So, I'd like to talk about getting off of drugs and talk about alternatives to it. So, certainly, we've all heard already, and you can't give a talk on atrial fibrillation to say how rapidly it's growing. Risk of stroke is six-fold associated with AFib. Anticoagulation is the cornerstone of stroke prophylaxis in atrial fibrillation, but left atrial appendage occluder devices were developed at first to address the unmet need of patients with contraindications to anticoagulation, primarily bleeding. The use of these devices has grown steadily since first approved, although there's very wide variations in usage rates by geography and by clinical centers. So, I just want to focus in my talk on the data in support of these devices and the limitations of them. So, the first major study, and the device that was out there by itself for many years was a Watchman device. And the first randomized clinical trial, big one, was a PROTECT-AF study, which was a comparator of the Watchman device versus Warfarin, so it tells you this was an older study. Patients had to have a CHA2D2 score, not a CHA2D2-VASc score of greater than one, and then they were randomized. And the primary endpoint was stroke, systolic embolus, or cardiovascular death. And it was 39 percent lower with implanting a device rather than anticoagulation. If we then look at the two studies put together, because there were some issues with PROTECT-AF, so another study had to be done by the, according to the FDA. And what we see, again, not surprising in many ways, is that hemorrhagic stroke was markedly reduced with a left atrial appendage device, because you're not on anticoagulation. But ischemic stroke was actually reduced with Warfarin. Again, not terribly surprising, because there are other sources of ischemic stroke other than left atrial appendage, which isn't being addressed by occluded devices. There's also this somewhat surprisingly reduction in cardiovascular and unexplained death in those patients who got left atrial appendage occluded devices. If we look at the combined data of major bleed, we see that major bleeding was reduced 71 percent by this device in atrial fibrillation patients. And I think importantly, if we now look at safety events across trials, often clinical trials may give us the best results, because they're very specialized, well-trained centers. And we see here the early studies had high complication rates, which led to further studies on it. And as we go from left to right in this slide, we see at the end, when we're talking about more real-world data of post-approval studies, we see a significantly lower rate of complication rate of only 2.8 percent. Importantly, pericardial tamponade is about 0.5 percent of 1 in 200 patients, and about 1 in 1,000 patients having procedurally-related mortality, 1 and the like, but still quite low. And if we look at these procedural complications, again, we see about a 1 percent tamponade rate. Procedurally-related stroke is very low, well less than 1 in 1,000. Embolization is low, and again, death, certainly related to procedure, is quite low as well. So reasonable risks of these devices. Well, the new kid on the block is Amulet, and that's the second now-approved device we have in this space. And since this was a modern-day study, it couldn't be compared with Warfarin, it couldn't even be compared against DOACs, because we know that we need something that's going to be protective. So this was a head-to-head trial of Amulet versus Watchman of about 940 patients or so in each study, and there were three major endpoints of this, co-primary endpoints, which was looking at left atrial occlusion with residual jet less than 5 millimeters, which is a threshold for considered high risk, and you have to go back on anticoagulation. There was a composite of procedural-related complications, all-cause death and major bleeding, and then there was the ischemic stroke or systemic embolus, or the efficacy of it. If we look at this study in a little more detail, this was not a healthy patient population, this was a sick group of patients. So the CHATS high-risk group of patients, the CHATS VASc score was between 4 and 5 on average here, with a high HAS-BLED score as well. And importantly in this study, we actually allowed patients with strokes and TIAs to be in this study, so more than 25% of the patients had a previous stroke or TIA being randomized in this study, and another 6% or so had history of systemic embolization. So again, high-risk groups of patients. So if we look at the primary safety endpoint, which is this composite of all-cause death, major bleeding, or procedural-related complications, as a non-inferior study, this was highly significant as being non-inferior, as very similar between the two arms of the study, at about 14.5% at a year. And if we look at the components in that composite endpoint, which I think is always important to do, nothing really stands out. A little higher procedural-related complications with amulet, a little lower all-cause death, and bleeding appeared to be almost identical. If we look at predictors of stroke following left atrial appendage occlusion, we see there were two strong predictors. The first one is prior stroke. Again, not surprising, because there's a lot of mechanisms for having a stroke, so both of these therapies are going to have a higher risk of having a stroke. And the second one is CHADS-VASc score, so again, we think of CHADS-VASc as a reason to anticoagulate, but it's also a predictor for a higher risk of stroke. If we look at the primary efficacy endpoint, which was ischemic stroke or systemic embolism at 18 months, it was actually a tie. They both did very well at 18 months, 2.8% risk of having an event, and it was identical for the two, so obviously non-inferiority was 0, 0, 0, 1. And again, if we look at the specific components of this composite endpoint, whether ischemic stroke or systemic embolism, there's not much difference between the two. If we now look at the mechanism of action endpoint, which was how frequently that they had a residual jet around the device, we see that actually that was significantly higher with the Watchman device compared to the Amulet device. And that difference was statistically significant, so the endpoint was non-inferior, but you could test for superiority, and Amulet was superior to the initial Watchman device. So just in summary, I think both Watchman and Amulet have excellent results for stroke prophylaxis with high efficacy and low complication rates. I think very importantly, which will I'm sure come up in the discussion, 82% of Watchman patients were discharged on anticoagulation, which was required for the trial because that's the labeling for Watchman, but only 18% of the Amulet patients in this study actually after the implant were kept on, put on anticoagulation. We know that Watchman has a long track record of success, whereas Amulet appears to be very safe in the absence of anticoagulation post-procedure. And clearly we need further research as needed to understand the factors favoring left atrial appendage device and the choice of devices. Thanks. Thank you.

anticoagulation

stroke prophylaxis

left atrial appendage occluder devices

PROTECT-AF study

Amulet device