This is Heart Rhythm TV, I'm Deepti Virgis. And I'm Michael El-Shami. We are about to start Session 2 of Late Breaking Clinical Trials, Clinical Trials Updates and Registries. Michael, tell us what you're excited about today. Well, I'm excited today to hear about some of the CIED Trials, the Protherian Excel Trial is an extension of the Protherian Trial with published outcomes of SICD versus transvenous ICD up to four years. The Excel Trial followed these patients an extra four years. So we have eight years of follow-up on SICD versus transvenous ICD. I'm excited for sudden cardiac arrest and the seemingly healthy. We're getting answers, the evolution of the emergence of diagnosis and unexplained. Another trial I'm excited about is the defibrillation outcome in the LEADER left bundle branch area pacing trial. This trial that talks about the outcome of patients implanted with the newer version of the ICD-LEAD, a small caliber ICD-LEAD that mimics the 3830 pacing leads. Finally, we have TRANSFORM-AF, yes, metabolic therapy in the EP world. We're talking about the role of GLP-1 agonists in the management of AFib. That must be very exciting to look at the outcome of GLP-1 agonists like Ozempic on AFib recurrence. And now, your late-breaking clinical signs. Thank you so much. I'm Mina Chung, and on behalf of my co-chair, Jack Sing, it's my pleasure to welcome you to this late-breaking clinical trials and science session. And we'll start right in with our first presentation by Dr. Olda Nordkamp, who will talk about more major and LEAD-related complications in transvenous versus sub-Q defibrillator therapy during long-term follow-up, the Pretorian XL trial. Well, thank you very much, Ms. Chairman, for this introduction. It's an honor for me to present today the results of the Pretorian XL trial about device complications in transvenous and subcutaneous ICD therapy during long-term follow-up on behalf of all Pretorian investigators. ICDs have proven to save lives, and transvenous LEAD placement for cardiac sensing and defibrillation was the standard ICD design for several decades. Device-related issues, including LEAD complications, are a known problem related to transvenous ICDs. For this reason, subcutaneous ICDs were designed to offer an additional treatment option that can overcome LEAD-related complications. The Pretorian trial demonstrated that in patients with an indication for ICD therapy but no indication for pacing, the subcutaneous ICD is non-inferior to the transvenous ICD regarding the combined endpoint of complications and inappropriate shocks at four years. Early concern of increased numbers of inappropriate shocks due to over-sensing since your introduction of the SICD have been mitigated by optimization in programming and new software algorithms. High rate and long detection duration programming also reduced inappropriate shock rate in transvenous ICDs. Complications with LEADs, especially LEAD failure and LEAD infection, and device-related complications generally continue to rise during long-term follow-up. Therefore, we aimed to investigate whether the subcutaneous ICD is superior to the transvenous ICD regarding device-related complications during long-term follow-up. The Pretorian trial was an investigator-initiated, multi-center, randomized trial. In the Pretorian trial, 849 patients with a class 1 or 2A indication for ICD therapy and no need for pacing were included and randomized one-to-one to subcutaneous or transvenous ICD therapy. Participants were included from March 2011 to January 2017 in 39 centers throughout Europe and the U.S. To compare the subcutaneous ICD with the transvenous ICD with regard to device-related complications over long-term follow-up, the participants of the Pretorian trial were followed up for an extended period of four years. This is the Pretorian XL trial. The primary endpoint of the Pretorian XL trial was all major and minor device-related complications. These include infection, hematoma, thrombotic events, pneumo- or hemothorax, cardiac perforation and tamponade, lead repositioning or replacement, and other device-related complications. Secondary endpoints were major complications, which are all complications which needed an invasive intervention, lead-related complications, mortality, hospitalization for heart failure, and major adverse cardiac events. The main analysis were performed according to the intention-to-treat principle. This is the flowchart of the study. 849 patients were randomized to either the subcutaneous or the transvenous ICD therapy. At the end of the Pretorian trial, 107 subcutaneous ICD patients and 93 transvenous ICD patients could not be approached for prolonged follow-up. The other patients were approached, of whom approximately 20% in both arms did not consent for further follow-up. Patients who did not consent for further follow-up were censored from December 1, 2019, and the median follow-up of the entire cohort was 87.5 months. These are the baseline characteristics of the study. The median age of the patients included in the trial was approximately 63 years, 20% was female, and the most common diagnosis was ischemic cardiomyopathy. A little less than 20% of patients received their ICD for secondary prevention in both arms. And this is the primary endpoint results. At eight years of follow-up, the cumulative incidence of both major and minor device-related complications was 8% in the subcutaneous ICD group and 11.6% in the transvenous ICD group. This was not a significant difference. The notable break in the curve can mostly be attributed to generator changes in the subcutaneous ICD group. Most subcutaneous ICD patients were implanted with first-generation devices, which had a battery life of approximately five to seven years, and implanters had limited experience in device implantation. Whereas the replacement itself was not included as an endpoint, generator replacements comes with complications related to the box change, and it's a natural moment to evaluate device positioning and device indication. When we further look into the most common complication in both groups, the most common complication in the transvenous ICD was leter replacement, and the most common complication in the subcutaneous ICD group was hematoma. Whereas the primary endpoint included both major and minor complications, the cumulative incidence of major complications, which was defined as complications in need of an invasive intervention, was significantly higher in the transvenous ICD group with a hazard ratio of 0.58. Also at eight years, the cumulative incidence of lead-related complications was significantly higher in the transvenous ICD group with a hazard ratio of 0.3. Mortality was not significantly different between arms at eight years. Also, there was no difference in hospitalization for heart failure and no difference in major adverse cardiac events. There were approximately 10% crossovers in both randomized arms. Reasons for crossovers from a subcutaneous ICD to a transvenous ICD or biventricular ICD were progression of heart failure in 5% and a bradycardia pacing indication in 2.6%. Reasons for crossover from a transvenous ICD to a subcutaneous ICD or biventricular ICD were progression of heart failure in 7.6% and patient preference in 1.4%. All complications occurred in patients who, during the course of the study, received the device different than the one they were randomized to. In the subcutaneous ICD group, 23% of all complications occurred in patients implanted with a transvenous ICD or biventricular ICD. In the transvenous ICD group, 4% of all complications occurred in patients implanted with a biventricular ICD and none implanted with a subcutaneous ICD. Therefore, an as-treated analysis with device type as time-dependent variable shows a significantly higher incidence of all device-related complications in patients implanted with a transvenous ICD compared to patients with a subcutaneous ICD. Therefore, to summarize, the subcutaneous ICD is not superior to the transvenous ICD with regard to the composite endpoints of major and minor device-related complications. However, the subcutaneous ICD is associated with a significantly lower risk of both major and lead-related complications. Moreover, there are significantly less complications with the subcutaneous ICD in an as-treated analysis and there was no significant difference in mortality between arms. Therefore, we conclude that the subcutaneous ICD should be strongly considered in all patients without a pacing indication who are evaluated for ICD therapy. I would like to thank all Praetorian investigators for contributing to this study and I am happy to announce that our study is now simultaneously published in circulation. And I would like to thank you for your attention. Thank you very much. I now invite Dr. Fania Miele to come up and give a commentary on this study. Thank you very much. I have to say that I am equally excited as Dr. El Chami to see the results of this study. What a nice idea and what a significant source of information for all of us. I would like to start with some initial thoughts. What we ask from the industry that provides us the opportunity to treat our patients is innovation and safety of the devices that we handle. Also what we need to remember is what sometimes makes sense may not always be true and therefore prospective and randomized trials are and have become and continue to be the cornerstone of progress in medicine. When it comes to the subcu ICD examination over the years the initial information came from observational case control cohorts and this is an example of meta analysis of five of those trials that showed that actually there was no significant difference between subcutaneous and transfinous ICDs but only for the complications related to the device and the leads. Eventually the Praetorian trial came and showed that the subcu ICD was not inferior to the transfinous ICD both in terms of mortality and even inappropriate shocks. But there was a significant difference in terms of lead related complications. And now we heard today about the Praetorian Excel trial which has added another four years for a total of eight years of follow up in these patients. So the same original group that was that the follow up was extended. Not everybody agreed to follow about 20 percent of the patients in each group decided not to follow up but still a very good number of patients. And just a reminder this was an intention to treat analysis. And as we heard the primary end point showed that actually the subcu ICD was not superior to the transfinous ICD. But when we came to analyze the complications we realized that a significant number of them could have been because of crossover of SICD to transfinous ICD. In terms of the secondary end points which I consider maybe the most important slide of this presentation there were significant differences in the lead related complication and major procedures that were required. Therefore I would like to add two more thoughts for the future. Comparing the two groups the lead complications could continue to increase in the transfinous ICD group. Should we continue to follow up these two groups for years. And also we will have to wait and see what the leadless pacing can add to the combination of the system. In terms of my take home points I want to commend the authors for an excellent work. The SICD did not prove to be superior to the trans transfinous ICD with an average follow up up to eight years. The lead complications though were significantly fewer in the SICD group with more invasive interventions in the transvenous group. And we should not forget that many of the SICD complications could have been because of the crossover to transvenous ICD or CRT. Therefore careful selection and consideration of our patients is of outmost significance. Thank you very much. Open to questions for this. I don't see anything. Feel free to send questions in through the app which I think all of you have access to. While we wait for questions should I go ahead and ask. So that was a great presentation Dr. Old Nordkamp. Quick question for you. I know the primary Praetorian trial also looked at inappropriate therapy. And how come the extended follow up did not include that or was it looked at and not found to be significant. No we didn't. We did. We didn't look at it yet. We are planning to do. But what we noticed is that most patients were implanted with first generation devices in this in this cohort because patients were implant participants were implanted from March 2011 to January 2017. And for example Smartpass was not available in most of these patients yet. So therefore we thought it would be not fair to compare inappropriate shock because the current inappropriate shock rate is really lower than was seen in our study because we had like early implanters and early devices. Makes a lot of sense. You have a question. Again congratulations on a wonderful study. Given that there's no significant overall difference I was wondering if and the fact that these were first generation larger devices did Praetorian gather any patient reported outcomes. Were there any differences in quality of life. Yeah. So we published a quality of life analysis because we did that in the study in the Praetorian trial and there was no significant difference in quality of life between patients with a transvenous or subcutaneous ICD in their body. Thank you. Very quick question. I know you did a as treated analysis. Did you do an intention to treat analysis too. So this was all modified intention to treat actually. And what that means is that patients who did not receive a device at all were not included but everybody who received the device was analyzed by the group the randomization group they they belong to. So even if patients had were randomized to subcutaneous ICD but they received the transvenous ICD which happens in the trial. They were analyzed in the subcutaneous ICD group. So all the main analysis are intention to treat. Thank you very much. I think we're ready to get on with the next study. The next presenter is Dr. Chen Han. He's going to be talking about the evolution and emergence of diagnosis and long term outcome of apparently unexplained cardiac arrest. Dr. Han. Thank you chairman. I would also like to thank the abstract reviewers and the organizing committee for the opportunity to present today. I don't have any relevant financial disclosures. I will note that I'm based in Australia but the content I'm presenting stems from my time in Canada and our ongoing collaborations. By way of background, sudden cardiac death and cardiac arrest are potentially devastating outcomes resulting from various cardiac conditions. In an all covers model, approximately 10% remains unexplained. In young people with sudden cardiac death and cardiac arrest, there is often an underlying primary arrhythmia disorder. Our own historical data shows that amongst this group, the percentage that remains unexplained is significantly higher. The understanding of these primary arrhythmia disorders has evolved with greater recognition of certain disease entities. This has occurred in conjunction with the development and establishment of institutions offering centralized care, including the Canadian Hearts and Rhythm Organization or HERO. HERO is a nationwide organization involving 25 centers across Canada. Clinically, HERO provides cardiogenetics care to over 7,000 patients and their first degree family members with inherited heart rhythm conditions, inherited cardiomyopathies and unexplained cardiac arrest. In this group, there is a defined process of care which occurs. Academically, the vast majority of patients are also enrolled as participants in a prospective research registry. Specifically, this study involved participants enrolled after an episode of apparently unexplained cardiac arrest. Cardiac arrest survivors with preserved ejection fraction registry, or CASPER, was established in 2006. Many in the room will be familiar with the initial CASPER study that defined the approach to otherwise unexplained cardiac arrest, which is now a central part of HERO. In addition, CASPER and its various collaborators have been instrumental in contributing to our understanding of various primary arrhythmia syndromes. Inclusion criteria for CASPER were all patients under the age of 60 years who survived an episode of cardiac arrest due to ventricular arrhythmia. All patients were required to have coronary assessment and structural assessments. Coronary assessment occurred via angiography or computed tomography. Structural assessment was achieved through echocardiogram. In these patients, initial testing did not reveal an obvious ion channel disorder. Excluded patients were those with significant coronary abnormalities, or EF less than 50% on follow-up testing. Participants undergo further standardized clinical evaluation to achieve an initial diagnosis, including MRI, signal average ECG, exercise testing, sodium channel blocker provocation, and genetic testing. During routine clinical follow-up, diagnostic re-evaluation is undertaken, including genetic variant review, to detect newly recognized causes of unexplained cardiac arrest or reinterpret existing patient investigations in line with emerging evidence. These care pathways have been informed by guidelines and are outlined in HERO consensus algorithms. On to results. From 2006 to 2024, CASPER enrolled 787 unexplained cardiac arrest survivors across 25 Canadian centres. Median age was 42 years, 36% were female. Median follow-up duration was 8 years. Unique to this registry is that some patients have had more than 15 years of clinical follow-up. The table shows the overall number of patients and their follow-up duration along with the percentage of patients in whom a diagnosis was assigned. The figure is a graphical representation of diagnosis rate. Overall diagnosis assignment was 7% at time of discharge, 19% at 12 months, 36% at 2 years and 43% by 15 years. From this we can tell that most of the initial diagnosis acquisition occurs by 2 years with minor increases thereafter. The next section of the results provides some insights into the reason for this occurring. So while all patients had coronary assessment structural assessment by discharge, additional testing occurred during the follow-up period. Of note, rate of genetic testing increases dramatically by the 12-month mark. One other thing to note is that patients won't necessarily undergo every form of additional testing. For example, you can imagine that if someone had a procainamide challenge that showed a type 1 Brigada pattern, they wouldn't necessarily go on to have signal average ECG or stress testing. Next is a breakdown of what patients had as their preliminary diagnosis. The figure on the left shows the relative overall contributions from the various groups of conditions that cause cardiac arrest. The figure on the right represents the absolute numbers for individually recognized conditions. You'll note a high number of patients being assigned long QT syndrome as their preliminary diagnosis. Now, recall the importance that was placed on re-evaluating patients and their histories during clinical follow-up. These two figures shows the updated diagnosis breakdown for these patients based on their most recent follow-up. And as you recall, in some cases this is over 15 years. So comparing directly, this figure shows the overall change in diagnosis for various conditions. For each condition, the lighter colored bar on the left shows the overall number that was assigned as a preliminary diagnosis. The darker colored bar on the right is the overall number that was assigned at their most recent follow-up. In total, 183 patients or 23% of the cohort had at least one change in diagnosis over time. The most noticeable discrepancy is that over 50 patients had a diagnosis of long QT syndrome which was redacted. Interestingly, the majority of those cases actually ended up being reassigned as unexplained cardiac arrest. One of the key reasons for this was the re-evaluation of patients who may have been given a diagnosis based on a positive epinephrine provocation test with recent evidence indicating a high proportion of false positive results. A couple of conditions which experienced an increase in diagnosis also warrant some comments. Malignant mitral valve prolapse, I think, really increased due to the greater recognition of this condition. Short couple VF is also in a similar vein but on top of that, by definition, these patients actually needed a secondary prevention ICD and a recurrent event for the diagnosis to be made. In summary, we report on a prospective cohort of 787 survivors with apparently unexplained cardiac arrest with baseline and additional cardiac testing. In those with apparently unexplained cardiac arrest, thorough expert evaluation can lead to a diagnosis in 36% of patients within 24 months. Repeat phenotyping is important and almost a quarter of our cohort had a change in diagnosis during their clinical follow-up period which occurred in conjunction with new literature about these various conditions. The results presented from our experience provide real-world insights regarding the evolution of understanding related to apparently unexplained cardiac arrest providing a reference point for centers caring for such patients and their families. This is our take-home message. Follow our patients periodically. Retest your patients over time. Re-evaluate the information that you have in line with new evidence. A couple of acknowledgments. First of all, I'd like to thank Andrew Crown for the opportunity to present this long-term data set from CASPER. I would like to acknowledge and thank the core group of hero clinicians and investigators who make this work possible. As mentioned, this study is almost 20 years in the making, if not longer, and many important contributors have since moved on but it would not be possible without a strong network of dedicated individuals. And last but certainly not least, a big thank you to the participants who allow us to collect their data and share it with the rest of the academic community. Thank you. Terrific presentation. Dr. Narsiman, commentary is all yours. Thank you. First of all, congratulations. It's a very difficult study in this day and age to do an 18-year follow-up study and congratulations both to Dr. Khan as well as Dr. Andrew Crown for leading this investigation. Now let me just, this is very relevant to what we practice. Don't think it's because it's genetic and other things, it's remote. This reflects the contemporary understanding of our disease processes. For example, the malignant mitral valve syndrome suddenly increased after mitral valve disjunction was described and arrhythmic risk was described. Similarly, short-coupled PVC leading on to VF suddenly increased as we have prolonged monitoring. So contemporary practice are probably responsible for some of the findings. It's an excellent study. It's not easy to do a 18-year follow-up study with a median follow-up of eight years. Overdiagnosis of long QT syndrome probably reflects what happens in several diseases. Whenever NGS came in, people took a candidate gene approach and they started over diagnosing problems. But then there is reclassification and therefore it was binned properly and there's less incidence of long QT. The main message is we probably under-recognize short-coupled VF and under-diagnose malignant mitral valve prolapse. These are very relevant because they are disease-specific therapies that are available for this. Now what are the strengths that we can think of? It's a very relevant but overlooked problem and they have described a framework which every clinician can use in clinical practice. Very extensive but clinically oriented and a long-term follow-up is the main strength of the study. And the implications are profound. So if you have a person who has been diagnosed to this problem, cascade screening will be able to identify and prevent sudden death and we'll be able to tailor and personalize therapy for several of these disorders. Now what are the limitations? This is a problem which we forget. Most of these malignant syndromes, patients don't survive to 40 years of age. So if you take a pediatric population, for example ARVC, I saw two presentations. It doesn't progress. When you do a 40 year old person, it doesn't progress. When you see it in a 10 or 15 year old, the sudden death is high. So median range of enrollment, had it been younger population, your yield would have been much higher in this. Second thing is we realize that there is always an environmental interaction. A person who had a long QT gene had a slight fall in potassium. On that day he tends to have a VT or VF. So there is an environmental interaction. There are several examples for this. Over years we have realized that there are epigenetic factors, transcriptomics, which modify the disease modifications are there. And with AI coming in, images and ECGs, we'll be able to risk predict these patients much earlier on so that we can personalize the therapy. Thank you. Thank you and I want to add my congratulations to really this really amazing study where you were able to standardize the testing. And I have two questions. One is, in that testing panel, were there particular tests that had higher yield versus lower yield? Would you do signal average ECG still on everybody for example? And then the second part of this is, what did you actually over the years retest with? Besides the genetic, you know. Yeah, that's an excellent question. I think in terms of the yield, we are somewhat also guided by, you know, the patient demographics. And so as an example, if you have, you know, a younger male who might be of Asian descent, then you know, we think about sodium channel provocation maybe a little bit earlier for that patient as an example. But the actual yield of the individual test, we are still looking into a little bit further just to figure out what, you know, gives you the best bang for your buck. In saying that, I think the genetic testing did provide a lot more information about these patients and revealed the diagnosis in a lot of these cases. In terms of the retesting, I think, you know, some of those additional tests, so sodium channel blocker provocation, exercise stress test, signal average ECG, I think in most cases once we've done one, one's enough. I actually have a personal memory of looking after a patient when I was in Canada where we did repeat a couple of those tests just because it was just the first test was just so equivocal. But oftentimes, you know, if one is clearly negative, then it's enough. Genetic testing is obviously a little bit different in the sense that as new literature comes out, there's always the need for kind of re-evaluation and, you know, having a rethink about what we've done in the past. In terms of re-evaluation, did you have a particular protocol that everyone was re-evaluated at six months, one year, or two years, or was it physician discretion and everybody did it independently? Yeah, yeah, I mean, look, to put it bluntly, sometimes it comes down to, you know, do we remember to re-evaluate? However, the team that we work with is actually very good. It's led by a group of genetic counsellors and, you know, they keep very close records of, you know, who's been re-evaluated and at what time frames. And ideally, it's kind of every three to five years, you know, we should have a rethink about the information that we've collected for that patient. Thank you very much. So, our next presentation will be by Dr. Ipugol Vijayaraman and it will be on left bundle branch area placement of a novel small diameter defibrillation lead, defibrillation results of the LIDAR LBBAP clinical trial. Dr. Chang, Dr. Singh, thank you very much for Heart Rhythm Society for the opportunity to present the results of left bundle branch area placement of a novel small diameter defibrillation lead. This study is to present the defibrillation results of the LIDAR left bundle branch area pacing clinical trial. This trial was funded by Medtronic. The use of omni-secure defibrillation lead for left bundle branch area pacing is investigational and left bundle branch area pacing indication has not been approved in any geography. These are my disclosures. Omni-secure lead is a 4.7 French, lumen-less, single coil, catheter delivered, integrated bipolar defibrillation lead. This lead is designed after the model 3830 lumen-less pacing lead that's been in market for more than two decades and has performed very well. The LIDAR pivoted trial was designed to assess the safety and efficacy of the omni-secure lead in a traditional RV location. And that study showed a 97.5% defibrillation efficacy at implant and a 96.9% lead-related complication free rate at 24 months of follow-up. There were no fractures and it provided stable electrical performance through 18 months of follow-up. And additional reliability modeling studies projected a 98.2% fracture-free survival rate at 10 years. I'm happy to announce here that the omni-secure lead based on those studies have been approved for traditional RV placement by the FDA recently. But not approved for left bundle branch area pacing. I just wanted to reiterate that. Why perform left bundle branch area pacing? Several studies have shown that the benefits associated with left bundle branch area pacing, whether compared to right ventricular pacing or biventricular pacing, include maintenance of synchrony or improvement in LV synchrony, improved LV ejection fraction, reduction in heart failure hospitalization or mortality, or need for upgrade to biv pacing as a composite endpoint. Additionally, recent guidelines suggest that left bundle branch area pacing can be used as an alternative to cardiac resynchronization therapy with biventricular pacing in some patients. More importantly, in CRT-indicated patients, left bundle branch optimized cardiac resynchronization therapy wherein you combine left bundle branch pacing with traditional coronary sinus lead placement has been shown to provide significant electrical synchrony, acute hemodynamic benefit, and greater echocardiographic response in some of these studies. So the leader left bundle branch area pacing clinical trial design was to confirm the safety and defibrillation efficacy of the omni-secure lead when placed in a left bundle branch area pacing location in an ICD or a CRTD-indicated population. The patients were primarily de novo ICD or CRTD guideline-indicated patients. The goal was to enroll 300 patients and with at least 150 large CRTD implant attempts. The primary efficacy endpoint for this presentation was the percentage of patients successfully defibrillated at implant exceeds the pre-specified threshold of 88% in at least 160 patients. The number 160 patients were established based on historical defibrillation data analysis and the number of patients required and the percentage to exceed was based on power calculations. The primary safety endpoint is to estimate the omni or secure ICD lead related major complication rates at three months and 150 patients will be reported separately. This is a high-level overview of patients included in our study. The data snapshot captured 200 enrolled patients. The reason for no implant attempted are listed on the right. Of the 191 patients implanted, 183 patients underwent successful implant and we'll get into the reason for some of the failure of the implants later. Of these successful patients, 162 patients underwent defibrillation testing. As mentioned previously, 200 patients were enrolled across 21 different sites and for this preliminary cohort analysis and you can see that 64% of the patients were from North America, 22% patient from the Asia-Pacific region and you can also see that the overall baseline characteristic of the patient represents the typical population that require ICD or CRTD and there were 42% of patients had left parietal branch block and 32% of the patients were women in the study, higher number than many other studies. The implant success for our trial was left to the discretion of the implanter but guidance was provided as follows. The protocol required that the physicians use electrogram criteria to achieve left frontal branch area pacing either in the form of ECG morphology QRS transitions during threshold testing, a demonstration of left frontal branch potential, demonstration of R waves in lead V1 with the LV activation time in the lateral leads to be less than 100 milliseconds or you have V6 V1 interpeak interval of 33 milliseconds or longer or you could have an anatomical criteria for deep separal implantation using imaging criteria by fluoroscopy and angiography. You can see the overall success for implant was in 183 patients out of 191 as per the physician determined criteria and the failure to implant was predominantly due to inability to achieve deep septal lead placement in six patients, T wave over sensing in one patient and poor R wave sensing in one patient. As you can see in the successfully implanted population 57% of the patients had single or dual chamber ICD and 43% of the patients were implanted with the CRT device which is higher than the leader population, an indication of our intention to study a lot CRT application in this population. The majority of patients had a left-sided implant, only three patients needed right-sided implant and the sheets used were C315 HIS sheets and fixed curve non deflectible sheets and 70% and 20% of the patients had C304 deflectible sheets. As you can see on an average three repositions were required per patient and the reason for repositioning was a desire to achieve optimal left one branch area pacing. The chest x-ray demonstrates how the lead was placed with the entire defibrillation coil within the RV and you can also see that the overall pacing characteristics were excellent with good thresholds, good R wave amplitude and acceptable lead impedance performance. Overall there were no procedure related major complications. There were no helix or lead fractures at implant and there were no deaths related to the procedure or related to the lead performance. The primary efficacy objective was percentage of patients successfully defibrillated at implant should exceed a pre-specified threshold of 88% in at least 160 patients. The defibrillation efficacy was either 18 joule first shock for the induced episode or a 10 joule safety margin. If unsuccessful additional repositioning and retesting to achieve a 10 joule safety margin. The decency for primary efficacy exclusion in these patients as noted previously with 21 patients had incomplete defibrillation, either 16 had no induced episodes and 5 patients the induced episode and subsequent defibrillation was not followed to protocol. At tipping point analysis excluding these patients did not affect the overall outcome of efficacy. I'm happy to report that the primary efficacy objective of the study was met in 100% of our patients with successfully defibrillated protocol. 98.1% of patients were defibrillated during the first induction with 82.7% achieved with the 18 joule shock and 15.4% achieved with the 10 joule safety margin. Only three patients needed additional testing either with or without repositioning. The limitations of our current analysis that this is a preliminary cohort with a focus on the primary objective for defibrillation efficacy. The final results will include total of 300 patients with respect to the procedural characteristic and safety of implant at three months. Additionally, implant location success was determined by the implanting physician which included both electrical and qualitative analysis. The primary objective of the lead study is the efficacy and safety of the lead. ECG characterization of the left bone branch area pacing is an ancillary objective and is pending further analysis. In conclusion, our study met our primary objective and exceeded the defibrillation safety performance. Additionally, this is a preliminary cohort. There were no major omnia secure lead related complications including depth or system modification related to the procedure. There was no helix fractures or lead fractures and this data set is a preview of more to come as we have completed enrollment of the 300 patients well ahead of the schedule within a year of starting the enrollment. I want to thank all the participating sites and participating patients and the study team for their excellent completion of this trial. And I want to thank Heart Rhythm Society for allowing me to present in this meeting. Thank you very much. Thank you very much. I invite Dr. Sergio Pinsky up to give the commentary. Thank you. I want to congratulate Dr. Vijay Charaman and the leader investigators for this very well-executed study. There is a clear need for the fibrillation lead for left bundle branch area pacing. If one wants to achieve this with commercially available hardware, one has to use either a biventricular device and connect the lead to the LV port, which can be off-label use for many of the manufacturers, or one has to use a DF1 lead and cap the IS1 pins. Furthermore, if you want to use load CRT with a defibrillator, this is extremely cumbersome. Not only one has to use a DF1 lead with a cap IS1, but has to use a total of four leads if the patient is in sinus rhythm. So I think this study clears one of the main concerns regarding the lead in this position. I think there was a good demonstration that the lead can defibrillate and they're reliable, and there is no reason to suspect that the lead won't perform as well to defibrillate spontaneous arrhythmias during follow-up. However, as any good study, this study answers a question but leaves open many more. From my understanding of the study protocol and the x-ray shown, I think it was mandated by the study to try to push the lead to create a coil in the right ventricle. This was crucial for two reasons. One, this lead being an integrated bipolar, one has to ensure that no part of the coil is in the atrium to avoid over-sensing of HL signals. And secondly, one has to make sure that the coil is very close to the ventricular myocardium to create the defibrillation field needed to defibrillate. So after thinking about this, I had many questions. Number one, is this easy to achieve to put this loop in the ventricle? Would the lead pull back over time and move the coil towards the atrium? Does this need to leave this coil in the ventricle limits the points, the size where one can affix the lead? It appears to me that the lead will have to be affixed a little more distant than the pacing lead for left ventricle branch pacing. So the question important is how easy is to achieve true left ventricle, true left ventricle branch capture versus just deep septal capture. And I think this is very important, especially when left ventricle branch pacing is used in lieu of resynchronization. Some other concerns, would the loop interfere with the function of the tricuspid valve apparatus? Would this loop in the right ventricle irritate the myocardium and be prorhythmic? Finally, would adhesions form between the coil and the cords and the lead would be dangerous to extract? So what I can conclude from all the data presented in these studies and previous studies of the omnia secure lead, I think the lead is reliable to defibrillate, has excellent electrical parameters, and I think it's a reliable lead. I don't think we should fear the performance problems that we had with the previous generation of downsized leads like the Riatta or the Fidelis. So with what I know today, I would not hesitate in implanting this lead in the traditional right ventricular apical position for defibrillator. However, I think we need to wait for more studies and longer follow-up before widely accepting the clinical use of this lead for left bundle branch area pacing. Thank you. Thank you. Unfortunately, we don't have enough time for questions, but many of the questions posed over the app were very similar. Congratulations on this study showing a safety defibrillation. We await further follow-up for the safety and efficacy. Many unanswered questions. Hopefully people will get a hold of you soon after the session. We're going to move on with the last trial for the session. It's called TRANSFORM-AF, Targeting Metabolic Therapy with GLP-1 Receptor Agonism for Secondary Prevention Atrial Fibrillation. Dr. Varun Sundaram is going to be presenting this for us. Thank you, Varun. Thank you, Chairs, and thank you, Heart Rhythm Society, for this opportunity. So today I'll be presenting, as mentioned here, the role of GLP-1 receptor agonism in the secondary prevention of atrial fibrillation. So here's a slide. Yeah. So probably I'm the only person who's not an electrophysiologist in this room. So this is a slide which all of you may know is the results of the ADVENT trial where conventional thermal ablation technique was compared with pulse field ablation in patients with drug refractory paroxysmal atrial fibrillation. But what is interesting in this is, I'm not able to move, yeah. So what is important to observe here is almost one third of patients had experienced a primary outcome within a year of follow-up. And even more important to observe here is there is the residual risk of atrial fibrillation here is there is almost a cumulative increase in the risk of residual atrial fibrillation. And yeah. Sorry, got it here. So yeah, a cumulative risk increases over time. And this is quite important to understand because this could possibly reflect progressive atrial substrate remodeling that persists despite initial procedural success. And in the context of AF ablation, this maybe is important because given the average age at AF ablation in the United States is around 60 years and the life expectancy exceeding 80 years, a patient undergoing AF ablation, most patients are likely to live for two decades post-procedure and which makes AF recurrence and the need for ablation very likely in a substantial proportion of cases during the follow-up. So and we all know that and there has been early evidence to show that one plausible mechanism for progressive substrate remodeling could be suboptimally managed cardiometabolic risk factors and obesity being the predominant driver in the Western population. So these are findings from the U.S. National Data Registry on AF ablation where almost half of the patients at the time of ablation had a body mass index of greater than 30. So we all know now with GLP analogs, which gives a promising avenue in terms of managing or targeting this risk factor in patients with obesity. However, we don't know what the long-term outcomes are of targeting this risk factor with GLP-1 analogs in terms of secondary prevention of atrial fibrillation. And this is a premise for the TRANSFORM-AF study where we looked at, where we investigated if GLP-1 use is associated with reduction in the residual risk of AF-related events in patients with pre-existing AF and obesity. So this is a multi-center pharmacopharmacological study involving patients from 170 Veteran FS medical centers across the United States and the base cohort of the study included those with type 2 diabetes because this was the initial reason why GLP analogs are primarily prescribed earlier and those with atrial fibrillation and a body mass index of greater than 30. So from this base cohort, those with new initiation of GLP-1 analogs were identified as treatment and those with DPP-4 inhibitor or sulfonylurea were identified as comparator. The rationale for doing so I'll explain shortly. So we conducted a secondary screening of the treatment and comparator groups to truly identify patients with active atrial fibrillation just prior to the treatment and comparator initiation. This was quite important as some of these patients could have had historical AF five years ago with no meaningful burden just proceeding to the treatment of comparator drug initiation. And active atrial fibrillation here was defined as either hospitalization with a primary diagnosis for atrial fibrillation, cardioversion or ablation for AF, and consistent ongoing use of antiarrhythmic agents just 12 months preceding to the drug initiation. So we used the active comparator new user design. So by that what we mean is, as I mentioned earlier, GLP-1 analogs were the active treatment and the DPP-4 inhibitor or sulfonylurea group were served as a comparator group. And largely because we used an active comparator new user as opposed to a non-user comparison to treatment, largely because patients with non-user are likely to be of those with mild disease or those with advanced disease with multimorbidity not being indicated for treatment. So we use inverse probability of treatment weighting to compare or balance the characteristics between the two groups and follow them for primary outcome of interest, which was time to first hospitalization with a primary diagnosis of AF, AF-related procedures, which is cardioversion or ablation or all-cause mortality. So most pharmacopneumological studies in atrial fibrillation pose unique challenges. And one of the important challenges being reliably identifying patients with true AF and meaningful burden at the population level, which has millions of patients. And the second issue being how to truly capture AF burden during long-term follow-up. We introduced certain methodological innovations to overcome and address these limitations. So this is a busy slide, but I'll deconstruct it step by step. So we first identified one and a half million diabetic patients. From this cohort, we identified those with atrial fibrillation, defined as those with a validated ICD diagnosis codes of AF and continuous use of anticoagulation. And to improve specificity, we excluded those patients who had alternate indications for anticoagulation. From a cohort of around 80,000 patients, base cohort, we identified those with new initiations of GLP analogs, which is treatment, and the comparator group, as mentioned earlier. We introduced a washout period. And the washout period, by that, what I mean is those in the treatment group who had exposure to comparator drug, here, DPP-4, over the preceding 12 months, and in the comparator group, vice versa, were excluded to prevent contamination and reduce carryover effects. And as mentioned earlier, we introduced something very similar to the pre-randomization run and face in a clinical trial, and mandated that all patients have active AF within 12 months preceding to the treatment of comparator drug initiation, and defined it as mentioned earlier. And an additional screening to improve sensitivity is to only include patients who had continuous use of anticoagulation. And finally, after including those with a body mass index of greater than 30, we arrived at a final code of around 2,500 patients with well-phenotyped atrial fibrillation and a body mass index of greater than 30. So moving on to the results, so the average age was around 70 in this cohort. But as you could see, the patients with the GLP analogs are much older, and very few proportioned were women, because this is a study from the Veteran Affairs Medical Centers. And the prevalence of cardiovascular and non-cardiovascular comorbidities among the group was much higher in GLP analogs compared to the DPP-4 inhibitors. So we performed, as mentioned earlier, inverse probability treatment weighting. And the post-balance diagnostics demonstrated a standardized difference of less than 10% for more than 30 variables, indicating reasonable matching. So moving on to the important aspects, which is the results. So during a median follow-up of 3.2 years, we accumulated more than 320 AF-related events, excluding mortality. And what we observed was a 13% reduction in the residual risk of the primary outcome in favor of GLP-1 analogs. And this 13% may not sound much just by the look of it, but these are hard AF events, as supposed to document in atrial tachyarrhythmias. These are hard AF-related events requiring a primary hospitalization of procedures. So moving on to the subgroup analysis, the subgroup analysis demonstrated heterogeneity of treatment effect with greater treatment effect with increasing body mass index. And by that, what I mean is a greater effect with GLP-1 analogs in patients with increasing BMI, body mass index. And this 13% reduction in the AF-related events, what was interesting was observed with just modest weight loss. That was only 4% increased weight loss with GLP-1 analog group, because these were diabetes management doses. So we also performed repeating event analysis to account for mortality as competing risk and modeled AF as repeating event and demonstrated. And what we observed was a 15% reduction in AF burden with GLP-1 analogs. So while our study has epidemiological strengths, it definitely does have limitations due to non-randomized nature. It's not immune to unmeasured confounding or residual confounding. So we did not have data on serial doses of GLP-1 receptor analogs. And I will caution about the generalizability because of less than 4% of the study population, including women. So in summary, the significant residual risk of AF post-ablation, especially in patients with suboptimally controlled cardiometabolic risk factors. What we observed was in this nationwide pharmaco-epidemiological study from the Veteran Affairs Health System was GLP-1 receptor analogs agonism was associated with a significant reduction in AF-related events that are secondary prevention at diabetes management doses. And this was observed with just modest weight loss. And this questions if there is pleiotropic effect of GLP-1 receptor analogs. And it is possible with weight loss doses and the newer GLP-1 analogs, like trisepidide, where you have profound weight loss, you could have a greater effect in the secondary prevention of atrial fibrillation than with diabetes management doses. And this is something which we have observed in HEF-PEF with higher weight loss doses of GLP-1 receptor analogs. And these findings should be viewed as hypothesis generating. But we would argue as investigators, we would argue a feasibility of an RCT, a randomized clinical trial in this area, might be quite challenging because we will have to randomize patients to the control group with no GLP-1 analog control group with obesity, with no GLP-1 analog exposure over a long period of time, because modifying a risk factor and looking for outcome means it's a long follow-up. So it would create ethical challenges. And to do so, even if you do, without reliable crossover to treatment group would be extremely challenging. So I'd like to thank all my co-investigators. Without this, it would have not been possible. And the NIH for funding this study. Thank you. I'd like to call on Dr. Saxena for his commentary. Good afternoon. And I'm pleased to comment on this study because it's not very often that I'm at a session where I see a pivotal change possible in our therapy of heart rhythm disorders. And we may be witnessing one such moment now. The TRANSFORM-AF trial has been designed very thoughtfully in a very difficult area to work in with many variables and a truly difficult area to do prospective randomized trials. Now metabolic therapy has not been in the forefront of what we do here at Heart Rhythm. And we discuss its mechanisms and other aspects of this. So I'm going to take a minute to talk to you about what Dr. Sundaram said in the end about the pleiotropic mechanisms involved. I think it would serve us well to look at what actually happens and what is now a national debate. So it's important to understand some of the history here. And here are two seminal papers, a 1940s paper by John Brobeck where hypothalamic hyperphagia was recognized. And the truly pivotal paper of B.K. Anand where the identification of a feeding center and a satiety center took place. Very important in this animal study was that both excessive feeding and excessive anorexia led to death of the animals. So to understand the mechanisms and pathology of obesity is beyond my commentary. But I show you this figure to point out to you the multiple organs and organ systems involved and a number of signaling mechanisms involved. And then areas in the hypothalamus that are anorexogenic and what are called orogenic where there is excessive feeding and various hormones involved in this aspect. What is important is on the right to see what happens to the hypothalamus in obesity. There is microgliosis, inflammation, changes in autophagy, and a number of changes that result in neuronal dysfunction and eventually death. Now some of these mechanisms are seen in the atrium, in atrial cardiomyopathy. And these are not unique to one organ system. What has been talked about much at these meetings is the possibility of an atrial myopathy with obesity and now we are seeing evidence at the hemodynamic level that you can see left atrial dysfunction and with weight loss there is some improvement in this left atrial dysfunction. So here is a piece that now connects to what we are talking about at this point. Now how do this nationwide, worldwide interest in GLP receptor agents, what do they really do? GLP-1 receptors are found in many, many organ systems that I showed you in this previous slide. So what does something like semaglutide do? On the left is a hypothalamic section with imaging of the hypothalamus showing the uptake of semaglutide in the hypothalamus. So these are agents that work in many, many organ systems in many mechanisms and the mechanisms are too many to discuss today but I want to leave it with you that these pathophysiologic mechanisms of potential benefits are many of these cardiometabolic drugs. Dr. Sundaram's study is important because there is so little data on atrial fibrillation recurrence. Most of it is a byproduct of other trials, a HFF trial or a meta-analysis of emergence of HFF in clinical trials. So let's talk about this study. A large number of hospitals and medical records, he has gone through all the steps of the selection of patients, the comparator group, and the composite outcome or time to first say of hospitalization or procedures or of course mortality. Now let's talk a bit of the data. So this data is 97% of the patients actually didn't meet the inclusion criteria or excluded. The subjects were matched and the follow-up was about three years and there was a 15% reduction as he pointed out and the high BMI group was the one that benefited most. So I think it's important to recognize up front it's retrospective. Large group of people were not enrolled. The EMR approach may lack clinical covariates. The AF burden endpoint that he talks about is a little different from the AF burden that we talk about using a measurement of actual atrial fibrillation. The use of background drug therapy is unavailable and it's AF impact, the treatment dosing and what was the compliance. So all of these are issues when EMR studies. The use of antiarrhythmic drugs. Now in a firm we learned that when you use an antiarrhythmic drug strategy you increase the number of hospitalizations and when you add that to the endpoint that is an issue. So serial hospitalizations can relate to serial treatment and heart failure and stroke endpoints are absent. Having said that, this study is a great strength that turns our focus to fundamental mechanisms of obesity and atrial fibrillation. Something we have not done a lot of in our time. The focus is now on the AF substrate and comorbidity issues. In the ARC AF trial we just reported of 2.4 million new AF subjects who could be candidates so only 0.9% got a catheter ablation. Public health demands preventative upstream comorbidity focus therapy in AF. The need for a well-designed prospective pilot hybrid therapy I think is necessary because the ITPW group that he talks about is not as good a matching process as randomization or even propensity score matching. So we need to do that well-designed study and then is the foundation for long IRD but I would like to congratulate Dr. Sundaram and his group for taking us in a new direction. Thank you very much. Unfortunately we again have run out of time and I invite you to come up to speak to the speakers and there's also a meet the trialists session where you can ask questions. I would want to make one comment and thank you very much for doing that study but I would challenge us, I agree with Dr. Saxena, that we need randomized controlled trials especially coming from someone like me who's been burned on these upstream therapy studies in the past.

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