I'm Dr. Janice Chu, cardiac electrophysiologist in New York and an assistant clinical professor at the Icahn School of Medicine at Mount Sinai. Joining here today are Dr. Prash Sunders all the way from the University of Adelaide in Australia, as well as my colleague Dr. Chris Chung from University of Toronto. Welcome. Today we will be discussing the SHAM-PVI randomized clinical trial Heart of Depress just presented at the European Society Cardiology Congress and simultaneously published in JAMA. Well, Chris, take it away. Tell us about the study. So thank you very much for the opportunity, Janice, and really excited for us to discuss this study. I think a lot of us have heard a lot of discussion, perhaps on Twitter or X about the need for a SHAM-PVI study and certainly this brings all that to the table for us to discuss today. And as you mentioned, very exciting that it was published and presented last week at ESC and simultaneously published in JAMA. So just to get to the nitty-gritty, the SHAM-PVI was a double-blind randomized controlled trial that was performed at two sites in the United Kingdom. There were about 126 patients that were enrolled in this study that were randomized to either pulmonary vein isolation or PVI through cryoablation procedure or a SHAM ablation procedure, which of course we'll go into the details of that as well. The patients that were included in this study were primarily symptomatic paroxysmal or persistent AFib patients that had either been on a class 1 or class 3 antiarrhythmic drug or had a history of antiarrhythmic drug intolerance. The exclusion criteria in this study was the long-standing persistent AFib patient, those that had a prior left atrial ablation, those that had a left atrial diameter of greater than 5.5 centimeters or an injection fraction of less than 35 percent. And now the procedures performed on these patients, and this is where the nitty-gritty, I think it's important to focus on some of these details. First of all, all patients had a Medtronic Reveal Link loop recorder implanted, which is very important. I think we're seeing a lot more of that these days for rigorous ascertainment of atrial fibrillation burden post-ablation, and we'll get into those results. And patients were randomized to the one of two strategies, either catheter ablation with the DC cardioversion for those that were in persistent AFib, or a sham procedure with DC cardioversion as well. And now specifically for the sham procedure, patients had two venous access sites placed, they had a five French pacing catheter that was advanced, and they paced a phrenic nerve, which is often done for cryoablation to avoid phrenic nerve palsy, and they paced it for four minutes on four separate occasions to essentially simulate the ablation procedure. And all these patients also underwent sedation for this procedure, again to simulate the procedure. So they certainly went through and tried to maintain blinding as well as possible. Now jumping a little bit into the demographics of this and the patients that were enrolled, the average age for these patients are around 66 to 67 years, which I think is pretty standard for our AF ablation patients. 80% of these patients were in persistent AFib, and their baseline antiarrhythmic use included a combination of beta blockers, 90%, sodalol at 27%, amiodarone at 22%, flecainide at 17, and dronedrone at about 11%. So certainly similar to probably what we would often see in the clinic for those that are already on antiarrhythmic drugs. The average CHADS-VASc in this population was two points. And getting into the procedure, I commend the investigators because they did a really impressive job making sure that these patients were as blinded and that the procedures were as similar as possible. So the average ablation time in those that underwent or that were randomized to a catheter ablation was 62 and a half minutes. And then the average procedure time in the sham patient was also 60 minutes. So certainly very, very similar. Of course, some things like fluoroscopy time were much less because of the nature of that randomization. But for most purposes, the ablation and the sham procedure times were very similar. And in both groups, approximately 77% to 78% still underwent ADC cardioversion. And that just highlights the persistent AF status because 80% of these patients were in persistent AFib. Now jumping, taking us to the top line results, and so certainly very interesting. A lot of this, and again, going back to the reason that for this study, I think a lot of us have been doing AF ablation for many years, and we are not surprised at some of these AF burden outcomes, but it's always nice to see this again. And certainly, reinforced by prior data with loop recorders as seen in, for example, circuit dose, where we saw huge reductions in AF burden with an ablation. So the investigators saw the same. When they looked at AF burden at six months, they saw a reduction in AF burden from 78.5% to 18.2% with the AF ablation PVI strategy. And then in the sham group, they reported AF burden rates of 78.2% down to 43% in the sham ablation group. And now specifically in the subgroup that had persistent AFib, so that's the 80% of the population that was in persistent, their AF burden came down from 94.2% to 22.8% with the AF ablation. So again, a very dramatic reduction in AF burden, which is probably what we expect to see with an AF ablation procedure and consistent with prior studies that have used implantable loop recorders. And similarly, the sham did show a 97 to 52% change in AF burden. So that was their primary outcome. And their secondary outcomes were the quality of life outcome. So they used the multiple metrics to evaluate this. Most familiar, I think a lot of us have seen the AF evaluation for quality of AF EQT used. And the AF EQT showed a pretty dramatic difference in AF EQT points in the ablation group, having an 18 point higher AF EQT score compared to the sham ablation group. So a substantially and a clinically significant improvement in quality of life compared to the sham ablation. MAF-SI, similarly, a significant difference between the two groups. And also the SF-36 quality of life score, again, a nine point higher score with AF ablation compared to the sham group. So certainly, very interesting. I think, you know, this builds on some work that has been done previously, for example, on the approval study that I'm sure I will have more discussion about, but very exciting results that were presented at ESC last week. So give us your thoughts too, Prash. Yeah, so I guess I wanted to focus also on some of the potential limitations in study design that we may be faced with here. So this is only a two center study, and these are two small centers in the United Kingdom. And perhaps the issue of recruiting over COVID, it took them four years to recruit this small group of patients. So I think we need to put that into perspective. The authors do need to be congratulated to getting the study done, but that's actually a slight limitation that we face. The second thing is the technique that's evaluated is only cryoablation. So, you know, in the era of having both radiofrequency and now pulse field ablation, how does that alter the results? Would there have been different results? Perhaps there's more variability in operator technique, which may come in with some of the other modalities. And so that could be a potentially important point. The actual sham side of things, I think we need to consider as well. Was this truly a sham procedure? Because they did have an intervention, they had cardioversion performed. Now they did do cardioversion in both groups, but there was cardioversion performed in this sham group. And as a result, we see that success rate in terms of burden that occurs during the follow-up. So it's a little bit hard to interpret whether this is truly a sham group that you're doing. And then I guess the other thing is the type of blinding that was done. These were not deeply sedated patients. They were not on propofol sedation. They were using benzodiazepines and opiates. And we're told that they were given headphones to distract from the conversation in the room. So again, maybe that there was some unblinding that could have occurred. It's hard to tell there. From a physiological point of view, you know, as our patients are having, we're recognizing they have more HFPEF in the AF population. Could a transeptal puncture have made a difference in terms of relieving some symptoms? We haven't excluded that. We have, so that was only performed in the ablation group. Now there'll be, I doubt it will have an influence, but I can't be certain that there is absolutely no difference. And I guess the other main flaw that I see that actually opens the door for further studies is that the primary endpoint here is actually AF burden. So despite the fact that we're looking at a symptom difference, that has become a secondary endpoint. And so thereby for by definition is not a powered endpoint that they're looking for. And so that would be considered a more of an observational information rather than the primary endpoint, which is burden. So I think with that in mind, we need to consider one, did we need a sham control study? And you know, in the era where we were doing ablation for symptom control as the main drive, yes, that's probably correct. It probably warrants it. But we've all seen such dramatic successes. We've moved on from there. We've moved on to show AF burden reduction. We've moved on to show hard endpoints in terms of hospitalisation, mortality benefits, such as what we've seen in Castle. So many of us in the field felt this was already a done deal. But nevertheless, I guess if our funders and our general cardiologists who are referring feel, is this different to normal? I think it's data that is important that we need to be providing. And so I think there is room for more to be done in this space. And it's a great point. I think one of the discussion points have always been like, do we need a sham control trial? And certainly that has been discussed many times over the years. I think it comes up in recurrent meetings. And that's where I want to highlight there was one prior study that was done by Mohanty and authors in 2013 published in Circulation where they had looked at patients with atrial fibrillation and flutter. And they looked at comparing either an AFib ablation or an AFib and flutter ablation versus just an atrial flutter ablation alone, CTI ablation. And they did show improved outcomes with the AFib portion of the procedure. So there certainly has been some evidence already building to support the need for or the added benefit often of an AFib ablation procedure, but certainly much more to discuss in many more studies to come. One thing I also want to focus on is, we did see reductions in AF burden in both groups, which I think has been subject to some online discussion. So as I mentioned earlier, there was a 78% burden that reduced to 20% in the ablation group, but also 45% in the sham group. And I think there are probably multiple explanations for this. I mean, first of all, a lot of these patients were in persistent AFib. And so simply the cardioversion itself may have maintained them in sinus rhythm for a number of months before they have had AF recurrence. And so certainly I think if we had longer outcomes that perhaps going up to one year or beyond one year, I think we would learn a lot more about these patients if we had potentially longer term follow-up than just the six months that were included in this study. And the other possibility is that some of these patients may also regress to the mean. So if you have someone that starts off with a very high AF burden that over time they may regress towards a mean to a lower AF burden, that may be partly what explains for the reduction in AF burden in the sham group as well. Yeah, I want to expand on some of these discussion points that the two of you have already raised. I think certainly from a clinical trial standpoint, I think sham studies for interventional procedures are awfully hard to do. So I think, you know, I share Prash's accolades for the investigator. I think kudos to them for at least attempting and pulling up a sham study. It's not always easy to enroll and to conduct a sham study. So that in and of itself, I think it's probably a feat, a clinical feat, a clinical investigation feat that they pull, they were able to pull through. Interestingly, actually, I was impressed by that little bit of the lack of crossover. So I thought that's one aspect that this trial did quite well compared to many of the other clinical trials that we've seen where there's been concerns about crossover really diluting some of the signal. As a review from this study, there's really no crossover in terms of the two groups. And that's another area I want to highlight for our audience here. In terms of the follow-up, Chris, I think that's an excellent point. This was a six-month follow-up. So the data we're looking at, burden comparison, symptom comparison, were all at the point of six months. Two points related to that, whether or not the cardioversion, the initial encouraging result from cardioversion that probably contributed to some of the burden numeric reduction will probably surge again later on. Perhaps at one year, things will look even more dramatic with substrate modification by ablation versus no ablation. The second thing is actually begs the question in terms of the other harder endpoints and how we go ahead and follow AFib ablation trials over time. Quite frequently, we do study only up to six months to one year. And this probably is a call to action for the overall community, where do we need to have further follow-up, further registry, post-ablation trial follow-up at the one-year, two-year, three-year, four-year, five-year point? How far can we follow them out? Where the funding may be coming from? And what are the clinical infrastructure and support mechanisms that will allow us to do that? So let's take our audience through some of the parting thoughts then. So where do we go from here? So now we have robust experience in data demonstrating efficacy of ablation using multiple energy modality. And now adding to that, we have a sham study demonstrating specific inquiry ablation, but it's presumably quite extrapolatable in terms of the comparable efficacy in showing that PVI does work. What do we tell our patient where this is at and how does this add to further support for our landscape? So Chris first. Yeah, I think that's a great comment, Janice. I think this really builds on our already very strong evidence base for afib ablation and pulmonary vein isolation. Certainly there were a lot of concerns that maybe this would be the orbita for AF ablation, but certainly that has not panned out to be the case. And I think we, in a lot of ways, expected that those of us in the EP community, because we have seen these dramatic reductions in AF burden already from Circa dose and from other loop recorder studies. And similarly, we've seen hard end points as Prash mentioned. So I think a lot of us were already quite confident that we are going to be able to achieve these hard end points, but I think it's another paper to really support the true benefit of AF ablation. Generalizability will always be a question, but I think there's going to be certainly good generalizability from what we've seen so far based on all our other studies. So another paper to support the emerging and expanding role for AF ablation. Now, certainly are there other populations that were not covered? Are there even less symptomatic patients? I think that question will always be up for discussion as AF ablation becomes more and more broadly used and safer and safer. But I think this is a very nice study to really support our growing evidence base. I completely agree with you, Chris. I think this is another piece of evidence to say that AF ablation really does make a difference. It's additive to the information that we have so far. And I guess one of the other points that was raised by the discussant on the day was there's actually two further registered studies for sham control, one which is being done by the University of Leipzig, which has five centers and is halfway through recruitment. So we are going to see more data coming out. And I don't think we have any doubt given the experience that we're having with AF ablation in which direction that's going to go. But it's useful for the community. I think it's also an interesting earlier point in terms of pointing out the reduction in burden even in a sham group. I think to that point, that would be quite interesting to see from the upcoming study what the sham groups actually look like, how much of those reflect some of the management strategies that were implemented via cardioversion and antiarrhythmic or simply the fact that these patients in clinical trials are being managed. But I think more data forthcoming and I think a very exciting time for all of us in EP. So stay tuned for future references. And thank you all for joining us today live from Atlanta. This is another episode of the Lee HRS podcast. See y'all very soon.

SHAM-PVI trial

AFib ablation

pulmonary vein isolation

cryoablation

quality-of-life