All right, so thank you so much, and welcome to our session reviewing the important trials of the past little while. The official title is Lessons Learned from Recent Randomized Clinical Trials of Catheter Ablation. I'm Jason Andrade from Vancouver, Canada, and my co-chair is Christian Sohns from ... Bad Oeynhausen, Germany. It's not so easy, but Germany. From a complex word. So welcome. Please download the app if you haven't already. The questions can be asked through the app, or we have a microphone here at the centre of the room. We'll start with my friend and mentor, Dr. John Sapp from Queenie Health Sciences Centre in Halifax, Nova Scotia, Canada, and he's going to give us lessons learned from the Vanish II catheter ablation or antiarrhythmic drugs for ventricular tachycardia trial. Well, thanks very much, and thanks for the chance to be here and to present our work. I'm here from sunny Halifax on the east coast of Canada, and I'm really presenting on behalf of our patients and the large team that put the Vanish II trial together. We presented Vanish II at late breaking at AHA in November, and it was published in paper form in February. The background, of course, is that we treat VT in the setting of prior MI, not just for symptoms, but to reduce defibrillator shocks and their harmful effects, both psychological and cardiac. I don't think it's news to anybody in this room that defibrillator shocks are associated with worse mortality, particularly when they cluster, and there's a dose-response relationship. The more shocks a person gets, the higher the likelihood of mortality. This is a sub-study from the RAF trial, and all 11,000 ventricular arrhythmias in about half the patients in that trial were closely correlated with mortality risk. Not only that, but there's a strong temporal relationship between arrhythmia clustering and mortality, and the risk of mortality after an ICD shock doesn't come back to baseline for about six months. So I think that is part of our motivation for suppressing ventricular arrhythmias. Again, we haven't proven that treating ventricular arrhythmias over and above what a defibrillator can provide changes mortality, but there are lots of reasons to suppress VT. I like to think of the clinical course of a patient with VT in this way. So a patient experiences some kind of cardiac injury or scar, and then over a period of usually 15 years after a myocardial infarction, for example, they might present with an episode of VT. Or they might get a defibrillator for primary prophylaxis and later develop VT. VT then can often recur. You might intervene in some way, and then it might recur again, and then you're looking at more interventions. You might be looking at storm shocks. They might be treatment refractory at some point, and then we're looking at heart failure and death. If this represents kind of the relentless progression of cardiac disease in patients with VT, but we have lots of opportunities at which to intervene upon that course, whether that's preventing the MI in the first place, giving optimal medical therapy to try to prevent that remodeling, responding to cardiac arrest in the community, prophylactic defibrillators, and then once VT occurs, using catheter ablation or antiarrhythmic drugs, and then of course advanced techniques when things are not going well at all. There have been a number of clinical trials of catheter ablation for VT, the majority of them looking at early application of catheter ablation. We did the VANISH-2 trial for treatment refractory VT, and sorry, that was the VANISH-1 trial, and VANISH-2 and the SURVIVE trial published a couple of years ago looked at first-line therapy for VT. The two main drugs available to us in Canada, at least, are Sotalol and Amiodarone, and then the alternative would be catheter ablation. We saw in the VANISH trial that when drugs are failing, catheter ablation provides superior protection from recurrent ICD shocks, VT storm, and mortality, with the big drivers being storm and shocks, a 28% reduction in that event, but not only that, there was also reduction in the amount of VT and the amount of shocks experienced by patients, with large reductions in the number of ICD events, that is device-detected VT, and even larger reductions in the number of shocks experienced over time. So having established that catheter ablation is effective when drugs fail, the next main question was, what should be the first-line therapy? Should it be catheter ablation or should it be those antiarrhythmic drugs? And that it was the rationale for the VANISH-2 trial. So we published the methods paper early in 2024. The study was funded by grants from the CIHR and also from the Heart and Stroke Foundation of Canada, from CanNet, and grateful for the support of industry who had no role in the trial design, or its outcome, or its reporting, and were still willing to contribute to the conduct of the trial, both from J&J and from Abbott. We included patients who had a myocardial infarction, and what we defined as a significant VT event. And it's a long history, anyway, it's like multiple ATPs, ATP with symptoms, at least one shock or VT storm, and we can talk about where we came up with that list if you like at the end. And of course, everybody had to have an implanted defibrillator. Patients were randomized either to antiarrhythmic drug therapy or to catheter ablation. And they were stratified. So if they were randomized to antiarrhythmic drug therapy, they would get Sotalol if they had none of these risk factors. So patients who had VT storm, had class III heart failure, or an EF under 20, were randomized to amiodarone versus ablation, and healthier patients, let's say, were randomized to Sotalol versus ablation. And the randomization was stratified so that those were essentially like parallel trials. The primary outcome was timed to any of the following, death at any time, or after a 14-day treatment period, appropriate shock, storm, or sustained VT below detect. It was published just in February. And I won't belabor the flow diagram of the patients, but obviously, we analyzed on an attention-to-treat basis. We had fairly good follow-up, very little loss to follow-up. The patients were kind of what you would expect, a mean age of 67 to 68, largely predominant men. We would have liked to balance that better, and we can talk about that in the question period if you like. And a small proportion of patients were experiencing their first episode of VT and did not yet have a defibrillator at the time of study baseline, but everybody had one in the trial. There were a mix of class II and I with a small number of functional class III patients. The mean EF was 34, and they were split about 50-50 in the two drug strata. They were well treated pharmacologically with high proportion of beta blocker, ACE inhibitor use. SGLT2 inhibitors were not really around at the beginning of the trial very much, so very small penetration of that drug, but a reasonable amount of entrustal use. The main results were a 25% reduction in that composite outcome, which over 4.3 years of follow-up seemed to be sustained, and that was statistically significant. It was driven by these outcomes. So a small, like a 16% reduction in mortality, not statistically significant independently, no difference in STORM, interestingly, which was quite different from VANISH1, and a difference in ICD shocks, again, not independently statistically significant, and then a large difference in treated sustained VT below the detection rate of the defibrillator. Defibrillator programming was standardized. I'll note that this only made up about 10% of the trial outcomes, however. There were no statistically significant interactions with any baseline variable that we had a priori identified, but I will note the following, that is, the two strata looked to have slightly different curves. So the SOTOL-eligible patients were healthier, and they had a better response to ablation and a worse response to drug, whereas the amiodarone-eligible patients were sicker. They had a worse curve than the SOTOL-eligible patients for the ablation arm, and a higher response than SOTOL to drug. If we look at the components, I won't belabor this, but again, there were not statistically significant benefits seen in any of those outcomes other than the sustained VT below detection, which was a large reduction with catheter ablation. I'll move on to the numbers of events. So in red are shown the numbers of VT events in the ablation arm in red and the drug arm in blue. So reductions in appropriate shocks. So this is not time to first event, but the overall number of events over the trial. Reductions in appropriate ATP, similar storm, and reduction in VT below detect, but you can see that those are actually quite small numbers. And then when you adjust per patient year at risk, the findings are similar. In terms of safety outcomes, they were actually fairly comparable between the two treatment groups with kind of the expected rates of pulmonary injury and thyroid and liver dysfunction on antiarrhythmic drug and fairly well matched between catheter ablation and drug. This is a high risk group with a high mortality rate over the time of the trial, a high recurrence of VT storm despite our best efforts, a high recurrence of appropriate shock, again, despite treatment. And I'll finish up with a couple of limitations. We couldn't independently assess mortality. I don't wish we had more female patients with VT, but I did wish we had better evidence for how to treat them and what the effect was. And I'll note that this was an ischemic cardiomyopathy population. So lessons learned, catheter ablation is a reasonable first line option. It's more effective than antiarrhythmic drug therapy. And if you look at the subgroups, probably similar in effectiveness to amiodarone in the AMIO eligible patients and more effective than Sotolol. The AMIO eligible patients are sicker and have worse outcomes overall. And most of the side effects that we saw in the drug group looked like drug and amiodarone side effects. So that's something that we're digging into in some sub-studies to come. Thanks so much for your time. Thank you. So we have on the schedule, the question period will be at the end for all of our speakers. So we'll just hold all the questions to the end. Now I'd like to invite up Dr. Xiang from Sir Runrun Shaw Hospital in Hangzhou, China. And he'll be speaking about lessons learned from PROMPT-AF, pulmonary vein isolation with optimized linear ablation versus pulmonary vein isolation alone for persistent atrial fibrillation. Ladies and gentlemen, it's my honor to be here to share my thoughts about the lessons. Yeah, my thoughts about the lessons from the PROMPT-A for randomized trial. I'm Chen Jiang from Sourang Rangsha Hospital, School of Medicine, Zhejiang University, China. And this is my disclosure, and PROMPT-A was published this year, February, in JAMA. And it's comparing enhanced PVI plus linear ablation and the PVI alone. And this is the outcome, the specified outcome of the study. The primary outcome is freedom from any documented atresmia, including AF, AT, and atrial flutter. Those longer than 30 seconds in the absence of AAD therapy within 12 months after ablation, with the blanking period of three months. And its secondary outcomes were as follows, free from any kinds of atrial arrhythmia and atrial burden, AF burden, and improvement in quality of life, and procedural complication, that's a safety issue. So results show the primary outcome, freedom from any atrial arrhythmia without AAD therapy was achieved in 70.7% in PVI plus lines and plus ethanol infusion of in marshal versus 61.5% in PVI alone in 12 months follow-up. Extended follow-up results are pending, maybe same as in one year, maybe it's unknown. The secondary outcome is regarding the documented atrial flutter, AT, within one year, between two groups, no difference. That means high-quality linear ablation does not increase atrogenic flutter. As we know, 10 years ago, STAR-F2 trial was published, and in that trial, it showed linear ablation didn't improve outcome in patients with persistent atrial fib, and the conclusion was the simple is better, PVI alone is better than PVI plus. And it's a very disappointing conclusion. And actually, many doctors, like me, including me, believe linear ablation actually can help to maintain sinus arrhythmia with the following reasons. The first is the results from Cox-Mais procedure, long-term follow-up. Ten years after Cox-Mais procedure, the maintenance of sinus arrhythmia, 77%, much higher than 18 months follow-up in STAR-F2 trial of the group PVI alone. And the second reason is linear ablation with cateters can be performed at sites of wavefront collision on the sinus arrhythmia, which didn't impair atrial physiology. And also, the endpoint of linear ablation was definite and replicable, which can be verified with mapping and differential pacing. Moreover, the linear ablation has more evidence. Like the trial extended follow-up data from Kepler trial published last year in European Heart Journal showed higher incidence of macular re-entry AT in the PVI plus posterior wall isolation group, which means no matri-ismos line and no tricuspid lines. And actually, matri-ismos line-dependent flutter is much higher, 17.3%. And CTI line also very common in this group. That means integrated anatomical ablation strategy is warranted. And this is results from the PROMPT-AVE trial. Even with enhanced linear ablation, the matri-ismos line still, line blockage rate is only 87.4%. The roof line blockage is 87.4% as well. That means there is still some room to achieve. And the challenge still exists in achieving complete, durable linear lesions. Because there are some unsolved anatomical barriers for matri-ismos line, because the heat with RF, heat-sinking effect of CS blood flow, and CS myocardial sleeve, and also GCV, AOA, epicardial connection, all of them prevent blockage of the matri-ismos line. For roof line, it's difficult to get blocked because of adipose tissue, which prevent energy transmission from endocardial sleeve, blockage of septal pulmonary bundle. And also, if we ablate the posterior wall, which may damage the esophagus, result in fatal complication of atrial esophageal fistula. And from the AFT trial, also, safety issue, pericarditis and pericardial effusion more common in PVI plus lines and ethanol infusion in martial group. So attention should be paid to this ethanol infusion technique. Safety is dissection due to dissection of the vein. So ladies and gentlemen, the lessons learned from PROMPT-AF is as follow. Optimized linear ablation added to PVI improves rhythm control in patients with post-assisted atrial fib. And effort is still required to improve the quality and the durability of linear lesions. Pericarditis and pericardial effusion is a safety concern. Attention should be paid to reduce this risk. And this study cannot be extrapolated to early persistent atrial fib. That means less than three months, which requires further investigation. Thank you. And so again, we'll do questions at the end. So please submit them within the app if you have the opportunity. Now I'd like to welcome Usama Wazni from the Cleveland Clinic, who's going to give us lessons learned from the OPTION trial, left atrial appendage closure after ablation for atrial fibrillation. All right. Thank you, Jason. And thank you, Chris. So I think we're going to start. The OPTION trial was funded by Boston Scientific, so that's a big disclosure. And I do the concern. That's the rest over there. OK. So let's see what lessons. First, I'm going to go through the OPTION trial itself, because I realize that some have not seen it yet. And for those who have, repetition is sometimes good. Thank you for being here. But so the OPTION trial basically compared left atrial appendage closure to anticoagulation after ablation. Why is that? It's because really, I don't know why this is happening, but anyway, the reason this is important is because the guidelines still say that regardless of the outcome of the ablation, you should continue oral anticoagulation based on CHAD's VASc score and not the result of the ablation. Why is this important? Because you can have silent atrial fibrillation. If you stop the anticoagulants, you may have a stroke. But on the other hand, if you had a really successful ablation, and you continue your patient on a blood thinner when they really didn't need to, and then they end up with a bleed, that is an issue, too. So then we thought, OK, why don't we just close the appendage, and then we don't have to worry about it? Another reason we really wanted to do OPTION is that the issue of noncompliance. A lot of patients stop taking their oral anticoagulation within a few years of taking it. So that's an issue. And then finally, the WATCHMAN device was not compared to the new DOACs in any of the pivotal trials that got WATCHMAN to be approved. So the objectives were efficacy and safety in patients with moderate to high risk of stroke. The primary efficacy endpoint was a composite of death, stroke, systemic embolism at 36 months for non-inferiority. Then the primary safety endpoint was non-procedural major bleeding or clinically relevant non-major bleeding at 36 months for superiority. And these are the definitions here. The clinically relevant non-major bleeding is bleeding that led the patient to seek medical advice. So it's not something that they can manage at home. A secondary endpoint was major bleeding, including procedure bleeding at 36 months. And this was for non-inferiority. Here's the study design and timelines. So basically, patients were randomized in a one-to-one fashion to the device versus oral anticoagulation. We followed them for 36 months. Importantly, in the bottom on your left, sequential ablation, sequential group was patients who had an ablation within 90 to 180 days from randomization versus the combined is the ablation plus the device within 10 days of randomization at the same time. So we do the ablation, then implant the device. We screened a lot of patients, 1,600 patients were ultimately randomized to Watchman versus oral anticoagulation. Follow-up was very good at 36 months in both groups. And 95% of patients were taking a DOWAC. These are the baseline characteristics. Their child's VASC score was about 3.5, about 10% in the device group versus 11.5% of those patients had a stroke before. So these are patients who have increased risk. And then on the bottom right there, you see that about 60% had a sequential procedure versus around 41% who had a combined procedure. These are the characteristics. Most of them were done under general anesthesia. And left atrial appendage closure was successful in the majority, 98.8%, with a very low risk of complications. And I'll go through them in more detail in the next slides. And then also of note here is that it didn't take too many devices to close the appendages. It was just about 1.3 device per patient. This is important here, on the bottom in the blue, 10% of patients in the device arm at any one point were taking anticoagulation. We'll ask why. Because some of those patients needed cardioversions or redo ablations. So that's why that 10%. And it's not the same patient. So it's different patients. But at any one time, 10% were taking anticoagulation. In the anticoagulation arm, about 85% continued anticoagulation. And these are the outcomes. The primary efficacy endpoint met the non-inferiority 5.3% versus 5.8%. And much better than the margin of 5%. And again, the absolute difference was really very small, 0.5%. So very good with the efficacy. This is an important slide here. The ischemic stroke risk was very low in both arms, 1.2% versus 1.3%. So very low. So even if you go to, for example, epixapone studies or the DOAC studies, the residual risk of stroke is much higher than this in those patients who are anticoagulated. Remember this is over three years of follow-up. So it's really very low. And I think that the ablation itself contributes to lowering the risk of stroke. So very important for our field to show in an indirect way that ablation decreases the risk of stroke. Now, how about the primary safety endpoint met superiority, 8.5% versus 18.1%. Even when we add the procedural reading, it's 9.5% versus 18.1%. So still very significant. And then the secondary endpoint met non-inferiority. And this was major bleeding at 36 months. Importantly here in this table, what is missing is effusion related to the implant. There were no effusions related to the implant. Now in the implantation, in the device arm, there were effusions later because patients had other procedures. In one patient, for example, PVC ablation. And they had an effusion from that, but it counts. And if you go through the subgroups, everything is consistent. So that's very good. And then even in the higher chest vascular patients, it's very good. So now, so this is the conclusion from the main option trial. I think it's a very good strategy to decrease the risk of stroke and bleeding. And also, if you can do a procedure, one procedure where you address the AFib, and patients won't have AFib anymore. And also address the risk of stroke and bleeding in one procedure, why not? So that's the combined thing. Now here we go through a comparison between the sequential group and the combined group. Now this is important here in the next slide. Just let me go here. So this is just telling you that in the device group, we had the sequential cohort. And in the oral anticoagulation group, we had a sequential cohort. And then we had a combined cohort in both of them. So this is just the design of the trial. And what I want to show here is that we are not comparing combined device versus sequential device. Because those were not randomized. That's not what the randomization was. The randomization was device versus anticoagulation. It wasn't randomized to check between combined versus sequential. But we're still gonna give you some data on that. So that's why you see that red arrow, and then there's an X on it. We did not do that comparison. Because the baseline characteristics are different. And you can see them here. Because these patients were not randomized in those specific arms. All right, so this is just to show that they were different. And you can see the persistent atrial fibrillation is different. Renal function is different. And also what percentage of patients were in sinus rhythm is different. So now if you go to lag versus or anticoagulation in the concomitant group, basically the results are reproducible. So even if you say, okay, we randomized the patient, and now we start them on anticoagulation and ablation, or put a device and ablation, the results are the same, basically. I won't go through the whole details because we're running out of time. But also people ask me, what about, does the timing of the procedure affect the seal? In fact, there's no difference. So here we did the combined versus the sequential. Complete seal was very good in the combined procedure. And also in the sequential procedure. So this is a question, it's like, what if, for example, if you ablate, then that affects the quality of your closure? And the answer from these two slides is like, it doesn't. And yesterday we had the late breaker. Somebody asked, and that's why we wrote that late breaker, is that, what if implantation of a device affects the quality of your ablation? And the answer was, it does not. So on the ablation side, the outcomes were also similar, whether you closed the appendage or you didn't at the same time or not. So that's important. So these are the new lessons that we're learning. DRT, is there a difference in DRT between combined or sequential? And the answer is that there is no difference. The DRT rate was very low in both of them. So 1% at 90 days and three and a half. And then in the sequential is 1.2, 0.7. They were on more anticoagulation, that's why. So in the end, the conclusion is that I think the option trials are consistent with combined or sequential, and is similar to other previous studies for WatchmanFlex. Doing it does not increase risks, and I think it's a very good option for us for ablation plus left atrial appendage closure. And thank you very much for your attention. Thank you very much for your presentation. It's time to say goodbye to Jason already, so goodbye, and thank you for sharing the session together with me. I also invite you, by the way, to ask more questions, as provocative as positive, because we want to discuss them later. And now we have one more presentation. It's from Mina Chung, and it's about lessons learned from the TRMM-AF trial, targeting risk interventions, and metformin for atrial fibrillation. We're looking forward to your presentation. Thank you so much. Okay. So I'm going to talk to you today about what we've learned from our TRMM-AF trial, targeting risk interventions and metformin for atrial fibrillation. So my disclosures. This trial was funded by the American Heart Association, and it's still ongoing. So traditional upstream therapies for AF targeting pathways, leading to atrial remodeling, have largely failed to reduce AF in randomized trials. But recent genomic studies that we and others have done suggest more specific upstream targets may be available. And what we found in our group was that AF was associated with a decrease in transcriptional responses to stress. And when we did co-expression analyses of AFib genetic risk loci, they implicated metabolic and other stress pathways, and other targetable genes, including a subunit of an enzyme called AMP kinase. AMP kinase is the master regulator of metabolic stress in cells. It looks at AMP-ATP ratios, and it can increase ATP generation, et cetera. And it turns out that metformin and caloric restriction, or dieting, and exercise have been reported to have beneficial effects on AMP kinase. So of course we know a lot about the data coming out of Australia that showed that diet and exercise can reduce AF burden, and it acts on AMP kinase, as does metformin. So we designed a trial to try to answer these hypotheses, that metformin and our lifestyle risk factor modification, or LRFM, would reduce AF burden, or AF progression, in patients with AF more than standard of care, and that the combination of metformin plus LRFM would perform better than the individual interventions in reducing weight, or AF progression, and that metformin and our LRFM would reduce AF burden at follow-up compared to baseline. So TREME-AF is a prospective, randomized, open-label, blinded, end-point, two-by-two study in patients with implanted pacemakers or defibrillators with atrial leads. That allows us to get daily AF burden and daily activity. There are four arms in this design, control, metformin, LRFM, and both. So we randomized stratified by device type and rhythm at enrollment. And the arms were as I showed you. The standard of care group received written materials on lifestyle, modification, diet, and exercise. The metformin groups, we tried to titrate the metformin up to 750 milligrams twice daily. And the LRFM group, we worked with our preventive cardiology colleagues to develop a pathway where they saw preventive cardiology, got an exercise assessment with an exercise physiologist and a tailored exercise prescription. They saw a dietician to get nutrition and diet advice and counseling. And they also had other risk factor reduction. As I said, we could get data from their pacemakers or defibrillators with daily AF burden activity. Our primary outcome was compositive change from baseline to one year of average daily AF burden after three month blanking period and then survival at one year. This shows the trim AF inclusion and exclusion criteria. Basically, we included patients who had a pacemaker or ICD with an implanted atrial electrode and at least one episode of AF lasting at least five minutes over the past three months. And if they had, they could have paroxysmal AF, and if they had persistent AF, there had to be plans for conversion. And we basically excluded people with permanent AF or longstanding persistent AF. Now, early on in the ramp up of the trial, COVID happened and required a temporary shutdown of all the study procedures and recruitment. And remote change to remote consent flexibility and scheduling the follow-up visits to try to coincide with their clinical visits. And we moved a lot of the required in-person visits, including options and included options for virtual visits or phone calls. We had to have flexibility in titrating the metformin. And eventually, we had to decrease the sample size to 150. So the first lessons we learned was that it's really hard to do a lifestyle risk factor modification study during a pandemic. We didn't advise it. And also, it was pretty complicated. We intended to gather a lot of data to drive a lot of secondary analyses, including some omics. A pragmatic, simpler design would have been easier. But we still got a lot of valuable information. And actually, one of the things that we looked at was the COVID pandemic allowed us to kind of have a natural history experiment where activity went down and what would happen with AF burden. So this is our concert diagram. We looked at intention to treat, modified ITT, and per protocol. And there were four arms. Basically, they had 35 to 39 patients per arm. Now, the first year of results of TRMM were reported at AHA in November. And this slide shows the primary intention to treat composite primary endpoint. The top three lines show the odds ratio of the randomized interventional arms compared to standard of care, with higher indicating worse. So our result was that metformin trended worse than standard of care at the three to 12 month primary endpoint with a p-value of 0.033. Our multiple testing level of significance for these comparisons was p less than 0.017. There were no significant differences in the LRFM group compared to standard of care or the composite groups, and the two individual metformin and LRFM arm point estimates were worse than standard of care. Although the combined LRFM and metformin point estimate was better suggesting interaction, which is significant with an interaction p-value of 0.001. So the combined LRFM and metformin was significantly better than metformin and trended toward being better than LRFM alone. Kind of complicated results. This slide shows the relative change in weight. All intervention groups lost weight, but standard of care did not. The combined LRFM and metformin arm lost the most at 4.4%. So it's still not all that great. The devices allowed capture of activity in active minutes per day, and the combined metformin group had a lower activity at baseline and throughout compared to no metformin. There are no other significant differences in activity between the two groups. So we were surprised to see that there was a marked reduction in AF burden in the standard of care arm. If there's any way to kill your trial, it's have your standard of care arm do really well. And so from our preliminary data, we did all this modeling, and we saw an increase in AF burden. So indeed, what we did was we did look at the period before our baseline period. And when you see that, you do see an increase in AF burden actually in all of the arms. So what happened? As soon as they joined the study, their AF burden went down. Now, why is that? It could be the Hawthorne effect where you're being observed. But we also realized that what we'd done in the recruitment process was that we had given our patients all some lifestyle advice to convince them to join the study. And the standard of care arm got some discussion, they got discussion, but they also got this handout, which we're now calling the magic handout. So whether or not that affected things, who knows? And the other thing is that three patients in the standard of care arm got AF ablation, which really reduced their AF burden. What we show here is an important secondary endpoint, AF symptom scores. And it's a component of this Toronto AFSS questionnaire. And the symptom scores improved in the LRFM arms compared to standard of care, and to no LRFM. So in contrast, the AF symptom scores didn't change significantly in the standard of care in metformin arms. So some conclusions on LRFM, the AF burden decreased over time in standard of care and LRFM arms, the LRFM arms failed to beat standard of care and reducing AF burden. Patients felt better with LRFM, they felt better trying to do some exercises. So in terms of our lessons learned, we learned that 4% weight loss, this has been shown before, is probably not enough to show a significant difference from standard of care. But the AF burden improvement from standard of care may have reflected some LRFM counseling results. All patients received some LRFM discussion during recruitment. Standard of care got these written LRFM materials. So maybe our patients actually listen to us more than we think. So we also learned some stuff about metformin. And metformin trended worse. And all these retrospective studies had suggested, or secondary analyses of randomized studies, just like other upstream therapies, suggested that metformin would do better. But in this randomized trial, it did worse. It was actually very poorly tolerated. And at one year, nearly half of the metformin arm and a quarter of the combined arm were off metformin. So one of our lessons learned was that metformin can't be recommended as upstream therapy for AF at this time. And overall, our lessons, we were able to actually achieve pretty good completeness of LRFM treatment, despite COVID. And I think our continuous AF burden data will be very valuable. We were able to harmonize CIED data across all four major manufacturers. And again, standard of care discussion and handouts may be effective. So please be patient. Hopefully, we'll see some more data from two years. Those are conclusions, our AF burden decreased over time. The more intensive diet and exercise contacts were not better than standard of care. And at minimum, I think what I learned is that as a physician and as our healthcare professionals and all that, at minimum, we should discuss LRFM with our AF patients, and that they do feel better with this. And also again, the results emphasize the importance of randomized trials for AF. And we await the two year results. Thank you. Yeah, thank you very much for this presentation as well. You are again invited to submit some questions. The majority of questions are against or regarding option trials, so be prepared. And we also invite you to come to the microphones. So if there are no more questions so far, we'll start with the first question. Was it a good idea to also isolate the left atrial appendage and then put a watchman inside? Is this the next step? What do you think? I don't know if it's a good idea or not. So it depends. We don't routinely isolate the left atrial appendage in our patients unless there is very clear evidence that it is causing AFib in that particular patient. And if we do that, then because of the edema, we're worried about stability of the device. So we would keep them on anticoagulation and wait a few weeks and then bring them back. That is if you do the isolation austerely. Now, some people are doing isolation of the appendage a different way. They isolate the whole lateral part of the left atrium. The anterior line, then the posterior line, so then everything's isolated. I think in that one, you can put the watchman at the same time, because you're not doing the isolation of the appendage austerely. It's just that they isolated the whole thing. I was just talking to somebody yesterday, and also they do ligament of Marshall. So everything laterally gets electrically silent, including the appendage. And I think then it is reasonable actually to do it to protect the patient from non-contractility of the appendage, rather than, because then the risk of developing a clot is very high. So the short answer is no. The long answer is that it depends on what you did to the patient. That's the question. The reason I ask that question is because PFA causes less edema than RF. So do you feel more? Yeah. Does or does not? It does not. It still causes- It causes a lot of edema. Okay. So the question was, or the thought was that PFA causes less edema, but that's not accurate, actually. PFA causes a lot of edema, and we look very, very closely, because we do a lot of combined stuff, and we look at the ridge on a routine basis. It can cause a lot more edema, actually. Yeah, and also remodeling process is not here. Yeah, yeah. So what I do now is that even if I plan to close the appendage because of an indication, if I think the edema is going to be in the landing zone, I don't put it. I will wait. But some other people say, no, it's doable, but we haven't been too comfortable doing that. The question is for Oussama as well. So in your sequential approach, did you discuss the fact of remapping the veins and checking if there were reconnection and reablating them if there were? Or there was no remapping of the vein at all? There was no remapping. And was there a reason for that, just to- No, it's just, so the sequential, you know what, and those, no. So if the, well, then they would be combined, because what if you find something and then you ablate? So some patients did, because they had an ablation, but they had recurrence. So there was not, these are not de novo ablations. They had recurrence, and then we again, then they needed, you know, they were in the study, so we reablated and put watchmen. But the reason we didn't, if they're doing fine and they didn't need another ablation, we didn't, no, we did not map anything. But it's a good idea, because if you ablate, then they'll all be combined, correct, if you find something and there's a reconnection, you're going to ablate, and then they'll be combined. It won't be sequential. Yes, but I think you get a remapping at some month after the initial procedure, so maybe you increase your success, because you're there, no? I agree, I agree. I mean, clinically, I think it is something you can do, but then it'll be a combined procedure. But in a study, because it's a study, and then that's how it is, yeah. Good point. The study is the study. I have also a question to you, Yijang. There's also the question whether PFA might have changed your results. You demonstrated, and also in line with the champion trial, which we have seen that terminal lesions create more, more, let's say, pericarditis or these effects. Do you expect different results from your study when you do PFA instead of RF? Yes, our next step is to do from the AF2, it's PFA. I think as long as we have a good, durable lesion, I think the result will be the same. Which catheters do you plan to use for these lesion applications? The Boston Scientific. Yeah, okay, the Fairfax, so, yeah, okay, good, good, okay. And I have a question for Wazni regarding the sinus rhythm maintenance. In three years, in three years is a long follow-up. Was there actually any difference between these two groups? No, no, they were the same. So this is what we presented yesterday, that there was no difference in groups. And the maintenance of sinus rhythm was in both groups, anticoagulation and the device was about 70%. And then in the device group, combined versus sequential was the same. So it did not affect the result of the ablation. And there was also one additional question, why a five-year outcome was not included in the study protocol? So even if you wait longer- Because Boston did not want to pay for five years. And the second question is my- And we thought we were going to get the answer in three years. Well, you can also wait for 10 years, I mean. Yeah, exactly, yeah, we'll do it. I have one more question regarding the stroke. Annually, it's 1.something, .2, .3, what's the reason? Embolic or thrombosis? Well, these were all ischemic strokes. Ischemic strokes? Yes. Yeah, it's a clot from the- But it's not going to become zero, even in patients who- This is a good question, but people forget that even in patients who are taking their anticoagulation without interruption, and they're very compliant, there's still a residual risk of stroke, especially when you get into the higher, which has vast scores. And that's about, actually, so this was very low, 1.2% over three years. So it's very, very low. If you look at the apixaban studies, it's about 1% per year, still residual risk of stroke. So it doesn't go down to zero. And this is when patients, you know, they ask me, well, I'm taking my- And that's why we're doing LAOS IV, by the way. LAOS IV is close the appendage and continue anticoagulation to see if we can even reduce it. That's from LAOS, you know, we got the idea from LAOS III. And it's the same group we're doing it from, Dr. Healy from Canada. Okay, next question is for Mina. So I like the idea of monitoring AFib burden and use this as an outcome measurement. But which patients benefit most? The sickest ones, where you can achieve something, or the already good patients when you randomize them? Yeah, thanks for that question. We haven't analyzed those types of subgroups yet. But what we have looked at is levels of weight loss and levels of activity. So we do see an inverse correlation between change in activity and AF burden. So there is an association there. But that will be presented in a poster tomorrow. And the quality of life, was it related to more activity or not? Yeah, we haven't quantified it. We just did it by arm. So the LRFM arms exercise makes you feel better. Hopefully, yeah. Yeah. Good, then the next question is to you. I mean, when we discussed- Oh, yeah, there's one more question from your side, yeah. Yes, I have one question for John regarding the VT. Do you think the population is ischemic VT? So what about the other VT? You will skip this question. That is a great question. And we don't have- I do not think that we can extrapolate these findings to the non-ischemic population. Amiodon probably works similarly well in the non-ischemics to the ischemics. But catheter ablation does not, at least in my hands, maybe in your hands. No, so I think, yeah, and even designing a trial because there's so much heterogeneity of disease is challenging. So we're kind of brainstorming now on what do we do about the non-ischemics. So I don't have a good answer. In my clinical practice, I'm taking them to the lab after they fail drug. But even that, we haven't proven the benefit of catheter ablation yet. Thank you. I mean, what I see from your results, and I always ask myself the question, or it's an idea, you waited 14 or 13 years until you randomized these patients because there was remodeling after infarction and so on. But when we look at the journey of VT ablation, we ablate earlier and earlier and earlier. And if there is a big substrate and less ventricular ejection fracture, why don't we ablate one year after infarction? Well, I think only a subset, probably a fairly small subset of patients who experienced infarction go on to get VT. So we know we have a fixed procedural risk, and that's only gonna pay off, I think, if the VT risk is high enough to outweigh it. You know, it'll be linear with an offset, a Y equals MX plus B risk comparison. So there are, as you know, the trials of prophylactic early ablation, but even those trials are taking people with their first VT. Most of our patients had one, like this is their first presentation of VT, or it's their first therapy for VT. So they maybe had a primary prophylactic defibrillator, or they've had a bit of VT, but not enough that they or their clinicians sought suppressive therapy. So this was their first suppressive therapy. And I think that 15 years of remodeling is a really interesting time period. I don't know what's happening during that time period, but similar to all the work that's been done on atrial FIB remodeling and FIB-induced FIB, I think we've gotta sort this out. But Christian brings up a good point, is that in the SMASH VT, did they have VT before the, I didn't think they had VT. They randomized them to, I mean, everybody got a device, and then they randomized to ablation versus no ablation. So the SMASH VT now is so old that, but it wasn't adopted. That's what I'm trying to say, is that because ablation of VT is not easy, and there is risks with it, it was not adopted that you just put a device and you ablate for VT. If you bring them earlier to the EP lab and do EP study and to induce VT. That's what they do. And I have one question for Mina. Metformin, in the study, metformin, as you know, it's really intolerable for many patients. What do you think, how about the SGLT? Yeah, so we, our group presented an oral abstract yesterday, Dr. Raina Kuti, and so we looked at large databases and found a decrease in AF with both SGLT2 inhibitors and GLP1 RAs. We also looked at it, at the effect of liraglutidin and empagliflozin in our inducible pluripotent stem cell derived cardiomyocytes that we grow as engineered heart tissues. And then we did RNA sequencing to try to look at expression changes, gene expression changes with and without pacing. And it didn't show anything. Now, it just may be because it's not targeting cardiomyocytes, it may be a secondary effect. The weight loss or effect on, who knows what. It's not those, the genes associated with those that are not, associated with those agents are not very highly expressed in cardiomyocytes. Thank you. Yeah, thank you. And it deserves a study, because we're seeing all these retrospective studies. And I hope it doesn't get burned like we did. Yeah, so if there are no more questions, I would like to say thank you, first of all, for the presenters and the investigators. Great studies, and we really appreciate it. Thank you for bringing this information to us. Thank you for the audience and the questions, and we're looking forward to continue this discussion maybe next year. Thank you very much. Thank you.

catheter ablation

left atrial appendage closure

cardiac arrhythmias

VANISH II trial

PROMPT-AF trial

OPTION trial

WATCHMAN device

TRMM-AF trial

lifestyle modifications