Good afternoon, everybody. How digital health can be best implemented in care of patients with AFib in this innovation session here afternoon at HRS San Diego. Before I start, I would like to thank the team that made this lecture happen, if the slides will work. This is the team, you see the pictures here, Dr. Massad, most of the data by Chen Ho Lim and his team at AI Engineers at Triad, but this is a team that makes, we talk and they work. Great team to be around. The whole lecture will be around this strip. My whole lecture will be around a strip of ECG that we get from our patient every day. Everything I'm going to talk about, I'm going to make that, this specific strip useful in our clinic and how we treat our patient, and I'll tell you some of the data and some of the work we're doing with Chen Ho Lim and his team at Triad. Digital health today, all of us talk about it, all of us get excited about it, every one of us get interviews about it, and Dr. Friedman probably, he was interviewed on TV and connected 600 times about digital health and medicine, and nobody can start even discussing it if you go to details. For us, and I think to be realistic, we get the tools, a lot of tools, watches, I bet you in this room looking around, more than 90% of you have something like my watch that does some kind of data that you report to yourself, to your phone, or somewhere. That's digital health, but realistically, to take advantage of this, we need the culture that we're living in today, which people like Chen Ho and Han put together, to the AI world we're living in. Without that, it would be impossible to even start talking about digital health and be in front of you today. So AI plus these hardware tools, the Samsung watch or the devices like ECG check or AliveCore make that useful for us in the clinic, I want to show you how and what we do with it in terms of AFib treatment and management. All of us today who manage atrial fibrillation, specifically, we use patches on the chest, we use an ECG 12 lead to record an ECG on the patient, see if she or he have an AFib, or we do a continuous monitoring, loops, pacemakers, and ICDs and so on. But recently, the last 10 years, we're becoming more and more excited about tools like this. Is it the watch, the Samsung watch example here, or the Apple watch, or the devices like AliveCores and so on that you can do, or using the phone with the light, like the HappyTac concept, from Yusuf and his team in Amsterdam. So this is becoming a standard of care. Everybody, in fact, this is data from us and it's published, more than 80% of the patients that we deal with in our clinics have some kind of device that records an ECG or a PPG. So think about that. So how can we leverage on this and take advantage of this data that's coming to us and available right there in front of us? So applying digital health in my practice, I want to talk from my perspective and from Dr. Massad's perspective, I didn't say Ghassan this time, I said Massad, see? Screening for atrial fibrillation, we use this routine, I'm sure, some data, optimizing treatment pathways when we see the AFib patient in our clinic, how we're using these tools to improve management, and last but not least, post-treatment risk assessment. So this is seen and published and talked about everywhere. I have similar data using, this is using the Apple Watch data, the Apple Heart Study, the famous Apple Heart Study where we discovered a lot of new onset atrial fibrillation out of detected episodes using the watch, just people walking around without, healthy population practically was included, you know, just online. As you know also, the data from Holland that Happy Tech presented using the light, we discovered like 5% in people living in the city, in Holland as a country actually, not a city, with atrial fibrillation. So the tools are available and there to screen atrial fibrillation, that's an established, that's there. A patient coming to us today, actually involved, in fact, if you talk to Monique Young sitting here in the crowd in the back, she would tell you two patients a week come to us with the smartwatch or smartphone, a-fib, meaning they discovered their own a-fib and they called us to have an appointment. And probably in your practice, you see this every week in and out. This is a heartline study which is, I'm part of the team, this is the executive committee of this trial with Dr. Gibson and co., where we took Apple Heart Watches or Apple Watches and Apple Watches. I forget the name because we're using Samsung now. So Apple Watch with Johnson together to look at how we manage the a-fib patients and detect a-fib. So this is a device and this algorithm in the watch, hopefully the data will present it in AHA, the late breaker, the watch itself not only detect a-fib in one group but also helps us manage that a-fib in that patient. The other group, we titrate the blood thinners based on the watch and we have some algorithm that they follow. So you can see already we're using these tools to manage our patients with not only detect a-fib but also manage. And tools are coming on to standardize this approach and hopefully Apple Heart Study or this heartline study will be one of those. SMIRDN. I want to talk about SMIRDN, where we take a simple ECG, the ones I showed you, a strip. This is data from, it's unique data, I was talking to Yung Shu yesterday and Chen Ho. The unique part of this where we can do the SMIRDN concept at Tulane is because of the data we collected from the D-CAF2 trial where we tried to ablate patients with fibrosis using MRI versus standard of care prospective randomized 840 patient trial. What's unique about that trial was we collected using the ECG check device, like an AliveCore device to record ECGs every day. So the patient will send us, the CEO is sitting there in the back, every day the patient will send us strips, 2016. So we end up with 850,000, I think that's the number that was given to me, strips of ECGs in these patients. So what we did, prospectively, following this patient with their quality of life symptoms and echoes and so on, we ended up with using that markers in everyday ECG and to define the SMIRDN concept, which we published a couple of times on this, it's Mariam Kheir who's sitting here, worked with Sherbert on this, and published a couple of papers, a lot of stuff and co. But we used this daily ECG to define the SMIRDN, the Smartphone Based Burden of AFib. One AFib episode divided by numbers of sinus rhythm gives you a SMIRDN number. Why this is important and helped us understand a lot of in this patient population and working on the continuous complicated patches and implantable devices, trying to avoid that, if you can tell from this slide, SMIRDN correlates very well with the quality of life of our patients at trials. So this is a marker you can use based on a single ECG sent to you by your patient from the Apple Watch or Samsung Watch or the RF Core or whatever device. You can see the correlations very well at zero months, three months, at 12 months. The less burden, the better quality of life, the less SMIRDN, the better quality of life. So we made that a very solid indicator for outcome after treatment of AFib. Also it helped us, and this is becoming now everywhere talked about, shortening the blanking period of our patients after ablation. You know, all of us who ablate AFib, we usually wait three months to consider success or failure. But now, based on the SMIRDN data, we're using the one month's 8% number or 10% as a marker. If you have less than 10, 8% SMIRDN, then it's a good outcome predictor of outcome. That's unique from a simple strip a day can get you far predicting outcomes. Also that same strip that I showed you from this, from your watch, from your RF Core device or EC check and so on, you can use it, or actually, you can show use it to tell you this patient, although today and now is showing you he or she on sinus, he might have with an ROC of 0.92 chance that have an AFib three days before or might have AFib three days after. It's a dynamic marker that you can use it because, as you know, everything changing and AFib is dynamic. But this is pretty cool. I like it a lot because now, if a patient sends me a strip a day or a week at least, if I miss a couple of them, I can tell the risk. He calls it the high risk and low risk ECGs or the bad ECG versus normal or healthy ECG. That's the nomenclature we're using. So you can tell strip a day get you far in managing your patients with atrial fibrillation. Today in our clinic, this is an algorithm from Chun Ho Lim who established our clinic working with Monique and her team. And we manage our AFib patients, we apply this. Send us a strip, we look at the strip, run the algorithm, should we give an antiarrhythmic drugs and wait, do more monitoring, or should we send them home, come and see me back in three months. Helped us a lot today and now in our practice. Now post-treatment management, I talked to you about managing the treatment or modifying the treatment and screening. But having said all this, AFib classification should be considered in our opinion based on the patient itself. We have enough data using these tools, specifically ECGs and the watches and beyond. I want to share our, since this is an innovation session, I want to share some of our work we're doing with Samsung and with our AI team sitting here to work on that using a simple ECG piece of data to change care. What's unique about this here, this is the heartbeat study which Samsung, as you can tell, opened for us, the blood pressure manager tools and other algorithms that Chen Ho and his team can access. They're all data that you don't see from your watch when you download to understand what's going on with our patient and build our algorithm. I'll show you some of what we're doing with that. Ten thousand watches at Tulane University for the state of Louisiana. I'm happy to announce that in December last year we started this trial, now we have more than 1,300 patients into the screening and processing and so on, and hopefully we end up with 10,000 in this year, a deluge of information and data that people like the engineers and I would love to see that, but I would like to see that as well because it's helped me a lot. I'm learning a lot myself and the clinical team. So this is our inclusion. We're getting people with different diseases and trying to understand the interaction with diseases. Arrhythmia is one of them. Aim number one, as you can tell from here, from this slide here, is the association between biometrics and cardiovascular events in these multiple disease and interaction progression of diseases. And every three months we have some algorithms and data being finished. And also the fingerprint, we call it. Every patient should have the biometric fingerprint that the watch will give you that alarm based on what we call the clinic on the risk finishing this. And this is the largest trial, if you look out there, with sick people because it's not an Apple heart study or a heart line with all like online recruitment. These are clinic patients we're recruiting in the trial, so we have a lot of pathology that we're tracking. Let's make this study unique, plus carving into deep, deep into the amount of information we're collecting from this study. So this is what the patient sees every week, what we see in continuous data of at least 20 hours a day. And I'm amazed actually by the compliance of these patients using these watches already. 12 hours a day of information plus a daily ECG on top of this, you can imagine what we're doing with this already. These are the first four goals we're working on, and we have data, we'll present it as we go, hopefully in the next three months. Preventing stroke, predicting patient high risk of strokes, there are a lot of stroke patients in there. Preventing hospitalization with heart failure, exacerbation, we have data on this already, we'll be presenting it soon, already, within three months of data. And then identifying high risk afib, the ECG I showed you from Yung-Chu, and then diabetes, and we have data on HB1C, using PPGs in this marker in the patient plus the ECG. Very exciting work because we have 20% of our population diabetics. So I can tell, having access to these tools, we're leveraging using AI engineers in the room to make this useful in daily practice and start fingerprinting our patients. And I want to, I'd like to show this slide, and everybody I bet you in this panel and this room agrees with me. It's unfair today and now to diagnose afib as paroxysmal persistent. We have more than that. It's not a yes or no question. That's actually a slide from Masad. It's not your, I debated the green cross, but he wanted the red one. So it's not. What it is, I think there's this concept of my afib, every afib is different. With all the information we collect in our patient, continuous monitoring of atrial fibrillation and the burden, the biomarkers in our patient, you know, and we collect it, cardiovascular disease interaction, and all this with AI, which we're doing as we speak, as I showed you from the example. I'm going to come back here, hopefully next year, if I get invited again by Dr. Freeman, to show you this patient's fingerprint, their afib, his afib, and her afib. It's not the paroxysmal persistent. It's this patient's specific afib with these fingerprints. I'm confident we're going to be there with my afib concept very soon. Going back, to summarize it all together, I started with this strip, I'm ending with this strip. ECG strip a day, as Mariam Kheir would say, we keep Maroush away. So we're doing the SMERDN from a single strip. I showed you all the data on the SMERDN and burden in the patient afib. Need for antiarrhythmics. We routinely apply this in our clinics. There's a trial we're starting as well with the University of Washington and Cleveland clinic, and predicting the onset of the afib. This is important, to find this high-risk population with a single strip. More follow-ups, more monitoring, to hopefully avoid higher and horrible outcomes in this patient. Thank you. Thank you, Dr. Maroush. I think we'll move on in the interest of time. So next up, we have Dr. Freeman from Yale University. All right. Well, thank you very much for the opportunity to speak today. I'm Jim Freeman, and I'll be talking today about stroke prevention and atrial fibrillation. So it's a lot to cover, the latest in stroke prevention and atrial fibrillation in 10 minutes, so excuse my pressured speech. I'm going to try and get through a lot very quickly. So when we think about stroke prevention, obviously we think about those with moderate to high risk for stroke. And then we think about drug therapies and device interventions, so I'm going to start with drug therapies. Obviously, the mainstay of therapy for, you know, now well over a decade are the DOACs, and that's really based on data showing that compared to Warfarin and this meta-analysis, you can see that there's favorable statistics with regards to ischemic stroke, rates of hemorrhagic stroke and intracranial hemorrhage, about half of what we expected with Warfarin, and then all-cause mortality about 10 percent lower, and that's largely driven by the intracranial events finding. That's counterbalanced by an increased risk of GI bleeding, and I think people sometimes forget that. It becomes particularly relevant in a world in which we're thinking about device-based therapies as an alternative to anticoagulation, because a lot of these patients do end up with GI bleeding. The new kids on the block from a pharmacologic standpoint are the Factor XI inhibitors. So the idea here is that the promise was that these drugs would deliver with less bleeding and similar efficacy with regards to stroke risk reduction in patients with atrial fibrillation. So how are things going thus far? There are three drugs. The first is a monoclonal antibody. The other two are small molecules. The first is subcutaneously delivered, and the other two are orally delivered. And of these, so far we've seen two Phase II studies, the Azalea Timmy 71 study and the Pacific AF study. Both of these did, in fact, show lower Factor XI levels and suggested lower risk for bleeding. The only Phase III study thus far is the Oceanic AF trial, and that's about 15,000 patients with atrial fibrillation at high risk for stroke, randomized to oral asyndexin at 50 milligrams a day versus Apixaban at standard dosing. And this trial, unfortunately, was stopped early. The primary endpoint was ischemic stroke or systemic embolism, and there was about a fourfold higher risk of the primary endpoint in the asyndexin group compared to the Apixaban group. From a safety standpoint, the bleeding rates were lower in the asyndexin group, but again, because of the primary endpoint finding, the efficacy finding, the trial was stopped early. So, a little bit of an auspicious start to the Phase III studies in this space, but we'll have to follow it closely. There are, in fact, three Phase III studies that will be evaluating each of these drugs in the coming years, and, you know, we'll have to follow this very closely. I think a lot of innovation happening on the device side, so I'm going to spend the rest of the talk talking about left atrial appendage occlusion. This space is growing extremely rapidly, near exponential growth here in the United States. This is as of July of 2024, over 425,000 procedures done in the U.S. We're now up to about half a million. Commensurate with that, the number of physicians performing the procedure, now up to over 3,200. The number of hospitals, almost 900 in the United States doing this procedure, so just huge growth in this space. The first big story that I think is sometimes under-talked about is the improvement in safety with device iteration, going from the first-generation Watchman to the second-generation Watchman Flex device. So this is work that we did demonstrating that the rates of major adverse events dropped by almost half, from 2.4 percent to 1.35 percent, and that was largely driven by a really remarkable reduction in pericardial fusion requiring intervention, from 1.2 percent to 0.4 percent. The rates of catastrophic complication, also importantly, really dramatically decreased, so now from one in 500 to one in 1,000. You have to remember, the average age of people undergoing this procedure in the United States is 76 to 78, depending upon what cohort you're talking about. Average CHA2-VASc score is 4.7, average HasBlood score is 3. A lot of these patients are really ill, so driving down safety events to this low a number is pretty remarkable. That did not come at a cost of a procedural outcome, so I think this was really good news. People had concerns that the device may not perform as well, and in fact, with the ability to reposition the device a number of times and optimize positioning, device implant success was markedly better with the new generation device, and this has really set the standard for safety in this space, which is a really big deal, and I think a very high bar for other devices, and we'll talk about that a little bit. With regards to effectiveness, we now have data five years out from the major randomized trials in this space, both PROTECT-AF and PREVAIL. We have five-year meta-analytic data. This is data we recently published using Medicare data linked to the LAO registry, showing rates of all-cause stroke about 1.8 percent per year, and very importantly, that remains very steady over time, okay? So there were concerns that there were going to be durability issues with this device and that over time we would see increasing stroke rates, and that's not, in fact, the case. Even as these patients age, the rates of stroke remain very steady over time. The other thing that I always remind people of is that the rates of death, all-cause mortality after this procedure, are about 8.5 to 9 percent per year. So by the time you get four years out, about 40 percent of these people are dead, and I always say this. This is a reminder that we really do need to engage in shared decision-making, be very thoughtful about this. You can only accrue benefit if you live a couple years from a stroke risk reduction, and so I just think important to remember to keep that in mind, that if people are at very high risk for dying from other things, then they're not going to accrue benefit from the procedure. The amulet IDE trial, I think the big thing to take home from the three-year data here is that the effectiveness was very, very similar to the first-generation Watchman device, and so I think very consistent findings that across devices and different modalities for closing the left atrial appendage, we're seeing very similar efficacy. The other thing to understand, though, about the amulet is that while safety events, if we look in the lower left-hand corner of this slide, that while safety events have come down with our real-world experience in the left atrial appendage occlusion registry, the eMERGE LAA registry is actually just a sub-registry of the left atrial appendage occlusion registry, rates of pericardial effusion remain persistently high, and I think that comes back to what I talked about, which is driving safety events very low with the device iteration with Watchman. I've handled the second-generation amulet device. That device has shorter anchors, they softened up the distal lobe, they invaginated the distal nipple. I'm very cautiously optimistic that the safety profile of the second-generation device will be similar to what we're seeing with WatchmanFlex, but for now, this device does have a bit of an Achilles heel in terms of safety with pericardial effusion. I think having addressed the pericardial effusion problem and really markedly improved that with the device iteration with Watchman, the next big thing that we need to be addressing in terms of major adverse events after left atrial appendage occlusion is bleeding. Okay, these patients are undergoing the procedure because they're bleeders, and particularly in the first six months after the procedure, they bleed a lot. And so that's because we have to use a period of antithrombotics after the procedure to prevent DRT, and so we need to be doing a lot of science around how to optimize what antithrombotic regime to be using in this time. We published two studies now in JACK showing that adding aspirin to DOAC after this procedure just increases the rates of bleeding and does not decrease thromboembolic events, and so unless there's a really strong indication for aspirin, I plead with everyone, stop adding aspirin to DOAC after this procedure. DAPT, we found similar rates of bleeding as with DOAC plus aspirin, but obviously we do have some patients that, no matter what we do, if we put them on DOAC, they're going to bleed, so that's a nice option as well, and we've demonstrated that. I think the next big study in this space will be the SIMPLIFY study, and this is a study of about 1,900 patients undergoing WatchmanFlex Pro, and the Pro device has a non-thrombogenic coating on it, and so the idea here is to see that with that non-thrombogenic coating, can we get down to single antiplatelet therapy with aspirin, or get away with half-dose NOAC or DAPT. It's a randomized trial, comparing those three treatment modalities post-procedurally, really important question to see if we can really minimize the anti-thrombotic regime afterwards and minimize the bleeding events. The option trial, I think everyone's probably fairly familiar with, but I will just talk briefly about it, 1,600 patients, randomized AF ablation plus a Watchman, either done concomitantly, which was done in about a third of the patients, and then in two-thirds, it was done within three to six months, or patients were randomized to AF ablation plus anticoagulation sort of standard of care. And what that study showed is that with regard to the primary safety endpoint of non-procedure related major bleeding or clinically relevant non-major bleeding, which is a bit of a mouthful, there was a favorable finding favoring those treated with the Watchman. Importantly, the composite of death from any cause, stroke, or systemic embolism was non-inferior really almost superimposed curve with regards to that endpoint, and I think very, very reassuring, and I think probably the take-home for me here is that finding. And then a trend towards an improvement in major bleeding in the Watchman group as well. There were some complications in the left atrial appendage occlusion arm of the study, but overall those complications were relatively modest and minor. So I think this is the first salvo in this notion of can we be using left atrial appendage occlusion as an alternative to anticoagulation even in patients without a contraindication anticoagulation, and in addition, because we had an opportunity to look at that third of patients who were undergoing concomitant procedures, I think the first really good evidence looking at concomitant and demonstrating the safety. We have another study from the LAO registry looking at concomitant procedures and showing some really favorable findings, so I think likely to see a lot of growth in that space. Champion is, I think there are really two big trials looking at this question, so Champion is 3,000 patients with moderate to high risk for stroke, randomized to Watchman FLEX versus DOAC, so best available device therapy versus best available medical therapy. I give them a lot of credit for this study in that it's a three-year looking at stroke, cardiovascular death, and systemic embolism, and then at three years looking at non-procedural bleeding, but then five years to evaluate for stroke and systemic embolism, so really doing the work to get follow-up adequately to really understand these two alternatives. Catalyst is the study that's very similar to this, about 2,650 patients undergoing the amulet procedure, and I think these two studies have very similar outcomes and endpoints and that will hopefully really help us answer the question of whether we can be thinking about left atrial appendage occlusion as an alternative to anticoagulation in basically anyone with atrial fibrillation who's at moderate to high risk for stroke. Real quickly, there are two devices currently in phase three trials right now, the conformal device, which is a device that's foam and then has this EPTFE coating to minimize the risk of DRT, and then the laminar device, which is really a completely different paradigm where you put an egg beater in the left atrial appendage, spin it, and then you have a small footplate that closes it and hopefully minimizes leak and doesn't have a great deal of retained material on the endocardium and can minimize that anti-thrombotic regime that's necessary afterwards. So, two really interesting, hopeful, hopefully sort of new paradigms in the space, and I think hopefully will give us some insight into other ways of addressing the issue of stroke. I'm going to finish by talking about the LAWS-IV study. So, this is a study of 4,000 patients, CHA2DS2-VASc score of four or greater, so these are patients at high risk for stroke, and they're randomized to WatchmanFlex plus DOAC versus DOAC alone. So, this is getting at the concept of residual risk that with left atrial appendage closure or DOAC, you really get about a 70 percent relative risk reduction with regards to stroke, but how do we get at that residual risk? So, if we put the two together, can we get it at that residual risk in these high-risk patients? And I think it'll be a really, really important study in this space. So, in conclusion, for anticoagulation, the DOACs remain the standard of care. The Factor XI inhibitor data thus far don't show substantial benefit, but we have three phase three trials ongoing, and they'll be really informative. Left atrial appendage occlusion use is very rapidly growing. Effectiveness has been very consistent, and we've seen real durability over time, and so super reassuring data. Device iteration has markedly improved the safety in this space, and I think it will continue to with the second-generation amulet. Post-procedural antithrombotic therapy is a huge opportunity to minimize bleeding, so as we think about that, just as they have in the PCI space and whatnot, I think we have opportunities to really improve outcomes for our patients. The option trial showed non-inferiority for stroke and systemic embolism and lower bleeding with left atrial appendage occlusion after a fib ablation, I think is the first salvo in terms of randomized trial data, looking at concomitant, and then similarly kind of gets us to this issue of whether we can be using left atrial appendage occlusion even in the absence of bleeding contraindications. And trials will evaluate this same question with both Champion and Catalyst, and then there are some novel device designs that could add real value in this space. Finally, the residual risk of stroke and bleeding remains with both anticoagulation and left atrial appendage occlusion, and so there may be a potential role for combining these therapies. Thank you. I want to thank our whole research group for a lot of the work we've done in this space. Thank you. Now we will continue with Dr. Paul Hess. His topic is Controlling Risk Factors for EF, where are we in 2025, Dr. Paul? Thank you very much to the chairs for the opportunity to present to this crowd. The topic for today is controlling risk factors for atrial fibrillation. Where are we in 2025? By way of disclosures, I've been funded by the Veterans Affairs for both a career development award as well as a merit award, neither of which will impact what I'll be presenting to you today. In terms of objectives, I'd like to provide a general context in terms of how we've thought about atrial fibrillation risk factor control over time using the professional guidelines as a rubric. I will then present class one and three recommendations per the most recent guidelines with regards to risk factor control for atrial fibrillation, then I'd like to discuss key data underlying each of those recommendations. By way of background, in 2014, there was not a single recommendation in terms of atrial fibrillation risk factor control. In 2019, there was an update where weight loss was specifically recommended. In the most recent guidelines in 2023, both primary and secondary prevention were discussed modeling it after atherosclerotic cardiovascular risk factor prevention. For the former, it was focused on lifestyle and risk factor modification, and for the latter, it was focused on weight loss for those who are overweight, physical fitness, smoking cessation, alcohol consumption, as well as caffeine consumption, hypertension and comprehensive care. Starting with the primary prevention, the guidelines read that patients at increased risk of atrial fibrillation should receive comprehensive guideline lifestyle risk factor modification targeting obesity, physical inactivity, unhealthy alcohol consumption, smoking, diabetes and hypertension. A study underlying this stemmed from the United Kingdom Biobank in 2007 and 2010. It was retrospective, observational and cohort-wise. They did a standard cost proportional hazards model evaluating the association between activity level and atrial fibrillation, and they also pre-specified interaction testing by sex. They found that there was indeed an association between physical activity and incident atrial fibrillation with a chi-square of 23.1, and secondarily, there was an interaction between physical activity as well as sex, women more so than men. On this slide, in the actual graphs, you'll see on the top slide that there was total physical activity, the top row. The bottom row was vigorous physical activity, and you'll notice that there was a benefit for women in both regards across the board regarding atrial fibrillation, and this was not seen with men. So with regards to total physical activity, it was a U-shaped curve, and with regards to vigorous physical activity, it was not helpful and, in fact, worsened with increased activity level. Interestingly, the next piece was weight loss, and the guidelines read that patients with atrial fibrillation who are overweight or obese with a BMI of 27, weight loss is indeed recommended with an ideal target of at least 10 percent to reduce symptoms, burden, recurrence, and progression to persistent atrial fibrillation. A key study underlying this recommendation came from Adelaide, Australia, and it was conducted between 2010 and 2011, enrolling 150 patients. It was single-center, randomized, and controlled. The intervention was weight management, and it was effective, leading to weight loss of 14.3 kilograms in the intervention arm as compared to 3.6 kilograms in the control arm. The intervention group had a lower symptom burden. They used a particular score, and it was 11.8 versus 2.6, and you can see on this slide here that there was early separation of curves that was sustained up to about 15 months. In terms of physical fitness, individuals with atrial fibrillation should undergo moderate to vigorous exercise training to a target of 210 minutes per week to reduce AF symptoms, burden, increased maintenance of sinus rhythm, as well as increased functional capacity and improve quality of life. A key study underlying this recommendation was Active AF, published in JAK-EP in 2023. Patients were randomized to either exercise or a control group. Those who underwent the exercise group underwent weekly supervised exercise for the first three months, followed by supervised exercise for the subsequent three to six months, and they were prescribed home-based physical activity with the opposite intensity, so increasing intensity over time during the study period. The control group received standard education regarding physical activity. And with regards to the primary study results, you can see in this Kaplan-Meier curve and unadjusted analyses, there was, in fact, a signal to suggest that there is a favorable benefit with physical activity with regards to AF recurrence. And in the pre-specified analysis, the risk in terms of the hazard ratio was approximately halved. In terms of symptom severity, there was a similar reduction in AF symptom severity among those who were randomized to the intervention arm. This was seen at both six months and as well as 12 months, suggesting that the intervention could be sustained. With regards to smoking cessation, patients with a history of atrial fibrillation who smoke cigarettes should be strongly advised to quit smoking and should receive guideline-directed medical therapy for tobacco cessation to mitigate increased risks of atrial fibrillation, cardiovascular complications, as well as other adverse outcomes. There's a nice study that came out in 2022 that was retrospective and was using the Rely Atrial Fibrillation Study, which was observational, and enrolled a little over 15,000 patients who were presenting to the emergency department. They did a standard logistic regression model, and the candidate covariates included not only the CHADS-VASc score components, but also key comorbidities. And interestingly enough, a number of the CHADS-VASc components fell out of the model, but tobacco use stayed in and was, in fact, associated with stroke risk, to the tune of an adjusted odds ratio of approximately 1.4. As far as alcohol consumption, the guidelines read that patients with atrial fibrillation seeking a rhythm control strategy should minimize or eliminate alcohol consumption to reduce atrial fibrillation recurrence and burden. A very nice study came out in the New England Journal in 2020 that was multicenter randomized and controlled at six hospitals in Australia. It enrolled patients who were drinking 10 or more drinks per week, and also had paroxysmal or persistent atrial fibrillation, and they enrolled 140 patients. At six months in the unadjusted Kaplan-Meier curve, you see an early separation of curves that was persisted all the way out to 180 days. And in the formal statistical analysis, the hazards was, again, approximately halved in terms of AF recurrence. And you saw a similar benefit with regards to burden among those who received the intervention. The burden of atrial fibrillation was approximately 0.5 percent as compared to 1.2 percent in the control group. And, you know, that effect was seen across subgroups of atrial fibrillation burden. This is a very interesting finding in terms of the caffeine consumption. This is a class three indication, meaning that there's no benefit. The guidelines read that for patients with atrial fibrillation, recommending caffeine abstention to prevent atrial fibrillation episodes is of no benefit, although it may reduce symptoms in patients who report caffeine triggers or worsen atrial fibrillation symptoms. A key study, and also a coauthor on these guidelines, was put together by Greg Marcus at UCSF. This was the so-called iSTOP atrial fibrillation trial, in which patients reported they actually pre-specified selection of triggers and tapped on the iPhone how often they were experiencing those symptoms. And it turns out that there was no clear relationship between caffeine and self-reported atrial fibrillation. So, compelling data self-reported via mobile phone. In terms of hypertension, the guidelines read that patients with atrial fibrillation and hypertension should receive optimal blood pressure control, as recommended by recurrence. This does reduce atrial fibrillation recurrence, as well as cardiovascular events. A key troll — I'm sorry, a key study underlying this was put out by Regenstrin colleagues in the European Heart Journal in 2018. It was a randomized controlled trial in which patients were — with atrial fibrillation, as well as mild and moderate heart failure, were enrolled. And they were randomized to four therapies or not, including mineralocorticoid receptor antagonism, statin therapy, ACE inhibition, ARB therapy, as well as cardiac rehabilitation. And then at one year, the assessment was a holter, and those who received targeted therapy were much more likely to be in sinus rhythm at 75 percent, as opposed to 63 percent among those who did not receive therapy, suggesting that there is, in fact, a benefit with an odds ratio of approximately 1.8. So, very compelling data. And to tie this up, in parallel to the primary prevention, there is also a secondary prevention guideline indicating that patients should similarly receive comprehensive care, addressing guideline-directed — sorry, guideline-directed lifestyle risk factor modification, atrial fibrillation symptoms, risk of stroke, and other associated medical conditions to reduce burden with regards to atrial fibrillation, as well as progression or consequences. And the same study that I mentioned earlier also undergirds that recommendation. So hopefully I have achieved what I set out to do, which is these three objectives in terms of where this stands. The process in terms of how this works is that those recommendations who receive — that are either class one or class three, i.e., we should be doing or we definitely should not be doing, are at least under consideration for performance measures, which in turn can be publicly reported and be potentially used for pay-for-performance as well. So it will be quite interesting to see where those end up in terms of the performance measure document, which will be hopefully coming out soon. Thank you very much for your attention. Thank you for your time. We have a couple of minutes for questions if anybody has any. Thanks so much. Now the presentation is open for discussion. Any questions from the floor? I have a quick question. Is there any compelling data on particular antihypertensives, or do you recommend — I mean, it's kind of mixed I've seen for ARVs, for example. The data that I've seen — the most compelling data are the sort of bundled care. That's what I presented there. The data that I've seen in terms of specific antihypertensives I personally do not find hugely compelling. I'll ask a question. Are you making any recommendations with regard to marijuana use at this time, or not yet? You must have caught that I'm from Colorado. That's very interesting. No, I think those are interesting. I'm aware of some studies that have been funded by the American Heart Association that will look into that. Certainly that was not a part of the discussion in the guidelines, but interesting comment for sure. We published some data showing a link between a-fib burden and diagnosis of a-fib and marijuana use, actually. Interesting. Okay. Thanks so much. Thank you for your time. Kara Pellegrini, her talk is about rhythm control for all. Great. I think my slides are coming up. It's such a pleasure to be here with you. Thank you to the chairs. And my topic is early rhythm control for all. And these are my disclosures. I don't think I'm too impactful for my talk. I do have a quick question for you to help wake you up at the end of a wonderful day. Six-year-old, obese, hypertensive woman with paroxysms of symptomatic AFib for six months is referred to your clinic. Do you move to ablation as first-line therapy? Do you say anti-rhythmic drugs first? Do you suggest metoprolol? Do you berate the referring provider that it's too soon to send you this patient after diagnosis? And I'll note in light of our previous talk that, of course, ablation of first-line therapy will include weight loss, blood pressure control, and all the other good stuff. We won't spend too much time waiting. I think we probably in this room largely agree that we would encourage ablation as first-line therapy. I think that there has really been a paradigm shift in the last several years to greater and earlier emphasis on rhythm control over time. It's supported by randomized control trials. It's called out in our latest guidelines. In fact, it's one of the top 10 take-home messages in our latest guidelines. And I think it's being practiced by many of us in our communities. So I suppose you could ask, gosh, Kara, what are we going to talk about today? And we do still have some things to say. So we're going to review exactly what are our goals of rhythm control and what supporting data do we have for that. We're going to dive a little deeper on ablation. We're going to talk about early rhythm control for all. And how early is early enough? So what are our goals with rhythm control? So beyond symptomatic control, beyond thinking about preventing or reducing progression of AF burden and AF stage, I think what's really most pertinent for the topic here at hand is that rhythm control can be useful for reduction of hard cardiovascular endpoints, such as reducing hospitalization, stroke, and mortality. And the evidence for this recommendation really comes largely from the EAST-AF4 trial, which we'll dive into here. So EAST-AFNet4 randomly assigned almost 3,000 patients who had earlier atrial fibrillation, that is, who were diagnosed within a year of enrollment, and who met either an age cutoff and or had other cardiovascular conditions to receive either early rhythm control or usual care. And this trial was actually stopped early due to efficacy. At a mean follow-up of about five years, there was nearly a 25% reduction in the joint outcome of cardiovascular death, stroke, and heart failure or ACS hospitalization rate in the early rhythm control group as compared to the usual care arm. And there were statistically significantly lower rates of the component outcomes of cardiovascular death as well as stroke, with stroke reduced by more than 30%. Importantly, this did not seem to come at a safety hazard. These patients did not have a statistically increased hospitalization rate despite the more aggressive care, nor were there other alarming safety signals. And I think we can think with regard to prior trials such as AFIRM that did not show a mortality benefit. The difference here is that most of the patients in both of these arms continued some sort of stroke prevention, continued rate control, continued other cardiovascular care, and ablation was a part of the rhythm control strategy as compared to earlier trials. It's interesting, though, that ablation wasn't a big piece of this trial, and I think that can be forgotten. Here in the rhythm control arm on the left panel, we can see that 8% of patients had upfront ablation initially, and fewer than 20% by two years had gone on to ablation. The vast majority of these patients were treated with 1C antirhythmics in green, amiodarone in pink, or dernetarone in orange. Now, this still was different than the usual care group where more than 90, where about 96% of patients had no antirhythmic care as intended initially, and only 7 percent went on to have AF ablation. So I think that still the role of first-line catheter ablation, what impact that might have on these cardiovascular outcomes, still is not even fully identified with this specific trial. And we do know that ablation outperforms antiarrhythmic drugs as first-line therapy for paroxysmal AFib with respect to AF recurrence. And this is a meta-analysis of some of these recent trials that showed a 38 percent lower rate of arrhythmia recurrence with AF ablation as compared to antiarrhythmic drugs. Additionally, though the early rhythm control group did have more numeric safety endpoints, the overall number was low and it was not statistically different from the usual care arm, as I mentioned. And as you can see, the ablation-related safety endpoints shown in green are lower, more infrequent than things like toxic effects of drugs, drug-induced bradycardia, and AV block. Again, further thought that as we lean more into this ablation strategy, we might even have more benefit. But really, is rhythm control for all? And for this, we lean into the guidelines, which suggest that there certainly might be patient-related factors, patients' preference, patients with fewer symptoms, for example, that we might think more about a rate control strategy being perfectly adequate. And then anatomic features, such as easily controlled heart rate, larger left atrium, things that tell us that the substrate is more advanced, similarly might predispose us to think twice before being aggressive in our rhythm control, while things like LV dysfunction would really prompt us to be as aggressive as possible in thinking about a rhythm control strategy. So if we do decide, okay, we're going to move on and press on the rhythm control piece, we're going to think about AF ablation, can we be more specific about how early is early enough? And here, I bring up the CircaDose study. And this was a study in Canada, eight centers, about 350 patients, randomizing people with AF for cryo versus RF ablation. And all these patients got some sort of loop monitor that was placed more than a month before ablation. And what's interesting in this secondary analysis is that the duration of longest AF episode prior to ablation was really a signal, a predictor, of how likely they were to remain free of atrial fibrillation. So this group at the top that had the greatest freedom of AF, their longest episode was less than 24 hours. And all the other groups, whether 24 to 48 hours or more than seven days, were statistically quite similar. And so the authors kind of suggest that we have this line in the sand. We dichotomize persistent AFs as more than seven days, but really, we should maybe be thinking about making a cutoff at more than 24 hours, that that might be a more clinically meaningful endpoint when we're thinking about how likely patients are to derive benefit from this therapy. And I think it's kind of interesting that that also is around the same cutoff that seems to be coalescing for stroke prevention with subclinical atrial fibrillation. They looked at preablation episode duration and the likelihood of what kind of burden these patients were having. And while you see that the preablation group — sorry, this didn't advance. There we go. And while you see that the preablation group as compared to — that the postablation group as compared to preablation, all of these patients drove benefit in terms of postablation burden. Those that had less than 24 hours of longest episode preablation had significantly lower burden as compared to those with two- to seven-day or seven-day burden. Now the diagnosis to ablation time, or DAT, is another way of thinking about prediction of atrial fibrillation recurrence later, or how significant the disease has progressed to this point. But some would argue that it's a more clinically relevant, easily accessible, and importantly modifiable predictor of AF treatment success. And this paper by Chu et al. looked at 11,000 patients in a nationwide cohort with newly diagnosed atrial fibrillation who were undergoing catheter ablation and found that for each one year of excess atrial fibrillation that they had prior to ablation, they had a 20 percent higher likelihood of AF recurrence and an 8 percent higher likelihood of hospitalization. And in fact, DAT was a stronger predictor of their AF recurrence postablation than traditional clinical risk factors such as age or prior heart failure. It's also notable that the risk seems to be linear here in this study between DAT and AF recurrence, suggesting that there's no threshold, that the earlier we can drive ablation, the more impactful our study, our intervention will be. Subsequent data has further looked into the complexities of DAT in predicting ablation success. This study looked at time from diagnosis to ablation in months against recurrence in years and found that over the first three years after diagnosis, there was a steep rise in atrial fibrillation recurrence from 27 percent to 40 percent. And then things seemed to level off such that after 90 months, there really didn't seem to be any further accrual of risk, suggesting again that earlier is better and there is no cutoff to how early is important, but that as it gets later, more time is less detrimental. And this effect was persistent across subtypes, but more pronounced among those in persistent atrial fibrillation shown here on the left as compared to paroxysmal seen on the right. Putting this together, early in the disease process, our goal really is rhythm control, and I think that's in large part because we're more successful at rhythm control then because there's been less atrial remodeling. So we have a greater likelihood of impacting not only AF-related symptoms, but other AF-related hard outcomes. But maybe we still aren't thinking even earlier enough. After all, by the time of diagnosis or time zero of DAT, we know that these patients are already having structural changes, are already having atrial pathology, and can we push that paradigm even further? And as was mentioned earlier, there's been a lot of trials looking at screening in AF, screening for AF, that have been kind of lukewarm results, right? We've found more AF, but we haven't really impacted outcomes. And perhaps the thought process shouldn't be all about oral anticoagulation for stroke prevention, and that's part of what we're hoping to study in our CSP2037, the Valiant AF screening trial, where we're going to be coupling patients who have screen positive for atrial fibrillation not only with recommendations with regard to anticoagulation, but with recommendations for aggressive lifestyle modification, and looking at outcomes such as stroke, mortality, heart failure, hospitalization, and bleeding. In the interest of time, I'll skip that. So we know that structural changes are happening in early disease. We're starting to see more fibrosis, shown here in green, that progresses to subclinical disease, as well as infiltration with inflammatory cells, shown here in purple and red, that progress over time with more and more fibrosis, and other electrophysiologic alterations that aren't seen on these slides. And perhaps we could do molecular imaging where we're using small molecules, peptides, antibodies, that are tagged with some sort of imaging receptor that then we can look with PET scans or MRIs and pick up these molecular probe signals early on, and recognize atrial fibrillation with an eye toward earlier treatment, not only of stroke prevention, but of thinking about perhaps aggressive cardiovascular risk factor modification, perhaps antiarrhythmic drugs, and might it be crazy to even think about prophylactic AF ablation in some of these patients. So in summary, I think there's really been a shift to more and earlier rhythm control, driven in large part by the impact that we can have on cardiovascular endpoints. Maybe not for all patients, of course, take into account patient and substrate factor, but for many, atrial fibrillation ablation really is our cornerstone, earlier is better, how early is early enough? Well, I would say certainly we're looking to bring these patients in before they have episodes lasting more than a day, and if possible, as soon as we can after diagnosis. Whether we'll get to the point of prophylactic AF ablation during my career, I don't know, but I wonder as we continue to make progress in making this procedure safer and more effective. That's all I have. Thank you. Thank you so much. Any questions from the floors? Do you think CHAT-VAS score is important for making our decision? Because as you remember, in East AFE, in it for trial, the benefit is only for the patient with higher than CHAT-VAS score for? For AF ablation? No, no, no. For? No, we are talking about early rhythm control. Oh, early rhythm control. Not only for CHAT-VAS ablation, early rhythm controls also consist of cardioversion. Yeah. Yeah. So, definitely, you know, the question was with regard to CHAT-VAS score and whether that might signify certain higher, certain patients who are more likely to have even larger benefit from early rhythm control. And I think undoubtedly, right, that the benefit is going to vary based on certain characteristics that some patients who have LV dysfunction, which is a component of the CHAT-VAS score, are going to drive even further benefit. So, in answer to your question, yes, I think that is important. And I think to Dr. Marocha's talk that was given earlier, the more we can individualize and personalize and think about these treatments based on a given patient, the better. I think, you know, a patient who has a single AF episode and then goes on for years without anything is clearly has a different phenotype than the patient that, you know, immediately goes into persistent atrial fibrillation, perhaps because their substrate is different. And so, thinking about something like DAD is obviously an oversimplification, but something to work with. Thank you for the great talk. My name is Yazan Mozen from Cologne, Germany. So, I mean, the data is very compelling, but just for you personally, would you ablate a patient with, like, first episode AF, like, with a few hours or a few minutes? Not a few minutes. A few hours, let's say. Yeah. No. You know, I get referred some of these patients, right? I don't know if you do, right? Patients who have had a single atrial fibrillation episode, and it does make me a little nervous, right? That you're bringing this patient to a procedure that does carry real risk, even today. And yet, we know that earlier is better, and earlier than earlier is better. And so, I think this is, I'm going to take the cop out of saying shared decision-making. I'm not completely opposed to it, but I'm not going to push these patients, you know, hard. And it's going to depend on, you know, how risky I think the procedure is for them, and what else do we have to go on? Do they have a degree of atrial remodeling on their echo already evident that, you know, it seems like the writing's already on the wall? You know, what other factors can we use to help make a decision? How likely is it that they can work on their risk factors, and maybe that's all that's needed? You know, we'll, obviously, it's not a simple question, of course. When do you think we'd reach the point when we could decide immediately, like whether we're going to be ablating or not, like from after the first episode? Well, I mean, I'm arguing that maybe we'll reach the point that we don't wait for the first episode, right? And that maybe someday as PFA or whatever gets so amazing, or we do it non-invasively, right? Wouldn't it be amazing if we could alter the substrate before the patients are even having AF episodes? Because we know that that substrate alteration is happening before subclinical AF, before clinical AF. We know that their risk of stroke and other things is going up over that time. Just like we think about CRT, right? With block HF, we started thinking, why wait until the EF drops? Why not, you know, put in the CRT early, you know, in patients that we think are at high risk of that? I'm arguing that we might get to the point of thinking about AF that way. Am I doing it in my clinical practice? It's not standard of care. I think you'd be putting your neck out. But just, you know, this is innovation, so thinking ahead, you know, what might the future hold? I mean, you really do have to individualize care, though. I mean, if someone's drinking a case of beer a day, you know, that's a very different person than someone who's- Optimized. Normal weight and already exercising and doing, and wants to be very proactive. So, you know, it's not a cop-out to say shared decision-making and tailoring care to the individual is the right call. Please. Last question. What are your thoughts on early rhythm control in terms of redo ablations after a patient recurs after their first procedure? How long do you wait? And do they still get the same benefit in terms of treating them as early as we can or in the first however long it is? Yeah, that's an interesting question. I think none of the data I presented was really about that question. I will say that I think we are moving past this idea of, you know, this blinded three-month period not being meaningful, right? I think we know that if you're starting to have episodes, it's just going to continue to progress. So, I don't necessarily feel that I need to wait to decide that they're going to have episodes. Now, whether it has the same benefit in impacting cardiovascular heart endpoints, I can't say, you know, that they weren't included in these trials. And it may be that, you know, that the horse is already out of the barn for some of these people. But if you're looking to at least improve symptoms and perhaps have other benefits, I have to think that, you know, that more AFib begets AFib, and kind of tackling things earlier in general, if you're going to do it, is beneficial. I don't know if anyone has different thoughts. I mean, it's a data-free zone about sort of how early do you need to reintervene. We really don't know the answer to that question at all, as Kara said. But, you know, again, I think it depends on how much people are having and whatnot. It's not a good sign if you have to go right back in. And I want to agree. I just, one thing we haven't discussed here is this issue of the blanking period too much. But I think the blanking period has been a real disservice to our field in terms of our patients' live and experience, where they're having lots of AFib for three months, and we really haven't been studying it well because of how we've designed a lot of our studies. So I think we should all be studying that period much more carefully. There's a lot we can be doing with very procedural antiarrhythmics and other things and fluid management and things of that nature. So just a call to be thinking about that period and studying that better. Thank you. Any questions? Well, great. Thanks, everybody, for a great session.

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