Next speaker is David Wilber, who will give us an update on the AMAZE trial. Dr. Wilber. Thank you. Well, it's a pleasure to speak to everyone today. And I want to provide you some perspective on the AMAZE trial, something that most of you have been aware of. So the arithmogenicity of the left atrial pangent has come under increasing scrutiny for the last few years. And many of you are familiar with some of the details. It's a complex structure with pectinate muscles, variable thickness, facilitates slow conduction and reentry, particularly in the presence of fibrosis. It's a source of both epicardial and endocardial focal automaticity. It's been noticed for many years. During AF ablation, it's been noted during stepwise procedures to be an important source of localized reentry, where AF can often slow or terminate. And then the initial observations from the Austin group, with many patients who had undergoing redo ablation, the appendage was identified as the source of triggers and focal firing in 27%. And with electrical isolation of the appendage, in addition to extensive standard ablation, the risk of recurrence was reduced substantially in this initial trial. Meta-analysis looking at electrical isolation of the appendage has suggested, irrespective of the approach, a fairly robust impact on the risk of atrial fibrillation and, again, reductions in the range of potentially even 50%. There are many issues, of course, with electrical isolation of the appendage that we've become aware of over the last few years, including left atrial appendage dysfunction and loss of contraction, and then the increased risk of thrombosis. And so those are some of the potential risks that go along with this. So as we'll talk about, Lariat offers a convenient solution to that problem. So clearly, there's effect of left atrial appendage ligation, epicardially, immediately on voltage. And this is just pre and post closure of the Lariat device. And this is an epicardial recording. And there's a mark reduction. The left atrial appendage, histologically, in both animal studies and in occasional human studies as well, demonstrates really a complete restriction of the appendage with subsequent death of the appendage around it. And long-term studies of both imaging and post-mortem studies demonstrate atrophy of the appendage afterwards so that, unlike other methods of left atrial appendage occlusion, this results in, essentially, elimination of the left atrial appendage viability. And so it differs from all endocardial approaches that we know of. And there's been no suggestion that those, in fact, have that impact. Reduction in AF burden. And in occasional patient, relatively small numbers. In this case, about 790. This is a long-term telemetry device. A patient had had long-standing persistent atrial fibrillation for a year, had left atrial appendage ligation, and within hours, converted to very rare episodes of atrial fib. And this was just one of those patients where it was the dominant driver for atrial fibrillation. So the inspiration for this study came from a non-randomized but comparative study looking at patients who underwent left atrial appendage isolation and then had pulmonary vein isolation in addition and suggested that patients that had the two in combination had much less recurrence of atrial fibrillation. Obviously, this is an observational study. And it was compared to a loosely matched control group. Nonetheless, suggested the concept that isolation of the appendage first, then followed by pulmonary vein isolation, may be beneficial. So a brief synopsis. And this is really a very straightforward trial, relatively simple in design. It's really to see what the added benefit of left atrial appendage isolation alone by the lariat adds to pulmonary vein isolation alone for patients with persistent and long-standing persistent atrial fibrillation. It's a two-to-one randomization. It's a Bayesian adaptive design for superiority. And so a total of 400 to 600 patients are allowed. And it's in up to 65 sites. There were two stages as it was initially designed. The first 100 patients had to be evaluated for safety to make sure that the study could go on. And then after that, then continued enrollment and pre-planned interim analyses at 400, 450, 500, and 550 patients. And this is obviously then to minimize unnecessary continuation of the trial if there's either futility or, in fact, success has been reached, predictive efficacy within that before the total 600 patients. So the primary endpoints are freedom from atrial fibrillation of 30 seconds and no requirement for a new class 1 or 3 antiarrhythmic drug at 12 months post-PVI using event-driven monitoring and 24-hour holters, and then a primary safety endpoint. So it's powered for TD Tech with 90%, 80%, an absolute difference of 15% between treatment and control. And because of the way the trial's designed, that would hold no matter what the control group recurrence rate may be. And the maximum sample size would allow a detection of a 10% difference, which we would judge as clinically relevant. And the effectiveness endpoint, again, is any documented episode of atrial fib and that documented by Holter monitoring and no new class 1 or 3 antiarrhythmic. Primary safety events are judged by an independent events committee and are those that are standardly recommended for AFib trials. There's also a technical success, meaning that the lariat had to have complete closure of the device by TEE both at one month and at 12 months post-procedure. And there's a core laboratory where all of this data is interpreted. And, again, looking at one month post and 12 months post. The population is, as you see, so persistent or longstanding persistent atrial fibrillation. There is a cutoff at three years of longstanding persistent atrial fib. The patient must have failed an antiarrhythmic drug, so again, a selective population of persistent atrial fibrillation. And you can see here the lariat ligation is done first, a month later, a pulmonary vein isolation is performed. Anticoagulation in this trial, this is not a determination of the success of appendage closure for prevention of thrombosis post-ablation. So this is, all patients are in anticoagulants in both groups until the end of the trial. And then after that's done, they have the six month and one year follow-up. Again, the ablation was very rigorous, unlike many trials which have allowed some investigative discretion. It's only PVI, nothing else is allowed for ablation except a CTI ablation. There's no trigger induction, no chasing of triggers. There's no burst pacing. And adenosine is used to unmask dormant conduction. So where the trial is, it's a relative, like I said, it's relatively simple to interpret. The trial started in 2015. It went through its initial safety evaluation with no issues or problems. We are now up to 493 patients enrolled. And so the critical 500 patient interim analysis will be done probably shortly next month. And this is where, and the reason that's important is that then we'll have something like almost three quarters of the total patients will have reached one year follow-up. And again, as with any Bayesian trial, if the end point is met, then the trial would stop at that point. Otherwise, we'll continue to 600 patients, which we anticipate will probably occur sometime, we hope by the end of the year. And then of course, they would still need to have additional follow-up if we need to have the full 600 enrolled. So I think this is a potentially exciting trial. It's a relatively simple and straightforward and rigorous design. And if successful, may have a substantial impact on how we conduct the ablation and treatment of longstanding and persistent atrial fibrillation. Thank you. Thank you, Dr. Wilber, for the excellent presentation. Are there any questions? So the trial has already been conducted for quite some time. Are you afraid of any inflammation processes that may even promote atrial fibrillation? I mean, in the early phase of Lariat, there have been pericarditis circumstances. Yeah, I think that that's always, and one of the things obviously we didn't have time to mention is that all of these patients have a relatively rigorous, with the Lariat procedure, they're on colchicine both pre and post, which has actually a dramatic effect on reducing inflammation and procedure pain and that sort of thing. And these were all kind of lessons learned in the early Lariat experience, I think, before the trial started. So that's had a major impact on reducing that and having atrial fibrillation as a result of the Lariat procedure, exacerbating it. I have a short question. I'm not sure if I fully understood, but one of your endpoints was that there's no requirement of new class I or III anerythmic therapy. Yeah, it's an old sort of FDA kind of holdover from many of the previous ablation trials, and that's actually been a standard definition of success, that patients were not, patients are encouraged, or rather, I should say both the patients and the investigators are encouraged to stop anerythmic therapy at three months, but at the discretion of the investigator, may be allowed to continue. We've strongly urged that, and the anerythmic drug use is relatively low in the trial as it's been monitored. So the neat thing is not only that the appendage is gone, but it's also taking care of the thrombogenic aspect maybe. So in clinical terms, how do you proceed with these patients when they completed their study? Do you stop anticoagulation? Yeah, we are. That also was by design, and again, I think the reason was not to do it until the end of the trial was simply because it's to keep the group's equivalent, and it wasn't meant to do that. We have subsequent sub-studies that we'll be looking at the outcome now, because all of these patients will be off anticoagulation after the first year, but will continue to be monitored. Now, that'd be interesting to see even beyond the scope of the interstitial. Yes, so there will be, and it's a large number of patients that we'll have that have been followed relatively rigorously, so I think we'll learn a lot more about the safety of that long-term. Curious to know. One more question. I assume you split out the two procedures just so you could better assess safety events related to the lariat. That's exactly right. I think that that was one of the requirements also for the FDA for this, was that they wanted to make sure, and to look at the potential adverse impact of the lariat versus the ablation itself. There are some advantages and disadvantages to doing both. I think that it still will make sense. Very early on, the lariat was done in anticoagulated patients, and the complication rates were relatively high and contributed to the sort of early impression that there was a lot of, this was a dangerous procedure, so I think that anticoagulation is withheld, and these are epicardial procedures done in the absence of full anticoagulation, but they are anticoagulated within days after the procedure, so it's really a matter, though, that it's done off, and that will probably still, I think, be the recommended approach. Okay. Thank you so much, Dr. Wilber. Thanks. Thank you.

Dr. David Wilber

AMAZE trial

left atrial appendage

atrial fibrillation

Lariat device