Good afternoon, dear colleagues, ladies and gentlemen, welcome to the session titled Rhythm Control for Recent Onset Atrial Fibrillation, Time to Think About This. This session explores the management of patients who present with new atrial fibrillation shortly after its initiation. This is a special joint session with the World Society of Arrhythmia. My name is Ali Otto, I am the president of World Society of Arrhythmia, and my co-chair is... Hi. Welcome, everybody. Thank you for attending. I'm Tristram Bonson. I'm one of the electrophysiologists and faculty at Duke, and it is with pleasure that I'll introduce our first speaker, Ben Steinberg, who is at Denver Health Medical Center in the University of Colorado. Thank you, everyone. It's a pleasure to be here. Thanks for coming. Thank you to the chairs, particularly my former colleague, Dr. Bonson. So I've been assigned today to talk about how to define recent onset AFib. And so I will, I think, make the case that we have a little bit of ways to go here. And I think it's important to recognize, really, what is our intent in terms of capturing recent onset, quote unquote, and what's available. So sometimes I think we don't necessarily know what we're referring to, for any Princess Bride fans out there. I'll start with a premise that I think many of us are familiar with, the recognition that AF, you know, begets AF and is a progressive disease. And so in part, this is the classic tracings of AF models, and the ongoing stimulation of AF that leads to more and more persistent, sustained disease. Other seminal work has demonstrated the pathologic progression of AFib and architectural changes within the left atrium specifically, reflecting more advanced disease. This overall progression is really nicely summarized in a recent review by the Vancouver group, which goes through interventions, well, first of all, goes through different markers of progression, as observed in this figure here, on different scales, from time to remodeling and clinical events and implications for therapy. And so I encourage everybody to take a look at that article. But I think it really gets at the rationale for identifying this group of patients. And this is a schematic of clinical trial, of the clinical trial paradigm. And on the left here is the idea of enrolling a heterogeneous population in clinical trial and yielding an overall treatment estimate that reflects the average participant, which doesn't exist. We have different participants with different phenotypes, but clinical trials summarize treatment effects for an average participant, which is sometimes less helpful. And this is a paradigm that was originally conceptualized by John Spertus and published by Bob Yeh and Dan Kramer. In contrast, our goal in general in clinical trials and therapeutics is to identify which patients will benefit and to be able to accurately predict and assign interventions that target those specific patients. What I would submit in an even more ideal case, and the reason we are trying to identify quote-unquote recent onset, is to turn all patients into candidates for effective therapy and to eventually yield effective therapy across a population. And so why are we trying to define this? I think this is why, in order to identify the appropriate treatment for the appropriate patient and deploy it most optimally. An oversimplification of the paper I presented earlier by the Vancouver group is how do we define early? I would submit that instead of recent, that I would use the term early. What we're really trying to capture is early in the disease process, which may or may not reflect a chronologic idea. And so we've talked about the pathology. There's macro structure and ways to measure macro remodeling related to AFib, left atrial dilation, mitral regurgitation, which may be a cause or effect. We talked a little bit about the pathology. There's electrical substrate that changes throughout time. And then we'll talk a little bit about burden as well. But these are generally the major axes we're looking at when we're defining atrial substrate. We don't always have these, obviously, in our patients, and so there are some surrogates we usually use. Symptoms is a bit of an outlier, often time to diagnosis, age, and sometimes comorbidities. So what's been used in the past in studies? This is not meant at all to be comprehensive, but simply a sampling of studies that included patients that were, quote unquote, new onset or recent onset of atrial fibrillation. So in the ORBIT-AF registry, we used six months for the purposes of oral anticoagulation. In the recent randomized control trial, the EAST-AFNet trial of rhythm control, they used 12 months. There was a meta-analysis of time to ablation that used 12 months. In the randomized control trial, CHANG-AFib, which was recently stopped last year, they used 120 days. And in the early AF clinical trial, they used 24 months. So there obviously is a span of chronology. And I think the first message is maybe that's not necessarily exactly what we're trying to get at. So this is actually, I'll present one brief case recently in my practice of a 55-year-old gentleman that was very active, had been diagnosed with persistent atrial fibrillation within six months of when I saw him. And for a variety of reasons, we brought him to the EP lab, and this was his electrical substrate within six months of diagnosis. So I would submit that six months was not necessarily an accurate reflection of his stage of disease. And so the timing can be misleading, and the date, frankly, is arbitrary. The other reason the date is arbitrary is this phenomenon, which is the idea that if you look across many different populations of atrial fibrillation, and we showed this across at least three different diverse populations, the distribution of AFib burden as measured on a continuous scale is actually quite bimodal. So the vast majority of patients lie at a very low burden or a very high burden. And what that means for kind of stage of disease is that low burden may reflect, may be rather specific for early disease, but this transition time may be highly variable, and a high burden doesn't necessarily reflect late versus early stage disease necessarily. And patients tend to spend relatively little time in between, if at all. And so time and burden are not necessarily great reflections of stage of disease. So what are our alternatives? Well, left atrial dimension certainly, again, is a macro remodeling reflection. It can be inconsistent to measure, at least in my experience, particularly on echo. Can be confounded by concomitant heart failure, again, and mitral regurgitation that may be a result of the AFib, not necessarily a cause. Conduction properties, which there is a fair amount of literature on P-wave morphologies and durations as a reflection of atrial substrate. Intracardiac measurements can be performed, but are not necessarily available prior to decision making. And then more complex phenotyping. What do we mean by more complex phenotyping? Well, again, what we're really trying to do is understand early disease. And there's been a number of approaches to what's called cluster analyses. These are a few different examples of looking at different outcomes using different computational models to cluster different AFib phenotypes. And I would submit that not only is this helpful for identifying early stage of disease, but frankly for phenotyping different patients. I think we're all familiar with phenotypes of AFib that vary dramatically based on comorbidities and age and athleticism and that sort of thing. And so I think we're moving to, hopefully, a more sophisticated mechanism for identifying the appropriate patients, again, for the right intervention. And lastly, groups that I'm involved in are taking an even more sophisticated approach at risk stratification using highly personalized approaches and very large data sets. And I think this can not only be applied in this example as shown in terms of stroke risk, but can also be applied to any number of outcomes and any reasons for different phenotyping. And so I think the future, in terms of defining recent or, again, early AFib, will come down to, hopefully, much more precise phenotyping of the AFib substrate beyond when was the first time it was diagnosed. And so, in conclusion, I would submit that the current state is to capture early disease in terms of recent onset, and again, time from onset, not necessarily a great metric. AFib burden, perhaps specific, but not necessarily sensitive. And again, that date is arbitrary, but where do we need to go? I think, first of all, again, we need different nomenclature. We don't want recent onset. We want early-stage disease. We need better disease markers of progression that are accurate and easy to measure and non-invasive, and ideally, more sophisticated phenotyping and risk stratification, not just for early-stage disease and rhythm control interventions, but stroke risk prevention and other management to prevent sequelae and adverse events. So with that, I will wrap up and happy to take questions. Thank you. I would invite the audience to ask questions, and while that's happening, I have one for you, Ben. It's clear that the ablation approach that we take is dependent, in large part, on what kind of atrial myopathy we find when we bring patients to the lab, and being able to predict that ahead of time would be very helpful, especially when we need to make decisions now about whether to use a one-shot system with limited mapping capabilities versus more comprehensive mapping systems. Clearly, there's a lot of work to be done. We've seen all the data on the fact that many outcomes are different if people have an AFib history of longer than a year, but I appreciate the dissociation that you emphasize between chronologic duration and actual substrate. So in your practice, with your knowledge of the field, are there some things that you clue into when you see a patient to help you understand what to expect when you treat the patient? Yeah, this is a great consideration. It's coming up a lot, as you alluded to, in terms of the ablative technology and the catheters that are available. In my practice, so as the example I showed, I still haven't gotten all the answers. I think in hindsight, I alluded to symptoms, and symptoms obviously are a really difficult thing to deal with, but one red flag is certainly the absence of symptoms really clues you into the fact that the duration is probably a very misleading set, at least in the case I presented would be one red flag. I think number two, macro remodeling I think can be helpful, particularly when there's cross-sectional imaging available. So I feel like I've gotten burned a fair amount on echo in terms of left atrial size. Probably hydration changes things, and so I think macro remodeling can be helpful. There probably are some clues in terms of the genetics and family history, which I think can be very valuable. There's clearly a hereditary component, particularly I used to practice in an area that had a lot of hereditary arrhythmogenic disease, and so I think that can be very helpful. And then I think lastly, these clusters and kind of trying to understand what really, what phenotype we're targeting and what type of phenotype of AFib we have, but I think we have a long way to go. Once again, thank you very much. The next speaker is Bülent Görenek from Eskişehir, Turkey, and he is going to give us a talk on early initiation of rhythm control in AF and associated outcomes, including atrial fibrillation recurrence and major adverse cardiovascular events. Bülent? Dear Professor, dear Chairman, first of all, I want to thank World Society of Arrhythmology and HRH for the kind invitation. Rhythm control is a relatively new definition and relatively new strategy indeed, which aims to restore and maintain sinus rhythm soon after diagnosis instead of waiting of symptoms to worsen or arrhythmia to become persistent. The data comes from East AFibNet4 trial, as you know. Let me remind you of this trial very shortly. Patients with early atrial fibrillation and cardiovascular conditions like hypertension and heart failure, et cetera, were enrolled in this trial, and early atrial fibrillation was defined as arrhythmia diagnosed one year before enrollment. And patients were randomly assigned to receive either arrhythmic control or usual care. Arrhythmic control included treatment with antiarrhythmic drugs or catheter ablation and usual care, limited rhythm control to management of atrial fibrillation-related symptoms. The primary endpoint or the first primary outcomes was better in early rhythm control group, including death from cardiovascular causes, stroke, hospitalization with worsening of heart failure or acute coronary syndromes. And what about the safety outcomes? As expected, early rhythm control strategy was associated with more adverse events related to rhythm control. But however, the incidence of overall safety outcome events was similar in both groups. What about the recurrence rate? Actually we don't know too much about this, because EAST-EFINIT IV investigators didn't collect detailed data or information about the recurrence of arrhythmia in both groups. I think this question is important. Does catheter ablation offer superior efficacy compared to antiarrhythmic drug for preventing arrhythmia recurrence in patients undergoing arrhythmic control? Actually the answer to the question is not so easy. In Monterey AF study and also in early AF study and finally in STAP-APFIRST study, treatment of atrial fibrillation with catheter ablation was associated with a lower incidence of atrial fibrillation compared with a drug therapy group. But however, these studies didn't aim to focus on early atrial fibrillation diagnosed in one year of enrollment. What about the cost? Actually either early rhythm control strategy or other strategy is not cheap. In Germany, estimated cost of delivering early rhythm control therapy indicated that health benefits of early rhythm control may come at reasonable additional costs. And I think this is also important question. As you know, EAST-EP-Net for trial is coming from Europe. Can we generalize this result or these outcomes to all countries all over the world? And as for this question, a group of investigators from U.S. analyzed the U.S. administrative database and the results replicated the clinical benefit of early rhythm control seen in EAST-EP-Net for trial. And what about the reality? What was the real-world data or data from general registries saying? Unfortunately, the results coming from a large European registry was not very good for the early rhythm control strategy. Only one-third of the European EF patients were eligible for early rhythm control. Early rhythm control was associated with higher risk of hospitalization and early rhythm control was associated with more healthcare resources use. And finally, there was no advantage for early rhythm control on primary outcome in this registry. At the second part of my talk, I want to focus on more with the sub-analysis of this important trial. First, the patient with high comorbidity burden and low comorbidity burden. A sub-analysis of EAST-EP-Net trial suggested stronger benefit of early rhythm control in patient with high comorbidity burden, which was defined as CHAT-VAS score 4 or more. Unfortunately, among patients with fever comorbidities, the risk of benefit ratio of early rhythm control may not be favorable. And these results also confirmed by large real-world cohorts coming from United States and United Kingdom. And what about the patient with heart failure? Early rhythm control using antirethmic drugs or cutter ablation was safe and reduced cardiovascular events in this category of patients. But however, the clinical benefit of early rhythm control was not associated with greater improvement in LV ejection function compared with that observed in usual care. And patient with symptoms or without symptoms. Actually, the clinical benefits of early symptomatic, stomach rhythm control was not differ between asymptomatic and symptomatic patients. And also, there was no difference in efficacy of early rhythm control between sex. The primary safety outcomes was also comparable between these groups. And finally, the impact of atrial fibrillation pattern. Early rhythm control reduced first primary composite outcomes in all atrial fibrillation patterns, including first episodes, paroxysmal EF, and persistent EF. And what about the suggestion or recommendations from the guidelines? Actually, guidelines, there is no recommendation or clear recommendation of using this approach routinely in the guidelines. But the current guidelines, the guidelines emphasize the importance of early and continuous management of the patient with atrial fibrillation that should focus on maintaining sinus rhythm and minimizing atrial fibrillation burden. For the conclusion, dear chairman, ladies and gentlemen, early rhythm control may provide long-term benefits, including a reduction in cardiovascular events like death, stroke, and hospitalization for heart failure. Decision about early rhythm control should be on an individual basis, considering the patient's specific condition, symptoms, and preferences. And according to me, more long-term data are needed to integrate early rhythm control into clinical practice. Thank you for your attention. Thank you, Dr. Burenek, for this excellent presentation. Now it's open for discussion. Any questions or comments from the audience? Well, I have one question, actually. This will go to both of you. Well, you tried to define the concept of recent onset atrial fibrillation. And now we have data for early control or early rhythm control. So how can we really couple these two concepts together for the practicing physicians or cardiologists? Maybe you can start first, and then, Bulent, and maybe you also comment. I think a lot of us are familiar with the AFNAT data, and it was an impressive study. I think the way we kind of understand those interventions are a few things. One is, again, time to diagnosis is a very rudimentary, crude phenotype. And so understanding the actual phenotype of the patients that was involved, I think, is very important. Number two is the actual interventions and rhythm control outcomes, as was alluded to. What do I mean by that? It wasn't an ablation trial, right? It was a rhythm control trial. And so those patients were on exceptional medical therapy, and a large proportion of them got antiarrhythmic drug therapy, as opposed to catheter ablation. Key to understanding that intervention is the achievement of sinus rhythm. And I'm actually curious if there's other panelists' opinion regarding whether that study suggests that achievement of sinus rhythm is important, but does it matter how we get there? In other words, catheter ablation may be more effective, but if you achieve sinus rhythm with an antiarrhythmic that has a relatively favorable risk-benefit profile, is that good enough? Yeah, maybe we will be more focused on the definition of recent onset concept. Bulent? I completely agree with you, Professor Otto. I think some things should be more clear, but I think we need more time for this, because in East EP-Net fourth trial, the early atrial fibrillation is defined as atrial fibrillation in one year before enrollment, but there are some other studies, but some of them accept this duration as two years, as you say. So we need some clarification, but I think we need some time for this. Thank you. Dr. Benson? Yes, thank you for the two excellent presentations. We as clinicians in the cardiovascular area, we always have the same problem, when to make a decision when and how to treat our AF patients, but I want you to make a mention that before making the decision how to treat the atrial fibrillation, to know the risk factors of these patients. It's not the same obesity, smoking, diabetes, all the things, hypertension, that are factors that provoke and maintain AF, and I would like you to make a comment on how to take that into account before treating the atrial fibrillation, per se. I think that's a great point. I think, as I alluded to at the NOAA-AF trial, those patients were treated exceptionally well in terms of comorbidity treatment, whether you call that treatment for AFib a comprehensive treatment for AFib, or whether you call that treatment of the other conditions the risk factors for AFib. The end result, fortunately, it seems like is that I think that contributed in a large part to the favorable results of the study and the relatively favorable clinical outcomes. So I think your point is very well taken, I think, at least from my standpoint. The decision regarding rhythm control is predicated on already having addressed, or at least attempting to have addressed, the other risk factors, and so with my patients, I stole an analogy from a mentor of mine, Dr. Bunch, who uses the dental cavity analogy, which is that the ablation may be filling the cavity, but it still means you've got to brush your teeth every night, lose weight, manage the high blood pressure, things that unfortunately tend out to be harder than getting a procedure sometimes. So I think this is a great discussion that has underscored the lack of knowledge that is being uncovered by this session. I think it's well established that rhythm control is better than rate control. There have been multiple meta-analyses looking at that, mostly with drug therapy. But the real question that we don't understand is whether or not a minimally symptomatic patient with atrial fibrillation can have definitive therapy deferred for several years at no consequence, or whether one should jump on it right away. I don't want to steal the thunder of the next patients. I think it's clear that patients do better with rhythm control, but the question is how urgent is it to achieve it in a relatively minimally symptomatic patient? I think I would just add to that, Tris, that the data from Australia, where they sometimes don't have a choice but to wait, and can implement lifestyle changes in those interventions that can be difficult, particularly here, has, I think, been very supportive of that approach, but it's not necessarily, I think, a passive approach that you're alluding to. Okay, go ahead. To keep on time, if I may, I'll introduce our next speaker, who is Werner Jung from the Hospital Munich South. Dear Chairman, dear colleagues, it's a great pleasure for me to be here. I will praise Torsten Lewalther. My name is Werner Jung and I'm a good friend of Torsten. I stay in the Department of Cardiology in Villingen-Schwenningen, that's a black forest in Germany. So my main focus will be the age and the utilization of risk control strategies for early onset of atrial fibrillation. We have heard about the discussion, what is really early onset, and I will take you through the presentation and show you some of the results here. What we see in the middle has been presented already by the previous speaker, that is data from the EAST-AFNET4 trial, that you can clearly see that early risk control is superior to usual care. The key question in my talk, however, is older age a relevant and modulating factor influencing the favorable outcome of risk control in early onset atrial fibrillation. First of all, I want to focus on the modalities that we have available to convert atrial fibrillation and I want to focus on ablation strategies. Here you see data from a Vicorian cryo-balloon registry, the baseline characteristics, and we want to focus on the patients, on the elderly patients above 75 years that has been compared with a match control cohort as shown here. In this registry, the median duration of AF was almost two years, so it's not early strategy, but I just want to show you some data. What is the result of ablation in the elderly patient population as compared to the younger ones? As you can see and we have heard from the previous speaker, in the elderly patients we have much more higher burden of comorbidities and the question is, is it worthwhile to convert these patients either by drug, cardioversion or ablation and do we have any benefit? Here you see the results from the Corian cryo-ablation registry for atrial tachyarrhythmias during the 24 follow-month period and the overall results are shown on the left-hand side. You can see that the results are more or less comparable, a bit better for the elderly as shown in the red line as compared to the blue line in the younger patients. This is true for paroxysmal atrial fibrillation and for persistent atrial fibrillation. So cryo-ablation, at least in this registry, showed a reasonable efficacy and safety profile in elderly population with atrial fibrillation that is comparable to that in younger patients. Our trial looked at left atrial remodelling and voltage-guided ablation outcome in persistent atrial fibrillation patients over 75 years of age. On the left pie shows the younger ones below 75 years and on the right-hand side you see the pie for the older ones. The pie charts show the number of regional low-voltage zone areas according to age and as we expect that the older ones have more regions for low-voltage female sex age above 75 years, renal function and an A-index volume where predictors of the low-voltage zones in patients with persistent atrial fibrillation. The results of a couple of myocurves are shown here, showing the cumulative ATF recurrence free survival rates according to age after a single procedure looking at low-voltage areas. And as you can see, again, for patients with persistent atrial fibrillation regardless of age, comparable outcomes were achieved with the first ablation procedure. So despite this significant fibrotic remodelling, they have a similar and favourable 36-month outcome after a single voltage-guided ablation procedure with low complication rates in both groups and no predictive factors for atrial erythema recurrence could be identified in the entire cohort. This data has been presented from our group in the last ESC Congress. It's long-term 30-year outcome data of AF ablation in elderly patients. It's a German ablation registry following almost 5,000 patients and approximately 1,000 patients were above 70 years that underwent long-term follow-up of almost 14 years. The six were matched more or less in a one-to-one ratio. And here you see the result, the long-term data, atrial fibrillation in patients aged above 70 years, the Kaplan-Meier curve, you see after 10 years an estimated mortality of 30%. This is high, this is low. If you compare it to an age-matched general population, you see that patients who have been undergone catheter ablation have lived two years longer than the age-matched general population. Cox regression independent predictors of mortality have been looked at, and as you can see, increasing age is, of course, not a favorable outcome. It has a higher hazard ratio, and again, long-standing persistent atrial fibrillation is also a worse outcome as compared to patients who have not long-standing atrial fibrillation. So for this long-term data, the outcome of elderly symptomatic AF patients 14 years after AF ablation was associated with a moderate mortality, which compared very favorably to general mortality in this age group. The majority of surviving patients indicated improvement of their symptoms 14 years after AF ablation, and this data emphasized that AF ablation in a properly selected older populations are not only feasible, but are also associated with an extended lifespan. Now we come to data that looks really at early rhythm control, and early rhythm control means as compared to the AFNA trial within one year of onset, and this is data from more than 30,000 patients, and if you break it down, you can see that more than 8,000 patients were older than 75 years, and 3,600 received rhythm control and rate control under approximately 5,000 of the patients. The positive outcome was the same as in the AFNA trial, cardiovascular death, ischemic stroke, hospitalization for heart failure, or mild cardiac infarction. The median age of study population was 69 years. You can see on the upper panel rate control data, on the lower panel and right rhythm control data, the median follow-up was four years in this patient cohort, and here you see the initial choice of early rhythm control. Also comparable to AFNA trial, this was a trial more or less in patients that received antiarrhythmic drugs, the patients who really underwent ablation was a minority of patients. As also in the AFNA trial, the amylorin was the drug which was mostly prescribed in both groups, age above 75 and age under 75. This central illustration shows the relationship between age at treatment initiation, the risk of a primary composite outcome in early rhythm control and rate control groups, above rate control, and on the bottom, rhythm control. As you can see, with increasing age, the benefit tended to be lower, but was still in favor of rhythm control. So the beneficial association of early rhythm control with cardiovascular outcomes was attenuated with increasing age, with larger benefits in younger patients below 75 years of age. No difference were found by age in treatment-related safety outcomes. And there was a trend towards lower incidences of ischemic strokes and myocardial infarction in patients above 75 years who underwent rhythm control. You see the subgroup analysis. There was no significant difference if you stratify the analysis based on the age groups. And here you see again the cumulative incidence curves for the primary composite outcome. On the left-hand side, for patients below 75 years, there was a clear benefit for those patients who underwent rhythm control as compared to rate control in blue. On the right-hand side, you see more or less a mixture. So the benefit was attenuated, and the older the patient was, but there was still a trend towards a better outcome also in those patients who received rhythm control. So in conclusion, Mr. Chairman, ladies and gentlemen, early initiation of rhythm control compared with a rate control strategy that is defined within one year of a diagnosis is associated with less frequent cardiovascular events in patients especially below 75 years of age. The protective association between early rhythm control and cardiovascular outcomes exhibited a linear decrease with advancing age. And although being attenuated with increasing age, a trend to a better cardiovascular outcomes for early rhythm control was consistently observed without affecting safety outcomes in elderly patients with AF. These results call for shared decision discussion, the benefits of early rhythm control therapy in older adults with atrial fibrillation. I thank you very much for your attention. Thank you, Dr. Jung. We actually have some questions from the audience. The first one asks, and I quote, it seems that most data presented and discussed would suggest no significant benefit in early rhythm control. If so, then why the recommendation in the guideline for early rhythm control? I think your data speaks to that in large extent, and I'll share the second question and perhaps you can answer them in aggregate. In the discussion of potential longevity benefits for elderly patients undergoing AF ablation with 13 years of follow-up, how old were the patients when the ablation was first performed in the German registry? For the second question, so these patients were above 70 years. All the patients who have been included in this registry were above 70 years, so it was quite a rather old patient population. And I think the data, as we discussed with the previous speaker, it's the definition what is really early rhythm control is somewhat conflicting. So the first big event showed some data from four or five various trials that the definition varied from a few months up to two years, I think. So mainly the newer trials focus on a one-year span, but this again is only when a patient is presenting with symptoms, so this doesn't really reflect the real time definition. So we don't know if there were any asymptomatic episodes before, so we can only count on that that the patient is presenting if he's presenting with symptoms. And I think if you look at the safety data, we can really tell that if you perform ablation regardless if it's cryoablation or radiofrequency ablation, it seems to be safe. Also in older patients where the safety profile is more or less fully comparable to younger ones even if they present with a variety of cardiovascular comorbidities. So I think at least if a patient is presenting with symptoms, I think it's fair and it's a good challenge to undergo a first treatment either with drugs or with catheter ablation in order to restore sinus rhythm. If there are recurrences, then I think you have to debate together with the patients if he still wants a second or third ablation procedure, for example. But if you also look at the data that has been presented in ablation with heart failure patients from Johannes Brachmann, then you can see that especially those patients who are sicker, they have the most benefit for catheter ablation in order to restore sinus rhythm. Can I just add, regarding the question about why ablation, you know, in my next slide, in my presentation, I hopefully convince you why I think it's recommended a little more aggressive, the first line or catheter ablation or rhythm control rather. But another question that I think is important to address, and maybe I'm wondering here from the panel, should we not call it early but maybe more naive, meaning to say patients have not received any type of therapy, right? So whether they were diagnosed six months ago or a year ago, but they really have not received either antirhythmics or ablation, right? How is that another definition we should potentially consider as compared to early or late? Because I think early refers, you know, it's difficult because we don't know if we're talking about histological changes or structural substrate changes more than clinical, and naive refers more to treatment, I guess, how aggressive we have been. Yeah, I mean, I think it's certainly a good question. I think that's why I alluded to kind of what's the goal, what are we trying to achieve, right? And I think to me, what we're trying to achieve is understanding what the potential benefit is of the intervention, and certainly prior treatment can influence response to treatment. It may or may not, to me, depending on who treated and how, and how actually deployed the treatment was. Are they using the CPAP? Are they taking the medication, et cetera, et cetera? And so to me, trying to understand the phase of the disease is a much more, is a classification that is perhaps more closely linked to response to intervention than has it been treated before. But certainly, I think, to a large extent, no one would argue that prior treatment of AFib, those patients that are coming back for an intervention, clearly, overall are going to have a lower response. I think we'll save more discussion until the end. Yeah. We have to move on, and the final speaker of this session is Dr. Ulzer-Fosay, and from the Richmond VA Medical Center, and his title will be Best First-Line Rhythm Control Approach, Ablate It Away or Suppress It with Drugs. So this is a long-term, long-term discussion and then... Well, hopefully, I'll convince you, I'll have a little bit more information whether you believe it or not. But first of all, I wanna appreciate the organization committee for inviting me to talk about how to first treat with rhythm control these patients that present with AFib, whether we should ablate them or should we treat them with antirrhythmic drugs. Antirrhythmic therapy, antirrhythmic drugs. So first of all, we need to start talking about really what is the natural history as we know it. And whether you have paroxysmal AFib or persistent AFib, what we know is that most of them are gonna recur 75% for persistent within a year, but I'm sorry, paroxysmal, but persistent is gonna be at 90% within two years. So again, this is something that we have to have control of because it's very likely we're gonna see it. Now, it's very important to understand what is that we're gonna be trying to achieve with treating these patients. And obviously our primary goal should be to improve quality of life and whether that improves palpitations, fatigue, or even heart failure, development of future heart failure, or even heart failure symptoms is important. But also we wanna prevent stroke as well as decrease healthcare resources such as ER visits and hospitalizations. So that is a spur of morbidity, but obviously ideally we also wanna be able to impact mortality if possible. So I'm sure many of you remember these studies where the staff, the race, and the firm study early in the early 2000s really showed that when they were comparing randomized patients with rate versus rhythm control, unfortunately there was no difference in morbidity and mortality. Interestingly, there were a few studies later on the same studies that they look at those patients that remain in sinus versus those ones that converted to AFib. And whether, regardless of the treatment, what they found was that those patients that remain in sinus, they had a better free survival as compared to those ones that remain in AFib. And when they look at the firm study, look at symptoms, they saw that those patients in sinus, they had a better near-heart association as compared to those that reverted to AFib. So again, these were always the early signs that say, hey, maybe sinus rhythm is important. The Kavanaugh study tried to really compare ablation versus antiarrhythmic drugs in more than 2,000 patients. And it was disappointing, I guess, to say that they did not necessarily show a significant difference between catheter ablation and drug therapy on an intention to treat analysis. However, when they look at the footprint on this, they saw that about 9% of the patients randomized to ablation declined PBI, whereas about 30% of the patients that were randomized to the antiarrhythmic drug received PBI. So as you can see, not as clean as we would have liked. But again, because it was an intention to treat, that was what was reported. But they took a step forward and said, okay, what if I do a pro-protocol analysis? And what they saw is that those, when you look at patients that had an ablation, that a true ablation, and those ones that did receive an antiarrhythmic drug without crossover, they actually had, those in ablation had a better mortality rate as compared to the ones with antiarrhythmics. So obviously, that has been an important point of this study that you could consider. And as previously discussed, the EAST-AF net came later with close to, or more than 2,700 patients. And as discussed, it was really shown that you had an improved cardiovascular death, stroke, and hospitalization with earlier rhythm control than usual care. Having said that, remember that here, you had antiarrhythmic drugs as well as ablation. So again, it's not necessarily still answering the question here of ablation versus antiarrhythmic drug. Now, a few years later came in the early AF and the stop AF. And these studies truly now start to compare ablation versus antiarrhythmic drug. In this case, both of them used cryo, and both of them had naive patients with naive AF. And importantly, these two studies, in case the early AF showed that ablation had a lower recurrence of AFib, AFlutter, and Atrial Tac as compared to the antiarrhythmic drugs. And this stop AFib finds similar findings, but it also saw that patients that had antiarrhythmic drug, or rather patients that were in ablation had less chances to have a redo of PBI or put onto antiarrhythmics, or again, had a better outcome in general than those ones with the drug therapy. Now, it's important to understand that these trials had obviously exclusion criteria, okay? And important to mention here that while it was extensive, and for instance, left atria more than 5.5 in general, patients with severe or moderate MR or stenosis, recent procedures, knee and heart association and cardiomyopathy, and congenital heart disease or significant kidney disease, there were later studies, and one of the key ones being the Casla AFib, in which they compare rate versus rhythm control. And in this scenario, they found that ablation versus medical therapy, they actually had an improved survival and free of hospital admissions. And they also had a better or improved, or decreased rather, death of any cause as compared to the medical therapy. And this also applied for worsening heart failure. And on top of that, a more recent study, the Casla Heart Transplant, evaluated patients that were considered for heart transplant evaluation and randomized them to medical therapy and ablation. So again, antiarrhythmics being on this medical therapy and ablation as the other group. And what they found was that patients on the ablation group had a lower incidence of death of any cause, implantation of ALV, CIS device, and urgent heart transplant. And similarly, findings with the ablation group where they had less death from any cause. Now, a more recent study, it was a cohort study from Korea. They look at these patients with end-stage renal disease and patients with stage two and stage three. And what they reported based on several thousand patients, they showed that patients on stage three and stage four, they still had some benefit on the primary outcome being cardiovascular death, hospitalization, stroke, and acute MI when you were randomized to ablation as compared to antiarrhythmic drugs. In this case, it was ablation and rhythm control rather than rate control. Now, I think there's two meta-analyses that really have provided quite a bit of information. And this is one of the first one published last year in which they look at 18 trials. And again, it's important here to mention this was rhythm control, not necessarily ablation, but rhythm control versus rate control. So these are 18 trials with more than 17,000 patients. And they show that rhythm control was favorable to decrease cardiovascular death, all-cause death, stroke, and heart failure. But the fascinating thing for me, at least on this paper, was that when you look at the early studies that we talk about, they had very little afib ablation in the y-axis. You see the percentage of afib ablation that they underwent. So these initial studies, where the hazard ratio was really not changed much, you had about 15, less than really 20% ablation, and mostly were antiarrhythmic drugs. And when you move to the right, most of these most recent trials, the CASEL-IFER, the CASEL heart transplant, the most of them have had ablation. And what they analyzed, when they analyzed the data, they saw that the hazard ratio reduction was about 0.18 for 20% increase in the ablation use. So again, I think we need to be aware of this data because I think this obviously speaks more towards the benefit of ablation as compared to antiarrhythmic drug. Now, this is another recent meta-analysis in which they truly now compare catheter ablation versus antiarrhythmic drugs. And what they saw was that whether it was mortality, hospital admissions was better off when patients were on, received ablation. And when you're talking about improvement of EF, of ejection fraction, and improvement of AT and AFib, it was also more favorable in patients that received ablation. Now, so you could argue and say, well, as I think it's mentioned, if ablation can be expensive. But I think as we move along, the safety profile has gotten better, and also now we're discharging patients the same day. And this thing, this speaks to the fact that we can really decrease the cost by discharging the patients the same day. And this was a study that had obviously an eligibility criteria, so these were low patients risk for having complications. And what they saw is that about 80% of the patients could have actually been, or were discharged from the study the same day. And only about 14% were not, but primarily was because of social issues and late termination of the cases, but not really because of complications. And important to say that those patients that were discharged the same day didn't necessarily have a worse outcome or more complications. So just to review the, and again, I think, I hope that provided a little bit more evidence of why the guidelines, I think, have done the right thing. And that is that the ACC AHA guidelines have catheter ablation as class one for symptomatic AFib that have failed at the rhythmic drug, so that is obviously something that we have done for some time. But now, really they recommend class one for symptomatic paroxysmal AFib as a first-line therapy. Now this is very much in line with our colleagues in Europe, in which they have also, on the more recent guidelines, they have catheter ablation as a first-line in patients with paroxysmal AFib. And they recommend 2B indication for catheter ablations in those with persistent AFib. So I wanna close with this slide just to kind of summarize a little bit about how I see it. Antirrhythmic drugs have benefits that obviously you don't have a procedural risk, maybe initially you have less costs. However, the efficacy to maintain sinus rhythm is modest at best. You really have challenges, mostly related to the intolerance to the medications, as well as the short and long-term side effects of this treatment. And in contrast, you have benefits from the ablation in which you avoid, obviously, these long-term effects of antirrhythmics. I think the maintaining, the restoring and maintaining of sinus rhythm is more effective. The safety profile obviously now makes it a lot more feasible to offer this with a better longer outcome. And finally, the risk, obviously, related to ablation are true, are present, but I think, again, in general, they are limited and a lot smaller. Now, it's important to not generalize this concept. I think this is something that I don't want people to misinterpret here because there was a lot of these studies that I showed you, they had exclusion criteria. And it's important, we always need to find whether the patients have reversible effect. Obviously, they cannot have a contraindication for anticoagulation. Size of left atria is important, whether they have significant valvular disease or prosthesis is important. These patients, for the most part, having excluded from these clinical trials, recent MI, patients with hypertrophic cardiomyopathy, congenital heart defect, end-stage renal dialysis, and pulmonary hypertension. Thank you very much. Thank you. Thank you, Dr. Halser, for this really excellent presentation and now is open for discussion. We have some time for a couple of questions. Well, are you going to ask question? Yes, please. So recently, I've had a, Greg Francisco, I'm here in San Diego at Sharp Hospital. I've recently had a couple of consults for guys in their late 40s, 50s, probably with longstanding persistent, but just diagnosed by my colleagues for first-line ablation. I just wanted to go over what you would recommend. And is there data that if I can maintain sinus rhythm on Amio or dofetilide just for a brief time, recognizing I am gonna ablate them, that my ablation would be more successful if I can have a period of time in sinus? Okay, I'll address that if I may. So there are two questions in the case you presented. One is if you're going to ablate them, what's the best way to do that? Should you restore normal sinus rhythm first for some weeks and then ablate? And I think there are data from several labs. I think the Bordeaux Group specifically published on restoring normal sinus rhythm for 30 days prior to ablation and showed that while it didn't necessarily improve long-term results, it did result in successful ablation with much less fluorotime and RF energy. So I think the concept of reverse remodeling is applicable in a situation like that. The larger question is what you do with a young guy like that who has longstanding persistent AFib. And I think the Cabana data are very clear. And is maybe even apropos to some of the presentation that we've already had, and that is that all groups did better with ablation than with anti-rhythmic drug therapy with regard to quality of life and AF density and AF recurrences. And the young age groups under 75 had a strong trend to actually have improved mortality with ablation over drugs. So in the end, Cabana did include people with longstanding persistent atrial fibrillation. So in this patient in particular, I would strongly support an approach of ablating them and maintaining normal rhythm given their young age. Those are my comments. Well, given the heterogeneity of the AF group in general, and also the data that you have shown us, would you think that one day AI would be really helpful to us to identify the candidate for the catheter ablation or anti-rhythmic drugs? Because you really nicely shown us that most of the special patient groups have already been excluded from the trials. So, well, we don't usually consider those groups when we are to decide really what to do. Early ablation or keep them a little bit more on drugs? What would you think? Yeah, I think that's a very interesting question. But in general, I think that how to identify really the substrate I think is where the AI potentially can help us to do better job, right? Because I think if AI can integrate CT and EKG and try to identify features there that can help us understand the progression of that or the presence of a substrate that may be futile at some point to offer an ablation, I think that is important. So, but yes, I think otherwise, for me, it's more important to, I think if we're gonna treat a patient, it's better to try something more definitive that is gonna have less risk on the long term. And again, unless you have a patient that is early and has more issues with this. And again, that's why it's important to have a shared decision with the patient. That's actually something that very clearly on the European guidelines, that they recommend a shared decision with the patient, whether you take them through antithrombics or you do an ablation. So I would invite any attendees that want to have further discussion to come up front. But given the hour, I want to thank the audience for their attendance and to officially close the session. Thanks very much and have a great afternoon and evening. Thank you.

Atrial Fibrillation

Rhythm Control

Early Stage Disease

EAST-AFNet Trial

Catheter Ablation

Antiarrhythmic Drugs

Cardiovascular Events

Personalized Care

AI in Arrhythmia

Heart Failure