Hi, this is Eric Prystowski. Welcome to another segment of EP on EP. It's a delight as always to have my good friend Hugh Calkins here, professor of medicine at Johns Hopkins. And Hugh, welcome to the show one more time. It's good to be back, Eric. Thank you for the invite. Yeah, it's always a pleasure. So, this is exciting. My understanding is you've just finished a trial on the use of chiroablation and persistent AFib, and I know it's one of the first trials with certain specifications of it. So, why don't you tell us about the trial and a little bit of the background and maybe the entry criteria, then we'll go into the results. This was an important trial because it was designed for FDA labeling of the chiroablone for treatment of persistent atrial fibrillation. And as you know, currently, none of the ablation technologies that we use day in and day out have that official labeling that they're approved for treatment of persistent AFib. So, this trial was to set up to obtain that labeling. So, it was a single-arm study using objective performance criteria based on all the trials that have been done. We sort of, the FDA is comfortable saying, if this, you know, the endpoints were a success rate over 40 percent, you had to be in a complication rate less than 14 percent. Less than 14 percent? Yes, using all the different bounds and statistical whatever, but those were the sort of the benchmark you had to meet to get across the finish line with a win. Okay, go ahead. So, let me ask you this then, just in the United States or other parts of the world? No, it was 25 enrolling centers in Canada, the U.S., and Japan. Great. So, how many people were enrolled in the trial? So, ultimately, there were 145 patients with persistent AFib that completed the trial. There were 165 that actually had the chiroablone ablation procedure. Some patients couldn't handle all the follow-ups, so we ended up with 145 patients, which is what we based the overall results on. And these were patients with persistent AFib of less than six months duration. So, this was not long-standing persistent of five years. It wasn't even persistent AFib lasting a year. It was sort of earlier persistent AFib, if you will, AFib less than, no episode could be more than six months continuous AFib. So, let me ask you a couple of other things, because this is always an interesting thing to me, because at least in the beginning, while I've been proven wrong on this, I would have assumed persistent AFib, you might need more than just isolating the pulmonary veins. I think all of us talked about lots of other things. So, what were the, like, left atrial sizes, things like that? Were there any things that you learned in this trial that would tell you which one of the patient groups might have been more successful than the other? We haven't done those analyses yet. The data just got sort of finalized, but that will be something to look at. I mean, this also excluded patients with huge left atrium who were not enrolled in this study. So, can you define that? What was your upper LA size? The cutoff was five centimeters. Five centimeters. Yeah, that makes sense. So, tell us about the data. Tell us about the follow-up. So, anyhow, so 145 patients were in the study. They got the cryo-balloon procedure. The definition of success was based on the consensus document. No AFib, more than 30, AFib, tachycardia, or flutter, more than 30 seconds from the three-month end of the blanking period to a year follow-up. And these patients all had Holter monitors at six and 12 months, and then they had a TTM where they had to transmit weekly, and also if they had any symptoms, they had to transmit. So, that was sort of the end point. And the bottom line is the procedure was successful. The success rate was 55 percent at 12 months follow-up, and the complication rate was 0.6 percent. 0.6, that's remarkably low. 0.6. There was only one complication, and that was in a patient who had the cryo-balloon procedure. It didn't work. The patient wasn't going to get a redo RF procedure, and during that procedure, the transeptal was misdirected, and the patient had tamponade, which was treated. So, that was the only complication in the study. And, again, the goal posts were the success rate had to be more than 40 percent, the complication rate less than 14 percent, and instead, we ended up with a 55 percent success rate and a 0.6 percent complication. So, my sense is that the FDA is going to receive this information favorably. I think that's wonderful, and congratulations on the trial. Let me ask you a couple other quick things. Phrenic is always something people worry about. Did you have phrenic, and if not, what did you do? What was mandated in the trial to minimize phrenic nerve problems? Yeah. So, I mean, it was mandated that you pace the diaphragm during energy delivery in the right superior and the right inferior pulmonary veins, but there were no phrenic nerve paralyses that lasted more than several days. So, basically, the incidence was essentially zero. That sounds great. The other thing is the listeners are going to know about on drug versus not on drug. So, I mean, all these trials, you know, a lot of times you may be on a drug through the blanking period, but at the point of a year, in the success group, how many were absence of antiarrhythmic drugs? So, 80 percent were off antiarrhythmic drugs at the end of the study. The definition of success was when you had to have an acute procedure success. You had to isolate all four pulmonary veins with a cryo-blown or the touch-up freezer catheter. So, that was the first part of the definition. The second was no AFib, ATAC, or AFlutter more than 30 seconds from 3 to 12 months. And the third was you could not have your antiarrhythmic drugs either increased or changed. You couldn't switch from flecainide to sodalol. That would be, you know, a failure. Right. And it was encouraged that all patients stop antiarrhythmic drugs at three months. At the three-month follow-up point, 40 percent were on drugs. By the end of the study, 20 percent of patients were on drugs. And when you looked at the success rate of those on drugs versus off drugs, there was no difference. I got you. So, have you, anybody restudied some of these folks? In other words, I always wonder about how much, because even though it's actually wonderful success for a first-time procedure and persistence without drugs, that's really terrific. But there's a lot of people who weren't a success. Too early yet to figure out why in those people or have any of them been restudied to find out if it's a question of veins not isolated versus an alternative site? Yeah. I mean, that's the question. What is the ceiling for PV isolation and persistent AFib? Right. We know it's important. We know it's the cornerstone. As you pointed out, many people believe, well, you've got to do more with persistent AFib. And I think this study has taught us, hold your horses, in more than half of your patients, you don't have to do anything more. And, you know, this issue about what's the durability of PV isolation, that's something that we're going to have to sort of collect as time goes by. Very few patients ended up getting a repeat procedure. I mean, even if they, quote-unquote, failed, that doesn't mean they're bad enough to justify a second procedure. They may have had 30 seconds and six months follow-up and failed on that basis, but there's no way that patient would end up back in the AP lab. So for me, as a clinician who sends a lot of these folks to the lab, I don't do them myself anymore, this is really outstanding information, because you can say to a patient now, based on your results, that you have a 50% chance with a one procedure to have drug-free success in a year. That's a nice piece of information with minimal complications using, if you follow the techniques of the paper, right? So that's really good information for clinicians. Well, and this issue about should you do more, I mean, if in 50% of patients, or 55%, you can get them effectively treated with just PV isolation, why go scarring up the atrium with all these additional lesions, which may be pro-arrhythmic, find that the patient needs a second procedure, and I think in this study, less than 10 or 15% of patients by the end of a year had had a second procedure, so the redo rate is extremely low. But if they do come back, and if the pulmonary veins are isolated, well, you may choose to do more, whether it's posterior wall isolation or non-pulmonary vein triggers, but you can get a lot of the way there just by effectively isolating those veins. And the other thing is, the criteria that you and I have always disagreed on about this 30-second rule, we'll leave it as a friendly disagreement, I think that I don't personally use it in my clinical practice, although I understand it's okay for trials, some of these people who are failures may have infrequent minimum AFib, technically, and not need any more regardless. No, exactly, and really, the importance of the 30-second definition, it allows trials like this to be performed non-randomized with these objective performance criteria based on the last 10 FDA-supervised clinical trials that got all of our paroxysmal catheters approved. So it's very useful if you want to design a non-randomized study, otherwise you can use a new endpoint, and then you can go randomize the patients, which as we all know is a much tougher to enroll. Hugh, thank you, great information for the listeners, and congratulations on a wonderful trial. Yes, it was a great team effort. Thanks, Hugh.

Eric Prystowsky

Hugh Calkins

trial

cryoablation

persistent atrial fibrillation