing could happen with AFib ablation that we can reconnect and then be at risk for a stroke. So that's what I warn people going into it. Anyway, any other comments or questions? I just wanna give you a chance as well. We covered a lot today. And I think we covered ablation, we covered both rare episodes, subclinical AF and atrial myopathy, the role of that and the future. What do we see as the future? Do you see any hope in terms of the factor loving all these other new anticoagulants that may or may not be selected? You mentioned that a little bit, Fred. Oh yeah, I think it's gonna be a huge future. I mean, Kristen, you know this better than I, so. No, no, no, I think we're still early but I think it is exciting. I think as a recap, I can't emphasize what you said earlier about emphasizing to people the difference with the DOACs. I had the conversation today where somebody only thought their option was Warfarin or nothing. But, and just to think about in five years where we might be with newer agents and it's been an eventful 10 plus years with the implementation of DOACs and I think we only have good things to continue to come. Right, and when we do have some help with some, I think some lower drug costs coming, it's still gonna be exciting, I think, but still hopefully some help with that. We hope so. Okay, any last thoughts? Okay, great. Well, with that, thank you all very much. This was really stimulating, really interesting being on the cusp of even more data coming in that will hopefully really help us with some of the gray zones that we've highlighted. But thank you very much and have a wonderful evening, everyone and hope to see you at HRS in San Diego. Thank you.

AFib Guidelines

anticoagulation

stroke prevention

non-pharmacological therapies

CHADS-VASc

left atrial appendage closure

PCI

chronic kidney disease

LAOS III trial

Watchman device

genetic testing