Atrial Fibrillation: Recent Clinical Studies, Latest Technologies, and Expanded Use in Heart Failure

With Randall Lee, MD, Kenneth Ellenbogen, MD, FHRS, and Hugh Calkins, MD

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In this special episode of The EP Edit podcast, Randall Lee, MD, talks with Kenneth Ellenbogen, MD, FHRS, and Hugh Calkins, MD, about the role of atrial fibrillation (AF) ablation in patients with heart failure, including recent clinical trials, new technologies, and the role of hybrid therapies. Randall Lee, MD, is an electrophysiologist at UCSF Health and VP of Medical Affairs for AtriCure, Inc. Kenneth Ellenbogen, MD, FHRS, is a Professor of Medicine and Chair of the Division of Cardiology at the Virginia Commonwealth University (VCU) School of Medicine in Richmond, Virginia. Hugh Calkins, MD, is a Professor of Medicine and Director of the Electrophysiology Laboratory and Arrhythmia Service at the Johns Hopkins Hospital in Baltimore, Maryland. 

This podcast episode is also available on Spotify and Apple Podcasts!

Randall Lee, MD: Hi, I'm Randy Lee. I'm a cardiac electrophysiologist at the University of California, San Francisco, and VP of Medical Affairs at AtriCure. I'm with Drs Ellenbogen and Calkins at the Western AF Symposium 2024. Could you introduce yourselves? 

Kenneth Ellenbogen, MD, FHRS: Hi, I'm Dr Kenneth Ellenbogen. I'm Chief of Electrophysiology at the VCU School of Medicine and I was one of the principal investigators for the DEEP AF trial, which was presented at the American Heart Association (AHA). 

Hugh Calkins, MD: I'm Hugh Calkins, I'm the Director of Electrophysiology at Johns Hopkins and I was involved with the CONVERGE trial. 

Randall Lee, MD: We're very fortunate to have my esteemed colleagues here and what we're going to discuss today is some of the topics being presented at the Western AF Symposium. In particular, we're going to focus on the role of AF ablation in patients with heart failure, especially with the recent data from the CASTLE-AF and CASTLE heart transplant (HTx) trials. In addition, we will discuss the role of hybrid therapies and which patients may be chosen for that course of therapy. So, Ken, you mentioned the DEEP study. Could you give us a synopsis of that study and the results? 

Kenneth Ellenbogen, MD, FHRS: I think the DEEP trial was one of 2 trials that looked at hybrid ablation for AF. There are really 2 types of hybrid ablation. One is concomitant, that is, in a single procedure, both minimally invasive surgical AF ablation and catheter ablation. That was the CONVERGE trial, which was presented and published several years ago. The other strategy for hybrid ablation is one in which patients undergo a minimally invasive thoracoscopic AF ablation and then come back approximately 3 months later to have the surgical portion of the AF ablation checked, particularly to check pulmonary vein isolation (PVI), check posterior wall isolation, and do cavotricuspid isthmus ablation as well as any other ablation that needs to be done that is clinically indicated. 

DEEP AF was a prospective trial looking at this sequential hybrid ablation therapy in patients who had persistent and long-standing persistent AF, as long as there wasn’t have massive left atrial enlargement. The results of that trial have not been published but were presented at the AHA meeting several months ago. Unfortunately, this trial took place during the COVID-19 pandemic, which led to the temporary discontinuation and reinitiation of the trial. But, as a byproduct of that, it resulted in some really good long-term follow-up for patients, showing that a hybrid AF ablation approach is highly effective for preventing recurrent AF using the traditional definition of 30 seconds or more of AF. These patients underwent CT scans to check left atrial appendage occlusion and underwent at least a 1-month monitor once a year, and was found to be effective in a group of patients who previously had a very low success rate and required multiple procedures with catheter ablation. 

Randall Lee, MD: Hugh, with the recent data, you're well aware of the CONVERGE trial, which showed superiority in long-standing persistent AF patients compared to catheter ablation. There was recent randomized cease data and also hard cap. How are you now choosing hybrid therapy versus PVI? Then, extrapolate that, given that there is no real data in terms of for heart failure patients. How would you use it, or would you use it? 

Hugh Calkins, MD: I think where the Convergent approach comes in is for patients whom we think catheter ablation standard techniques will result in a low success rate. I think the most powerful predictor of a bad outcome of catheter ablation, a standard endocardial procedure, is the duration of continuous AF. If someone has had persistent AF less than a year or maybe less than 2 years, then I'll do a catheter ablation procedure first. If that fails, you certainly could think about the Convergent procedure as a second stage. But for patients who've been in AF for 3, 4, 5, or 6 years, certainly the chance of an endocardial approach working is extremely low and that's where the Convergent procedure really showed superiority, a very significant margin, and a better outcome with that approach. In terms of heart failure, it's amazing how the heart failure story has evolved. Early in the days of catheter ablation, we would never have thought of bringing a patient with heart failure to the EP laboratory to do an AF ablation. Now, between the CASTLE-AF and CASTLE HTx trials, we know how it seems to be quite safe and really improves heart outcomes. The other thing which is striking from these studies is the success or improvement in outcome did not require that all AF be eliminated, it's just a reduction in burden. So, if the AF burden dropped to 20% or less, you'd see these tremendous improvements in outcome in terms of heart failure class and in the need for a transplant and so forth. Even though many of these patients would continue to have brief runs of AF for 5 minutes or an hour, that's not what is important. It's really all about the AF burden. So, I think we have a whole new perspective on the heart failure patient with AF. 

The other thing I want to make clear is the new AF guidelines from the American College of Cardiology and AHA have very clearly said that if a patient presents with AF and heart failure, the goal needs to be restoration of sinus rhythm, not rate control. You must get these patients back to sinus rhythm—that's where the best outcomes are achieved. Then, the question is will a catheter ablation endocardial procedure going to be best, or is a hybrid procedure best? Again, that will depend on specific patient characteristics. I suspect if someone is on the transplant list, it's probably unlikely you're going to do a Convergent procedure and another open-heart surgery or minimally invasive surgical procedure—it would make the transplant more difficult. So, I would think for someone on the transplant list, hybrid ablation would probably not be the best option, but for someone before that where you don't think a transplant is needed, that's where whatever technique gets you to sinus rhythm or reduces AF burden the most is going to be the one I'd recommend. 

Randall Lee, MD: Ken, you've been very involved with biventricular (BiV) pacing, and Hugh brought up the point that it's really about reducing AF burden, restoration of sinus rhythm versus rate control. So, where do you see BiV pacing fit into this? 

Kenneth Ellenbogen, MD, FHRS: Before I answer that, I want to add something to what Hugh said. I think the other group is sometimes the patients who say they just want one procedure or are really reluctant. If you tell them, "you've been in AF for 2 or 3 years, you're probably going to have multiple procedures and perhaps need a drug to restore slightest rhythm," they ask, "if I could do one thing or procedure, what should I do?" So, in some of those patients, I think hybrid is good, because they want a procedure. As a single procedure, the success rate is pretty high. As a single procedure, you also take care of the risk of stroke. So, that's another group of patients I would consider for hybrid ablation. In addition to what Hugh said, I think it really is amazing to me too that we've come from AFFIRM, where we didn't know what strategy, to heart failure, because we've known for decades that patients with heart failure and AF do poorly. However, we never made the assumption that if we get rid of their AF, will they do better? That was never made. But as Hugh said, in these studies and meta-analysis of these studies, while some of them are pretty small, there are enough of these studies now that they really seem to suggest a real benefit from catheter ablation for AF in the maintenance of sinus rhythm. So, when you ask me why anyone should ever get BiV pacing or conduction system pacing and atrioventricular (AV) node ablation, which I find we're doing more and more, I would reiterate what Hugh said. I think for the vast majority of patients, even up into their mid-80s, maybe AF ablation in the left atrium, if the duration is really prolonged, more than 5 or 6 years, and their left atrial sizes are quite large, 6 or 5.8 centimeters. The chances of helping those people with an AF ablation are particularly low, but in the vast majority of patients, I think you start out with an AF ablation. If after AF ablation it doesn't give you a good result, what do you do next? I think the next step would be to consider BiV pacing and AV node ablation, or conduction system pacing and AV node ablation. Again, there are only small randomized trials suggesting people with conduction system pacing do particularly well. They may even do better than BiV pacing. It appears that way, meta-analyses of small sample sizes and small numbers of trials. We've looked at that, too, in large, non-randomized registries or databases, and it does seem like the patients do very well. So, I think if they fail catheter ablation and cannot maintain sinus rhythm, you tried once or twice, and particularly in patients who have been in AF for a long time or already have a BiV, it's hard to resist that urge now that we have good data on that.

Hugh Calkins, MD: Ken, one question that comes up is if you have that patient who failed ablation and are elderly, in terms of doing a BiV device and AV node ablation, do you restrict that to patients who have uncontrolled rates? In someone whose average heart rate is 70 or 80 at rest, do you think there is benefit in regularizing the rhythm where you would deplete the AV node and put in a BiV? Or, do you really restrict that for patients where you're having a hard time with rate control? 

Kenneth Ellenbogen, MD, FHRS: That's a tough question and somewhat of an important question. There's some data that suggests ablation and pacing, because it regularizes the heart rate. It gets rid of the autonomic dysfunction caused by AF. Think about that, because if you think about all these baroreflexes in the body that regulate the autonomic nervous system, they are affected by pressure, which is basically stroke volume. So, if every single beat has a widely variable stroke volume, I can understand how their autonomics would be dysfunctional, their cerebral blood flow is dysfunctional because of that, and probably most of those patients will do better with a pace and ablate strategy. There are only at least maybe 2 studies, one reasonably good, that have looked at patients with rate control and heart failure and randomized them to continuing medical therapy versus BiV pacing in this one instance, and they've done better both in terms of heart failure but also in terms of mortality. So, I think there is some data that suggests that might be the case, but I'd like to see more. I think there needs to be more for everyone to feel comfortable. Personally, I like to look on a monitor at how variable their heart rate is. The mean heart rate is 80 and their heart rate is between 60 and 110. I think those patients do better than the ones whose heart rate is between 45 and 150.

Hugh Calkins, MD: The heart failure story is amazingly mentioned in all the small studies. Over the last 10 or 15 years, there has been about 10 of these small studies. Years ago at the Cleveland Clinic, Andrea Natale did one of them, which was ablation versus even an ablation and a BiV device. Every one of these studies has always been positive, but it's finally when we got these randomized trials that the world's view of heart failure and AF shifted to the complete other direction. So, it's interesting. 

Kenneth Ellenbogen, MD, FHRS: The other thing I find quite interesting is the heart failure doctors who said, “no, we'll just keep treating them with medicines.” Now, with heart rate control in some of the sicker patients with heart failure, the patients feel terrible and part of it is the beta-blockers. So, they will be like, “why don't you back off the beta-blockers?” We're like, what? Heart failure doctors not backing up beta-blockers? What's that's about? But it does make patients feel poorly, particularly on the high doses, and it does lead to decreased cardiac output. We've known that for a while. Just to amplify that point, and not just Natale, but there was a study from Bordeaux in the New England Journal of Medicine comparing PVI and then it was BiV pacing. It was a small study, but the patients all had heart failure, and the patients who underwent PVI did better. The heart failure community tried to say, "Well, it’s just a small study." But as you said, every single study has shown a result of that finding, so I guess people finally woke up and saw that the data really is there. But you see that all the time. People come into the hospital with heart failure, and often it is AF that causes their deterioration.

Randall Lee, MD: With the increase of pulsed field ablation (PFA) in heart failure patients, we're going to be inundated as electrophysiologists in terms of more and more procedures. Do you think it will come to a point like, say in the UK, they're starting to institute 2 ablations. Do you think that will occur in the US? If so, what about hybrid therapy? As you suggested, if a patient wants a particular procedure, you give that patient what you perceive as the best shot. What do you think? 

Hugh Calkins, MD: Yes, the whole concept of go big or go home, going with one procedure’s maximal success rate right at the beginning versus dipping your toe in the water doing one procedure, then a second procedure, and then a third procedure doing a hybrid AF ablation. I think that comes down to patient preferences and values. You mentioned a patient who said, “I just want to go through one procedure; what is going to give me the best success?” Then, other patients don't mind the notion of having to get a second procedure. So, I think a lot of that is going to come down to the patient. I don't think in the US, we're going to see payers say you get 2 AF ablations and then you get shut down, because there is always new technology and new approaches. You can always justify why is it that you're doing that third procedure. In some of these patients, their first one was 20 years ago, they needed another 5 years ago, and now they're in for the third, but you got them 5 years of sinus rhythm. So, I cannot imagine the payers clamping down on that. One of the other things that has come up at this meeting is some payers being hesitant or declining to pay for PFA, because it's 2 to 3 times more expensive in terms of catheter costs. I think that's going to be very interesting to see how that plays out, the huge cost of these PFA systems and how that impacts what we're allowed to do or can do. These are interesting times. 

Kenneth Ellenbogen, MD, FHRS: I have to add that I think there's a possibility that insurance companies will sort of try to weigh in on this and say they are not going to pay this much money for an AF ablation unless you can show them the results are better. So far, the data shows that the times may be a little less and the safety is very good. We don't have to worry about complications, which have a very low frequency but are devastating like atrial-esophageal fistula or phrenic nerve palsy, but it's a lot more expensive. With so many patients getting AF ablations, that's a real hit to the insurance industry and reimbursement. 

Randall Lee, MD: I would agree with you that it's mixed. But with increased stratification of patients, whether it's artificial intelligence (AI) or using simple left atrial size, we know as left atrial size increases, PVI in and itself decreases dramatically, it may be possible down the road to start to stratify which procedure you're going to do for which patient, in addition to the duration. 

Hugh Calkins, MD: Yes, there was a talk at this meeting about appendage occlusion devices where they have an AI or algorithm that says you should use this device or that device to get the best chance of success. You can imagine that happening with AF. You put in all the parameters. I agree with you on this issue that at the end of the day, it's all about left atrial size. Fifteen years ago, we wrote a paper on that, and every study is basically showing the same thing. The bigger the left atrium, the worse the outcome. So certainly, that's going to be one of the most important things in whatever algorithm gets developed. 

Randall Lee, MD: Right, and you've mentioned, Ken, in your hybrid therapies, you manage the left atrial appendage. I think that's a volume reduction. There is data that will be coming out of the aMAZE trial demonstrating that that is beneficial. 

Kenneth Ellenbogen, MD, FHRS: Yes, well, of course it makes sense, right? Because the bigger the left atrium is, it's not necessarily the left atrial size, what is a left atrial size, but it also is a marker of how advanced the disease is. First, I cannot imagine insurance companies limiting the number of ablation procedures any more than they can tell a patient, you can only have 2 CAT scans, and if you have an angiogram or MRI, you cannot have a CAT. I don't imagine that's going to happen. But obviously it may be harder, with more precertification. But I think the data that goes back even before Hugh published his data, when all we had was surgical AF ablation. People looked at the predictors of surgical success with Maze surgery. There weren't thousands of patients like Hugh had, but there were hundreds of patients and they did a meta-analysis that showed it was left atrial size and duration of AF. Those were the 2 variables that were incredibly powerful. Even with “old-school” surgical AF ablation. But that’s just duration of AF. How does that have anything to do with it? Well, it probably does through left atrial size, but it's a chronic and progressive disease. We may intervene and it's amazing. You may not see patients for 5, 10, or 15 years, but then they come back and have more AF. It's like a mystery disease. We don't understand the nature of the progression, but I think, particularly if the surgical handling of the left atrial appendage is relatively clean and for patients who really cannot take blood thinners, it’s good because you don't have to worry about device-related thrombus, which hopefully we will defeat in the next couple of years anyway. 

Hugh Calkins, MD: The issue between left atrial size and duration of AF is an interesting one, and it's more than just duration of AF. I think we've both seen patients with early-onset persistent AF with a 5.5-centimeter atrium, and then we've seen patients who have been in AF for 3 years with a 4-centimeter atrium. Overall, the longer you are in AF, the bigger the atrium will get. But there are these outliers that have what Hans Kottkamp used to call fibrotic atrial cardiomyopathy. They just have a primary cardiomyopathy of the atrium where the atrium dilates first. It's not the duration, it might be mitral regurgitation or some other factor. But it's interesting that those 2 things we hold true, duration of AF and left atrial size, that people have known that for decades, we just keep forgetting the old literature and then republishing. You would think we have something new!

Randall Lee, MD: I think you're right. It's remarkable that we forget about left atrial size in terms of when we're doing or choosing which procedure.

Kenneth Ellenbogen, MD, FHRS: Yes, and I think Hugh hit on something with this fibrotic atrial cardiomyopathy. We go in there for a first-time AF ablation and everything is tiny. All the atrial signals are really small or fractionated everywhere, and that's sort of disappointing. But it goes back to the comments you made. Why do some people have AF for years, paroxysmal, and then some people have symptoms for 2 months and they come in and they're persistent? It almost seems like a different disease. Like, they come in, their left atrial size may even be normal, but they present with persistent AF. They have an Apple Watch and they say “I didn't have AF, and all of a sudden I had AF. Three weeks ago it was paroxysmal, and now it's persistent.” Most people have had it for years before it progresses, so that's really interesting. They talked about that a little at this meeting. What is the disease? They're very different in the way they present and progress.

Randall Lee, MD: You touched on burden, especially in heart failure patients, in terms of reducing the AF burden. In CASTLE-AF, the burden reduction was quite a bit. So, do you have a gestalt in terms of from the literature, what level of burden do you need to achieve to achieve benefit in heart failure patients? 

Hugh Calkins, MD: My interpretation of the approximate given is an AF burden of 20% or less. I think 50% is clearly too high, and 10% is probably too restrictive. I think it's 20%-25%. If you say most of the time the patient is in sinus rhythm and a minority are in AF, it sort of makes sense. So, I think an AF burden of 20%-25% or less seems to be sufficient to achieve those really impressive improvements and outcomes. It's a whole new way of thinking about things. 

Randall Lee, MD: Yes. As we wrap up, I have to ask this question to both of you. You both use hybrid therapies for selected patients. You have been involved in the PFA trials. Where do you see that playing out, PFA in hybrid therapies? Do you think it will be complementary, or do you think PFA will transplant the need for hybrid therapies? Because especially for targeting the posterior wall, it's this asynchronous epicardial/endocardial and then the epicardial connections that we're really trying to achieve.

Hugh Calkins, MD: I think it's just too early to know. With PFA, you can blast away on the posterior wall and not worry about the esophagus, and electrophysiologists may assume that's going to translate into full thickness, transmural isolation. Whether in fact that's going to be the case, we just don't know. We saw some talks at this conference on the thickness of the posterior wall and also the different layers, and just because it's silent on the endocardium, that doesn't tell you. Rod Tung presented very nice data showing if you do epicardial mapping on the posterior wall, you still have signals. So, whether PFA is the magic bullet that's going to give us beautiful permanent posterior wall isolation or not, it remains to be seen. I think I'm somewhat skeptical. We used to think that radiofrequency could do it, we thought that cryo could do it, and we keep learning they cannot. Now, we have a new kid on the block, everyone's trying it, and we'll see over time, but it seems hard to imagine that the lesions will be deep and thick enough to get the kind of posterior wall isolation that was achieved with a Convergent procedure. 

Kenneth Ellenbogen, MD, FHRS: That is the question, I think. The one thing that is very clear is that catheter ablation has been getting better and better. I remember in the beginning of hybrid, we sent people who had 2 catheter ablations to the surgeon, and sure enough, they put a mapping catheter on the epicardial surface of the PVs and they were a patchwork of PV potentials. It was very humbling, and that was just the PVs. Now, I think we feel like 90+ percent of the time, we can isolate the PVs transmurally. So, the question is, since that's such a big part of what hybrid brings, is whether pulsed field can get transmural ablation of the posterior wall. Because if it doesn't, it just leaves behind another epicardial/endocardial gradient with sparing in areas, and sets up for left atrial flutters and even AF. So, we don't know the answer. It would be great, though, if people do some pulsed field posterior wall ablation and send them for hybrid and put a high-density mapping catheter in the posterior wall. That would be fantastic. Even if we're only talking 10 or 15 patients, it would be nice to have some idea about how well we're doing. 

Hugh Calkins, MD: I know one of the clinical trials that is just wrapping up enrollment with the PFA system is for persistent AF and their lesion set is the PVs in the posterior wall, and every patient is getting an implantable monitor. It's not a randomized study, which is unfortunate, but we'll have hard data on what the true efficacy is with that system. Again, one PFA system is one PFA system. But anyhow, it'll be very interesting. It will probably finish enrollment next month, so we've got at least another year to year and a half before we see the results. So, we just got to be patient and data will come. 

Randall Lee, MD: The one thing that has been highlighted as we get newer technologies and more experience with them is the potential downside. We've heard talks today on hemolysis and renal function, and if we start to expand on the posterior wall... 

Kenneth Ellenbogen, MD, FHRS: But hold on, we actually did, we participated in this clinical trial. It doesn't take that many lesions to isolate the posterior wall, and it is posterior wall from the roof, and very low, inferiorly, almost to the mitral valve. But yes, I think the argument is that a lot of that pulsed field hemolysis, not just related to a number of lesions, but that the catheter may not be making contact with the tissue. So, it's hemolyzing because there's blood, and so I don't think we know the final story on that. I think Hugh is right that it's going to be a while until we know. 

Hugh Calkins, MD: One of the great moments of the Boston AF meeting was Hiroshi Nakagawa with his “ablate like hell” syndrome, or ALH. At the same meeting, we heard about people delivering 150 PFA applications during the AF ablation and getting renal failure, hemolysis, and dramatic drops in creatine. The solution is 2 liters of fluid during and after the procedure, which of course needs a Foley. But I think today we also heard from Boris Schmidt that the ALH syndrome is probably not the best approach. His strategy is to limit the number of applications to 70 or 80, not 150, which is a little too much. 

Kenneth Ellenbogen, MD, FHRS: In our experience, in an average patient, it takes about 40 lesions to do the posterior wall. But you have to map, and as Hugh said, then you have a mapping catheter, an intracardiac echocardiography catheter, and a PFA. 

Randall Lee, MD: Well, the one thing about PFA is, once you start ablating, you lose the ability to map. We all know with the posterior wall about the epicardial connections. So, it may be down the road that we're using PFA epicardially, and we don't have to be concerned with direct contact with the blood.

Kenneth Ellenbogen, MD, FHRS: It would be interesting. 

Randall Lee, MD: Yes, well, I think this has been a good meeting. There's more to come. I thank both of you for taking time out to join us and give your perspectives. I'm sure our colleagues will enjoy the session!

The transcripts have been edited for clarity and length.

This content was published with support from AtriCure, Inc.