Hi, this is Peter Cohey from Lankin and Heart Institute at Thomas Jefferson University, and my task today is to talk to you a little bit about where we are with AF ablation, specifically what is the state of the art in 2020. I think it's reasonable to begin here by pointing out that I, like everybody else, have potential conflicts of interest and things to disclose. I don't do ablation procedures. I used to do them, and I don't anymore, but I do chair the NCDR EP steering committee that includes the AF ablation registry. I've also consulted with lots of industry, including companies that have an interest in antiarrhythmic drug development as well as devices, and I hold an equity interest in biotelemetry. So this is it. This is what atrial fibrillation looks like on a 12-lead electrocardiogram with a rhythm strip, and I suspect that everybody on this phone call knows what it looks like. So we won't spend a whole lot of time describing its architecture, but I think it's important to point out the scope of the problem. This is absolutely an epidemic. It's not quite to the level of a pandemic, but it's a ubiquitous disease that affects millions of people with a variety of cardiac diseases, some of whom have no overt cardiac disease. Unfortunately, I think over the years, we've grossly underestimated the burden of the disease, especially in the elderly. We have a primitive understanding of its pathophysiology, and that has greatly impeded our ability to come up with definitive treatments. We suspect, as time goes by, that the prevalence of the disease will rise because of the aging of our population, but also because we're keeping people around a lot longer with diseases that used to kill them, like heart failure, and we're also monitoring patients much more aggressively, not only with proprietary devices, but the consumer-purchased devices. We're seeing an explosion in the number of devices available to monitor for atrial fibrillation. Antithrombic drugs are limited, and unfortunately, simply controlling the heart rate in atrial fibrillation, providing for systemic anticoagulation, is not an adequate therapy, especially in younger patients who have lots of symptoms. So why the need for catheter ablation? There's several reasons. One is that no matter what we do with the antiarrhythmic drugs, they don't always work. In fact, they work in a majority of patients, but not in a substantial majority of patients. In the absence of a correctable underlying disorder without effective therapy, recurrences are highly likely, and the most commonly used drug in the world for atrial fibrillation is amiodarone, and it doesn't work in all patients, and it is, frankly, it is a dangerous drug that requires very comprehensive monitoring. Because it is a difficult regulatory pathway to approval for a new antiarrhythmic drug, we have not had the approval of very many drugs, especially oral drugs. Zofedolide was approved in 2001, dronetarone is the last oral drug approved in 2009, and realistically, there's nothing that's on the immediate future, on the immediate horizon for approval for atrial fibrillation suppression with drug therapy. Drugs have a limited role in the management of atrial fibrillation, and we all know this. A lot of it is because, as I said earlier, we have a very primitive understanding of the pathophysiology, and in fact, most of us believe that it is multifactorial in etiology. That is, in any given patient across any given population, there may be an endless number of reasons why people have atrial fibrillation, and so one silver bullet approach to curing the arrhythmia is simply not going to happen. What we've also learned, and we'll go over this in a little bit more detail as I go through this brief talk, is that, in essence, anthraemy drugs are inferior to catheter ablation in a sizable percentage of patients in whom the two treatment approaches have been appropriately compared. Ablation is kind of a nebulous term, and it really encompasses a series of different kinds of interventions, different in terms of the energies that have been applied, as well as the places that energy has been applied, and the techniques that have been used to apply the energy. So, when we say ablation, unfortunately, it isn't really very descriptive. It doesn't really help us to understand exactly what are we talking about. Well, for the most part, the most popular approach to ablating a focus in the heart is to go after the pulmonary veins, and Hasseger's seminal paper in the New England Journal in the late 1990s set the stage for a much better understanding of the idea of isolating triggers that are present in the pulmonary veins in a substantial percentage of patients who have paroxysmal atrial fibrillation. You probably have seen pictures like this or like this. This is looking at the high-tech image of a heart during an ablation procedure, showing you where these lines are being placed in relation to the pulmonary vein anatomy. The high-tech approach here is obvious, and the sophisticated mapping techniques have really assisted us in making these lesions much more secure, much more reproducible, and much more effective in isolating the pulmonary vein sleeves where these foci originate. But here's the biggest problem we have. The biggest problem we have is we don't know how effective ablation is. If you look at this slide, it's a little bit old. This goes way back to 2005, but the data haven't changed a whole lot since 2005. Depending on how you define success, we're dealing with the procedure that may be as ineffective as 20% in some populations to as high as 90% in other populations and in other studies. Most of us are very interested in the blue bars, the light blue bars that tell you what are the chances of a successful procedure without having to use an antiarrhythmic drug post-procedure for the long term. Again, I don't think that these numbers have changed very much over the last 15 years or so. We're still dealing with efficacy rates in that range of 20% to 60%, probably with the new technology a little bit much, much more on the higher side. But when reading the literature, it's very difficult to come out with the right numbers because of some of these problems that are listed on this slide. There are many different forms of atrial fibrillation. We tend to try to use a taxonomy that depends on the timing of the arrhythmia, whether it's paroxysmal or persistent. Patient selection is very important, who gets excluded from an ablation procedure. We certainly aren't ablating patients who have very long-standing atrial fibrillation or permanent atrial fibrillation. We have a publication bias. Publications generally come from the most experienced operators. When reading the literature, we're usually getting the most optimistic view of what the success rate might be. As I've already said, the definition of success is highly variable depending on whether one counts those patients who have repeat procedures or whether or not patients have repeat procedures. The other part of the problem with ablation is understanding its risk. It has really evolved tremendously over the last 20 years. I think that this is a safe procedure, especially in experienced hands. What was really a revelation, and we'll talk a little bit later about the CABANA study, one of the seminal studies in this field, was how well patients did in CABANA. Again, remember, these are very experienced centers with very, very skilled people doing the procedures, and that has to be taken into account. As you can see here, the complication rates were extremely low and very acceptable for any form of ablation procedure, let alone a procedure in which we're going across the interatrial septum, which is what AF ablation means. However, and I come up against this all the time when I'm talking to patients, in the absence of a truly controlled study, and this slide comes from an editorial from John Mandrol, it was in Medscape, in the absence of a true sham controlled trial of any invasive procedure, the effect size is not knowable. We really don't know what the true effect size is for HFR ablation, including pulmonary vein isolation. One of the big reasons for that is the third bullet on the slide, which points out something that all of us in medicine have been highly aware of, and that is how powerful a placebo effect there is in patients who undergo an invasive procedure. If you put catheters in patients, or if you operate on patients, the tendency is to believe that it must have worked, and that placebo effect is extraordinarily important. As we've learned, as we've learned from properly controlled clinical trials of various invasive procedures like knee arthroscopy, for example, the placebo effect is extremely important. I want to just highlight three very impactful randomized clinical trials published within the last couple of years that I think have in fact moved the needle and have helped clinicians to come to some conclusions about how to best employ atrial fibrillation ablation in their clinical practices. The first is CASEL-AF. One of the questions that has been asked for quite some time is, if you take a group of patients with heart failure who have atrial fibrillation and ablate their atrial fibrillation, is it possible in this very vulnerable and susceptible and ill population that you might actually afford them a better outcome? When I say outcome, I don't mean just suppression of the atrial fibrillation. I mean, can we reduce things like total mortality or heart failure hospitalizations? This study, which is published in the New England Journal from Marouche, is a seminal study because the results suggest strongly that, again, in the right hands in a randomized trial, there was an improvement in outcomes in patients who had atrial fibrillation ablation and with heart failure. This is the table from the New England Journal article that allows you to see that the primary composite endpoint achieved statistical significance, as did a number of the components of the primary endpoint that were listed as secondary endpoints, a study that actually showed a reduction in mortality for atrial fibrillation ablation, and again, in a heart failure population. Well, there's lots of things that happen in clinical medicine, and when an article is published like this, it undergoes intense scrutiny, as it should, and this article was scrutinized very carefully by a number of people who do randomized trials. This is an excerpt from an editorial that Milton Packer and I wrote in circulation shortly after the publication of CASEL. These are some of the problems with CASEL. One of the largest problems is that it took them eight years to randomize 397 patients at 33 sites, which means that each site recruited about one patient per year. Now, you know that these sites were seeing a lot more heart failure patients. In fact, they screened 10 times more patients than they enrolled in the study, so one becomes quite concerned about the possibility of selection bias. There were also imbalances between the groups. There were crossovers. Heart failure hospitalizations for the first three months were not counted, and unfortunately, there were a number of patients who were lost to follow-up. I would say that despite these limitations, what CASEL-AF has done for me is it has changed my threshold, perhaps, for sending patients for atrial fibrillation ablation and congestive heart failure. It hasn't convinced me completely that there's a heart outcome benefit, but I think this kind of a study goes a long way to helping us to understand which patients might benefit the most over and above symptomatic improvement in terms of achieving better outcomes. The second study is CABANA, and again, by way of disclosure, I was on the steering committee for CABANA. I was a co-author on the primary publication that appeared in JAMA, and so I have something of a vested interest in this study. As you can see, Doug Packer, who was the principal investigator in this study, worked very, very hard over a long period of time to accrue a sufficient number of patients for analysis, and this was a study that basically asked the question of whether you could demonstrate an improvement in heart endpoints in patients who were subjected to catheter ablation as a relatively early intervention versus antiarrhythmic drug therapy or rate control in patients in the other arm, and this was the principal endpoint in CABANA, and as everybody knows, for the principal endpoint, which is a primary composite of these things that you see on the slide, CABANA did not reach its primary endpoint. There followed, of course, great debates in the literature about what does this mean in terms of the interpretation of the CABANA results, and I would just sort of capsulize all of that controversy by saying this is still a very important study because it taught us that although we could not achieve that primary endpoint that was described, we did clearly show that there was a reduction in atrial fibrillation burden and improvement in quality of life, fewer hospitalizations in patients who had ablation procedures compared to those who did not have ablation procedures, and so again, despite all these limitations that Doug Packer has in his article in JAMA, and there's even another page of these limitations including crossovers and unblinding and significant thresholds and adjustments, all these things are important, but I don't think they take away from the essential message, which is atrial fibrillation ablation has value in terms of treating patients, even though we may not be able to promise patients that we can save their life or prevent a stroke. The last of the three studies before we get into some Q&A that I just want to feature is EAST. This is a study that was published very recently in the New England Journal of Medicine. It's required reading for anybody who's interested in treating atrial fibrillation patients because it is an extremely well-conducted clinical trial that randomized patients early in the course of their disease, that is, within several weeks of the onset of their atrial fibrillation, randomized them to what was essentially a rate control versus a rhythm control strategy. If this sounds very familiar to you, it's because it's exactly what the intention was in AFIRM, the trial that we carried out several years ago, but in this particular study, the emphasis was on trying to get the patients early in the disease process, on the theory that one can intervene and be successful earlier in the disease than later in the disease. It's important to point out here, although we're discussing ablation, that only 20% of the patients in EAST who were put into the rhythm control arm of the trial actually had an ablation procedure. The majority of the patients were treated with antirhythmic drugs, and as usual, the most commonly used antirhythmic drug was amiodarone. However, it was a very well-treated population, as you can see with the vast majority of patients being anticoagulated and beta-blocked, again, somewhat different than what was carried out or what was achieved in AFIRM. The primary endpoint was this composite that you see here, and in fact, the trial was discontinued early because of an efficacy signal. This was the efficacy in EAST. There was a 1% absolute difference between those groups on that four-component composite in favor of early therapy, 5.0 versus 3.9 events per patient years for a p-value that you see there on the slide with a couple of O's in front of the five. The absolute difference in cardiovascular death was 0.3%. There were more patients in the early group who maintained sinus rhythm, although there was no difference in hospitalized days, symptoms, or left ventricular function. As you would have expected, since people in the rhythm control arm were having interventions, there were more serious adverse effects in that early group. Those of us who have looked at EAST remain a bit puzzled, frankly, about why the study was discontinued early with this magnitude of treatment difference, but it was. We're gratified to see that early intervention in this population was helpful. I have to be honest with you that I'm not sure that the magnitude of the difference here necessarily propels me in a different path for taking care of patients with atrial fibrillation. It gives us some information that guide our treatment of patients and the individualization of therapy that must go on in the treatment of atrial fibrillation. As I conclude, what do I think are the remaining issues that we need to settle in atrial fibrillation? one of the things that really remains a conundrum is what to do after ablation in patients who have recurrence. We typically use antiarrhythmic drugs in those patients if they don't have a second or third procedure, and even if they do sometimes, the problem is we don't know what drugs are best. We don't have any randomized trials showing what doses of what drugs are best. So this area remains an open area for clinical research, I think. We also don't know exactly what to do about anticoagulation. Clearly, in low vascular risk patients, it's pretty easy. You stop the anticoagulant. The problem is if you're ablating patients with high vascular risk, at what point do you feel secure in the decision to discontinue anticoagulation? And if you do, what kind of monitoring is required in those patients in order to guarantee that they're not at risk for a thromboembolic event? We know that PVI is a terrific procedure. What happens if PVI doesn't work? Or what do you do in patients with longstanding or persistent atrial fibrillation? Does one necessarily add other things to the PVI algorithm or not, and when? And those questions also remain to be answered. Another large question that I don't think we've adequately answered yet is what are we gonna do about energy sources? We've seen the advent of some very interesting new energy sources coming to the fore, but most of us in our clinical practices are used to seeing patients having radiofrequency or cryoablation. Which of these will emerge as the most effective and safe over the course of the next few years is still a bit up in the air. How best to monitor patients post-ablation? How aggressively should we monitor patients post-ablation, especially as it relates to the anticoagulation issue? How best to keep our patients safe from the adverse events that we fear the most, like esophageal injury, for example? We still wrestle with this question and don't really completely understand how to do that. And then, of course, although the EAST trial gives us some guidance as to pursuing rhythm control earlier in the treatment paradigm of patients, when should ablation absolutely come first? EAST doesn't answer that question for us, but we are getting closer, I think, to that truth. And the last thing I'll say before I finish is I'm gonna plug the AF Ablation Registry. So as I said in the very beginning, I chair the NCDR steering committee that oversees the ablation registry. We desperately need this. We need comprehensive data across hundreds of centers across the United States in order to be able to understand what's going on. The literature is overpopulated with studies that come from places that we all know about, and their results are always excellent, but it's a very, very strong publication bias. We have inadequate information about what happens at the community level, especially with regard to safety. And I'm afraid that we're really not gonna be able to answer a lot of these questions without comprehensive data. That is not to say that we can't embed within these registries randomized clinical trials to answer fundamental questions. In fact, if the registries are large enough and comprehensive enough, we can exactly do that. And I think that's the way that we're going to answer questions in the future, rather than trying to carry out large randomized clinical trials across multinational studies that will cost a tremendous amount of money and take years to complete. So I'll finish with Yogi Berra's quote, most of the future is ahead of us. I personally think that the future is bright for atrial fibrillation therapeutics. We have a lot of things that are coming through the pipelines that I think will be extraordinarily helpful to treating atrial fibrillation patients, both in terms of terminating the arrhythmia, preventing recurrence of the arrhythmia, and protecting patients against the ravages of the arrhythmia over the long term. So I'll stop there. I really appreciate the opportunity to have addressed you today and be very happy to take questions. Thank you, Dr. Cohey, for an excellent presentation. I do have a few questions. When AFib prevention with antiarrhythmic drugs has failed, what other factors does electrophysiologists or a physician consider when selecting AFib ablation as a treatment strategy? Thank you. I hinted at this several times during the presentation. I think it's worth, I'm glad you asked the question because it really deserves emphasis. Atrial fibrillation management, unlike almost anything else that I can think of in medicine, really demands that the physician individualize the treatment. There are very few patients with atrial fibrillation that I see in the office who I think should get exactly the same treatment as the person I saw last. My fellows go a little crazy because they see patients with me in our offices, in our clinics, and I'll do things that are almost diametrically opposed going patient to patient, but it's always predicated on the patient's clinical profile, their expectations, what they think, what their symptoms are like, what their quality of life is like. And what their risks are for invasive procedures. So for me, in a patient that you just outlined, a patient who's got an antiarrhythmic drug or two and is still having atrial fibrillation and is highly unhappy because they're still having severe symptoms, atrial fibrillation ablation is frequently a recourse for us. It isn't always a recourse because some patients don't wanna have it or I consider them to be too high a risk or there is something about their disease state or their comorbidities that make me more bashful about recommending an ablation procedure. But in many of those patients, atrial fibrillation ablation is a reasonable alternative. Then the question is, okay, so you have referred this patient to a person who you think is going to do an ablation procedure. Then we get into this whole argument or discussion about what is that procedure? Is it pulmonary vein isolation? Is it pulmonary vein isolation plus? And how those decisions are made in terms of substrate ablation can be quite difficult. So it's a difficult question to answer because there's no blanket answer to the question other than saying that we really do need to take all of the patient characteristics into account. Okay, thank you. You have a slide about success rates. But what about second and third procedures? Does data exist for the success rates for those procedures? Absolutely correct. We do know, I think it's safe to say, that if a first ablation procedure fails, that there is an accessory yield from a second ablation procedure. And they're probably from a third ablation procedure. Now, the problem is, of course, that the accessory yield probably goes down as one progresses through this because you're now beginning to select out patients who have truly resistant disease. Second problem is what is that second and third procedure? In many patients, fortunately, it's as simple as completing the lines of block around the pulmonary vein sleeves so that we can prevent the emergence of those triggered beats in the pulmonary vein sleeves from emerging into the atrium. So that's called the old touch-up procedure. That one is pretty straightforward and does actually carry a fairly good accessory efficacy rate. The problem is if the pulmonary veins have already been sufficiently isolated, now we're getting into substrate ablation, and that becomes a much more slippery slope because the efficacy of those procedures is reduced. However, I think we're beginning to learn quite a bit about what kind of accessory procedures might work the best. As an example, I'm sure you've heard of this so-called converge procedure, which incorporates an epicardial approach in addition to the endocardial approach, where it looks as though, compared to endocardial ablation alone, there may be a fairly substantial accessory yield. We're learning a lot about these things. I think we're gonna learn a lot more over the next few years, but yes, absolutely, that is a recourse for patients with a failed procedure. So on that topic of convergent procedure, do you feel the evidence suggests it's better as a standalone or a primary procedure, or is it best for a secondary or tertiary approach? That's a very interesting question. The CONVERGE study, that is the study that supports the approval of this device, and it is going through a regulatory process, was actually a first procedure for persistent or longstanding persistent patients. I don't see it that way. The people who did the study were asked to do it that way because the regulators wanted to see those data, and I understand why. But in real practice, I think that the CONVERGE procedure is likely to be a follow-on procedure. So a patient has a pulmonary vein isolation, it fails, the patient's highly symptomatic, they're brought back to the laboratory, the pulmonary veins have been sufficiently isolated. I think CONVERGE may be a very realistic option for many of those patients. Again, the percentage of the patients who come back who should be CONVERGE patients is arguable, but clearly having that as an alternative has been, I think, a good thing. Okay, and on that same theme of one procedure selection over another, when would electrophysiologists consider cryoablation versus radiofrequency? Well, that's a really great question, and it's difficult to answer it. So it looks like for pulmonary vein isolation procedures that the efficacy for the two procedures is probably comparable. There's probably not a whole lot to pick. So then the question is, is there a safety difference? Well, there may be a safety difference in terms of, for example, esophageal injury or pulmonary vein stenosis. But the reason why that's somewhat difficult to ascertain is because those complication rates are very low. And so unless you had a very, very large trial, it would be hard to differentiate those things. The next thing that comes along is procedure facility. So how easy is it to do these procedures? Well, it turns out that cryoablation may be a simpler procedure for people to learn and to do. I know that there are some people who are very pro-cryo because they've been doing it, they like it, they've gotten good results, and that's all fine. It's very analogous to a lot of other procedures in medicine where you say, is it better to do A or B? And it turns out, well, if you like A and you do A well, then that's probably the procedure you should do versus B. And I think we're sort of in that category here where the two are radiofrequency and cryoablation are probably pretty close to each other now. Whether some of the newer energy sources that are being developed will eclipse both of them or not is still to be seen. But I'm optimistic that as we move forward, we'll get better at this as we have, and we'll have a better understanding of the relative efficacy of all of these energy sources. Yeah, it speaks to your comment earlier about the need for real-world data, that data outside of large randomized trials. So thank you. And talking about some of the newer energy sources, I've been reading a little bit about the Magnetic Resonance Imaging, MRI, electromapping systems. Can you tell us a little bit about that? And are they showing, you know, results in efficacy and visualizing catheter depth of lesions and, you know, that sort of thing? Well, advanced imaging in general, including MR, is going to revolutionize lots of things in medicine. At our center, we have invested very heavily in the development of advanced imaging, several different modalities, including MR, because I think it's pretty clear that the better you can image, the better off you are in terms of procedure and success. MR is interesting because there are two, there's two ways that MR might make atrial fibrillation a better procedure. One is by identifying those patients who have scar in the atrium as individuals who may not necessarily respond to just the pulmonary vein isolation, may need substrate ablation as well, or may not be a good candidate for an ablation period, depending on how much scarring there is in the atrium. And the other way, as you've intimated, is using MR during the procedure to help us to guide not only the location, but the depth of lesions and the success of lesions. I think all of these imaging modalities have tremendous potential. Now, the problem is, as you advance the imaging sophistication, you decrease the number of places where you can apply it. I mean, every community hospital in the United States is not going to have advanced MR imaging in their electrophysiology laboratories. So we create something of a treatment gap, if you will, by putting into place modalities that may have a significant impact on the efficacy and safety of a procedure, but it's not practical to apply in the general population. That's one of the reasons why cryo has been popular, because it is much more easily implemented in community hospitals, for example, where the volumes may not be necessarily as high as they are in university hospitals. Okay. So what new ablation strategies are on the horizon that we may not have heard of yet? Well, I think we need to do a much better job of identifying individuals who are high, have a high chance for successful ablation procedures. I mean, we're getting better using, and we were just talking about imaging, which is one of the modalities that can help us, but I think we're doing a better job of clinically profiling individuals to help us to pick out those patients who have a much better chance of success. The other thing that we need, desperately need, and I know that there are many, many basic scientists around the world who are working on these things, we need a much better understanding of the pathophysiology of the disease. We're dealing with a multifaceted arrhythmia, and we're using a relatively primitive, blunt approach, and that never works. It's like giving the same antibiotic to everybody with pneumonia. It's just not gonna work if you can't characterize the arrhythmia and do a better job of classifying and understanding the pathophysiology. So two fronts. One is a better understanding of AF itself, and the other is better patient selection and better application of the techniques. And the other thing that I think we're doing that I'm very hopeful about is I think our operators across the country are becoming much more skilled and much more facile with the technique. The technique doesn't take as long as it used to, and when we don't have people in the lab as long, the complication rates go down. I think we're doing a much better job with safety, which is one of the reasons why we're optimistic that this procedure will be around and will be helpful to us for a long time. Okay, excellent. And my final question, the quality of life with patients with atrial fibrillation is often a driver for continuing to try new therapies. Have there been demonstrated quality of life improvements with AFib ablation? Yes. I think Cabana probably did the best job on this and has already published their quality of life information showing a substantial improvement in patients who had ablation compared to patients who were treated with antiarrhythmic drugs. But let me just, and I think that, I think it's true. I think that there's a lot of evidence I think that, I think it's true. I do. What I don't know is how true it is. What is the, how to quantify that improvement in quality of life? And the reason is because, as I, and I've said this in several places and I've been quoted by several different people when I say this, it is very, very hard to assess quality of life in studies in which the patient and the doctor know what intervention the patient received. We have been, we should be ashamed in medicine how many times it's taken us to understand the power of the placebo effect in patients who undergo sham procedures, for example. It's maddening. So if you have an ablation procedure, you're going to want to feel better. The person who gave you the ablation procedure is going to be telling you that you should be feeling better. And the chances are you're going to feel better. I don't think that accounts for all of the improvement in ablation. I don't think that's true. I don't think you can wipe out all the benefit and quality of life just with that explanation. But I think there's a certain proportion of the benefit that can be explained that way. Unfortunately, since we don't have a truly controlled ablation study, and we never, for practical purposes, I don't think we ever will, the magnitude of that improvement in quality of life from placebo effect is really is unknowable. Yes, thank you. Well, this has been a very informative presentation and we really want to thank you for taking time out of your very busy schedule. And I know everyone has been very appreciative of your sharing of your knowledge and your experience. Thank you. Thank you, Michelle. It was a pleasure.

atrial fibrillation ablation

catheter ablation

pulmonary vein isolation

individualized patient treatment

advanced imaging

AF pathophysiology

improved outcomes