Our next speaker needs no introduction, but Matt Gillespie is the director of the Cath Lab at Children's Hospital of Philadelphia, where he's been for his whole career. He's been part of a lot of device trials, has been the PI for lots of national studies, and he's going to talk to us about the clinical outcomes so far of the two self-expanding platforms developed in the U.S. Great. Hey, thanks, Konstantin. Thank you to Sky for putting this together, and Konstantin, thank you for organizing and for including me. Good. These are my disclosures. First up, up front, I'm going to rehash the two-year data from the Harmony and Altera trials, and both Athar and Shabana did a great job presenting this data at PICS and World Congress. I'm just going to basically repeat their presentations, and we'll make up some time and go through here quickly. So, we'll start with the Harmony trial, because this is the one that went off first. By background, this is the first early feasibility trial for non-conduct, non-bioprosthetic pulmonary valve replacement. We've published the early outcomes, six-month outcomes, one-year outcomes in manuscript form. The five-year outcomes from the initial 20 early feasibility studies has been published, and we're just putting this data out in tranches as we move forward, and the most recent is the two-year outcome from the data. So, this is the Harmony valve. Everybody knows it. Harmony did a great job reviewing the screening process and the shape and sizes of these. Currently, the TPV22 and TPV25 are the two commercially available devices. The Harmony trial overview, you know, again, it happened in three separate phases. First was early feasibility from 2013 to 2015, and then the pivotal trial, 2015 through 2017, continued access study on through 2019 or 2020, and you can see what the follow-up is going to be. And the good news is that for the pivotal and for the continued access patients, we're going to have 10-year prospective follow-up data to answer all the questions we're all going to have about durability. This data represents patients who left the cath lab and had the valve in place for 24 hours, typical inclusion-exclusion criteria for a trial, and basically, if you look at the patient flow on the left, there were 21 patients implanted in early feasibility, 31 in the pivotal, 37 in the continued access trial. In addition to this, there was a transitional device that was introduced between TPV22 and current 25 that that data is reported separately because what's relevant are the two commercial devices that are available. This is what the patient cohorts look like, about 40% of them are women. You can see with the average ages there, the overwhelming majority of these patients were tetralogy of flow patients and or pulmonary stenosis. Other, about 15% of them had preexisting pacemaker or ICDs, and everybody had at least one open heart surgery for the most part. Here's the procedural data. These procedures were quick, low fluoro times, pretty rapid procedural times. If you consider that this is a relatively new therapy, two hours of total procedure time really isn't bad. This is what it looks like on the left. You have a wire in there and a baseline angiogram. On the right, you have the device partially deployed and then being opened fully, and I'm sorry, in the middle, and then on the right, you can see what the device looks like as it's being released from the coil catheter, the proximal inflow zigs flare out there. So that's what it looks like. Well, how did we do? Well, they, you know, and you'll hear the same for the Altera. You know, the outcome's good. From a mortality standpoint, there were no procedural deaths. There was no death within the first year of follow-up. There were two deaths that were non-device related between years one and two, and you can see that reflected in the Kaplan-Meier curves there. As I said, two deaths is an all-cause mortality, but not device related, and otherwise really a pretty benign force over the first two years for these patients. Two cases of thrombosis noted on the valve. Both of these resolved with anticoagulation therapy, and interestingly, in the trial cohort, no endocrinitis at the two-year follow-up. Also, these patients, something that we're looking at with all of these platforms is the amount of ventricular tachycardia, and there is non-sustained ventricular tachycardia in all of these devices that we put in, but the good news is that it's all non-sustained, and they all tend to resolve over the course of two years. Does the valve work? The answer is yes. All these patients started with severe, with moderate to severe regurgitation, and at two years follow-up, they have trivial to none, no regurgitation. Is there a perivalvar leak at two years? No. It doesn't look like it. It looks like it's really at one year, and it seems to be holding steady at two years. Are the valves unobstructed? Yes. They have low gradients. The TBV22, mean gradients less than 20, and the TBV25 with mean gradients in and around 10. Here's an echocardiogram showing the harmony in place in the parasternal short axis view. At two years, it looks like a stable device position, and you see the delicate leaf that's moving there. How about reoperation and reintervention? There were two patients who had surgically re-urgently within the early feasibility study, and there were three patients in the trial that had subsequent catheter reintervention requiring valve and valve, as you can see there. So you're looking at a 92 and 100% freedom from catheter reintervention in both of these cohorts. Stent fractures is another end point that we looked at, and again, really no major stent fractures at all, consistent with CPV function being very high, above 91 and 95% for each of these valves accordingly. How are the patients feeling? All patients on the quality of life forums, the questionnaires, reported an improvement in physical function, energy, and fatigue, both initially, and that was sustained at one and two years. So in summary, the outcomes are good at two years. It looks like we have good valve function, no device-related mortality, no significant morbidity, no, in the trial cohort, no infections, and no sustained ventricular tachycardia requiring anything in the study cohort. And as I said, these patients are going to be followed moving forward. Let's talk about the Altera adaptive pre-stent trial, and by way of background, this is the Altera pre-stent, and Amy showed an example of how we screen for this. So this is a two-step procedure where you put the pre-stent in first, and then into that you place a 29S3. One of the advantages, this laser-cut nitinol pre-stent is deployable and recapturable during the procedure, so it's a pretty stable way to implant. Based on the strength of the pivotal trial and the early feasibility study, they received approval in December of 2021, same inclusion criteria, same exclusion criteria. Primary endpoint was dysfunction at six months, and it looked very good, so none of these valves were all functioning at six months. Secondary endpoint was improvement in regurgitation at 30 days, and again, all patients had an improvement by echo, and all devices were implanted. There were no deaths or explants in the 24-hour of the procedure, and all that was reported in six-month and one-year forms, similar, really mirroring what, as the Harmony data has rolled out, the Altera data has been rolled out, and again, it's very positive. So here's the patient flow, again, 61 patients were enrolled at 11 sites, 60 devices were implanted, and at two-year follow-up, 58 of those patients were still alive. This is what the follow-up data is, and again, Amy went through the pre-procedure evaluation, so we can skip that. The majority of the patients were sort of in the young adult to teenage range. All the baseline characteristics were what you would expect for patients with MRI characteristics in that they had dilated RVs with significant regurgitation. Same in the Harmony cohort, the vast majority of patients were tetralogy of flow or pulmonary stenosis other, and most patients had at least one previous surgery. If you look at the technical success, it was excellent, 100% Altera pre-stent implanted in the intended location, 100% of the subsequent sapient implanted in the intended location. And no surprise, the valve functions well. All these patients had severe to moderate, moderate to severe regurgitation when they came in, and at follow-up for two years, at most mild, maybe one patient with moderate regurgitation, giving you a 92, 93% of patients really with good valve function. If you look at what the effect on that, and they look at a paired analysis, you can see that between baseline and one year, the regurgitation fraction by MRI went down, and corresponding with that, what you saw was a reduction in MPA regurgitation fraction and an RV and diastolic volume, which is again reflected here in this chart. Are these valves obstructed? No. Again, low mean gradients by echo that were found at 30 days, just one year, and sustained now at two years. And if you look at the adjudicated safety outcomes, again, it's proven to be relatively safe. Very rare. No device-related mortality, no significant morbidity, really. One vascular complication reported within the first year, and it looks like the rest, again, just like in Harmony, within the first year, 34% reporting some non-sustained ventricular tachycardia, with really not a significant increase beyond that. And this is the one patient who had a reintervention. It looks to me, I was not involved in this case, but it looks to me that the proximal inflow part of the altera pre-stent was perpendicular to the plane of the RV outflow tract. This was treated successfully in the cath lab with an endovascular graft. Again, low, really low incidence of any of these adverse events at all. There was some TR, I will say, especially early in the trial, before they modified and came out with the pulmonary delivery system, which seemed to have alleviated concerns for tricuspid valve regurgitation moving forward. The observation on CT scan, the way the pre-stent is designed, it has, you know, it flares out the proximal distal end, and it comes to these points, and those points can bite into tissue. It's part of how this device anchors. So when you look at this on CT scan, it can look like some of those prongs or points are, in fact, going into the surrounding tissue, and in some cases, through it. In the presence of mediastinal scar, it doesn't seem to be a problem, meaning that there has, in the trial patients, there wasn't any substantial bleeding or effusions or anything that required explant. And then the TR we talked about before, early in the trial, without the pulmonary delivery system, TR was a problem. If you have a competent pulmonary valve, the TR seemed to improve with time as well. No perivalvar leak, and all these patients felt better. So the Neurocardiac Association class improved, and their quality of life surveys reflected that both at 30 days and was sustained at two years. So in summary, look, the Altera works well, and it looks like in two years, there was no deaths, endocrinitis, dissections of surgical explants, low reintervention rates, frame fractures don't seem to be an issue, the valve is working, and it's not leaking, it's not obstructed, and patients are feeling better. Now, importantly, for both of these trials, these are highly controlled environments, highly selected patients, and the outcomes have been very positive in two years. For both of these trials, the sponsors, Medtronic and Edwards, are planning to follow their patients at least five years, and I think up to 10 years. Certainly that's true for Harmony, Shabana can tell me if it's still true for Altera, I think it is. The real-world data, I will tell you, you know, the commercial experience, the post-approval studies are going to be very important, because it's going to be a larger cohort followed over 10 years. I will say that some of the trial data, i.e. around infection and device-related trauma, I know anecdotally of issues with both Harmony and Altera, so there are signals that these devices can be traumatic, and there's certainly going to be an incident or prevalence of infection. And then, we just don't know what it is now, and I'm only bringing it up because I think the trial data is really pretty ideal, and, you know, we're in the process of sorting what these technologies are going to mean for our patients in the real world right now. So with that, I'll stop, and hopefully we have some time to talk and answer questions at the end.

Matt Gillespie

Cath Lab

Children's Hospital of Philadelphia

Harmony

Altera