Hi, this is Eric Pustowski. Welcome to another segment of EP on EP, and I have a special guest with us today who has actually appeared on the show before, Dr. Jonathan Pacini, who is the head of electrophysiology and professor of medicine at Duke University. John, welcome to the show again. Great to be here with you, Dr. Pustowski. So this is going to feel odd for you. We're going to talk about randomized trials. I know you have very little experience in that area. Don't have a lot to say about randomized trials. So here's what I'd like to do, John. I'd like to talk about randomized trials in atrial fib. And you are really a master at RCTs, much more than I, for sure. And here's the question I'd like to pose to get us going. Do you really think in atrial fibrillation ablation we've learned anything more than you've got to isolate the veins? And I know that's tongue-in-cheek a little bit. I'll start with that and let you go. Yeah. No. So I don't think we have. And it pains me a little to say that because we've done many, many trials and we've learned a lot. I think what you're getting at is, do we know what to do more than pulmonary vein isolation? And I think the answer is we don't. The studies we have done have not been conclusive and have not shown benefit. And not just one trial, right? We have a whole cadre of trials on specific additional lesion sets that haven't showed durable benefit. That's why I think we need to continue to do trials. Like a tool vermis star AF3, we're trying to get at what we need beyond PVI. But I think the aggregate evidence to date, that's why PVI is a class one recommendation and everything else is not. Yeah. Well, can I push you a little bit on that? Let's talk about patients you and I both see. And I know you have some thoughts on this. When you get a patient who comes back after a PVI and you get back in a lab and the veins are isolated, I don't know that anyone has a good feel for what to do. So what kind of a trial would you might think of that would help us get that answer? Yeah, I think it's a great question. And I think clinical trials, we want them to be robust and we want them to be well-designed, but they also need to be pragmatic. They need to answer the questions that all of us see in day-to-day practice. And there's nothing fun about being in the lab, the veins are closed, there's no additional triggers, what do you do? And I think one of the challenges we have in AFib ablation is that 99% of our clinical trials in AFib ablation are focused on someone coming in for their first ablation. Should we do PVI alone or should we do PVI plus something else? We should be doing randomized trials of patients who need redo ablation. Everyone could enroll well in those because those are patients that we see all the time. So I think not only is it a question of what lesion sets, but you're exactly right, who's the patient? And I think focusing more on patients coming in for repeat ablation is a really important area that we really haven't delved into yet, despite the fact that it's something we talk about all the time. So I love that idea, but doesn't it really go to the idea that we don't know the mechanism of AFib other than sometimes they, or mostly they come from the veins? Because if we had a better understanding, right, of the mechanism, then you shouldn't have AFib if the veins are still isolated, I mean, theoretically. So what do you think about that and how would you, in other words, how would John Cuccini set up this trial? You've had years of experience doing trials. What would be, what would you test against each other? Yeah. You know, I think one of the things that's really humbling, and I just retook my board so I had a chance to go through the whole board review process. You know, one thing that I don't think has changed since, you know, probably you were a fellow, is the fundamental hypotheses of the mechanisms of AFib. And I think, so not a lot has changed in that regard, but I think what's encouraging is some of the work in computational physiology, artificial intelligence, understanding of the myocardium as a three-dimensional structure and not just as a flat surface. I think we're going to get close, but I don't think we're ready to start doing clinical trials, you know, that target fundamental mechanisms yet. I think we still need to develop some technologies to help us with that. Maybe, you know, electrographic flow is one of them. Maybe computational modeling of reentry around scars is another. But when we have those tools, then I think we really will be ready to personalize. I'm also intrigued by the possibility that we often do ambulatory monitoring on patients. The group at Mayo Clinic is showing you do an EKG and you can predict who gets AFib. Yes. I think that works actually quite exciting. Right. So, should we be able to take a seven-day holter and then figure out what lesion set someone needs based upon how many different P-wave morphologies they are and what they are? Yes, exactly. But that would presume that we have an idea of the mechanism. So this is why I'm pushing you a little bit. Every trial I see come out, and you sort of, you know, said that was true, has to do with how many ways, you know, do I knock off the veins? Do I put two motes around them, one mote, a mote plus, right? That's what you said. Right. Yeah. But when the veins are isolated, that shows our lack of knowledge of what's really going on elsewhere. Yeah. Right? So, based on what you know now, would you do any more, I know this is not fair, would you do any more trials that dealt with PBI? I mean, do you care about that? No, I think it's a proven benefit. Now, what I worry about is if we start using new ablation modalities that we're not as familiar with, like PFA, you know, and there are different changes with impacts on autonomics, will that be associated with decreased efficacy long-term? I don't think we see that. But I think you're making a really good point. No, I would not investigate PBI further. I do think a healthy investment is to be made in pre-procedural evaluation that make us smarter. Yeah. I actually like that a lot. I think AI is going to help us there. John, this is a technical specialty. A lot of the work you've been involved in, it's placebo versus a drug or a device versus this. This is a procedure. Some people are more gifted than others doing a procedure. So, have you ever given thought to randomizing the actual investigator? I mean, so EPA doesn't get a chance to do all the ones that EPA, he or she is best at? Is that a crazy idea or what? No, I don't think it's a crazy idea. We know that volume is associated with outcomes. And there's techniques in clinical trials to incorporate that into the result, whether it's an adjusted analysis by site. There's lots of different ways to do that. We're both basketball fans, right? Yes, we are. Same team, in fact. That's right. Well, sort of. You have a bit of Notre Dame in you. Yes. Right? So, one thing that is always impressed upon me is that it's a team approach. And so, for a procedure, I think we really need to focus on making procedures repeatable. So, I do get a little bit nervous if there's a technique that only a handful of people can do. You're a trialist of great renown. I'm going to ask you to give me a trial on the spot, and that's not fair. You said it yourself, we really need to be looking at people who have a recurrence and what to do. And I understand we don't have all the answers. I give you that. And we still need a lot more to do. But right now, from what you know, and you're a really smart guy, what trial would you put for the people who come back and have the veins isolated and you've got to do something else? What do you think is reasonable, at this point of knowledge, to do? If I could do a clinical trial of patients undergoing repeat ablation, once they came to the lab, we knew their veins were isolated. I would randomize those patients to trigger testing versus empiric isolation of the posterior wall. Okay. So, let's push on that a little bit. I mean, Frank Marchlitsky and his lab have been the uber-trigger people for years. And they did a study years ago where it wasn't as impressive an outcome as they think they had wanted, or certainly we didn't want. So, the triggers like, what, high-dose iso, what kind of triggers, or just guessing places where they come from? No, I mean, I think either spontaneous or with high-dose isoproteinol, and ideally triggers that induce some form of sustained arrhythmia. And I think, you know, why were those prior studies not as impressive? Well, either because those patients still had PV triggers and that was the mechanism, or they weren't the right patients. But that's why I think, you know, this idea of randomizing them after you know the veins are isolated, I think really is the best way to answer that question. So, but not just a box, right? I mean, just take out the posterior wall, right? Yeah. I mean, I think, I don't know that you have to ablate the entire posterior wall. I think there's also the possibility of injury when you do that, obviously, but I think high-output pacing at 20 and 2, something to make sure that you're really, truly isolated and that you're going to have a durable result is really important. Would you include appendage? I am not a fan of electrically isolating the appendage. Okay. Well, let me ask you one last thing. I know it's a little off topic of the trials, but... Would you isolate the appendage? I would not. And I get very upset when any of my team tells me they've isolated the appendage. We set that patient up very quickly for a left atrial appendage occlusive device because you're putting someone who may have been in minimal stroke at stroke risk, right? There is some stroke risk. So that's the last thing I want to ask you. Would it be a reasonable trial to have some people get a left atrial appendage occlusive device put in at the time of the first ablation? Who are criteria for it, right, versus waiting? Because I've heard from people who do this, they like to wait because they're concerned, but I don't know that's true. So there's a clinical trial that's going to be addressing that option that we participate in and enrollments close and we'll be getting outcomes soon. So Jonathan, thank you so much. So much fun. Fabulous as always.

EP on EP

Eric Pustowski

Dr. Jonathan Pacini

randomized controlled trials

atrial fibrillation ablation