Hi, this is Eric Kostowski and welcome to another segment of EP on EP. What a delight it is for me today to have two good friends and major players in the field of cardiac electrophysiology, Dr. Nasir Maroosh, who is a professor of medicine at Tulane University Medical Center and also director of electrophysiology and triad, and the newly thinned out, but still Douglas Packer, who is a multiple title, but we'll just give him a short title. He's professor of medicine at the Mayo Clinic and he directs the cardiac research labs there gentlemen. Welcome to the show. Good to be with you, Eric. Thank you, Nasir. Good to see you. Good to see you, Doug. Okay, so here's what we're going to do. I think that the two of you have had an enormous impact on this whole area of ablation of patients with AFib who have heart failure. The CASLA-F trial in Cabana has really helped the field enormously. Nasir, I'll start with you and just maybe a brief kind of summary of the major findings regarding heart failure. I mean both trials had lots of data, but I'd like to focus on the heart failure. Give us the audience sort of the high points of the CASLA-F and what you learned about ablation and heart failure. Thank you, Eric. So CASLA-F looked at patients with any kind of AFib practically, paroxysmal or persistent with LV dysfunction, so EF less than 35%, so half-ref patient population who had an ICD or IVICD and we randomized them to ablation versus pharmacological treatment, either rate or rhythm control. The major finding, as you all know, we published this in 2018 February in the Journal of Medicine. We showed that the composite endpoint of mortality and hospitalization for heart failure, all-cause mortality by the way, was reduced significantly in favor of ablation by relative risk reduction of 39%. We also showed that the mortality, we have an improvement in mortality due to the ablation procedure with relative risk reduction of 47%. The same thing applies for hospitalization. Also this is a couple of papers coming out in the next, hopefully to see them in press in the next three, four weeks. We showed that the AFib burden plays an important role due to ablation, which is interesting. We're trying as we speak to build the next study based on that finding is reducing burden in our population, in the half-ref population was crucial in improving mortality at least by 50% at six months follow-up. That's interesting enough was only finding in ablation, not in the pharmacological treatment. So practically if you improve burden by ablation procedure, you improve outcomes. Also we could define that the 30-second rules that all of us still apply for endpoints did not make a difference in terms of mortality. So early recurrence in terms of first time to recurrence of 30 seconds did not make a major difference. Now that the burden was important. New York high class three and four did not do as well as New York class one or two. In fact, this is a paper coming out as well in circulation EP showing that the sicker the patient, the less benefit they would have. That's another part of the CASEL-2 that we are putting together as we speak and hopefully start soon. Also, the patient with scars did not do as well as others, atrial or ventricular scars. So that's to summarize what we found with CASEL-AF. That's great. Nasir, I'll come back to you with something that I want to follow up on after Doug talks a bit about cabana and that is in the class three and four and the fact you mentioned that they didn't do as well. One of the questions I'd like you to think about that I'll come back to is it, did they have less reduction in burden, for example? Maybe you can give us some more insight into that. But Doug, I'd like to pivot to you. Cabana obviously was a major trial and there's lots of observations, but again, could you enlighten everybody on the key observations in folks that had heart failure? Sure. So Eric, we had 2,200 patients in cabana and of that group, 15% had heart failure. Now in looking at those patients, in looking at the subgroup analyses, the thing that we learned, a little bit surprising, is that patients with heart failure and it was heart failure phenotype. So it's class two or class three, if you wanted to go to congestive heart failure, then we had 20% of the patients in the trial had congestive heart failure. But let's look at the phenotype of class two or three. About one third of those were HFREF and the rest of them were HFPEF. And the thing that we found is that those patients showed a substantial reduction in mortality and a substantial reduction in the primary endpoint of mortality, stroke, severe bleeding and issues like sudden death. So it's a little bit different than the trial as a whole, which was neutral. But if you just hone in on heart failure patients, you get the same thing that you do if you were just looking at people under the age of 65, the same thing that you would get if you were looking at minorities. And so get what? A substantial reduction in overall mortality, the composite endpoint, and we're talking about a hazard ratio down on the order of 0.72 and that's way off the null line. So it's not neutral. It's clearly positive and this is all by intention to treat. Now if you look at this a little bit further, then these patients had a substantial reduction in heart failure hospitalization and in total mortality as a composite. They also had a dramatic reduction in recurrence. So the recurrence reduction was about the same as the trial as a whole, whether you're persistent or whether you're paroxysmal. And we're looking at about a final freedom from atrial fibrillation of about 60% in the heart failure patients and it's about 35% in those who were treated with drug compared to those who were treated with ablation. If you go a little bit further, we looked at quality of life. So in patients who were phenotypically heart failure, whether it be HepPef or HepRef, then the quality of life was also substantially better if you were ablated than if you were treated with an anti-rhythmic drug. And we're talking about all the way through 60 months. So it's pretty much the same. This is the work that Dan Mark did. And then if you look at the presence of normal sinus rhythm and what it means or the progression and regression of arrhythmia in patients with heart failure, less progression. In patients with heart failure and sinus rhythm, they did better than those who did not have sinus rhythm. That's combining both drug treated and ablation treated. So sinus rhythm was important in heart failure patients. Ablation was substantial, but even more impressive was the difference in total mortality, mortality and hospitalization and the recurrence. So phenomenal review from both of you. Two major trials that have, for me, changed the way I actually look at this. For years, I was a little jittery, to be honest, sending patients with class two and three heart failure for an ablation, I mean, years ago. On the other hand, I never bought into the CHF STAT trial because I had many patients do so much better in sinus rhythm than in AFib. But your two trials have clearly shown, and our groups move that way, that we should be moving closer. So let me go back to Nasir and let me get you and Doug both talking and maybe as a conversation here. It seems to me the one thing I'm hearing from both of you is kind of class one and two. I'm not hearing a lot of enthusiasm, should I say, to jump in on class three at the moment. Maybe I've misunderstood, but it seems like both of you are showing very positive data on class two and maybe a little more reticent. Is that the right word on class three? And yeah, obviously, back to Nasir, you don't have to eliminate all the AFib, right? So tell us a little more about that burden that I asked you about before, then I want to see where Doug's at as far as where the two of you now would recommend to the field. So Nasir, tell me a little bit more about that, like that class three group. So class three group and class four, it seems whatever reason, they died earlier and faster. We lost them. And I have to keep in mind that class four, we saw them in the study. They deteriorated and went on the study, but didn't have much numbers to make a big conclusion on class four. I have to warn everybody, the class four population was not big. So we say class three and four together, and this is described in the paper coming out. It's really the class three, and if you look at class three, there's two, 3A and 3B. They differentiate them from each other. Yes, we could not get the burden down. If you look at this population, the burden is not going down. It's an ongoing process in terms of systems, in terms of volume of a load. The recommendation is that can we do something about this patient in terms of fine tuning them first before we send them to ablation? Maybe that should be done and take your time, take a week or two to either ease them, get them improved in terms of symptoms and bring them back in. But interestingly enough, the after that make a difference rather than symptoms. So Nasir, before I go to Douglas, the burden is obviously you're showing us a key, but is there a magic cutoff? Is there a burden that you shoot for? You have to be careful in this population because we have EF at 35%, half-life population. In this population, a 50% reduction in your device from the moment you've been ablated to six months at the ICD. As you know, we have ICDs in everybody, so we have minute by minute or second by second data. So if you cut this number by half at six months, you have to get the rest of your patient and your burden went down by 50%, then you show the mortality benefit independent from your patient's symptoms or quality of life. So that's what's important, but that was only in the ablation arm. So that's a trigger for next, you know, what we're trying to put in CALSO2 now is adding this information as well in terms of outcome, looking at that in terms of continuous monitoring. But that's a trigger that there's a sign that the burden means something. Is it 50% cutoff? That's what we learned from CALSO, lower down as much as you can, but 50% doesn't have to be suppressed completely, obviously, and that's why it's important to know that even if you lower it down, you have some benefit for your patient. You don't have to suppress it completely. So Doug, let me get your views on what you would recommend to us based on what you found, and I'd like you to maybe speak a little bit. I know that you've done work in the basic lab. I was always, from my reading, I mean, patients with heart failure tend to have increased atrial fibrosis. So is the message that we should be quicker to the ablation and not wait so long? I mean, what would you tell the community now when you're getting a patient who has, let's say, a mild heart failure? Let's argue there. I mean, what have you learned and what would you tell us as far as next steps? I mean, should we wait or should we be more aggressive? So Eric, good questions, but first, I have to be very clear that we didn't look at class one failure patients. So I'm talking from CABANA standpoint about class two and class three. We excluded patients who had class four, and so the CABANA data applied to class two and three, and we've separated that out in half PEF and half REF, but see, you have to be pragmatic about this, and you and I treat patients all the time, and we have them referred in, and a lot of times they're referred in, and the question is, what do I do by ventricular pacing or do I do an AF ablation? I think one of the most important things that the clinician needs to, you know, realize with this is you look at a patient that's got heart failure, and whether it's heart failure, valvular heart disease, congenital heart disease, they may have a lot of symptoms. They may have fatigue. They may have a decrease in exercise tolerance. You're not real sure about their palpitations, but you think that you have them. So number one, sometimes you have to split out where is your misery coming from, where is the true burden. I don't like the term burden. I think it's worthless, and so, you know, when you talk about patients' symptoms, sometimes you have to know what it is that's creating the problem, so how do you do that? Well, frequently, we'll do the amiodarone stress test, and so if we're not quite sure about this heart failure patient, whether they're in trouble because of the heart failure or because of the atrial fibrillation, we'll put them on amiodarone, and what we'll do is we'll take them out, say, two or three months and get them back into sinus rhythm. If they feel substantially better, if their quality of life is better, and even if their ejection fraction starts to come out, I think that that says something. On the other hand, if they go back into atrial fibrillation and they don't know the difference, they can't tell the difference when they went back in, and in fact, they don't know anything about when they went back out, then I think trying to ablate somebody like that for the purpose of quality of life, burden, you know, recurrence, and that sort of thing is a little bit tricky. So I'm not sure that I would go guns ablazing, you know, the maverick approach in that population. If you don't know whether it's the valve that's causing the problem or whether it's the heart failure or whether it's the atrial fibrillation. So that's one group, but you and I see a lot of patients that have a lot of different kinds of symptoms, and in fact, maybe they're a tachycardia-induced cardiomyopathy. I think it's very reasonable to go forward with them as a first-line therapy. I think it's very reasonable to consider whether it's biventricular pacing or whether it is ablation to be considering more on the side of ablation. So when these patients come in and the question is, which one do you do? We may be more likely to give atrial fibrillation a try, providing we know that the atrial fibrillation ablation is going to do something. If we have no evidence that it's going to do anything, I really wouldn't get that aggressive with them. But I think that this is the place where we can spiff it up. We can move it up a little bit. I think Maroush's data are great. I don't think you can say a whole lot about, or I can't say a whole lot about class four, but I think that there's plenty of reason to move this a little bit faster, a little bit forward. Have to be careful about complications. But in Castle and in East and in Cabana, the ablation rate complications were pretty darn low. I think that you're looking at two sides of the fence. You're looking at risk on one side, you're looking at benefit on the other side. I just think you have to know that you're going to get benefit. You're not going to hurt them, and in fact, it's the atrial fibrillation that's creating the problem. In that case, move it on. So it's funny. I never thought I'd say this, but I think I'm a little more aggressive than you, Doug, right now. I think you're being very measured, I think, which is appropriate. I mean, you ran a major study. But I got to admit, I'm a pretty good reader of the literature, and when you plow through Cabana and Castle, I mean, it's hard to come away without thinking that if I want sinus rhythm, okay, and that's a key point, that ablation is the way to go. So let me summarize, and you guys tell me if I'm doing it justice. First of all, I'm going to say it one more time, and not just because you're both good friends of mine, but because it's just true, running the kind of trials you both did are hard. I mean, I've only done something like that once with the MUST trial, and I know how difficult it is to recruit and run, and you're both to be congratulated for your tenacity and for what you presented to the field. My takeaway, listening to both of you, and I've had the advantage of talking to both of you many times, is that I think earlier is better, as long as, and I give Doug what he's saying, that you have a pretty good handle on the symptoms that are there are somehow related to the atrial fibrillation. But my own takeaway from both of your studies is that get in there a little earlier, don't wait so long, don't give everybody Amio for five years, I mean, start approaching ablations earlier. So I hope that's the message you both wanted to put out, but it's been a wonderful interview with the two of you. Thank you for what you've done for the field, and both of you stay healthy and stay away from the big COVID. Until next time, gentlemen. It's good talking with you, Eric, and I think that you hit it on the nail on the head as to what we're wanting to say. So go out there and get them. Thanks guys. Good to see you all. Take care.

ablation

atrial fibrillation

heart failure

CASLA-F trial

CABANA trial