Pulsed Field Ablation: A 10-Minute Update

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Featured is the presentation entitled "Pulsed Field Ablation: A 10-Minute Update" by Vivek Reddy, MD, from Session 1 at the 2025 Western AF Symposium. 

I will be discussing a few devices that do not have regulatory approval. So, with pulsed field ablation (PFA), there has been a lot of activity. If you look at the time from the first-in-human studies to European approval and look at the number of cases performed, look at what happened. Then, US approval happened a year ago. As of January, my understanding is over 200,000 PFA cases have been performed. Not surprisingly, there has also been an increase in the number of manuscripts. So, to cover all of this in 10 minutes is going to be a little tricky. I'm going to focus on a few areas and there are going to be obvious, glaring holes here. 

The ADVENT trial was published a couple of years ago. The trial compared PFA to conventional ablation. What you saw was that there was no significant difference—the conventional conclusion is that PFA is not more efficacious than thermal ablation. But is that really true? We know that the historical 30-second binary end point is really not clinically relevant. There is increasing data that atrial fibrillation (AF) burden actually tracks better with outcomes that matter, patient outcomes and health care utilization. So, we did a post hoc analysis of ADVENT that we published last year. The first question was what is the burden cutoff that tracks with clinical outcomes like quality of life changes and health care utilization? Second, using what we hope to find a more relevant burden cutoff, are there differences in technology outcomes? 

So, in terms of quality of life, looking at different burden cutoffs, it looks like the 0.1% burden cutoff, meaning residual burden after ablation, tracks best in terms of quality of life, although I should note that all these patients showed improvement in quality of life. Similarly, it was the same cutoff that tracked with the least health care utilization, so less than 0.1% AF after ablation. So, using this, what would argue more relevant burden cutoff, is there a difference in outcome between these randomized modalities? It turns out that yes, there is. PFA statistically significantly improved clinical outcomes compared to thermal ablation.

Now, I should caution, this was a post hoc analysis—this was not prespecified—but there is the data. So, what we would say is the burden cutoff should be 0.1%, which by the way, is completely consistent with the CIRCA-DOSE trial and several other trials that have looked at this. Using this cutoff, yes, PFA is actually thus providing increased efficacy. This is for paroxysmal patients.

What about persistent? Well, it turns out there is no data, at least that I'm aware of, that has really looked at this in a very large cohort. The ADVANTAGE AF trial, which was recently presented and hopefully will be published soon, was a large single-center FDA trial looking at pulmonary vein isolation (PVI) plus posterior wall and cavotricuspid isthmus (CTI) ablation in those patients who had atrial flutter. The patients were followed, there was a 3-month blanking period and follow-up as typical, and there were primary safety and efficacy end points. Importantly, there was no fistula, PV stenosis, stroke, or tamponade in this relatively large study. There were some other adverse events such as pulmonary edema and pericarditis, and there were a few other events including hemolysis and renal dysfunction. I should note that when this study happened, we as a field didn't really appreciate the whole issue of hemolysis-related renal failure. 

What about on the efficacy side? After the 3-month blanking period, you see the success was 63.5%. This is using the traditional 30-second cutoff. By the way, it is worth looking at outcomes as a function of operator experience. This trial is a little unusual, because you see the number of operators—87 operators—is about 3 times the number of operators in these kinds of trials. So, if you take the median number of cases, which is 3 cases, and you look at outcomes by the first 3 cases that any operator did versus any case beyond the third case, you see there's actually improvements in outcome, about 71% in the full cohort. If you look at symptomatic recurrence, it's better. 

What about the burden issue? Because I'm telling you that 30 seconds probably doesn't matter that much. Well, we tried to do a similar analysis of burden, and again, the first question is, what is the residual burden that tracks with outcomes in this persistent cohort? Then, using that metric, what do we see? Of course, we didn't have implantable loop recorders in this population, so we used intermittent monitoring, which is an important limitation here. But here is the data. In terms of quality of life, there was no real cutoff where we actually saw a difference, but the greater than 10% appeared to be a little better. In terms of health care utilization, again, 10%. I wouldn't use that number. I think the number of 10% is limited by the fact that we didn't have a dense amount of monitoring. But I think within this study, if we use this 10% cutoff, what we see is that the majority of patients—80% of patients—fared well with less than 10% residual burden. I think the point is that the majority of patients do well without health care utilization. 

So, that is on the efficacy side. What about safety? We published this last year, MANIFEST-17K, which was the European experience. What we saw was the overall major adverse event rate was around 1% and minor event rate as you see. Importantly, if you look at some of the complications, we really worry about esophageal fistula, PV stenosis, or phrenic paralysis, we didn't really see any of those. The majority of the complications were vascular, which is not a big surprise, I suppose. The tamponade rate was 0.4%, which is pretty impressive. It's a large number of patients. The stroke rate, importantly, was 1 in 1000. the mortality was less than that. There were 2 other events that we saw—the coronary spasm, which occurs around 100,000 patients, and hemolysis-related renal failure. So, let's talk a little more about that. In terms of spasm, and we've published this before, a spasm can occur. If this video was playing, you'd see a coronary artery spasm. What is an effective dosing strategy? It seems you need to give very high doses of peripheral intravenous nitroglycerin to get a high enough local concentration to really prevent spasm. We have a protocol where we give 3 milligrams of nitro and then start ablation a minute later, and that seems to work. Should we give it prophylactically or expectantly? My own feeling is prophylactic is better, but that needs to be studied. Is it effective in all patients? There are relatively few patients who had coronary disease that this was tested in, and we need to learn that. What about late coronary effects? We know from preclinical studies, and there's several of them, that intimal hyperplasia can occur late after PFA, whether it's endocardial or epicardial next to the coronary. What about clinical data? There are 2 studies. This is one that we did where we looked at patients who underwent CTI or mitral isthmus ablation; there was a total of 30 patients, a few with coronary disease, and we studied them a median of about a year later, none had coronary stenosis. So, that's good. Of course, this was a small number of patients. 

But here is another study that has not been published yet, but it was presented at APHRS last year. This looked at patients who underwent PFA for atrial flutter after PVI. They did receive some intercoronary nitroglycerin, although not a very high dose. Importantly, they did OCT imaging before ablation, during ablation, and 3 months after. If you look at baseline to 3 months, there is a 10% decrease in luminal area, and importantly, in one of these patients, there was about a 40% decrease in luminal area. So, we need to understand this better. Of course, I’m pretty sure this is not something that is going to be unique to pulsed field—that this happens with radiofrequency energy. We just haven't had very many studies looking at the coronary late after ablation. 

What about hemolysis-related renal failure? I'll make 3 points that I think we've learned. One, deliver only the necessary lesions. This seems obvious. Avoid poor tissue contact. This is an in-vitro study that we did where if you look at the amount of hemolysis as a function of number of applications, when you have poor tissue contact, or in this case, poor contact with myocardial tissue, you have more hemolysis, just because I think it's as simple as there's less of the electrical field that is in the tissue and more that is floating in the blood, and hence, lysing the red cells. We know from other studies, from Andre Natale’s group and others, that if you deliver a high number of lesions and you have a lot of heme released, you should give saline to try to flush that out and avoid what we really care about, which is renal dysfunction.

This is most of the data with the pentaspline catheter. There are a number of other catheters, including 3 of them that have received regulatory approval in the United States. With the lattice tip catheter, there was a large randomized trial that was published that showed that it worked as well as standard ablation, maybe even better. There is the circular catheter; the effectiveness was 75%. It met the safety profile, but there were 2 strokes in the study. We need to understand this better. 

There are a number of other devices and first-in-human studies looking at these devices, which I do not have time to go through. I'm also really excited about the fact that we're seeing a number of studies of ventricular tachycardia (VT) ablation with PFA, both scar-related VT and PVCs. I think we're going to see some important clinical trials and this is going to change our field. 

Finally, and I don't have time to talk about this, but reversible electroporation pulses, so-called pulsed field mapping, is something we published on. I thought this was going to disappear, but fortunately, this is work from Andrea Sarkozy's group. They use the strategy in a number of patients undergoing atypical flutter ablation; they found that it was reproducible and highly specific. So, I hope this is a tool that we start using more in our field. Thank you very much.

The transcripts have been edited for clarity and length.