All right. Welcome, everyone, and thank you for being here. Before I turn it over to Bernard to make some opening remarks, please take a moment to familiarize yourself with our cautionary statement. You guys all know this. It's an important slide behind me. During today's event, we may be making forward-looking statements, and it is possible our actual results can differ from our expectations. Here's the agenda for today's session. We'll spend the first 20 minutes on TMTT, discussing the results of the CLASP IITR, and then we will move to TAVR and talk more about the long-awaited results of the PROGRESS trial. We are very privileged to have the physicians with us here today, so please try as you might to focus the questions on the trial's results and what the physicians will focus on.
With that, I'll turn it over to Bernard for a few opening remarks.
Good evening, everyone, and thanks for being here. It is obviously a very exciting day for Edwards, and more importantly, for the many patients we serve and the many patients who are going to benefit from the result of today in tricuspid and TAVR. I like to always start with a quick reminder that this is truly a result of our unique innovation strategy as a company. We are committed to bringing a breakthrough innovation across the portfolio, TAVR, mitral, tricuspid, and we are also laying the foundation for AR and structural heart failure later, but also our commitment to world-class evidence. That's not easy to do that. It takes courage, years of investment, years of belief, having a vision.
I want also to recognize our field organization, which is very unique at Edwards, where every day, they take care of patients, one patient at a time, to make sure that physician can have the best patient outcome. At the end of the day, when Edwards lead, everyone benefit. The patient receive the best therapy, great outcome. Physician have access to breakthrough technologies. In many of the cases, even like today, we are enabling the change of practice and evolving medicine, but also providing economic benefit to the entire healthcare ecosystem. So I'm very proud about what we do, what the 17,000 employees across Edwards are doing, ensuring this kind of impact. Let me now introduce the first session. The first session will be focusing on one therapy, PASCAL, in our TMTT portfolio. What we are going to talk about is mainly about CLASP IITR.
A little bit also, Charlie Davidson will be able to talk about that, but also Ted, about TRIC-I-HF, which is also a study that has been presented a little bit earlier this year. Important data for tricuspid patients. We are joined by Charlie Davidson. He is the Chief of Cardiology and Medical Director of the Bluhm Cardiovascular Institute. He is deeply involved in trial leadership across TMTT portfolio for many years, including serving as the global co-PI of the CLASP IITR trial. Also on stage with me, please, Devin, Ted, and Dr. Davidson, please join me. Also on stage with me is Devin Chopra, our leader of the TMTT business. Devin joined us about eight years ago and has deep expertise in med tech and at the company. He has overseen the TMTT success over the last several years as we have introduced the portfolio.
Finally, someone that everybody knows, Dr. Ted Feldman, he is our Senior Vice President of Medical Affairs of TMTT. Ted has been the brain behind many of our clinical evidence initiatives. Before Edwards, he has been a pioneer, a global leader, a researcher, and innovator. Again, thanks for the panelists here, and I am going to turn to Charlie for a quick overview of the data, and then we will take questions. Charlie, back to you.
Thank you, Bernard. My pleasure. Thanks for having me here this evening. I am just going to take you through a few of these slides. Many of you probably were at the presentation today, so you have already seen this. This is not Oh, sorry. Let me go back here. You already saw the whole presentation. Can you get me back to the first slide? Thank you. There we go. Okay, so this is the presentation that Suzanne and I made earlier today.
So I am going to bring you right to the primary endpoint, which was a six month analysis. The study was started in 2020. The first patient was enrolled right the month that COVID started, in March, and it was originally designed to be a two-year endpoint on this trial. Through the course of first four years, it stayed that way as people then became other devices approved.
We had TTVR approved, EVOQUE. We had TriClip approved, and what we found was there was attrition in the control group, and that started in October 2024, when FDA approval came for that. At that point, it was moved back to a one-year endpoint. Following that, a year later, we had CMS approval for coverage for those devices, and there was further attrition and went back to a six month endpoint. So, we are presenting six-month data here. We have one-year data that we presented. You saw that today. These patients are going to be followed annually out to five years. There will be more data to come behind this. But just to understand how we got to the evolution of a six-month endpoint. The six-month endpoint was a composite endpoint of mortality, RVAD or heart transplant, tricuspid valve intervention, number of heart failure hospitalizations, and KCCQ improvement.
This is fairly similar to what you've seen in other tricuspid trials, in TRISCEND II, TRILUMINATE. TRIC-I-HF, which I'll speak to later, is slightly different. What you're seeing here, the main driver of the endpoint, as again, as is in almost all these trials, is the marked improvement in KCCQ, which I'll get into a little more detail here. In this trial, there was also some attrition. Remember, this is at six months, so this is before we started seeing attrition from the control group to a treatment arm. With all of that, the main win ratio was 1.98.
That means that people are twice as likely to get the benefit of this device, that if they received that compared to optimal medical therapy, and optimal medical therapy in this trial included things like SGLT2 inhibitors, which were not routinely used in some of the earlier tricuspid trials. So, better medical therapy in this trial than what we've seen. TRIC-I-HF, again, I'll speak to, also had very good medical therapy. Going to move to the next slide, and this is basically showing the KCCQ improvement. As you can see here, 57% of those that received the device had a large to moderate improvement, whereas 25% of those that stayed in the control group got worse. Remember, the control group included people that moved over, and we had 20 patients that moved from the control group to a attrition to a treatment arm.
They stay in the control group in the analysis, because if we do it by a modified intention-to-treat analysis, they're still counted in the control group even though they've been treated. With that, there still is 25% that got worse, and with this, we had 57% that got better. The conclusions from this trial, and then I'm happy to answer a lot of questions, is it met its six month primary endpoint, demonstrated superiority of the system with medical therapy compared to medical therapy alone, in patients that had severe or greater tricuspid regurgitation, and that was primarily driven by KCCQ and somewhat by TVI. There was no difference in mortality or heart failure hospitalization between the two groups. Also, I'm more than happy to speak to mortality. It was not significantly different.
Why you saw a very low mortality rate in this trial, which in the control group, which was 4%, is interesting that we've not seen in any of the tricuspid trials to date. Some of that, I think, is due to medical therapy, but there's also that attrition in the TVI group in this population that accounts for that. The treatment in the PASCAL system resulted in significant TR reduction, 80% of patients achieving less than or equal to moderate TR at one year, compared to 30% in the control group, which was significant. There was substantial improvement in patient-reported healthcare outcomes, fully evident by 30 days, and really was persisted out to 1 year. This trial demonstrates the safety and efficacy of the PASCAL system to improve health status in symptomatic patients with TR.
I can tell you, as someone that has been treating patients with TR for now eight or nine years with different devices, I can tell you the number one thing that people want is to feel better. We want to have them live longer, do not get me wrong. A six month trial is no way powered to determine a mortality difference. I think the enrichment that we saw from TRIC-I-HF, which I want to get into here, is a trial that would really look at hard endpoints. That is one of the things we have been lacking in the tricuspid trials, is to show that we can impact heart failure hospitalization and potentially mortality. What Jörg Hausleiter did, a good friend and colleague, which was really a brilliant design, was he took and enhanced the patients that were enrolled in the trial.
Remember, we have taken all comers that are symptomatic with severe TR. He took particularly patients that had cardiorenal, so they had impaired kidney disease, CKD, and had TR, or they had a hepatorenal, so they had evidence of hepatic dysfunction and had severe TR, or they had a previous heart failure hospitalization. What he also did was to allow these people that once they presented for their next heart failure hospitalization, to then get treated. So, it was really a terrific design to really enhance outcomes and enhance, excuse me, events to show hard outcome differences. What he did and show this was that he was able to show a difference in death and heart failure hospitalizations, as you can see in panel A. Panel C shows freedom from hospitalization for heart failure. I think this was a very important trial.
Now, I think they followed out the three years, which is another piece of this. They do not have complete three year follow-up at this point, but at least there was a suggestion there that there is a potential mortality benefit. When you think about going back to some of the other trials, those of you who are familiar with the COAPT trial, that was a trial that was done in people with functional mitral regurgitation, and it randomized medical therapy to edge-to-edge repair for mitral valve disease. That trial did not get positive for a hard endpoint of mortality until three years. If that trial had stopped at one year or two year, we would still be sitting here not treating patients with FMR with devices. So, I think we need more of this if we really want hard endpoints.
Quite frankly, I really believe most of the patients want to get better, and they will take the hard endpoint if they get it. With that, I am going to stop, and hopefully I will have some more provocative questions. Thank you.
All right, we will open up for questions. We will be able to take a few questions.
Hey, thank you. Mike Polark, Wolfe Research. On the topic of clinical evidence in the tricuspid space, TRIC-I-HF seems to have breathed some energy in on the hard endpoint differentiation. What are you looking forward to what is happening now in trial land that could further the more persuasive endpoint claims for TEER?
I mean, I spoke to that a little bit. I mean, would we like more trials showing hard endpoints? Yes, but I honestly feel like at this point, we have at least showed strong benefit with the therapy. I think our biggest question now is who to treat and when to treat. It is probably the thing I would like to learn more about. I mean, it is not that I cannot make them better. It is at what point in their disease process should we be intervening?
Because right now, most of us are still waiting for symptoms, unless they have severe RV dimensional changes or dysfunction. Do we want to make sure we are not missing people on the back end? So, we are on the front end that we need to go, and we are in the back end. I think the timing of intervention and who to be offering this to is important.
I think the other piece that is a big gap is that we are still highly underdiagnosing tricuspid regurgitation, both at the general cardiology level and in the echocardiography laboratories, where often patients are not being diagnosed early or then not being referred on. You think about the journey with aortic stenosis, which is fairly easy, anyone can measure a gradient, and even with that, it took us a while to raise awareness and to do some of the great work that Philippe has been doing with EARLY TAVR and now with PROGRESS. I think in the journey with tricuspid, we are really just scratching the surface on what the true population is here to treat. I mean, I have seen a huge acceleration in referrals in the last eight, nine years. I mean, basically, we were digging them out of charts, finding people. Now they are coming in.
That's not that it means we're not still doing that. I think we need to get better at being able to get those people diagnosed early and get them treated when they become symptomatic.
Pito.
Hey there. Pito Chickering, Deutsche Bank. When you talk to the general cardiologists, the referral sources, one of the biggest debates we keep having from them is the quality of life indicators versus sort of these primary endpoints or to change the treatment paradigm. What is your view around, say, which of those sort of starts changing actually the referral source's behavior?
Well, I think most general cardiologists and even internists want their patients to feel well, right? We do hip replacements and knee replacements, and not because they're going to live longer. We do that because the patients want to feel well and to have a better quality of life as they're moving on. I don't think it's a problem in getting them to refer for that. I think it's a problem in being able to recognize the disease. It's not an easy murmur to hear. The echo maybe gets one view and may not get all the information, and many of the patients don't even get to that. If they're seeing patients with edema or ascites or shortness of breath, the symptoms are also indolent. They're a little bit of shortness of breath, fatigue. It's not clear symptoms on these.
Educating both patients and physicians on what the signs are, signals are to get additional testing and then potentially refer on, I think that's, to me, where we need to move. I don't feel like anyone is going to deny someone. The nice part about these treatments, and particularly TEER, is it's very safe therapy. All the trials show very low event rates early on and throughout that. I think it's important to realize that. What's nice is now with replacement, we have a larger portfolio, which is very important for us, because unfortunately, TEER is great when you can apply it, but it's not for everyone, and same thing with replacement. We can get into the details of one or the other, but I think that's still evolving.
But it's nice to have both of those technologies available in order to have the full complement of therapies for patients.
Patrick.
Hey. Patrick Wood at UBS. Just jumping off of that exact point, where in your mind is the latest debate on repair versus replace? How do you think that's evolved recently, and does the data presented at this stage change how you think about that referral pathway?
I just want to make sure I ask the question correctly. When do we decide whether to repair or replace?
Exactly.
Is that what you're asking? Yeah. Well, that's a complex question, but I'll start to begin on how we think about this. I think you have to look at clinical characteristics of the patient, and then there's the anatomic ones. And the clinical may be looking at things like bleeding risk and anticoagulation, and it may also be looking at what's their right ventricular function look like, and then what does the anatomy of the tricuspid valve look like? And if everything being equal, I'd rather repair than replace in patients. I think it's very safe. Some of the bleeding risks that we've seen with replacement, I think it's mainly not because of the replacement, it's because of the population, but you don't have to deal with that, and the pacemaker risk is a little bit less. All of those things become good reasons to want to repair.
But having said that, the majority of patients I treat, I end up replacing because their anatomy is such that they're not going to be getting a good result. And a good result has changed over time. When we started this trial, everyone was moderate or less. That's great. That's what we want to go for, and that's how we behaved through most of this trial. But as data has evolved, as time's evolved, we realize we want to get to mild or less. So now we have scores, one of which we developed, the GLIDE score, to help decide can people get to mild or less, and I think those are types of things you need to be thinking about. If I can get them to mild, I want to repair them.
If I can't, and those are a larger proportion of what we see today, let's go ahead and replace and virtually eliminate TR. I don't know if that answers your question, but it's a first step on it. Bernard.
One more question. Last one.
Thanks, Dave Rescott with Baird. I wanted to ask about a little bit of a follow-up on the prior question, or one of the prior questions. When you think about how evidence kind of makes its way out into the field, I think we saw some data yesterday from the, I think it was the NEDA, N-E-D-A, database about how the mortality rates in some of these tricuspid patients is more significant than what you assume. So, when you think about how data comes out, how that impacts the adoption of some of these transcatheter tricuspid interventions, is it something where you expect more data to kind of slowly progress on that solely increases the interest in utilizing these types of technologies? Or would you assume something that, like these mortality benefits arising at three years, being something that really creates a more flipping point behind the adoption curve here?
Well, look, you have heard the forgotten valve 100 times or 1,000 times. Until nine years ago, no one even thought about treating anything mechanically on the tricuspid side. It was all diuretic therapy. That is all that is in the guidelines right now in the U.S. So really, there was no medical therapies, no transcatheter therapies, and people just kind of shrugged their shoulders if they found it. I think that needs to evolve to understand that there is a mortality price to pay. There is also a tax on morbidity. Now we have safe and effective therapies that can augment whatever medical therapy comes along to help these patients have better quality of life. If it also has a mortality benefit, wonderful. I do not think that is going to necessarily impact our ability to treat these patients.
People want to get better, and their physicians want them to feel better. That is, to me, where the focus could be. Would I like more mortality trials? Absolutely. Do we need them? No. I would rather understand better when to treat, and then does it cause a mortality benefit or heart failure hospitalization benefit? I mean, I will take that, but I do not think that is the number one question in my mind.
Great. Well, thank you for the questions. We will now transition to Bernard.
Dr. Davidson, thank you so much. Ted, Vin, thank you for the great panel here. Let me briefly summarize here what I heard and what we know. We have a growing body of evidence who have established this foundation of life-changing benefits to patients, for tricuspid patients. A quick reminder, 10 years ago, it was a vision. Our sizable investment in the space, in technology and science, our deep commitment to serve the many patients in need, has now resulted in TMTT having a full portfolio. We have this full portfolio of repair and replacement for mitral and tricuspid in both Europe for some time, and now in the U.S. All of this was possible with, obviously, the many patients who participated in this trial, physicians, TMTT employees who trusted us from the beginning. We are visionary. We learn together.
And today, we are partnering with physicians to change patient lives. Again, thank you so much, Dr. Davidson, Salomon, and Devin. We are now going to transition. Thank you so much. Sorry. We are now going to transition to TAVR, the long-awaited and important result of a PROGRESS trial. Who better to provide you with this additional perspective of what you heard in the last eight minutes that Philippe were on the podium about the trial results? Who better than the two pioneers in TAVR therapy? Dr. Philippe Généreux, Co-Director of the Structural Heart Program at Morristown Medical Center, and Dr. Martin Leon, Professor of Medicine at Columbia, Director of Cardiology at NewYork-Presbyterian. Both Dr. Généreux and Dr. Leon have impacted the field in such a profound manner and saved millions of patient lives around the world.
They will be joined by Dan Lippis also, leader of TAVR. Dan has deep med tech leadership globally, more than 16 years at Edwards, in a very significant role across the company, much of his time in TAVR. Now let me turn to Philippe, who is going to go into the PROGRESS trial, but also ACTIVATE. I do not know if you have seen ACTIVATE yet. Philippe?
Thank you so much. All right. Hi, everyone. Good to see you. Thanks for the insight. I do not like this timer already. All right. You can turn off the timer. I get a PTSD here. We are going to talk about the PROGRESS trial that was just-- Thank you so much. I feel better now. So we are going to talk about the PROGRESS trial here that we just were presenting, investigating the role of TAVR or clinical surveillance, as you know, and was published in the New England Journal of Medicine. If you have a little QR code, you see we have a QR code, you can download the New England on the right. You also have on your card, I believe. Truly a transformative trial. This is truly, I would say, a turning point, like Dr. Leon liked to call.
I call it a revolution because I am French, but I guess you can say a turning point. Just to clarify what the PROGRESS trial was, we enrolled patient with moderate aortic stenosis, and the definition of moderate was very rigorous by the ACC/AHA guideline. We want to identify patient that were known to be at risk or to develop either heart failure or to progress fast. We know that there is certain at-risk features that were previously published, and those patients were known to be at risk to progress fast or to develop heart failure or to die. Those risk features, you have them here. Symptoms, diastolic dysfunction, increase in calcium score, LVEF drop of less than 60, NT-proBNP, AFib, and stroke volume index. Just to give you an idea, those features are very readily available for a cardiologist. They are easy to collect.
They're not very difficult. Symptoms, AFib, and low EF, this is something a cardiologist has every day in his office. This is not complex. No surprise, the symptoms were the first one to pop up, 96.4%. Most of the patients in PROGRESS were symptomatic. 44% patient had a diastolic dysfunction, and you can see the rest. Interestingly, 72% of those patients had at least two at-risk feature, and 40% at least three, really pointing out that this patient population were very sick, had comorbidities, and they were 78 years old. It was a all-comer population, only 45% with low risk, so 55% with high-intermediate or high risk, and that's important for the results section. These are the at-risk features that are easy to get. We enrolled this trial in 18 months. Just to give you an idea, we enrolled EARLY TAVR in five years.
Just to give you how eager the physician or the patient are to be treated and how easy it is to actually screen and enroll those patients. Obviously, the first role is to show, is it safe to do TAVR in moderate AS? We've never been there before. Is there enough calcium to anchor the valve? Are we going to embolize the valve? Are we going to leak the Actually, it was definitely safe. As a matter of fact, it's probably the safest time point to do a TAVR for a patient. 0% mortality and 0% disabling stroke. We never saw that before. Primary endpoint of safety at 30 day outcome was met, and we had a margin of inferiority, and we exceed the margin of superiority for this endpoint. This is the main findings.
You can see the TAVR, strategy of TAVR compared to clinical surveillance significantly reduced by 33% risk reduction, the risk of death or heart failure event with or without hospitalization at two years, with a number needed to treat of 14 patients. It is very compelling. You can see that there's early separation of the curve. Moderate AS is not a benign condition, and clearly there's heart failure event that happen quickly. Importantly to say with this is, this was mainly driven by a reduction in heart failure hospitalization. The benefit of TAVR, and this is a very important slide, was consistent across all subgroup, and including subgroup we would have thought that maybe early intervention or awaiting was better. For example, there is no interaction for the severity of the aortic valve.
Whether you have a severity of AV of less than 1.2 or more than 1.2, TAVR was superior. Same thing for the presence of biomarkers such as of heart failure, BNP, elevated or not. TAVR was good for both type of patient. Also the calcium score, so elevated or not. There was no interaction, there's no subgroup where waiting was better, and all the subgroup benefit from an early intervention in the trial in terms of death and heart failure event. This is a very important slide because some people say that heart failure event may be soft or not clinically significant, but the main benefit of PROGRESS can be summarized in one line. There's a 52% reduction in heart failure hospitalization. We know that heart failure hospitalization is associated with subsequent mortality.
All the trial in heart failure, if you get hospitalized one or twice, then you're going to die from infection, acute kidney injury, et cetera, et cetera. Heart failure hospitalization, 52% reduction is very significant for a patient also, is known to be associated with mortality in the future. One learning of the PROGRESS trial is really about the natural history of moderate aortic stenosis. We didn't have good prospective data on how patient with moderate AS evolve through time. We have registry from the 1980s or the 2000, but we don't have a good prospective trial. The progression to severe AS actually was very frequent and unpredictable. You can see among the 371 patient enrolled in surveillance, 204 actually underwent AVR within two years, with 27% at one year and 57% at two years.
Among the patient that underwent an AVR, 80%, so 81.4%, crossed to severe aortic stenosis with a Class I indication for AVR. That's very important because this is a curve you're going to see in all the textbook of medicine. What is the progression of moderate AS to severe? This is this, okay? In a very well-controlled environment, where you follow patient carefully. This is one of the most important slide in my opinion. When you look at the 30-day outcome, how did we do with AVR in general when the patient need AVR? We did well. Both group was good, lower rate in both. But when you look at the rate at 30-day post-TAVR in the TAVR group, this is where I get chills because you have 0% mortality and 0% disabling stroke.
To be able to say to a patient that I'm confident I'm going to do a procedure with 0% mortality and 0% disabling stroke is very powerful and reassure the patient. You can see if you wait for severe AS, for example, the stroke rate go to 2.5%. Stroke is the most feared complication when you do a procedure, both for the family, the patient, and the operator. To see those result of 0% disabling stroke, don't underestimate that, they are very powerful to convince people that this is the right thing to do. I truly believe that this difference is probably triggered by the calcium score, the level of the aortic valve, and we can discuss during the discussion why this low rate of stroke compared to the waiting. But there's a physiopathology of this, which is the amount of calcium on the valve.
Pacemaker was 13% or 10% in both group, was similar. The other improvement was really the improvement in quality of life. You can see when we do a TAVR immediately, patient immediately feel better, 15 points. No surprise, we fix the aortic stenosis. This is very important because that mean that the symptoms that the patient was having was valve-related. Some people that like to write a tutorial will say that the symptom were not related to the valve. Well, this is the proof that when you do the valve, you improve by 15 point, significant improvement, the KCCQ score, and immediately. On the other hand, people will say, "You can wait." But if you wait, you're going to have a TAVR at one year and two years, there's no doubt.
But you're going to have a little decline in your quality of life, a significant drop up to 10 and sometime up to 20. Then of course, you're going to have a TAVR, it's going to be great, you're going to improve your quality of life after that, but you're never going to go as high as the other group. So yes, TAVR improve quality of life immediately and prevent meaningful decline in health status. This is important for patient, no stroke and no disabling stroke, no mortality, immediate improvement, which actually validate the fact that we did something right for the patient. This is really the conclusion, where you can see that moderate AS with at-risk feature, unparalleled safety, 0% mortality, 0% disabling stroke. We show superiority at two years for the primary endpoint death or heart failure.
And we reduce heart failure hospitalization by 52%, and we improve quality of life. I think that really validate the fact that TAVR could be a great treatment strategy for patient with moderate aortic stenosis with at-risk feature. This is on the right, the most important slide that I didn't have the chance to present this morning, and I'm going to take my time because every line is important, because it's about the patients. Clinical implication for the patient is that moderate AS is not benign. When someone talk about moderate AS, they think we can wait. We just showed it's not benign, and I'm going to show you data even more powerful that it's not benign. These patient will benefit from earlier referral to a valve clinic for more comprehensive evaluation to establish the optimal medical management strategy.
I think we established that rather than waiting to severe, PROGRESS supports TAVR for patient with moderate with at-risk feature. This is a paper that I elected to do in parallel to the New England PROGRESS trial. It's called the ACTIVATE study, and there's a little QR code as well. This is a JACC publication that was online at 2:50 P.M. today. This is a real-world large analysis of 15 million patient in 50 centers in U.S. to identify what is the proportion of severe, what is the proportion of moderate, and what is the proportion of moderate with at-risk feature in the real world, and what is the impact? What we show from 54,000 patient with moderate or severe AS, 35% were severe, 65% were moderate. Twofold bigger population with moderate. In the moderate group, what is the percent of patient with at-risk feature?
80% had at least one at-risk feature. If you remove symptoms because you think the symptoms are not because of the valve, it go down to 70%. So, in the real world, to have one moderate AS with at-risk feature, you can see the mortality, the two years mortality when you have moderate AS with at-risk feature is almost the same as severe. It's twofold higher compared to moderate with no at-risk feature. Same finding for heart failure hospitalization in real world. Almost the same as severe with twofold increase compared to not having at-risk feature. So, not only moderate AS is 2 x more frequent than severe, not only at-risk feature is 80% of the moderate AS patient, but is associated with increased mortality. Then you're going to look at the mortality curve, 20% mortality. In PROGRESS, we have 7%. How is the difference?
Because in a clinical trial, we do better. Both groups do better. It is very hard to show a benefit in mortality in a trial where everybody is followed like a hawk by the clinical nurse, the research nurse that follows the patient every six months, that calls the patient to know how it feels. It is not real world. This is real world. Moderate AS is frequent, it is bad, and it is especially bad in the real world patient. I guess I am going to stop here and I am happy to take questions.
Larry?
Thank you. Larry Biegelsen from Wells Fargo. Can you hear me okay? Philippe and Marty, congratulations. Marty, I lost track of how many New England Journal publications you have on TAVR, but it is a lot. So, a two-part question. Of the data you just showed, Dr. Généreux, the 23.5% versus the 20% for the mortality for the severe and moderate, but you did not show a mortality benefit in PROGRESS. What is the difference? Why would we saw mortality benefit in the severe trials with TAVR, but not today in moderate? Second, you had the 80% with at-risk features. The editorial everybody here read, and the first message I got was it was not very positive, but there was one statement that stood out, which was, it said something to the effect, "Clearly, TAVR is not appropriate for most patients with moderate AS." I am going by memory.
What is the disconnect there, the editorial versus what you showed today? Thank you.
Yeah. I think Catherine Otto did not read my paper yet, so maybe she will change her mind. I will say the first, the mortality question. The mortality question, very similar to EARLY TAVR. We are in a clinical trial setting, okay? Those patients are followed very, very carefully, which is not at all representative of what is in the real world.
That is the first difference, and you can see the difference in mortality, 20% roughly in the real world compared to 7%, 8% for the PROGRESS trial. Second, we did not power the trial to have a benefit in mortality. We powered the trial based on the safety, and also we expect 30% to 15% difference in heart failure, mainly driven trial. The third point I will say, if you refer to EARLY TAVR trial. EARLY TAVR trial was a mean follow-up of three point eight years. We have two years.
Everyone is at two year here. When we do a landmark analysis of EARLY TAVR, we see the difference in mortality and stroke start to happen beyond two years. Two years is very short in a lifetime of a patient with moderate AS. There's still 40% patient that didn't converted, but beyond two years in EARLY TAVR, we see the curve, which actually is exactly parallel at two years, okay, and sometimes a little bit worse with TAVR, and then start to, beyond two years, two, three, four, five, to spread, in EARLY TAVR. I'm expecting, and I'm speculating, but I'm expecting the same phenomenon will happen, especially with the 40% patient that remain untreated. Life will not be rosy for them. It's not going to be better than being treated earlier. I'm not surprised, and I was not expecting neither the mortality.
But the fact that we have 52% reduction in heart failure or hospitalization in spite of a quintessential follow-up trial, like from a trial setting, is unremarkable, and that's because moderate AS is not benign. The second part of your question, do you think that moderate AS is a niche disease and most of the patients should not be treated? I strongly disagree. I would say that we randomized this trial in 18 months in a record time with a lot of enthusiasts. Second, the ACTIVATE data or the JACC paper completely, I would say, contradict this statement. When you have patient in the trial, and what I believe that Catherine Otto referred to is most of my patient with moderate AS don't have those features. She's referred to the 1.4, the 1.5 valve area that actually were probably mild. Of course, those patients are not the same. They're mild.
We have 1.1.2, 1.3, a little bit of 1.4, but mainly, truly moderate AS. I think that there's a matter of definition, what she's thinking, and I think people don't realize yet because maybe they don't pay attention, so yeah.
Martin?
Yeah, that's I mean, just to go forward a little bit with this. I haven't read the editorial yet.
Me neither.
I haven't seen it, but I know Catherine Otto very well. Catherine Otto is an echocardiographer who works at University of Washington and rarely travels outside of Seattle. She was also responsible for many of the guidelines, and she's a very, very strong academic. She's not really what I would describe as a clinical cardiologist, nor does she refer many patients for TAVR, although she does read a lot of echoes. She's got strong opinions, and those are somewhat ossified in terms of new therapies for any form of valvular heart disease, let alone aortic stenosis. I'm not so surprised that she would come to that conclusion, but it's an ill-advised conclusion. It's not just the ACTIVATE study that Philippe discussed in a real-world population in the U.S.
Almost a decade ago, the NEDA trial from Australia, an echo-based trial just looking at the prevalence of different forms of aortic valve disease, demonstrated that moderate aortic stenosis occurred at at least two to three fold a higher frequency than severe aortic stenosis, and that the mortality was different only by a couple of percent untreated. What ACTIVATE showed really was confirmed with a quarter of a million patient echo registry that was reported more than a decade ago and got us thinking about the importance of moderate AS. We did a whole bunch of studies trying to define the at-risk features that were then incorporated into the PROGRESS trial. We did another trial called the UNLOAD trial, which was a moderate AS study in patients with reduced ejection fraction and clinical heart failure, because those patients had a 50% mortality untreated in the first two years.
This is a prevalent disease, at least twice as prevalent as severe aortic stenosis. The frequency of at-risk characteristics, as defined in this study, is the majority of these patients, at least in a U.S. population. We can see, at least from ACTIVATE, untreated, they had a two year mortality and heart failure hospitalization, which is unacceptable and worse than most subgroups of patients with severe symptomatic aortic stenosis. I just totally dismiss some of the conclusions and some of the comments that were made in an editorial capacity by someone who really doesn't take care of patients and who really doesn't know the data. Why didn't we see a mortality difference? The first clinical trial we did was PARTNER 1B. It's the only other randomized trial we did where we compared the current standard therapy, which was surveillance, in patients that were not surgical candidates.
Yes, these were the sickest of the sick patients. These patients had STS scores above 10, and the untreated one-year mortality was 50%. We showed with the earliest version of a TAVR device, and we were not sure what we were going to show, but the primary endpoint was a headcount, was all-cause mortality. We had an absolute difference of 20% in the first year in reducing all-cause mortality in that population. Yes, that was historic. We are not in that era anymore, and we do not treat many of those patients anymore. This is a very different era. Now we have a therapy that does not have the kinds of complications and the kinds of burdens that we did in the earliest days of TAVR.
We have a therapy that we can apply with a one-day hospitalization, and in this population, had zero mortality at a month and no disabling strokes at a month. We have never seen that in any population. This is, I would argue, this is no riskier than having a colonoscopy in terms of the therapy and its safety, as demonstrated in a huge number of sites, broadly applied, not just in the U.S., but elsewhere. I think the safety, and when you look at risk-benefit, you have got to always think of the risk. The risk of the therapy, does it negate the potential benefit that might be achieved? In this case, the risk is de minimis. That, I think, needs to be put to rest. Philippe’s point, which is, this may be the best population to treat with TAVR. We can fully expand the valve.
We get the lowest complications. They can get out of the hospital literally overnight. We think that the hemodynamics, by the way, achieved with this therapy in these patients were better than in any subset population that we have ever treated with balloon-expandable TAVR. We had mean valve areas of greater than two. That is going to translate, especially with RESILIA tissue, into long-term durability. I think everything about this from the standpoint of safety and the quality of the result is as good, in fact, was beyond what we had expected. When you look at a population like this and you do close surveillance, which is what we did, this was not real-world surveillance. In the real world, 20%-30% of patients who have moderate AS do not get an echo within two years of the diagnosis. We were following these patients every six months.
They had intense scrutiny, the kind of oversight that you would like to see. If there is anything that comes out of this study, it is, if you have moderate AS, you better not just sit in somebody’s office. You better get your butt to a valve center to have what we call extensive investigation and what would be, what we believe, is optimized therapy. Not what we have been doing before, which is just waiting for these patients to present ultra-sick, too late, and not achieving the kind of clinical benefit that we can achieve. I think that that emphasis that we have now understood that this is not the first words out of that clinical implication slide, this is not a benign disease. Every clinician cannot feel comfortable just watching moderate aortic stenosis anymore, and that includes Dr. Otto, because that disease should be put on alert.
That means you have to have qualified people doing further investigation, trying to define what would be, we think, an at-risk population that would be amenable after careful discussion and after weighing all the facts, getting a CT scan, seeing what the anatomy is like, that these patients first, would they qualify for TAVR, and if they do, an open discussion about whether or not that would be the preferred therapy. Both to prevent more than 50% reduction in heart failure hospitalizations in the first two years and a significant reduction in those patients who had decompensated episodes with an average 17 point drop in KCCQ score. I would not want my mother to be waiting for a 17 point drop in KCCQ score or until they get severe aortic stenosis before applying a therapy that could prevent those things with a 0% mortality and a 0% disabling stroke rate.
Again, getting back to the mortality, why did not we show a difference? Because the surveillance was so good. I mean, these patients progressed more quickly than we thought to severe AS, and they were treated, so they did not die. When you look at the control arm, you do not see a difference. But I am still not sure that when we wait, not at two yearrs,
but when we wait to three years, four years, five years. Now we are seeing, if you look, and you know the data better than anybody, when you look at EARLY TAVR now, we just presented the median follow-up at New York Valves at five years,
Now we are seeing a change in hard endpoints. Now we are seeing death and stroke at five years with a median follow-up in asymptomatic severe AS is better with preemptive treatment. This is only the first look, but this is a turning point, but it is also a starting point. This is the first look at a dataset that is going to continue to mature, and there will be other studies that will get done, and there will be corroborative studies that are already in the works, that this difference is meaningful.
It did not show a mortality change at two years. It might by five, or further down the line. We never thought, we never were powered to show a true mortality difference, especially with the kind of surveillance that was applied to the control arm. If the control arm was community care of moderate AS patients, we would have shown a mortality difference.
But that's not what the control arm is or could be in a trial like this. We were not surprised. And holding the study up to that standard is absurd, frankly.
Thanks. Robbie Marcus, JP Morgan. There's a much more favorable TCTMD article up.
Which I also didn't see.
I saw it. It was great, Martin.
I'm sorry to get emotional about this, but I've been doing this since, we began enrolling patients in these clinical trials in 2005 when we did our first case at Columbia, and started enrolling the predicate studies to PARTNER. This is the 32nd New England Journal of Medicine manuscript that I've co-authored and been involved in. I would argue potentially is the most important. As we continue to talk, I'll tell you why.
So, there were a lot of great points you touched on there. We're all financial people. I think it's clear this is going to be adopted by physicians moving forward with such good clinical data. How should we think about some of the timelines going forward? Is this enough for FDA approval? Is this enough for indication expansion? How should we think about reimbursement timing? On adoption, how should we think about how quickly this can start to roll into practices? Are these patients being seen already? Some of the referral challenges or pathways that need to be opened up. Thanks a lot.
Do you want to answer any of that?
Sure. I think firstly, from a what does this data say about what can be done immediately, it certainly, if you're a physician out there, it certainly wouldn't stop you from doing an advanced screening on a patient or certainly wouldn't stop you for referring a patient with this disease to a heart valve clinic for further assessment. Clearly, an indication is important if it's going to enable us to better serve this very underserved patient population. We don't typically speculate on the timing of indications, et cetera, or the relative impact of that. What I suggest is as we sort of get into our December investor conference, we can talk a little bit more about what our anticipation or how we're thinking about that in 2027, and perhaps the longer term impact beyond that in December.
Maybe I can give you a glimpse of response from our clinical work. When we start to screen for PROGRESS, we advertise and people start to send their patient. For every 100 patient I was seeing, 30% were severe actually. There is a big misdiagnosis in the community. There is a big underestimation of the severity of AS. What is labeled as moderate aortic stenosis out there, when they come to us in valve clinic where we do a deeper echo, another screening echo, when we do a CAT scan, we realize this is a valve is severe or critical. There is a high proportion of the patient that were excluded from PROGRESS, okay? Which is the main reason, it is like almost 40%-50%, because the patient did not have moderate AS. He had either severe or mild, but most of the time severe.
The first thing people will say, "Hey," and I will really start to do this and, "Bring me your moderate, we are going to stratify them," and a third at least would be severe. There is a lot of thing we can start tomorrow. You follow them, and the follow-up should be every six months, and then they are going to express themselves as severe at six months, 12 months. This is going to be the direct impact. Every time I did a PARTNER trial, a PARTNER trial got published. When PARTNER 3 got published, I finally could treat all the intermediate risk. When EARLY TAVR was treated, all the PARTNER 3 were coming and it is not a problem. I suspect though this trial will unleash all the severe with no symptom and also the patient that have mild symptom not ready to be treated.
I think you are going to have an uptake in the severe because that is confirmed that severe you should not wait anymore, and send me your moderate because you may have misclassified them for a couple of years. I think this is the side effect, and I already see it because obviously we are a center and our TAVR is like exploding because we screen moderate and we find a lot of severe. There is more to just, "Oh, I am going to get CMS approval," before we can start to do those patients.
Travis?
Hey, congrats on the data. Maybe first of all, we touched on this a little bit earlier, but just curious, like of the moderate population, what portion, is it roughly half maybe of these patients likely are at risk that you would see in the real world? Do you think the FDA label and
Reimbursement would probably have a similar restriction on the moderate patients to be more like you have in the trial. I know the NCD left a pathway for moderate coverage up to the MACs, so I don't know if there's anything to say on the NCD. Just curious on the reimbursement. I know one other thing was heart failure hospitalizations, a big economic impact too. Just curious how that ties into the reimbursement conversations.
Yeah, I would start by saying that this population, the bucket of at-risk feature is at least 60%, but actually the ACTIVATE showed that it's 70%-80%. It's not a niche, for sure. It's the majority, and the majority defined between 50%-80%, depending how you capture the data actually. But the vast majority. For the rest, I will let you answer this.
Maybe the simplest way to answer your questions is the study was designed in collaboration with the FDA, right? It's the important. There shouldn't be any surprises on what the indication is when or if it is given. Again, we can't really speculate exactly on how they're thinking or exactly what that might look like. We can maybe, similar to what I was saying before, have another conversation about how we're thinking about that in terms of what it means for 2027 and beyond, and how we're thinking about what the longer-term impact might be. As far as reimbursement goes, you kind of touched on it, right? We have an NCD in play. It was just updated from a reimbursement perspective.
While it didn't specifically include moderate AS patients, nor can it, because it's not an indication that exists, there is room in there for the first time, deliberate room in the language that was provided by CMS to talk about how reasonable and necessary applications of TAVR can be used by working directly with the MACs. That's important, and that's going to be super important for this population. I'm sure the physicians would agree, given that these patients, the disease is not benign, and they're looking for something that's going to help them make them feel better and potentially reduce some serious cardiovascular events.
Yeah, I'll just follow up for a second.
Sure.
If that's okay. Remember, 95% of these patients were symptomatic, and a third of them had NYHA Class III/IV symptoms. This is a very symptomatic population of patients that were being treated optimally by their physicians and were still symptomatic, and severely symptomatic. The relationship with the FDA is a very good one, a very close one. We can never predict exactly what they're going to do, but they're very fully aware of this study. They were involved in every aspect of its development. They even tried to work with multiple sponsors to see if the endpoints can be not unified, but made similar, so that when they looked at the totality of the data, they'd be able to be looking at endpoints that they could relate to from multiple different studies. That's the level of engagement that the FDA has had on this.
They view moderate AS as being a significant clinical problem, and I would certainly, I'd personally be very surprised if the extension of the indication to the moderate population wasn't done with all due haste. Reimbursement, I think, is another matter, but I think that's something that we're going to be able to overcome given the compelling nature of the quality of the outcomes here. I'll alert you to another late-breaking trial that was presented yesterday by Neel Butala, which was a cost-effectiveness study of EARLY TAVR, which was a fascinating trial, and we never thought that this would be cost-effective. But they, with their statistical wizardry and extrapolations and imputations and all kinds of other things, looking at now the median five-year follow-up data, indicated that this was strongly in the cost-effective range of treatments compared to other therapies that are currently being reimbursed by CMS.
That's asymptomatic severe AS. When we do the cost-effectiveness studies with this, there's no question that this is going to be a cost-effective therapy as well, which I think will add to the reasonable and necessary component. But look, it's one study. We're not going to get a Class I indication on a single randomized trial. If they were to reclassify, it'd probably be Class II-A to start, but there may be a second study coming before too long. If it corroborates these results, you can expect that there would be a Class I indication for treating moderate AS aortic stenosis within the next several years.
Matt?
Thank you. I appreciate the comments on the editorial, and I am happy to bash that with you more later. I did want to follow up on your comment, Marty. You said that you had 32 publications, and this might be the most important. That was a real teaser. I want to hear why you said that, what this could lead to, why is it the most important?
Well, because I think this opens the door for us really exploring something that we have all been thinking about for more than a decade, which is this anachronistic, dichotomous, categorical description of aortic stenosis is not human biology. We do not deal in buckets, mild, moderate, severe aortic stenosis. The disease is a continuum, and defining it only on the basis of echo hemodynamic severity at the valve level is not an appropriate clinical classification. We have identified a subgroup now that very clearly has clinically significant aortic stenosis that does not qualify into that neat bucket of being severe symptomatic, and it is going to result in a redefinition of how we define this disease, how we follow it, and how we treat it. Whether we use terms like clinically significant aortic stenosis rather than moderate or severe, we will come up with the right terminology.
Whether we start to impute other factors to be able to define what that clinically significant population is, this is going to change the way we think of the disease, change the way we follow it, and change the way we treat it. It allows us to get back to the continuum of human biology as opposed to the categorical way that we currently describe things, which were developed more than a half century ago. Unfortunately, Gene Braunwald is no longer with us. He was truly an iconic pioneer. We had this discussion before he died a few years ago, and he, who categorized these different buckets of aortic stenosis, clearly realized that that was artificial and anachronistic. What we want to do is to bring aortic stenosis therapy into the modern era.
This is a turning point and a starting point, and that is why I say it is potentially transformational in terms of opening up the therapy options for this disease.
One last question. Joanne?
Thank you very much. Joanne Wuensch from Citibank. Thank you for your time this evening. If I hear you correctly, a year, two years at some stage in the future, we're not going to be talking about moderate AS and severe AS. You're just going to have AS.
Well, that's a little bit simplistic. I mean, we're going to go much further. We're going to be able to define the characteristics that differentiate patients that have clinically significant disease, and the trigger point for therapy is going to shift. It's not going to be just AS. It's going to be AS with a continuum, but that continuum is, yes, hemodynamic severity, yes, the effect on other cardiac structures like ventricular function, yes, but it's also going to be a variety of other clinical factors that makes patients vulnerable and defines them to be at risk, requiring treatment a little bit earlier in the hemodynamic sequence. So the hemodynamics do not predict the clinical outcomes.
Follow-up. When physicians leave TCT and go back to their practices, how do you think they change their practice? How do you think they change viewing the patients, and do they have sort of a pool of people that were like, "You can come in now"?
I'm going to start to this, but yeah, absolutely. What's happening is, good news is this paper is in New England, so all the doctors in the universe will see this paper. They will look at this and say, "Oh, shit, I have to treat my moderate AS patient now." They're going to freak out. They're going to call a guy like me, "Hey, Philippe, what the hell? I need to treat those patients?" I said, "You can just start by sending me the patient, and we're going to do a CT scan, a repeat and echo, and we start by then." "Okay, perfect. Which one I should look at it?" "Start with the one with symptoms. Start with the one with AFib, and start with the one at low EF, or you know what?
Start with sending me everyone, because actually it's 80% of the population." Okay? That's exactly what's going to happen. I can tell it's already starting. My phone is blowing up because, "Should I treat patient with moderate AS?" The reality is we're not going to treat everyone with moderate AS, okay? We're probably going to treat 80%, okay? It's not going to be tomorrow. I know I'll treat this in patients, but it's going to be really gradual. What's going to happen is, and I can tell you right now, is if one patient go see a cardiologist X and say, "Hey, I read this paper," because everybody's well-informed right now with ChatGPT and everything. "The [inaudible] said that we need to treat me." He said, "No, no, we don't do that here." She's going to go see someone who's going to know.
My office is full of patients that want to, since already TAVR in PROGRESS, and with the trial. That's what's going to happen. The patient is going to be The answer will be in the end of the patient. "I don't feel well. They tell me I'm moderate, but I feel like severe. I feel like shit. So I'm going to go see the doctor who's going to listen to me and help me." One thing that was clear in PROGRESS is when I treat those patients at 30 days, they were thanking me. They say, "I feel so much better." This quality of life is not only a bogus number, it's real. This is where one day I had a nurse who came to me and said, "Philippe, this is working. This patient feels completely different.
He has better color, and he's feeling better." This is real. This is not only me saying this. We do this for patients. I think that to Marty's point, we're not going to treat all the AS. What's going to happen is going to cause, I think this patient need it. If it's approved for severe, it's approved for moderate, it's going to give back the power to the physician to decide who needs it based on clinical judgment and adverse feature, and will be able to help the patient that needs it. I think that's what gives back the power to the clinical judgment to who's needing it, and there's a lot of patients that need it. That's the reality.
Yeah, Philippe's correct. I know we're running over, so I'll be brief. I'll try not to be as emotional.
Usually I'm the emotional guy.
Yeah, it's true. We're going to make everybody feel very uncomfortable about moderate AS. The fact that 20% don't even get a repeat echo, the fact that 80% don't get a BNP drawn, the fact that none of them ever get a CT scan to see if they're even a candidate for therapy at some point in the future, even with severe symptoms, is ridiculous. We're going to change the way people think about this disease and make them very uncomfortable about just watching these patients. Many of the practitioners who see them for the first time are going to be equally uncomfortable about doing the necessary evaluations, so they're going to get rapidly referred to expanding valve clinics. We're going to do the necessary tests. We're going to get a BNP. We're going to get a CT scan.
We're going to look at the echo more carefully. We're going to try to understand more about the patient's symptoms, then discuss whether or not they fall into an at-risk category that would potentially qualify them for therapy. It's this issue of recognizing moderate AS is not a benign disease, first. Second, that many of these patients, if not all of them, should be referred higher up the chain to qualified centers that can do a comprehensive evaluation, which is not hard to do. It can be done very easily and very quickly in a single day. There now are other treatment options, and the therapies are going to be more advanced, but those will be discussed with patients, and it'll be prioritized. There are going to be all kinds of reasons why you would or would not do a TAVR immediately.
But you certainly are going to follow these patients more quickly and more carefully. You're going to recognize when they convert to severe AS, and you're going to be applying the kind of appropriate management that prevents mortality, as we demonstrated in the clinical surveillance arm in this trial.
Great. Well, thank you for all the questions. We'll turn it over to Dan.
Thank you. So, maybe as a reminder, just stay, gentlemen, just for a quick second. As a reminder, our investor conference is in New York later this year, and Marty is based in New York, and Philippe is based in New Jersey, which is very close. I highly recommend that you read the papers that we're talking about, because there might even be a test before you can ask another question. So, what I'd like to do is just very briefly summarize. I think there was so much rich discussion here. Oops. Let's go one more. Marty mentioned it, Philippe mentioned it, we're at a turning point. We're at a turning point in our both understanding and the management of moderate AS.
The data is not only of the highest quality, but as you can appreciate from what our leaders, the trial leadership here are talking about, it's very, very important. It's important for three reasons. One, clearly identifying that there is an underserved patient population here that is sizable, and that moderate AS doesn't fit in a box. This is a heterogeneous population in nature, and it is not benign. The second point is that TAVR in this particular patient population, which is moderate AS with at-risk features, provides a significant benefit. The results, both from a safety perspective and from a superiority to the composite primary endpoint for effectiveness, shows and validates that TAVR with a SAPIEN 3 in moderate AS with at-risk features is valid.
The third point here is, and what we were just talking about here, it forces us to challenge the current guideline-directed surveillance paradigm, which is passive in nature. No matter how you look at it, the disease progression was unpredictable. Over 60% of the patients in the control arm ended up having delayed AVR, and not with better outcomes by waiting. We just talked about this. We have to move away, and we are going to be forced to move away from passive surveillance in the community to active surveillance, whereby comprehensive tests is done early, and we get the right information to determine the optimal treatment strategies for these patients to get them the optimal outcome. So it is an exciting time. We are very happy with these positive results.
I cannot thank both Dr. Généreux and Dr. Leon enough for their trial leadership, and I would like to pass over to Bernard for closing remarks.
Thank you, everyone. I know that we are past the time here, but what an insightful conversation here. What I would like to do is a little bit of a big picture comment at the end. What did we know before today? We know that SAPIEN is the most studied TAVR valve, 20 years of landmark trials, thousands of patients studied, millions of patients globally benefited. We know that we had seven-year data. So this platform is durable. All of these results, we were very careful about talking about TAVR today, but all of these results were possible with SAPIEN. Not only it is an exceptional TAVR platform, but it is a durable valve platform. What we learned today is few things. The disease is not benign, and the progression to severe AS, frequent, impossible to predict. So think about the patient, think about the opportunity.
Think also about what we have ahead of us to do all together. SAPIEN has shown remarkable performance, unparalleled safety. Moderate patient population is a large one, and it is also redefining the way we are going to think together about aortic stenosis. Also, we talked a little bit about it, Dr. Leon talked about it, but I think Dr. Généreux also. I like to take the two disease study together, EARLY TAVR and PROGRESS. These studies are advancing the understanding of aortic stenosis and how clinicians should manage this patient going forward. So it is an exciting time, a ton to do, pivotal moment for physicians, for patients. I want to recognize all of the investigators in all of these studies to have made this possible.
15 years ago, 20 years ago, I know Marty can talk about that, it was a vision again, and this vision is happening, and there is still a lot to do here. What you can expect from us is we are going to continue to innovate. We are going to continue to bring evidence. We are going to continue to educate the field, to train physicians, and to take care of all of these many patients. I cannot close without recognizing the leaders who had the vision, how many years ago? Seven, maybe eight years ago, the vision for this PROGRESS trial.
Obviously, Dr. Leon, Dr. Généreux, but also Dr. Raj Makkar and Dr. Jeroen Bax, who are not with us tonight, and the many investigators globally who have made this possible, together with the Edwards employees, the TAVR employees, who have been working very hard to bring these landmark trial results today, which is going to change the way we are thinking about the space. Again, thank you, everyone. Thanks for your interest. I hope you are very excited about what we were able to achieve today. Thank you, and have a great evening.