Thank you, and I appreciate having the opportunity to meet with you all over these couple of days. I've got the minor task of reviewing all trial work in a FIB, a nice concise topic area, but this is an area that, you know, fills my day every day almost. And for the uninitiated people who have heads buried in the device research lab, a FIB is out there. If you watch late night TV, you see it on TV commercials all the time. It is prevalent. It impacts people's lives. It causes symptoms. It causes strokes. It causes concern. And so there's a lot of energy and, quite honestly, a lot of money out there trying to figure out the answer to a FIB. So there's a lot of material, and I apologize, again, you should have copies of my slides and you can review them in a more leisurely fashion. So I'm going to kind of race through to touch on the high points of the trial work being done in this field. So these are what I listed in my mind as the hot topics that are still in need of answers for trials from trials in a FIB, and it is a long list, and that indicates that there'll be plenty of work for plenty of people to do in the years ahead. So starting out on the natural history of AF trials, and with the advent of new modes of monitoring and the question about the significance of subclinical AF, this is something that is really burgeoning. And I think one of the, it's not a recent trial, but one of the ones that was so striking was the ASSERT trial that looked at subclinical AF events in people who had implanted pacemakers. And they found, out of this group of 2,580 patients, 51 of whom had CVAs, and then they went back and looked at their devices, and fully half of those patients had evidence of subclinical AF. And so that highlights the strong relationship of the two. But the thing that blew me away when I read this trial, if you look at these little red bars, these are the actual AFIB events. This is when the stroke occurred, and you can see the temporal relationship between AF and the stroke event is poorly correlated in this ASSERT trial. And that, you know, made me rethink my entire story as I was talking to patients about stroke risk, and it really brings up the question, you know, are patients with AFIB ever safe from stroke? It does look like AFIB burden is important, and this is a trial of patients in the Kaiser Permanente system with paroxysmal AFIB, and these are patients who were not on oral anticoagulation, and when they looked at the risk of stroke, the highest tertile of AFIB density in their study, these were people with a greater than 11% AF burden, were the ones in whom strokes were observed. So it does make sense that more AFIB does seem to predispose people to higher stroke risk. Now finding AFIB out there in the real world took a huge leap forward with the advent of the ready availability of wearables, and this is a market that is just, you know, we're basically seeing the tip of the iceberg. I think one of the most amazing things about the Apple Heart Study was this line, 419,000 patients enrolled over an eight-month enrollment period. I mean, that's impressive. Now, of course, this is a younger population, worried well people who tended to enroll and get the watch, and they only had 24,000 patients who were over age 65. Of the entire population, they only had 2,161 pulse notifications. So the yield from this huge study was relatively small, and that's good news. That means that there's not a huge amount of AFIB out there, but it does show that this was a useful device to pick this up. And what they did is they followed up with wearable patch monitors to see if they could correlate with actual ECG-documented AF events, and they found that the positive predictive value of just using the regular tachograms as the marker or the algorithm that they used in terms of sequential episodes of irregular tachograms had a relatively high positive predictive value for AFIB. So we're going to see more and more and more AFIB as these monitors become diffused into the community. So the ongoing subclinical AF trials, there are a number of them, and I just hit the highlights. The silent trial in Artesia in particular are saying, okay, so you've got low-burden subclinical AF picked up on your implantable device. Do you have to anticoagulate those people? Do you improve outcomes, reduce stroke by anticoagulating? The GARD AF study, this is ambitious, 52,000 patients. This is a study underwritten by a pharmaceutical company, and clearly this is a goal to identify a whole new market out there for prescribing oral anticoagulants, and if they can say that randomly checking, screening people with ECG monitors, identifying AFIB, and initiating oral anticoagulation improves outcomes in those people, then that would be a huge market for them. And the number is so big, has to be so big, because the anticipated improvement from the intervention is going to be relatively small. And then I thought this was an interesting trial using smartwatch monitoring to look for evidence of subclinical AF in patients with history of stroke. Okay, what about lifestyle modification to prevent AFIB? We all know obesity, sedentary lifestyle, alcohol, all of these things have an adverse impact on AFIB, and we know that aggressive intervention improves outcomes in pretty much whatever subpopulation you look at, post-ablation or just a general AFIB clinic population. So this was aggressive risk factor modification and followed people clinically and showed significant improvement. So there are a number of trials that are looking at that same basic theme from different angles. The most interesting one, and I'm sure you may have heard about tall, fit bicycle riders or marathon runners seem to have a high prevalence of AFIB. And it's not entirely understood why this happens, but there's actually a trial on detraining elite athletes with AFIB. So maybe if you pull them away from their exercise addiction and put them in a Barco lounger in front of the TV, they may have less AFIB. We'll see. What about oral anticoagulant trials? Again, lots and lots of data with the oral anticoagulants, the DOACs that are in use, but which drug or drug combo is the safest and most effective? And in particular, can you ever, ever stop oral anticoagulation in a person with thromboembolic risk factors after an apparent successful catheter ablation? Well, the WOS trial was the first in a series of trials looking at the Nettlesome issue of triple therapy, and a lot of these AFIB patients have coronary disease as well and get stents and they're on clopidogrel or ticagrelor plus their oral anticoagulant plus aspirin. And WOS looked at double therapy, which was just warfarin plus the clopidogrel versus the triple therapy group and saw significant reduction in bleeding and also an improvement in overall mortality. So triple therapy, we all agree, is something to be avoided if at all possible. And so there have been other trials as well, Pioneer AF, PCI, and Redual PCI that looked at the same thing. Each one of these uses a slightly different formula for combination of oral anticoagulant plus antiplatelet therapy. The big problem with some of these trials is that they use lower than appropriate doses for stroke prevention in the protocol. For example, the Pioneer AF PCI trial, one of the arms was rivaroxaban, 15 milligrams plus antiplatelet. Well, 15 milligrams is not the appropriate dose to reduce stroke, and even though the bleeding rate was lower with that group, and even though there was no measurable increased risk of stroke, they didn't test 20,000 patients. The event rate is low enough that you don't really know that it's not just an underpowered trial with regard to stroke prevention. And so it's a very nuanced issue, and there's a lot of noise out there, a lot of data that I think doesn't necessarily apply to the patients that I see, because I want to first and foremost prevent stroke in these people. So in terms of ongoing trials, there are multiple NOAC versus NOAC trials. There are trials in patients who are post-catheter ablation to determine what the appropriate anticoagulation regimen is, and to see if you can stop oral anticoagulants. This particular trial is using an MRI evidence of cerebral embolic events as an endpoint in that trial, too. So those will be useful data going forward. What about left atrial appendage devices? We all are familiar with the PROTECT-AF trial. This is the Watchman device, Boston Scientific. It's the one device that's been commercially available in the US. And in this trial, you see that the outcomes were similar, Watchman versus Warfarin, but the curves diverged. And actually, after five years, the Watchman arm looked better. That was primarily driven by an increased risk of intracranial hemorrhage in the Warfarin arm. And that risk was much higher than the ICH rate seen in the Warfarin patients in the big NOAC trials. And let me explain that. So in Watchman, these are very tough patients with very labile INRs, exactly the type of patient that you expect to have too low an INR with Warfarin and potentially be at risk for stroke, or too high an INR two weeks later and be at increased risk for bleeding into their head. And I think that that's what we saw in the select population. My guess is that when DOACs are compared to Watchman, it's going to be a wash. And in fact, that trial or those trials are happening, the PROG-17 and the OPTION trial are going to be looking at modern anticoagulant therapy versus LA appendage occlusion for stroke prevention. In addition, there are some new devices that are out there that may be better, may be worse than the Watchman device. What about antiarrhythmic drugs? Can I have a raise of hands? Who from here is in pharma? Okay. So pharma is a particular challenge because it is very expensive to bring a drug to market. Last new drug for oral suppression of AF was dronetarone, and that ended up with a black box warning in patients with heart failure due to excess mortality observed and has sort of unfortunately taken a second row position in the use of drugs. We haven't had any new drugs in testing for a while. So there's not a lot of new data, but the one trial that I think is really interesting is inhaled flecainide. So if you can bolus a drug like flecainide or procainamide or ibutylide, any of these drugs, and get a very high level transiently to get the cardiac effect and potentially convert somebody, and then you redistribute the drug in the body and you get down to low systemic levels of the drug, you could have a very salutary effect in terms of AF conversion. And what's the best way to kind of mainline the drug right to the coronary arteries and the cardiac tissue? Take it in through the pulmonary vasculature. So this is a study that's just in dose ranging right now where they are solubilized flecainide and take it in through an inhaler. And it's sort of a supercharged pill-in-the-pocket approach to termination of AFib. Now, the catheter ablation trials is where most of the action is. And what are the modalities? Are there new modalities? What's on the horizon there? The two trials that got the most press over the last couple of years were, first of all, CASL-AF, sort of a small trial, but it was a trial in a heart failure population looking at the benefit of catheter ablation of AFib in terms of mortality. And it was a positive trial in terms of mortality in this population of patients. And so this is really gives very strong credence to the hypothesis that we can actually improve outcomes, heart outcomes like mortality in some of our patients with AFib. CABANA was the larger NIH-sponsored trial that followed looking at AF ablation versus medical therapy in a broad medical population. And it was a negative trial based on intention to treat, and both in terms of primary and secondary all-cause mortality endpoints. Now, the authors and steering committee pushed very hard to publish the efficacy analysis because there was a significant crossover from the drug-treated arm to the ablation arm. Just to review in the intention to treat, there was no significant reduction in the primary endpoint of all-cause mortality, but there was reduced mortality or CV hospitalization. So these people did do better. They felt better. There were a lot of crossovers to ablation. There was a lot of reduction of AFib with AF ablation. And if you did the treatment analysis, assigning the crossover patients to the ablation arm, there was a reduction in the primary endpoint. But I don't think that that is a statistically valid analysis to do. But I think it says that ablation is an acceptable treatment strategy for treating AF with a low adverse event rate, even in higher-risk patients. So ongoing ablation trials are primarily new devices. This is a catheter. Boston Scientific is testing balloon catheter. This is the BioSense Webster balloon. This is a new Medtronic point catheter. This is a BioSense QDOT catheter. This is the Cardio Focus laser balloon. They've got a Gen 3. This is a new supercooling Adagio Cryo coil. This is the Globe. This is kind of a medieval device, or it looks like a mace. But it kind of expands in the heart, and you can map and ablate from this. And this is a very cool device from Afera, the Lattice catheter, Sphere 9 catheter. So all of these are in varying stages of testing to see if they do a better job at terminating AFib. But the real story is post-field ablation. This is a different energy form. It's high voltage, ultra short pulses. And you can just see the preclinical studies, animals. This is a PFA lesion. This is an RF lesion. You can see how complete this lesion is. So it's highly effective. But what's really exciting about this is that it is really, really, really safe. It doesn't damage arteries. It doesn't cause pulmonary vein stenosis the way radiofrequency does. It does not damage the esophagus. So that most of the morbidities related to pulmonary vein isolation procedures with RF or cryo just go away with PulseField. So I think that this is going to be an exciting era that we are going into. Ongoing trials that are of interest. The AMAZE trial is going to be pretty close to reporting, looking at PV isolation versus left atrial appendage, snare and strangulation with the Lariat device. Renal denervation as an added add-on to PVI seems to have very strong benefit in pilot studies. Scar-based ablation, the decaf trial, we're waiting for them to finish enrolling. RAFT3 is coming out, just a drug versus ablation as first-line therapy, some testing of new tools. But then PulseField ablation is going to be, I think, the next big story. And I'm sorry I'm running a couple minutes late. I'm summing up right now. The big brass ring everyone's reaching for is how to map the source of the AFib. And the problem is, what is AFib? Is it a focal thing? Is it a micro re-entry? Is it a rotor? Or is it, like Alessi said, sort of a worm type of pattern? If you don't even know what AFib is, and I'm sorry to say in 2020 we really kind of don't, how do you map it? And there was a big push with a technology called FIRM. And the initial trials showed huge benefit from using this FIRM mapping. But I think the cautionary tale is it was unbridled enthusiasm by all parties who were participating. And a strong promoter of the technology and subsequent trials showed no benefit from this mapping system. And then finally, the company that purchased, the small company, did a big study to test it and showed no benefit of this additional mapping. So there's a lot of stuff out there. You've got to be careful in terms of assessment of it. This is a cool technology. I won't go into those details, but it has some benefit. Charge density guided ablation may have some benefit. The CARDO finder is BioSense's new approach that seems to maybe have some benefit. But all of these are tested in very small series. And there are ongoing studies of these new technologies. But the coolest one that I think may be the future is Natalia Trianova's computationally guided ablation. And basically, she takes an MR scan of the atrium and puts it into her computer modeling program that she's been working on for a decade with 20 grad students and creates a map, a virtual map of virtual AFib, and then is able to direct the target for ablation of these potential sites. And they've reported 10 patients with good outcomes, and they've got a randomized trial underway. So we know who our AF patients are. We will know in the future who our patients are, whether they know it or not. Hopefully, we'll be able to optimize stroke prevention strategies. We'll be able to optimize treatment, whether it's rate, rhythm, control, or catheter ablation for each individual patient. And hopefully, we'll prevent stroke, heart failure, cognitive decline, and death caused by AFib. Thanks. Thank you.

atrial fibrillation

subclinical AF

anticoagulation

lifestyle modifications

catheter ablation

research