Hello, everybody, and welcome to our webinar entitled Early Rhythm Control, the New Paradigm for Atrial Fibrillation. This webinar is a component of the HRS Compass Early Rhythm Control, excuse me, this is a component of the HRS Compass Early Rhythm Control Project supported by Sanofi and Biosense Webster. Thank you all for registering and attending today, and I'd like to take a moment to introduce our moderator for the webinar, Dr. Andrea Russo. We all know her well. She is currently a professor of medicine at Cooper Medical School of Rowan University. She's academic chief of the division of cardiology and director of electrophysiology and arrhythmia services, and director of the clinical cardiac electrophysiology fellowship program at Cooper University. She has been the past president of the Heart Rhythm Society and the author of numerous manuscripts, some of which I've had the pleasure to work with her on. She's been the author of guideline statements and appropriate use guidelines. In addition, she serves on the editorial board of multiple journals, including Circulation Rhythmia and Electrophysiology, and she's also just been an outstanding leader and advocate for heart rhythm disorders. And we thank you so much for moderating today, Dr. Russo. Great. Thank you. Thank you so much, Jared. I appreciate the introduction and appreciate everyone attending today. So this is, you know, welcome to the COMPASS webinar, and this particular webinar is entitled Early Rhythm Control, a New Paradigm for Atrial Fibrillation. We certainly have an incredible group of internationally recognized faculty who will talk with us today about why early treatment is so important for atrial fibrillation, and they'll share the latest data on this topic. So I'm going to go ahead and introduce our esteemed colleagues here for tonight. Dr. Jason Andrade is going to be our first speaker, who is director of electrophysiology at Vancouver General Hospital with a joint appointment at the Montreal Heart Institute. He is an associate professor of medicine at University of British Columbia, assistant professor of the University of Montreal. He is co-chair of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines and the Device Therapy Guidelines, as well as the chair of the Canadian Heart Rhythm Society Device Committee. He has authored over 230 scientific publications and was the principal investigator on some of the most valued studies, including early AF multicenter trials. Dr. Jared Bunch is the chief, just a few minutes ago, is the chief of the section of electrophysiology at the University of Utah, as well as professor of medicine. He's the founding editor of the Heart Rhythm Case Reports Journal and serves on the editorial boards of the Heart Rhythm Journal, Journal of Cardiovascular Electrophysiology, Europace, American Heart Journal, and others. He has received numerous research and leadership awards and has published over 260 manuscripts. Dr. Mina Chung is a cardiac electrophysiologist and also a translational scientist at the Cleveland Clinic. She founded and led a multidisciplinary group focused on genetics and genomics in atrial fibrillation and is exploring artificial intelligence and big data analyses in cardiovascular medicine using machine learning. She's also directed the AHA's COVID-19 Research Coordinating Center and is currently serving as HRS's second vice president. She has received numerous awards and achievements in research and has contributed to multiple guideline documents, including one that's ongoing right now, the HRS Guideline on Cardiac Physiologic Pacing. Dr. Jonathan Pacini is a cardiac electrophysiologist and professor of medicine at Duke University Medical Center and Duke Clinical Research Institute. He is director of cardiac electrophysiology at Duke Heart Center, where he focuses on atrial fibrillation and complex arrhythmias, with emphasis on catheter ablation and lead extraction. He has more than 500 publications in the field of heart rhythm medicine and is the associate editor at Jack Clinical EP. He has also chaired several clinical trials and registries, including the AHA Get With The Guidelines program, and currently he serves on the board of trustees at HRS. Dr. Andrea Natale is an executive medical director for the Texas Cardiac Arrhythmia Institute in Austin, Texas, as well as EP national medical director for HCA, spearheading innovative advances in AFib and ventricular arrhythmias. He has many scientific achievements that are well known, and he's being the first EP in the nation and the world to perform many of these pioneering procedures. He is also an extremely prolific author and an incredible speaker. Dr. Thomas Dearing is the chief of the arrhythmia center and chief quality officer at Piedmont Heart Institute in Georgia. He also serves as the chair of the cardiovascular governance center for Piedmont. He has served on various roles for the Heart Rhythm Society, including past president of HRS from 2018 to 2019. He's also moderated and spoke at multiple national and international EP and cardiology meetings, and has authored numerous publications addressing cardiac arrhythmias and cardiovascular quality issues. Dr. Dearing currently chairs the quality improvement committee of HRS. So for tonight, we'll have four short talks on the webinar, followed by plenty of time for Q&A and panel discussion. We want this to be an interactive experience. However, you can start answering, even though we won't answer the questions until after the four talks, you can enter your questions in the Q&A function on Zoom. I'm going to go ahead and really just turn this over to Dr. Andrade, who is going to talk to us about progression of atrial fibrillation and why we should treat early. So Dr. Andrade. Thank you so much. All right. So I'll give you a breezy overview of why I think we should treat early for atrial fibrillation. Here are my disclosures. And so I think setting the stage, we all know that atrial fibrillation is a chronic progressive disease. It's a disease that starts as an isolated electrical problem where the pulmonary veins are firing. This leads to episodes of arrhythmia. But over time, the effect of those cumulative arrhythmia episodes leads to changes within the body of the heart. And that change within the atria leads to more likely abnormal substrate, which increase the propensity towards having more sustained episodes of arrhythmia. From a clinical perspective, what we see is that the episodes of atrial fibrillation start as these short events, which are discrete and self-limited. Eventually, with time, they cluster more frequently, become longer episodes. Eventually, they become prolonged to the point that we either need to cardiovert them to stop them or they're lasting longer than a week. And so then what we call persistent atrial fibrillation. And in some cases, it goes on to progress to permanent atrial fibrillation. When we look at epidemiological studies, the rate of progression is typically around 7% per year from paroxysmal AF to persistent AFib. But that's heavily modulated by a bunch of clinical factors. So patients who are older, patients who have underlying structural cardiac pathology, or concomitant conditions like heart failure, are much more likely to progress. And so there's been various risk scores that have been used to estimate that rate of progression. The key point, though, is to recognize that it's not a static disease. It's not someone has paroxysmal AFib and that's what they will be for the lifetime of their disease. You really have to conceptualize AFib as a chronic illness and a chronic illness that will progress. So then the second part of that is why do we care? So if we look at studies of stroke prevention, so these are anticoagulation studies. To get into these studies, patients would have been classified as paroxysmal or persistent atrial fibrillation. And you can see that just being persistent AFib is associated with a 22% adjusted increased risk of death. So right off the bat, persistent atrial fibrillation is associated with a higher mortality, but it's also associated with a 40% increased risk of stroke. So despite being on these very effective stroke prevention therapies, merely being persistent with your atrial fibrillation rather than paroxysmal is associated with a higher risk of thromboembolism. Now to take this one step further, there is some data out of Japan which looks at that time period around progression. So if you take the rate of stroke with paroxysmal AFib in this series, it was 1.3. With persistent AFib, it was 2.1. So very consistent with the meta-analysis data. But now what you're seeing is that as you go through that period of progression, so going from paroxysmal to persistent, the rate of stroke is actually a hazard of four times over paroxysmal. And then it settles down once you get to persistent. The same way we see that heart failure hospitalizations also increase significantly during that peritransitional or progression period, and then settle down at a much higher rate after you've transitioned to persistent AFib. And so we have to consider this progression as part of the life cycle of the disease, and really it becomes a target for intervention. Because if we can prevent progression, we may see beneficial effects on outcomes. And so what do we know about treating early? Well, the first thing that we know is that ablation is much more effective than antiarrhythmic drugs. This has been consistently observed in first-line studies, on the left side of the slide, as well as second-line studies. So the concept of trials of antiarrhythmic drug therapies to temporize probably is not a good option when we think about what therapy might be the most effective therapy. The second consideration is that we know that ablation for paroxysmal atrial fibrillation, the blue line here, is associated with a much greater success rate compared to ablation for persistent AFib. So these are two cryo-balloon studies, so same technology, same procedure, only difference being the population. And the rates of recurrence are going to be much higher when we ablate persistent AFib. If you look deeper into that paroxysmal AFib population, we know that treating patients when their episodes are less than 24 hours in duration is a much better success rate. Once patients are having episodes that are lasting 24 to 48 hours in the orange line, or two to seven days in the brownish-grey line, their outcomes are essentially no better than when we treat persistent AFib. So even within that group of what we define as paroxysmal, their outcomes are going to be much better if we ablate them earlier. And that's because really, when it's early, it's a focal problem of the veins, and we can deal with a focal problem of the veins with PVI. But once it progresses to persistent AFib, when we have left atrial substate, there is a smorgasbord of procedures that have been tested and employed, but the outcomes are not always consistent, and they're not necessarily as good as we would expect with doing PVI for patients with early AFib. Another thing to consider is that when we do ablation for persistent AFib, the rates of subsequent hospitalization or emergency room visit, and even all-cause mortality, is higher after the procedure relative to patients with paroxysmal AFib. And so this is data published out of Ontario, showing that when we do these procedures for more advanced forms of atrial fibrillation, the outcomes are not necessarily as good as we would want them to be for those hard clinical endpoints, not just arrhythmia recurrence. A different way of looking at this is a concept called the diagnosis to ablation time. And so this is data that I'm sure Dr. Pacini and Dr. Bunch know well. And so the idea that if we diagnose someone with atrial fibrillation, if we perform an ablation within a year, so data very consistent with that enrollment criteria for the E-study, which you'll hear about later, the outcomes in terms of preventing arrhythmia recurrence are going to be much better than if we wait. So again, temporizing with antiarrhythmic trials with the idea that we'll do an ablation later is not going to improve the outcomes in terms of atrial fibrillation recurrence. And again, if you take that one step further, patients who have had their ablation procedures delayed more than a year from diagnosis have higher rates of being hospitalized and higher rates of stroke or heart failure admission. And so delaying the procedure doesn't seem to confer any benefit. And so if we know that we need to do an ablation, that really is the onus on us to do that procedure earlier. And the last thing to comment on is to circle back to that very beginning, and that's the concept of progression. And so there's a meta-analysis here on the slide showing you in blue population studies using antiarrhythmic drugs, and in red you have catheter ablation studies. And what they did in these studies is basically plot all this observational data and perform some analyses, essentially showing that if you had an ablation procedure, your rate of progression over time was very, very low. Whereas if you are treated with antiarrhythmic drugs, there's a steady progression of paroxysmal to persistent atrial fibrillation. And on the right side of the slide, I'm showing you essentially the complex pathophysiology of atrial fibrillation. And one of the arguments that could be made is that antiarrhythmic drugs may have effects on the ion channels, potentially on calcium handling, but it doesn't really touch on multiple areas within this complex pathophysiology. And so as the focal firing leads to re-entrant substrate, you see that there's autonomic control structurally modeling all sorts of other pathophysiological processes that impact the disease and allow it to get worse. And in contrast to antiarrhythmic drugs, ablation does actually target multiple areas here. When we do PVI, we're containing those focal areas, we're dealing with the re-entrant substrate, we're causing autonomic system changes, and we're also improving the structural remodeling. And so catheter ablation may be a disease modifying therapy as implied by this observational analysis. And as Dr. Russo alluded to at the beginning, we did perform a study called Early AF where we randomized patients to antiarrhythmic drug therapy or catheter ablation as a first treatment. So these were treatment naive patients, they were low risk patients, they were younger patients, and then we followed them with a loop recorder for three years. And what we saw with this continuous monitoring data is a significant 75% reduction in progression when you received a catheter ablation as your first treatment in comparison to antiarrhythmic drugs. And so in summary, the whole reason to treat early is that we know that atrial fibrillation is a chronic and progressive disease. These more advanced forms of atrial fibrillation are associated with adverse clinical outcomes, and catheter ablation is effective at preventing these adverse outcomes, and also may be a disease modifying intervention. And so we may have a way to alter this trajectory when we perform ablation early in order to have beneficial effects on those adverse cardiovascular endpoints. And so thank you very much, and I guess I'll pass it back to Dr. Russo. Great. That was amazing. That was terrific. Such an important message to get across. So I want to hand it over now to Dr. Chung, who is going to talk to us about rate versus rhythm control and historical perspectives. Mina? Thanks, Andrea. Let me see if I can get this to... Are you seeing my full screen? No, still a split view. Okay, sorry about that. Okay, how's that? That's great. Okay, so thanks very much for inviting me to speak on this. And I want to talk about rate versus rhythm control historical perspectives. As you know, a firm is... Did it advance? I'm sorry. I'm having... Let me just... Okay, let me try this again. I'm going to try sharing. Very slow here. Good. You're not seeing the full screen yet, right? Not yet. That's a split screen. That's it. Thank you. My problem is that I cannot seem to advance, but that's okay. As you know, AFIRM is the classic rate versus rhythm control study, and it was published in 2002, and it randomized 4,060 patients with AFIB, who were over age 65 or had a risk factor for stroke, and they were randomized to rate versus rhythm control. The primary endpoint was total mortality, and as you see here, there's no significant difference in total mortality between the groups. In fact, there is a strong trend toward rate control being better than rhythm control. But if you look a little deeper at some of the sub-analyses of AFIRM, if you look at this type of on-treatment type analysis, patients in sinus rhythm actually did better. They had better survival than those who weren't in sinus rhythm, and patients on warfarin also did better. In contrast, there is a higher risk of mortality in patients who are on antiremic drugs or on digoxin. Also, if you look at this functional status sub-study, the patients who were in sinus rhythm had significantly better NYHA functional class throughout the study. Also, in the rhythm control arm, the patients had significantly farther walk distance on six-minute walk tests. Part of the problem with AFIRM and other pharmacologic rate versus rhythm control studies of that era is that the rhythm control strategies then didn't do a very good job of maintaining sinus rhythm. In AFIRM, only 23-64 percent of patients in rhythm control arms maintain sinus rhythm. We have to remember that AFIRM was performed before the era of catheter ablation. This slide shows the AHRQ systematic review and meta-analysis of rate versus rhythm control strategies. It included 16 randomized control trials, 13 were pharmacologic rate versus rhythm control. One was of pulmonary vein isolation versus AV node ablation with a pacemaker, and two was PBI versus rate control medications. As you can see, since AFIRM, as we head into the era of catheter ablation, there's actually a trend toward lower all-cause mortality in the rhythm control group. There's no significant difference in cardiovascular mortality or in stroke or in bleeding events. We now know that pulmonary vein isolation, as you heard from Dr. Andrade, is far superior to anti-rheumatic drugs and being able to maintain sinus rhythm. From this meta-analysis, we see an odds ratio of 5.887 favors pulmonary vein isolation over medication with P-value less than 0.001 and a high strength of evidence. This brings us to CABANA, which randomized 2,204 patients to catheter ablation versus anti-rheumatic drug therapy. This trial enrolled symptomatic patients with atrial fibrillation, very similar to AFIRM, either older than age 65 or less than age 65, with one risk factor for stroke. They were randomized to catheter ablation or rate versus rhythm drug therapy. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. This intention to treat analysis showed no significant difference in this primary endpoint nor in all-cause mortality, although there was a significant difference in the endpoint of mortality or cardiovascular hospitalization favoring catheter ablation. If we look at subgroup analyses, there are trends that can highlight some of those who might benefit most from catheter ablation. There were trends toward favoring ablation in patients who are younger, under age 65, those who were non-white minority groups, which was defined as Hispanic or Latino or non-white race, and those with heart failure. If we explore this heart failure a little bit more, CASEL-AF, CASEL-CABANA, and this is a slide showing CABANA, just analyzing the patients of heart failure. As you can see, the primary outcome was significantly better in this heart failure group. There's also lower all-cause mortality in this group with heart failure with catheter ablation. Now, CASEL-AF was another randomized study in a heart failure group with symptomatic AF, who either didn't respond or had side effects to antiretroviral drugs or who just didn't want to take these drugs. They randomized 179 to catheter ablation, 184 to rater rhythm control medical therapy, and the composite primary endpoint was all-cause death or hospitalization for worsening heart failure. Catheter ablation in this group did significantly better in the primary endpoint, as well as the individual components of death from any cause and hospitalization for worsening heart failure. Now, advancing. This now brings us to the topic of today's webinar with EAST-AFNet4, which you'll hear a lot about later. This trial was one of several recent randomized controlled trials that showed us that early rhythm control for AF is preferred. In this study, most of the patients were treated with antiretroviral drugs, not ablation. The study showed that in 2789 patients with early AF randomized to early rhythm control, our usual care, that the primary composite endpoint was better in the early rhythm control arm. Also, as you heard from Dr. Andrade with this wonderful study that showed that early AF ablation may help prevent AF progression to persistent AF. I think over the years, our paradigm has changed from looking at rate versus rhythm control medical therapy towards rhythm control with catheter ablation, which produces much more of what we want, maintenance of sinus rhythm and progression or decrease in progression to AF. In summary, rhythm control didn't improve survival or stroke risk in a firm, but subsequent studies show early rhythm control has better outcomes in rate control. These early studies were limited by very poor rates of sinus rhythm maintenance and potential antirhythmic drug side effects. If ablation is clearly superior to antirhythmic drugs and maintaining sinus rhythm, and in certain subgroups like heart failure with reduced AF may actually yield some survival benefits. Early rhythm control with antirhythmic drugs or AF ablation appear superior to rate control and early ablations associated with reduced progression of AF. Thanks very much. Great. Thank you so much, Mina. That was great. Just a huge amount of data. Ever since a firm, I think we have a lot of randomized trial data that shows the benefit of rhythm control. Let me turn this over now to our next speaker, and we'll hear more from Dr. Bunch. Jared Bunch will give us information about details about the impact of rhythm control and what we learned from East AFibNet for. Thank you very much. It's great to be here and be with all of you in this amazing panel. I have the pleasure to talk about the impact of rhythm control and what we really learned from East AFibNet. I think it's a critical trial of few aspects of the management of atrial fibrillation I'd like to discuss. These are disclosures to consider, none of which are involved in atrial fibrillation management evaluation and monitoring. As we consider this, we're really examining the impact of rhythm control, sinus rhythm maintenance on atrial fibrillation outcomes. It's an old question with new data that we get from East AFibNet. I think we first need to step back and say, what is the impact of atrial fibrillation on general health? Well, we know that atrial fibrillation is associated with stroke. There's racial and demographic variances, but anywhere of a lifetime risk between three and seven percent. We know that the stroke is just the tip of the iceberg, that multiple alterations to the brain or presence that can lead to cognitive decline, reduce quality and quantity of life to mention other disorders. But we also know from Framingham, the lifetime risk in patients with normal cardiac function of developing heart failures is at least 30 percent. But that's not all. When we start to look at organs that are sensitive to rhythm, we see the same trend such as macular degeneration, people with atrial fibrillation compared to those that have a much higher risk. Pancreatic insufficiency or diabetes, atrial fibrillation patients match for every demographic that we can have higher rates in patients without atrial fibrillation. Patients develop worsening creatinine based upon their presence of atrial fibrillation and go on to develop higher rates of renal failure. This is a systemic disorder that's progressive, as Dr. Andrade talked about, and how management really has inroads to the body as a whole. As a consequence, it's not surprising to see that as we look at mortality in men and women over time, over almost 50 years, we've done little to impact the mortality related to atrial fibrillation, where the vast majority of our patients, over 50 percent in 7-10 years will be dead. We know that atrial fibrillation has an impact on general health and both locally and systemically, and then what is the role of rhythm control, us that are interested in this, how can we impact on these outcomes? As Dr. Chung talked about, we consider old data that has asked these questions of firm, race, staff, this older data, it was persistently impacted by failure to main rhythm control in the rhythm control arm, which was almost parallel at times to the rate control. And so we never were able to fully answer the question of, is sinus rhythm better? And as presented, a firm showed no benefit, but those patients that were in sinus rhythm actually did much worse, but those that were on the drugs to maintain sinus rhythm did worse. So this paradox of a marker of favorable outcome in the most common used methods to achieve that outcome harboring risk. And this is the staff data showing the same thing, that patients that undergo rhythm control, failure to rate control had no benefit over time. So what does EAST-AFNET show us? So this was a unique trial with contemporary managed cardiovascular disease in which they looked at early rhythm control as shown with medications and much less commonly with ablation versus usual care. Often usual care meant delaying management as they worked on risk factors. And what was seen for the first time compared to those other trials that early rhythm control was superior. And the trial was stopped early after five-year follow-up because of better efficacy. So why is this so? And I think that answering that question is helpful. Well, I think the first thing that is unique to this trial compared to those others that were shown by Dr. Chung and on my prior slide is that timing matters. This was a trial of early intervention patients that underwent rhythm control within 12 months of diagnosis. Dr. Andrade has shown in his randomized trial the burden of fibrillation is exceptionally low when we address this early with effective therapies. But that's not all that this trial was about. It was about comprehensive management. And I think that's why it's important to understand the systemic effects of this disorder. And you can see in the early rhythm control and usual care arm, the use of medications, many of which are disease modifying, was profound. 90% were on anticoagulations, 70 to 80% were on a beta blocker, almost 70% were on ACE inhibitor ARB, it's 40 to 50% on a statin. These were patients that were comprehensively managed. What's really interesting is some of the other insights that can be gleaned in more recent analyses of East AFNet4. And one is the fact of looking at the role of sinus rhythm. So we're engaging in the rhythm control early. Is it helpful to main sinus rhythm or is it just the comprehensive process that we're using? And what they found over 12 months, if there was any recurrence or if they maintained sinus rhythm throughout, that those patients that maintained sinus rhythm had the greatest reduction in the primary income point, almost had a 23 to 25% reduction. Where if they weren't in sinus rhythm at 12 months, there was no benefit. And without any recurrence, that drove most of the trial. So it gets back to the importance still of effective rhythm control strategies, because if we can maintain sinus rhythm, they do better, even in the context of comprehensive management. I think this is critical as well. And I think it gets at some of the paradigm of our management of atrial fibrillation is we often consider management based on symptoms. But if you look at people that had no symptoms at baseline to very extensive symptoms across all arms, there was a benefit with early rhythm control. So our patients that are asymptomatic should be considered. And in fact, when you engage them in early rhythm control, their symptoms are less over time. And what I thought was interesting is those patients that came and said, I did not have symptoms at the beginning, many went on to have symptoms that were more significant over time. So even our patients in which they're questioning the symptoms of fibrillation tend to benefit when we engage them early in an effective strategy towards rhythm control. I think, and this is work from Dr. Puccini, he led a task force on this that I thought was outstanding. But we have to consider this again in the context of multiple other care providers in a strategic team. When we include all these people, we can effectively manage the patients. And in East AFNP4, what was again significant is if you look at the end use of drugs, it was outstanding. I've done anticoagulation trials and specifically, and we achieved nowhere near a 90% compliance over the complete study follow-up, which they did in East AFNP4. And you can see across all the drugs, there was no difference over follow-up. So this was an engaged team in their management. I share this as this is from the CABANA's trial showing the same thing. In CABANA, the primary endpoint of death, disabling stroke, serious bleeding, cardiac arrest. And those patients that were in sinus rhythm compared to those weren't. There was a significant reduction in this primary outcome. And this was seen whether they were on medications or ablation. So there's value in effective long-term management. So what's the importance of sinus rhythm? Well, atrial fibrillation is a marker of systemic disease and is also associated with independent risk of stroke, heart failure, death, and as I showed, multi-organ dysfunction. Sinus rhythm in patients with atrial fibrillation is a marker of lower risk. We know that early rhythm control, patients experience the most benefit compared to usual care. And that is driven primarily by the restoration of sinus rhythm. Now in East AFNP, that was done effectively both with medications and ablation. Rhythm management alone without systemic disease therapy is unlikely to provide long-term risk reduction. And from other trials, as Dr. Andrade said, we know ablation is a superior rhythm approach. And even when not fully successful, it does reduce that burden. And we also believe that is a favorable marker similar to sinus rhythm. Thank you very much. Great. That was really terrific, Jared. So really a disease that affects not just the heart. This is something we need to treat the whole patient here and consider all this information we have. So we're going to turn this over now to Dr. Pacini, who will give us the final talk tonight before our question and answer period. How do we define early rhythm control? And should we consider rhythm control after the first detected AF? So this may answer one of the questions that was in the Q&A there. John? Well, thank you, Dr. Russo. It's great to be here with everyone in the COMPASS program, and particularly with such great colleagues who've taught me so much about atrial fibrillation and maintaining sinus rhythm. Sorry. So atrial fibrillation, I think as we've already covered this evening is a progressive disease. And I would echo some of Dr. Bunch's comments that it's not just a progressive disease in the myocardium itself, it leads to progressive changes outside of the heart. So for example, pilot data has shown that the functional connectivity of the brain that can be assessed with functional MRI changes as the density and extent of atrial fibrillation progresses. And shown here on the right are structural changes associated with advanced stages of atrial fibrillation where we might not be surprised that it's more difficult to maintain normal sinus rhythm given increased fibrosis and isotropic conduction in the myocardium. And we know that the greater the extent of these changes as shown by decaf, but also other studies that have used modalities other than cardiac MRI have shown that the more fibrosis, the more the extent of atrial myocardial disease and myopathy, the more difficult it is to maintain sinus rhythm. And one question comes, well, what is early atrial fibrillation? And I think many of these mileposts we put on the road are in some ways artificial. We know in any statistical analysis, for example, the best assessment of an impact of phenomenon is a continuous variable approach, but we do need in clinical medicine to use categories. And if we just look at, for example, within one year of diagnosis, as many studies have defined early AFib, this is work from Derek Chu that shows that you've seen earlier that ablation within a year of the diagnosis of the disease is associated with improved maintenance of sinus rhythm. When we look at both early atrial fibrillation, but also all comers, we've actually seen in multiple clinical trials now evidence of improved cardiovascular outcomes. You've seen some examples from that, including EAST-AF NET4 this evening, but there are also historic trials as well as ATHENA where treatment with trinetarone was associated with decreased cardiovascular hospitalization and cardiovascular events. And it's not just clinical trials that show these data. If we ask how generalizable they are and do they generalize to nationwide populations, these are data from the National Health Experience in Korea, which look at initiation of rhythm control within a year of diagnosis. And again, they show an association with a significant reduction in cardiovascular events that appears to be blunted or not as apparent in patients treated greater than one year. But what if we peel the natural history of atrial fibrillation all the way back to first diagnosis? What data do we have for treating first detected atrial fibrillation in terms of the highest quality evidence randomized control trials? And if you're wondering to yourself, I'm not really familiar with any clinical trials, that's because there are not any. So we need clinical trials to help us manage these very common patients who present with new onset AF. And in the United States, one in five people who present to a healthcare facility for acute care of atrial fibrillation, indeed, it is their first diagnosis. Well, in order to move early AFib all the way back to first presentation and ask what is best practice for the management of these patients, the Change-AFib Steering Committee designed this clinical trial, which is sponsored by the American Heart Association, in which 3,000 patients within 120 days of a new diagnosis of atrial fibrillation will be randomized to usual care or usual care, plus a well-tolerated anerythmic drug, dronetarone, 400 milligrams twice a day. And this trial will seek to determine if early initiation of rhythm control improves cardiovascular and long-term outcomes in patients with first detected AFib. And the primary endpoint will be CV hospitalization or death, which is an endpoint used in many studies of both atrial fibrillation, heart failure, and other cardiovascular disorders. The exclusion criteria, those you might imagine, for use of an anerythmic drug. So patients cannot have advanced forms of atrioventricular block without the presence of a pacemaker. And obviously, for purposes of the comparison, they cannot have a planned ablation or other rhythm control strategy. Or certainly, if they progress, then they should go on to receive any treatment as they would in clinical practice. And we're gonna be looking at a wide host of outcomes, including a win ratio modeled after the EAST-AF net trial. We're gonna be looking at AFib progression, which we've heard a lot about this evening. We're gonna be looking at the development of a new diagnosis of heart failure, needs for more advanced forms of rhythm control, and days alive and out of the hospital, also known as home time. And we'll also be looking at patient reported outcomes. And many ask, well, why dronetarone? Well, it is the most well-studied anerythmic drug in clinical trials for rhythm control of atrial fibrillation. It's well-tolerated. It has few comorbidity restrictions. It is effective at preventing recurrent atrial fibrillation, as shown in many clinical trials. It has been shown to reduce cardiovascular hospitalization. It's safe. And there are several post-hoc analyses, and my own clinical practice is consistent with this, that it performs particularly well in patients with early forms of atrial fibrillation. So in conclusion, we know that early rhythm control appears to improve cardiovascular outcomes from not one, but several clinical trials, but there's no randomized trials to guide treatment for first detected atrial fibrillation. I will say I am a big fan of catheter ablation, and it is probably the biggest part of my clinical practice, but I would also say I don't think patients should receive catheter ablation after their first diagnosis or one episode of atrial fibrillation. And Change-AFib will test the hypothesis that earlier administration of a well-tolerated anerythmic drug will improve cardiovascular outcomes and patient-reported outcomes in persons with first detected AFib. And thanks for the opportunity to speak and participate in this august panel this evening. Great, that was terrific, John, and look forward to hearing more in the future about results of Change-AF. I think that's gonna be unique and another really important study in what we have for data related to this. So now we're gonna move on to the panel discussion, and what I will do is maybe just start out with, we have two additional panelists that are with us, and let me just, I think I was really happy that Jared brought up the topic of symptoms because our guidelines are classically, a lot of them initially, we're looking at symptomatic patients, and I think showed some data related to the benefit of maintaining sinus rhythm with or without symptoms. And I'm also gonna just ask, maybe I'll ask Dr. Natale, what about age is something else that we think of? So when people are referring patients for ablation, is age a problem? Is there an age cutoff? Should we only be ablating young people? Or is there a certain age where we should say, no, we don't have data or we shouldn't ablate at all? Well, that's a very good question. I think is more, right now with ablation is more about comfort because that's a group where you have to be certainly more careful during the procedure. But usually when I see an older patient, I look at the patient and make sure he's a functional patient because if they're functional, then I think the benefit of sinus rhythm apply to that group as well. So it's more about the patient in front of you. I think the oldest that I've read is 96. And he was a very active gynecologist, they exercise every day. And if he was really disruptive to his life, so I think it's a clinical judgment, but the age should not be a deterrent or a reason to exclude those patients from the benefit of ablation or in general from the benefit of sinus rhythm. So I would say any age, as long as you're functional active and especially if a fib is affecting your life. Yeah, great. No, thank you. I'm sorry, go ahead. Andrea, just to add to what Andrea said, I think that we all get a little bit more uncomfortable as people age, but their functional capability is really key. I think that oftentimes what happens is there is a tendency to attribute older people's symptoms to being old. And sometimes that is a component of it, a large, medium or small, but trying to reestablish sinus rhythm and seeing how they feel. And I do that a lot with just a simple cardioversion. And if I see an improvement, assuming it's successful, that makes me wanna be more aggressive. Now, I agree that ablation is riskier in an older population, but so are antiarrhythmic drugs. And they often have comorbidities that make those more difficult. So that's really where it's important, I think, to try to figure out what the patient's goals are. And then in addition to that, looking at the pros and the cons, the risks and the benefit and moving forward with a shared decision. And I think that's a great point because people kind of may adjust to not feeling well over time. And then all of a sudden you cardiovert them and they say, oh, wow, I do feel a lot better, right? So that's a great point, but they may still get even some of the longer term benefits of the more hard clinical outcomes as we saw in one of the earlier slides. And I think there's a question, and if I'm interpreting this correctly in here, so what if they have heart failure and exacerbation and is there any stronger or lesser reason to consider maintaining sinus rhythm? What are people's thoughts or what's the data related to heart failure and AFib in sinus rhythm versus rate control? Go ahead. No, go ahead, Nina, go ahead. No, I think some of our strongest data on even mortality effects with catheter ablation is in the heart failure group. So they have not, as we show you, there's a cabana, there's a cath way up. And so it's just, I think that they're a higher risk group, but doing rhythm control and ablation earlier in that group makes a lot of sense. Great, thank you. Andrea, I'll tell you a story that kind of combined both the older age and heart failure. This is a patient that was 91 and is amyloidosis. And it was fairly functional and then develop AFib and all of a sudden he's bedridden, his BMP is above 1,000, no matter what they try to do with medical therapy. And so they talked to me and when they told me he's 91, I said, 91, really? They said, no, you need to see this patient. So I saw him and I said, he looks a pretty good 91. So we treated him. And after the ablation he's been in sinus, back to being functional. And before, right, the cardiologist actually pushed me to do it. She was very attached to this patient and the other heart failure specialists that they were taking care of him, they were considering putting him on hospice because in AFib he could not walk across the room. He was really, really royally sick. So this is an example in the case of the big difference that sinus resuscitation can do for some of these patients. So I think that's something that we need to consider and keep in mind. That's a great point. So it's a lot, it could be patient specific and really can be a dramatic change in lifestyle with maintaining sinus rhythm. I do have, Jared, you've done so much work, I mean, so many different areas, but in one of the areas is, you know, bringing up AFib as a more systemic disease or in terms of even talking about the brain and other, it's not impact potentially on dementia. And I, you know, I don't know, can you just share some of the data you've learned about in terms of the role of, or maintaining sinus rhythm or treating AFib to perhaps impact on that or what you're doing moving forward? Yeah, sure. No, thank you. I think we've shown there's been a number of studies, both ours and others that have looked at the role of ablation and dementia rates after, and they've been lower. And we've also seen from a number of trials that early and effective anticoagulation lowers risk of dementia. I think some of the areas that have been exciting to me recently have been those that have gotten to mechanisms because we have these patients that we all see. To Tom's point, the elderly often don't say, I feel short of breath running up a flight of stairs, but they say, I just can't process and think right. And sometimes we're not asking the right questions. But one interesting study there's been, we did was we took healthy dogs who have a vascular network in their neck that blocks strokes. And then we measured their cerebral perfusion and their reserve capacity at baseline. And then at, and put them in atrial fibrillation at three, at six months. And what is interesting is our brain's ability to reserve and to compensate for hemodynamic stress actually becomes maladaptive at three months and only partially recovers, which I find fascinating. And it's almost instant. It can give us some insight into our patients that just don't think right. And another study was looked at CO2 reactivity. When we were exposed to CO2, we hold our breath, our brain vessels dilate. And patients with atrial fibrillation have a, in human patients, 30% reduction in reactivity just from the presence of atrial fibrillation. And that's even compared to people that have hypertensive disease. So it's not just the vasculopathy, the rhythm is doing that as well. There's been a number of studies now that have looked at catheter ablation to pursue cognitive function. And it tends to help predict in the domain of memory. And there's been a few studies with catheter ablation that have shown that perfusion of the brain is better after it's six months. Particularly, and to some of Andrea's comments, it's seen most, it's most apparent in the sicker patient study. So often the ones we don't do catheter ablations because I think there's a lot of exciting mechanistic data and it's all giving us understanding of why people after ablation tend to do better in the community, which we didn't fully understand before. Great, thank you. Lots of reasons to be treating. And Jason, you showed so nicely the progression treating early, why to treat early, why it makes sense. And so, if we do treat and maintain sinus rhythm, some of that remodeling that it's demonstrated, can that get better or do we kind of, are we stuck with what we're left with at that point? Can any of that improve? Jason, you're on mute. Sorry. Sorry about that. I didn't put it into this presentation, but there is some animal data looking at this. And so they've taken some animals, taken a look at electrical parameters and structural parameters, and basically looked at whether you treat them with antiarrhythmic drugs or ablation. So compared to a control at baseline, atrial fibrillation has all these abnormalities. When you treat the animal with an ablation, those abnormalities regress. And so I think you see differences pathophysiologically that get you back closer to the baseline after an ablation procedure that you did not see when treating with antiarrhythmic drugs. And I think that that explains part of the disconnect. So if you look at early AF, the patients treated with antiarrhythmic drugs, they did reasonably well from an arrhythmia recurrence standpoint. They had a relatively low burden of atrial fibrillation on follow-up. So it's not that there was no benefit to antiarrhythmic drugs but despite a relatively low burden, you still saw substantially more patients going on and progressing to persistent AFib when they were treated with antiarrhythmic drugs relative to ablation. And so I think it's just ablation targets more manifestations of the pathophysiology in the heart compared to drugs. And that's why you start to see a difference. Jason, you make some very good points here. I'd like to ask all the panelists and including you as our moderator, Andrea, and Andrea as our panelists, is there a role as a primary choice for the antiarrhythmic drugs? I mean, you've all made a very strong case about how this is a chronically progressive disease and we know that sinus rhythm is better. Jason, you've spoken very nicely about how, you know, maybe ablation is a disease-modifying strategy on a pathophysiologic basis to minimize progression, but are there patient populations that you would say, gee, I think I'd prefer to use a drug first rather than an ablation, assuming that there are no limitations with space, time, or money? Maybe you could start it off, Meena. That's hard to answer that, hearing Andrea's experience with 90-year-olds. But, you know, the CABANA study, the one group, you know, I think there's a trend toward medical therapy first being ablation in age 75 and older. That being said, I would suspect that some of those 90-year-olds should try some medical therapy before going to ablation. But, you know, those, and then, you know, for heart failure, you want to, there's all this data for ablation, but I think this data for ablation, but I think you probably want to stabilize them first. So, you may actually buy some time by, and stabilization, hemodynamic stabilization, if you can restore sinus rhythm with an antibiotic drug before you go to ablation. And that makes sense, too, because might risk factor modification and treating comorbidities and then ablating oftentimes results in a better outcome. Yeah, because this is a question, the reason I'm posing this question is it's so frequently asked by patients and by referring physicians, and oftentimes referring physicians do try multiple drugs before they refer. So, I'm just trying to get a feel for what our audience should be thinking, given the recent data that's out there. So, someone else want to weigh in? That's actually a great point, Tom, you know, because I think the paradigm has been, you know, for years, it's like people used to say, oh, I'm going to try rate control for a while. And then all of a sudden, you know, you're way along in the disease and they try five different drugs and then send you for an ablation after someone has an atrium that's six centimeters. And that's clearly not the right, the way to do things. And we have data, you know, not to do it that way. But I think all of us have seen, I mean, we have patients that come in and we offer them, obviously we offer ablation, but people, some people, they don't want a procedure. You know, some people just don't want a procedure. So, we need to, you know, give options and use a shared decision-making approach or, you know, and it's not for everyone. I think also, and I think someone in the Q&A chat here, you know, brought up, and I think it was actually for John, Dr. Pacini mentioned not ablating for one episode. So, your first episode, you know, do we, is there a role, you know, for ablation? Do we have data? We don't, you know, do we have data after one episode? You know, what do you do for the patient who's just had a first episode? And I don't know if John, if you want to expand on that. Yeah, I mean, I think the theme, I think we're all, you know, trying to get across here is that atrial fibrillation is a lifetime disorder and there's, there are a bunch of critical points. I actually think there's a role for medications and I think there's a role for ablation. And so, at a very first diagnosis, someone has a single episode, I have a hard time imagining that that person's going to be well-served by catheter ablation. But, and I think this is a core goal of the COMPASS project, I think all patients with atrial fibrillation after a first diagnosis should get appropriate heart rhythm care and should benefit from seeing a heart rhythm specialist and should know if they continue to have atrial fibrillation that they should, you know, strongly consider either an antiarrhythmic drug or rhythm control. And I think one of our hypotheses in Change-AFib is that one of the ways we may see improved outcomes is by getting patients on rhythm control at day one. And then that way, if they do have progression or their episodes become more frequent, they can then benefit from greater forms of rhythm control. I'd say the other like milestone is patients who have AFib becomes more frequent. And we always tell our patients in clinic that, you know, if the AFib episodes are getting longer and longer, it doesn't matter if you're in between visits, we want you to call the office right away and come in to see us, you know, out of schedule. Great. And I think, Jared, you have your hand raised. Yeah, I just wanted to, I agree. I think what's critical though is we can measure the same brain markers of concussion at very low levels on that first diagnosis of atrial fibrillation. So oftentimes when they present it, there's been things going on underlying before the actual presentation and shorter episodes. And I'm hopeful I saw in the chat, the heartline trial is a trial where you take an Apple watch in first detection of fibrillation. Can you educate somebody, have them get appropriate therapy and does that influence outcomes? And I think that's going to be an interesting trial as we put diagnosis in the hands of patients for the first time and how can we as physicians work with that device and education to help people. But when you see it, just most of the people recognized have had fibrillation to some degree before they come in. And so it gives you, I think, as John said, an opportunity to intervene at that time. Yeah. And I think the comment to that, thank you. It was Dr. Church, I guess, put a comment about bringing patients in earlier. So the Apple or any kind of wearable device, I guess, can detect it earlier. I actually curious to see what the panel does if you haven't, one detection of AF on a watch, is that considered enough to start treatment for a short detection on an Apple watch? What do you do? I mean, we see this all the time now, right? We probably don't see it half as much as the primary care physicians and the cardiologists, general cardiologists do in the office. What should we do with that? And I don't know, Tom, your hand is raised, or did I miss that from before, maybe? No, that was from before. I mean, I'll give you my thoughts on it. I put it in a clinical perspective. I mean, if the patient is presenting with palpitations problems, they think they're having atrial fibrillation, and we're diagnosing them for that time. So they're symptomatic enough, then I would be aggressive in doing that. However, if they're pretty much an asymptomatic patient, and they're just worried about potentially developing something, and I saw a very short burst, and they were pretty much asymptomatic from it, I would not go in that direction. But I would look at risk factor modification, and I would look at treating comorbidities to try to prevent it from progressing to a further stage at a later point. And I would have them continue to use their monitor to see how that manifests over time. Great. Thank you. I would, yeah, I usually tell the patient with the first session, we need to understand what, when is the next going to happen? Because if the next is going to be in one year, there is no reason to escalate. I think that it's important that they're aware of the potential risk, so that there is a way to detect the next episode. And today, I think with the wearable, it's becoming easier and easier. I think there are very few patients that we see in the clinic that do not have already some sort of wearable that help us to sort of treat them more properly. But you know, the first episode probably right now for me is a way, you know, as Tom said, to talk about the other things that they should worry about. And then if that comes, if the second episode comes soon, you know, in the next month or two months, then clearly, you know, we need to intervene and do something. But if it's in one year, I think it's okay to watch them as long as they are safe. You know, and probably stroke is the worst thing that could happen to a patient with AFib, and that's certainly something that needs to be addressed. Thanks. And Dr. Salim put a comment in here for tying in cardioversion. And I don't know if I'm interpreting the question right, but you know, one of the things is, does it matter if someone comes in and their first episode is requiring cardioversion, and how do we tie that into treatment or, you know, outcomes in that first admission? Do you cardiovert them, send them home on anticoagulation and beta blocker? Do you, is that first episode different, and should that be treated? Or do we enroll in John's study, I guess, is the other possibility. What do people do with that? Does it matter if it's a sustained episode that requires cardioversion? I mean, I think that a lot of presentations to the emergency room are people who have no awareness of what they're experiencing, right? So they feel their heart racing, they have chest pain, they have shortness of breath, they don't know what's happening, they've never had this happen before, they go to the emergency room, that's their first diagnosis of atrial fibrillation. If you show up in the emergency room with a clear onset, you get cardioverted. And that may be within six hours, that may be within 24 hours, who knows. I think, you know, for us, we have a rapid access pathway from the emergency room to the AFib clinic, they see a general cardiologist in the AFib clinic where they get their comprehensive care, their education. And maybe we do nothing at that point, depending on what we see on the Echo and the Holter and the things that come within the first two weeks. So, you know, cardioversion as part of the first presentation doesn't necessarily change anything, at least in our perspective. I think if, you know, the first presentation is decompensated heart failure, you would treat that person differently than someone who's, you know, 40 and went away on vacation and drank too much and had an AF episode, right? It's a spectrum with a lot of context. Great points. Any other comments? I want to ask, maybe Jonathan and Jason, based on some of the data that we have on antiarrhythmic drugs, you know, there are certain drugs that might impact mortality and other don't, you know, do we need to address this or do we need to sort of, because I still see a lot of patients that come first line antiarrhythmic drugs amiodarone, even if they're young. So that's something that I think our community should educate both primary care and cardiologists to avoid. What do you guys think? Yeah, I would say that it's very disappointing how many times we get letters from insurance providers, you know, saying that I would just put the patient on amiodarone, it's more affordable. So certainly that's a class three recommendation in the guideline. If they're eligible for other medications, there's a nice analysis done by Michael Field, you know, looking at nationwide data and shows that most clinicians use antiarrhythmic medications in a very thoughtful way, but there are still these gaps and you highlighted the biggest ones, probably use of amiodarone in patients who don't have structural heart disease and are eligible for many other medications. So certainly I agree, lots of opportunity for improvement with respect to that issue and others. Yeah, I mean, I think the other thing is historically CAST put a shadow over class one C's. And I think in recent years, we've understood that it's not, they're not a problem when used properly. And that was one of the big points in East is, you know, they saw mortality advantage using predominantly flecainide and propafenone, whereas Sotalol and amiodarone have been associated with increased mortality. And that was the dominant antiarrhythmic drugs used in AFIRM and AFCHF. So potentially that difference is there. I mean, in the same analysis, jornetarone seemed neutral, so it's not harmful in terms of increasing mortality. So it's probably a reasonable medicine, like flecainide and propafenone as a first choice. Let me just ask the group one other question, because this comes up all the time from referring physicians and patients all the time. So, you know, patients have an ablation, it kind of looks like things are going well the first six months and, you know, they want to get off their anticoagulant and they have a CHADS-VASc of two in a man or three in a woman, you know, what do we do? What do we tell them? And, you know, is it safe or do you think there's a point where it's safe to get off anticoagulant? I mean, I think the guidelines clearly tell us that you should make the long-term therapy based upon the CHADS-VASc score. And we also know that whether it be an antiarrhythmic drug or whether it be ablation, none of those therapies are 100% effective. And sometimes patients are symptomatic, sometimes they're not. Sometimes they're blocked at the avenodal level and that minimizes their symptoms or they have atypical symptoms. So although it's problematic, I typically do not stop the anticoagulant. And my rationale behind that, Andrea, is the worst thing that can happen to an AF patient, you know, is probably a stroke. I mean, we know that it does progress with other symptomatic problems, but that's really a life-changing and sometimes even life-terminating event. So I look at it and if they do read the appropriate CHADS-VASc score, I continue it. I will argue that we do need more information on better risk factors in addition to that. And I would argue that there are some patients in whom you can get that off who, you know, maybe don't have, you know, underlying and can follow the atrial fibrillation by a monitor, either implantable or with a regular wearable. But even then we don't know until Jeff Healy and others give us data from their studies. It's a question mark. Great. You know, I would agree with you. I now tell people going for AF fibrillation, your body has a remarkable way of healing across what we try to do to it. So, I mean, we've seen some late reconnections. That being said, you know, I'm looking forward to studies like REACT-AF, Rod Pausman's study that will take patients who have rare episodes of AF that, you know, are no episodes of AF perhaps after ablation or otherwise, and randomize to a pill in the pocket, no AF. So that might be a way to go in the future along with left atrial appendage inclusion strategies. Great points. I did say last question, but there is, I do have to ask the panel this last question that's put up there is, so when do you decide what AFib burden on their maybe implantable loop or whatever device they might have in or monitor, do you say it's time to reablate? Is there a number? Is it 1%? Is it 10%? Is it 20%? Or does it depend? I think it depends on the patient. There's a discussion here with a patient, you know, their patients are extremely symptomatic. Even, you know, an hour is enough to sort of trigger anxiety. And so I think it's a discussion you have to the patient. I don't think there is a magic number that you can apply across the board. I mean, this is the way I usually discuss it with them. I want to make a comment about the anticoagulation because we, for many, many years, we actually, with appropriate monitoring, we have allowed patients to stop the blood thinner, as long as you have a sort of an ongoing, and this is something that you have discussed with the patient. You know, I think the easiest thing is, you know, those are the guidelines, just stay on blood thinner. But the reality is that most patients will stop it anyway. So you might as well have a discussion with them and say, you know, listen, this can come back as long as you have a plan and a way to detect the recurrence. I think you're fine. I think today with the wearable is becoming very easy. I think in the past that both our group and the parent group, we used to teach the patient to keep their pulse and tell them, if all of a sudden at night when you're in bed, relax, your rate is 15 beats faster, next day you come and see us. Now with the wearable, it's very easy. You know, you get your cardia or your Apple Watch recording, something is different. And I think it is becoming safer. So, you know, obviously we need to study to prove that, but I think if you have a good monitoring strategy, I think we've shown many, many other groups have done the same, that it's safe to do that. Great. Great, great comments. Great discussion. I do need to close. And I want to thank, so first of all, our speakers, panelists, you know, thank you to HRS, to Sanofi and Biosense Webster, who supported this, you know, COMPASS program. Thank you again to everyone who's attended, asked great questions, and really appreciate that. So this webinar does offer, so it's actually 1.25 ACE credits, and that'll be available to view on the HRS 365 website next month. And so while you're there, there's also, this is the third in a series of three COMPASS webinars, and the first two in March, the first one was different facets of AFib management and my patient as AFib, what now, kind of covering the whole spectrum of the management of these patients. So they're all wonderful presentations and discussions, so please, you know, take a look at those. And all of these, you know, COMPASS webinars are complimentary and offer the credit that'll be available on the site and for up to, you know, three years. So thank you again, thank you very much for a great discussion, and thank you for your participation. Thank you. Thank you, Andrea.

early atrial fibrillation

treatment

sinus rhythm

cardiovascular outcomes

antiarrhythmic drugs

catheter ablation

individualized treatment plans

shared decision-making

wearable devices

monitoring AFib

research