Artivion, Inc. (AORT) Earnings Call Transcript & Summary

Good morning, everybody. Thank you for joining us here in New York at the Pierre. I'm Pat Mackin, I'm the CEO of Artivion, and welcome to our Analyst Day. A quick look at our forward-looking statements. Let me walk you through the agenda. So this morning, we've got a really, I think, a full pack schedule for you. I'm going to do a brief overview of the company. I'm going to be followed by John Davis, our Senior Vice President of Sales and Marketing, to talk about the On-X franchise. He'll be followed by John Alexander, who will -- from Duke University who'll talk about the PROACT Xa trial. We're then going to do our first Q&A and that's going to be covering whatever topics we've already been through. We're then going to go into our stent grafts. Our Head of Europe, Karl Will, who is here from Germany, will present our stent graft franchise. And then it will be followed by 3 speakers. Dr. Kempfert on AMDS; Dr. Shrestha on Neo; and Dr. Tim Resch, who's here with us from Copenhagen on E-nside. Dr. Kempfert and Shrestha will be remote. One of their flights was canceled due to a German TSA strike, like there isn't enough going on in the world. We'll do our second Q&A session after that. And that's about a 30-minute session. I want to make sure you have plenty of time for the physicians. And then our final session will be Dr. Marshall Stanton, who is our Senior Vice President of Clinical and Medical Director, will talk about our pipeline and then Ashley Lee, our CFO, will take you through our financials. I'll do a quick wrap-up, and then you'll have the third and final Q&A. So we want this to be very interactive. We've got about an hour for questions in the program. So without further ado, let me kick off. So welcome to Artivion. This is a company that's been 7 years in the making. I joined the company about 7 years ago, and my vision was always to get to this day prior to the pandemic that they may have been 2 years ago, but here we are today. And as you can see in the slide, our Artivion represents really our vision to become a leader in the aortic field, and that's all through innovation. And what I want to do is take you through the story about how we actually got here today and the powerful organization that we've created over these last 7 years. So first, if you go back to the roots of the company, I joined the company right around 2015. The total addressable market for then CryoLife was about $500 million. That represented their focus primarily with 2 products. Tissue valves for the aortic. We had the pulmonary valve and the aortic valve as well as BioGlue. Great products, great franchise, great brands, very small TAM, growing mid-single digits. When I joined the company, I saw the opportunity to really change the way we could do things going forward. It was at that time, I sat down with the Board, and we put together a plan to create a world-class aortic franchise. And we started with the building blocks, our mission, our vision, our strategy and our leadership team, and I'll walk you through each of those. So first, the mission of the company is quite simple, right? We work with surgeons for them to treat their patients. In the middle of that is our patients and our surgeons treat the patients. What powers the culture here is the 1,300 employees of Artivion, through collaboration, focusing on results and focusing on customers. And our customers are both the surgeons and the patients they treat as well as shareholders. We try to bounce that very appropriately. After this, we set a very bold vision for the company, right? We put a stake in the ground that said, we want to be recognized as a world leader in providing technologies to patients with aortic disease. The next was the strategy, how are we going to accomplish that vision. We spent a lot of time with our executive team with the Board, and it's a pretty simple strategy. We plan to grow double digits over the next 3 years by focusing globally on cardiac and vascular surgeons who treat the aorta. And the secret sauce in that is how we will win. We seek to understand the biggest clinical challenges that those surgeons face and bring them technologies, whether we acquire or develop those technologies, so they can treat their patients better. I spent a great deal of my time with physicians doing just that, and it's extremely rewarding. Next, to implement this strategy, we needed a strong leadership team. I joined the company almost 7 years ago, and I brought in the majority of the executives you see you here on this slide. I spent about half of my career at Medtronic and the majority of that running their largest business. And through that part of my career, I met some of the best executives in the cardiovascular device field, and you can see some of them pictured here. John Davis was one of our senior leaders at Medtronic in the heart rhythm field. You'll hear from him today. Jean Holloway was my Chief Council when I was at Medtronic. Marshall Stanton was our Head of Clinical when I was at Medtronic. He's also a trained cardiologist. Drew Green worked at the FDA, our Head of Regulatory; Dennis Maier, worked at Medtronic at one of our manufacturing facilities. All 4 of our commercial leaders are brought over from Medtronic. We have a world-class leadership team, and you're going to hear from many of them today. So with the mission, the vision, the strategy and leadership team in place, we needed to go to work to build a world-class aortic franchise. And we have actually done just that. We've invested $700 million to build a world-class aortic franchise. The components of that franchise, our investment in M&A, our investment in R&D, our investment in our manufacturing facilities and our investments in our global sales team. This is a world-class aortic franchise, and I'll walk you through the components of this. First, on the M&A side, I already told you we started with BioGlue and tissue 7 years ago. Our first acquisition was of On-X back in 2016, a world-class mechanical valve platform that you've only beginning -- you're only seeing the beginnings of what it can do. It is now, as you'll see from John Davis, the market leader in aortic valves in the mechanical segment in the U.S. We then followed with JOTEC in 2017, a very innovative German stent graft company, who was focusing on the most innovative technologies in the rapidly evolving areas of the arch and the thoracoabdominal region. We then did a deal with the Israeli company Endospan. They had one of the very first technologies in what we call the next frontier, which is using catheters to treat the arch for aortic disease. We then followed with the acquisition of Ascyrus. That is the first and only stent to treat acute type A dissections. And you'll hear from Dr. Kempfert about that. That's almost $0.5 billion in acquisitions over a 6-year period to build this franchise. And what you'll notice from the portfolio that we've created from this franchise is our TAM has gone from $500 million in 2015 to almost $6 billion in 2022. The other thing you'll notice is that we can treat aorta from the aortic valve all the way to the iliac artery and no other company can do that. The other thing that's important about this slide is this is all through cardiac and vascular surgeons who focus on the aorta. We can access them with a dedicated sales team that we will fill out in our investment period over the next couple of years. Let me show you how this portfolio stacks up and why we're a leader in this space. If you go by our 4 segments that we report, starting with tissue. There are 2 players in the tissue segment. We are the market leader in this segment. We have the only proprietary valve in that area called decellularized xenograft. No one else has it, no one else will. The Ross procedure is growing like crazy, and we're benefiting from that with our valve. The second category we report on is our sealants. This is where we have BioGlue. We have several large competitors. But in the cardiovascular sealant space, we are the #1 or #2 player and have been for a decade. If you move to our stent graft portfolio, we have no competition for AMDS. If you look at the frozen elephant trunk category, we have one competitor for NEO. We have launched a new product, NEO, which you hear about from Professor Shrestha. We are the fastest growing, and we're taking market share. If you look at the NEXUS, which is the arch technology, we have the only off-the-shelf device. The only -- the other competitors only have custom-made devices. If you look at the thoracoabdominal, it's kind of the same story. We've just launched the E-nside. You'll hear about that from Dr. Resch. We have an off-the-shelf device where other companies take 2 and 3 months to make products for their customers. And then last, but not least is our mechanical valve segment. We compete against the likes of Medtronic and Abbott and have taken 30 points of market share in the last 5 years with PROACT aortic and you'll hear about that from John Davis. So what's interesting about that picture, no company lines up like us. We are a leader in the aortic disease space already. And with our investment in our pipeline, we'll further extend this. The second thing we've been doing while we were building the portfolio is building our channels. Go back to the roots of the company 30 years ago, it was a tissue company focused on North America. With the launch of BioGlue in the next decade, they basically built a small team in Europe, and then it was just Europe and U.S. with BioGlue and tissue. That's what the company looked like when I got here in 2015. In the last 6 years, we've doubled the size of the company. We've expanded the product portfolio as I just showed you, and we've expanded it simultaneously into Asia and Latin America. Where that puts us today is we now have a sales team globally approaching 200. We have 6 channels in Europe and the U.S. We're still investing in Asia Pacific and Latin America. And what's important about this, I mentioned this earlier with the product portfolio. We're going to stop investing in Asia and Latin America because we're going to get to the size we need in the next 2 years. And then we do not have to invest incrementally going forward. That's extremely important to the cash flow generation of this company going forward. Once those channels are fixed, you've got a big part of your income statement that's fixed going forward. The next area of investment is the pipeline. I joined the company, as I said, around 6 years ago. We had one product in the pipeline PerClot. And we've obviously divested that to Baxter because it was not synergistic with our focus on aortic disease. What you see left there is $1.3 billion in 6 PMAs. All focused on the aorta in cardiovascular. Marshall will give you a deep dive on each one of those clinical trials. The next area of investment was in our factories. We've got 3 major platforms for our factories. We have our On-X factory in Austin, Texas; our BioGlue & Tissue in Atlanta; and our stent graft factory in Hechingen, Germany, which is just south of Stuttgart. We've invested about $20 million into Austin and Germany to support our growth going forward. We built a brand-new facility in Germany as well as expanded our clean rooms in Austin. We can double capacity in both those facilities. Those investments have already been made to support our growth. So the combination of that $700 million is a big investment. And our management team and our Board are committed to deliver on these investments. Our shareholders have yet to receive those investments come through, but their patients will be rewarded. And if you watch what I'm going to walk you through, you will see how that will happen. So next up, what are we going to do over the next 3 years? It's very simple. We have 3 key initiatives to drive double-digit growth. Number one, we're going to focus on our key products in our growth areas, On-X heart valves and stent grafts. You're going to hear from John Davis and Dr. Alexander on On-X . You're going to hear from Karl Will, our Head of Europe as well as our 3 physicians on stent grafts. And I think by the end of that, you understand how we can drive the growth in those segments. I've also already talked about our investments in Asia Pacific and Latin America. With all these acquisitions that we've made, we are bringing those products with regulatory approvals every day into Asia and Latin America as well as putting feet on the street over the next 2 years. We're expecting 25% to 30% growth out of those 2 regions over the next 3 years. And then the third bubble, we've got 2 PMAs under review with the FDA, PerClot and PROACT Mitral. And then following right behind that, at the end of '24, early '25 are 3 PMAs that generate almost $1 billion in revenue at 90% gross margin. AMDS in the U.S., NEXUS in the U.S. and PROACT Xa. Marshall is going to cover those last 2 bubbles. And what does this mean to our shareholders? This is an illustration of our revenue profile that we're shooting for over the next 3 years. We ended 2021 at $299 million in revenue. If you apply a CAGR of 10%, that gets you to $400 million. And if you go into the 4 segments, we think our stent grafts are going to grow in the high teens to 20%. We think On-X is going to grow 10 to the mid-teens. We think Tissue will grow in the mid-single digits, and we think BioGlue will be low to mid-single digits. That delivers you $400 million in revenue over the next 3 years. Finally, we will deliver very strong financial results. Let me focus you on the right side of the chart. This plan contemplates a 10% revenue growth 200 basis points increase in gross margin, taking our EBITDA from $44 million in 2021 to $75 million to $80 million in 2024 and dropping our net leverage from 5.9 to 3.0. Ashley Lee will go into a deep dive on all of those. If I can orient you to the left side of the chart, this illustrates the incremental creation of value over the next 3 years. Incremental revenue is $100 million from $300 million to $400 million. Gross margin with a 200 basis point increase takes you to a 69% gross margin or $69 million in gross margin. We will split that equally between the investments, incremental expenses to run the business and returning 50% of that to our shareholders. So I hope through the history of how Artivion came to be, you feel as passionate and excited about this opportunity as I do. So with that, I'd like to turn it over to John Davis, our Senior Vice President of Sales and Marketing, who's going to kick this off with a deep dive on On-X. Thank you.

Thank you, Pat. So we're going to talk a lot about the growth of On-X. You've already heard from Pat a little bit about the growth of On-X. I'm going to tell you a little bit about why this happened, the characteristics of the valve, the clinical activity that's going -- happening around the valve that's really driving this. So getting it right into the total available market that Pat alluded to and why we believe that, that is a very real market. So we believe that we have every right to get every patient 70 years and younger. And together, that constitutes a $720 million TAM split out between $610 million in aortic side and $110 million on the mitral side. Now you're going to come to understand through this presentation why we believe this is a very credible thing to go after and why we believe we deserve every patient under 70 years of age. So the story of growth that Pat alluded to over the past 6 years. You can see that we started at 24% share. We now are the market leader at 51% share. And during that time, we grew 13% overall. Now the rest of this presentation really is going to be why that happened because if you think about the aortic valve segment and the mitral valve segment, physicians do not like to change valves. Once they become comfortable with the valve, the last thing they want to do is change it. So this is a lot of heavy work getting from 24% share to 51% share, and it's going to take a lot of work to get further from 51% and up. But you'll see what will compel physicians to want to do this because they're not going to do it just because they think that we're nice people. So here is the material side of it. There's a material side of the story. There's a clinical side of the story. Together, they're going to -- it's a very, very compelling case Starting with the material side. You can see that on the On-X -- on the left-hand side, these are all characteristics of the On-X valve. On the right-hand side, all characteristics of all other bileaflet valves. So the first and the second one kind of go together, that is that the 90-degree opening. We are the only valve that opens, what you refer to as, all the way, so that it's completely out of the way of the flow of the blood coming through the valve. So with that 90-degree opening and the flared inlet at the bottom, and you can see #2 there, the height of the valve is much higher than any other valve in the space. And that flared inlet toward the bottom organizes that flow as you kind of see illustrated in #1 to the right there beside of 90-degree opening. Those 2 things together contribute to what is called -- referred to as a laminar flow or a less disrupted flow as the blood comes across the valve. And then finally, something that's very easy to see just by the naked eye, and that is the pure pyrolytic carbon and the surface of that carbon on the On-X side versus the silicon alloy pyrolytic carbon on the right. And it's easy to see. These are magnified images obviously, but it's easy to see how one would be far less -- have far less thrombogenicity than the other and it would be very much more difficult for blood cells to adhere to the On-X surface than to a silicon alloy surface. So all of these things together. When you put all of that technology together in one valve, that, along with the clinical side that we're going to talk about now is what's kind of caused our growth to this point and will cause additional growth into the future. So now to the clinical side. In 2016, the PROACT aortic trial was completed. And in that particular trial, it showed a 60% reduction in bleeding with a low INR of 1.5 to 2. Later this year, the PROACT mitral trial will be published and that shows a low INR of 2 to 2.5. Now you need to understand the relative nature of this. So the low INR of 1.5 to 2 compares with every other mechanical valve in the aortic space of 2 to 3. And on the mitral side, the low INR of 2 to 2.5 compares to every other valve of 2.5 to 3.5, okay? And INR is something we throw around as if everyone understands it completely. I know it's probably something you don't understand necessarily. INR stands for International Normalized Ratio. And it's simply a number that refers to how viscous our blood is, how thin our blood is or how thick our blood is. And so Dr. Alexander will get into that in a little bit. Finally, and this is what's going -- you've seen here -- and with PROACT aortic kind of what's fueled our growth to this point. PROACT Xa. This is what everyone we've talked to, every physician I speak to, they all say the same words. And in fact, they say it as if somebody has told them all exactly what to say, they all say game changer. And I really do believe it's going to be just that because you're going to go with PROACT Xa if we are successful and we are well enrolled in this trial, about 3/4 of the way there. If this is successful, you will go from warfarin which when you measure INR, you're measuring the warfarin levels. This will go from low INR to no INR because you're going to have a drug, in this case, in our case, Eliquis which will require no blood test, no diet restrictions and people will begin to live a normal life with a mechanical valve. And so they're no longer faced with a choice of get a bioprosthetic valve, you don't have to have Coumadin, but you're probably going to need another one. And then the old song of get a bioprosthetic valve, then get a TAVR valve, then maybe another TAVR valve. These are the choices that are currently being presented to patients. Think of what will happen when a choice is presented to a patient that says, you can get this valve and it will be your valve for life. And there is no blood testing, there is no diet restriction, you just take this pill. We believe that will be very compelling to people because every -- people refer to valves as it's a very benign choice. You get this valve, and you get a TAVR valve and you get another valve. All of those procedures carry risk. And patients are becoming more and more aware of this. And I think that all of the increased patient awareness, together with the possibility of PROACT Xa, we're already seeing physicians proactively begin to implant the On-X aortic valve just in the hope of PROACT Xa. So much more to come from Dr. Alexander on that in just a few minutes. So in other words, the same valve throughout all of this lifetime advancing indications because of the unique qualities of the valve, the material and design qualities allow this clinical progress to be made. This is a chart that you really have to understand because this is -- if I had one chart to say this is our thesis, this is it. And that is that if you go back to in the green section there, that is showing the original PROACT trial and where we landed in the sweet spot, if you will, from the INR of 1.5 to 2. So if you think about blood as it goes up the scale there, your blood is getting thinner. As the numbers go up, your blood is getting thinner. By the way, all of you are sitting here today at an INR of about 1. You're not at 0. Everyone is at 1, okay? So 1.5, you can -- it is not that much higher than you're sitting here today. So as you go up the scale, 1.5 to 2, you could see the sweet spot between bleeding because your blood -- as you go up, your, blood gets too thin and you just bleed versus a thromboembolic event, which is measured in the green there, going across the x-axis. So the thromboembolic event is a blood clot typically. So there's 2 types of strokes. There are hemorrhagic strokes and there are occlusive strokes. And we're talking about a thromboembolic event here. So if your INR is too low, you have a risk of a clot. If it's too high, you have a risk of a bleed. So we have the sweet spot here where you can see the red and the green lines meet, that's precisely where we run INR for the On-X aortic valve. So going forward, I want you to pay attention to this area around 3.5 to 4. And this is where all other bileaflet mitral valves are and the next section to it is where all other aortic mechanical valves are, okay? And you can see how that bleeding rate just shoots up the further you go. Okay. And the mitral side, you just saw the On-X aortic. Now here's the On-X mitral. The On-X mitral can be run at 2 to 2.5 versus all other mitral mechanical heart valves at 2.5 to 3.5. And you just saw what happened at 2.5 to 3.5 and the bleeding that increases very dramatically there. Being able to run a patient at 2 to 2.5 is going to allow -- and this is the last point at the bottom allow bridging to happen for routine procedures. This is a big deal for patients to have to go off of their medicine to go in to get a routine either dental procedure, colonoscopies and so forth that happen all the time. This will be a real impact there. The other one is if you look at where all other mitral mechanical are up at 3.5, that's called a range where overshoots can happen. So if you're supposed to be in 2.5 to 3.5, it's not unusual, it will go up to 4, and you can look back and see what happens when people go to 4. And how dramatically that pops up. So those overshoots are a real problem and this will keep those to a minimum because you won't be anywhere near that range with PROACT Mitral. Okay. So this is the slide where I think that we really illustrate where we believe that 70 and under that we absolutely deserve those patients and that those patients should think about the On-X aortic valve. These are the average ages on the Y-axis. This is the mean age at the time of implant. I know that's a little small. And then -- so you can see that the bioprosthetic valve is going to be compressed on both ends. They're going to get it from the top end from TAVR because TAVR is going to come down a little bit from where it is right now. That 73, that's been the mean age for all of the TAVR trials. And they have conflated 2 terms, by the way, the TAVR companies and that is low risk and young. They're not the same. But as they come down a bit, they will press on the upper end of the bioprosthetic valve market. We're going to compress it hard from the bottom because we believe that if you present a patient with a choice of getting a valve and rather than saying, "Hey, and if this valve doesn't work, if it doesn't last very long, then you can get a TAVR valve. We can say, "Hey, here's a valve you can have for the rest of your life and you don't have to do blood testing, your lifestyle isn't impacted. You have to take this pill". So that is why we believe that we have a TAM that we talked about earlier of $710 million in total when you combine the 2. And that is why we believe that On-X is going to continue that growth trajectory that I showed you in the early slide of 13%. We believe that's going to continue on the promise of the clinical trials that surround this valve and the unique design and materials that allow that to be possible. Thank you for your time. I'm now going to introduce Dr. John Alexander. Dr. Alexander is a Professor of Cardiology at Duke University and Duke Health. He's been a cardiologist there for 22 years. He has over 600 publications to his name. He has been involved in many medical device and pharmaceutical trials and has brought those to FDA and eventually to the market, a depth of experience, and we are very proud to have him talking today and affiliated with, in fact, the On-X aortic valve. Thanks, Dr. Alexander.

Thank you, John, and it's my pleasure to be here. I'm -- as John said, in my introduction, I'm a clinical cardiologist at Duke, I spend about half my time taking care of patients and the other half of my time running multicenter clinical trials. And I've spent most of my academic career actually on anti-thrombotic therapy. So the anti-platelet drugs and anticoagulants that John just alluded to. And I'm going to talk a little bit more about those in their relationship to valves, particularly mechanical valves in the next few minutes. Just another slide. Those are my disclosures, which I have always show. And I'm going to whiz through about 10 slides of background, and then I'll -- my last 2 slides are really about the design and current status of the PROACT Xa trial. So the aortic valve, as you probably all know, is 1 of 4 heart valves that sits inside the heart. It's the main valve that separates the left ventricle from the aorta. So the left ventricle pumps, blood goes out through the aortic valve to the whole body and then circulates around through the circulation. Aortic stenosis is probably the most common major valvular heart disease. There's really no treatment for aortic stenosis until it's end stage, and we replace the valve. So it's a -- it's a disease of aging in most people. It does -- there are some diseases of the aortic valve that make it occur earlier, but you get progressive narrowing of the opening of the aortic valve until you get severe aortic stenosis, which causes symptoms of heart failure and that valve then needs to be replaced. So aortic valve replacement. You've heard some about it. There's -- there are bioprosthetic and mechanical valves. That's one way you can lump them. And then the bioprosthetic valves can be placed either surgically or over the last 10 years by transcatheter techniques with TAVR. We think of these and most clinicians and the guidelines think of these as categories. But there's obvious, as you can just see on this slide, there's differences among the transcatheter, among the bioprosthetic and among the mechanical valves. And we've been increasingly interested in these differences in recognizing their importance to the longevity of these valves and to antithrombotic therapy that's needed with them. As you heard from John, the current guidelines in both the U.S. and EU recommend mechanical valves that last longer for younger patients, bioprosthetic valves for older patients with who have 10 -- the valves have a 10- to 15-year longevity, it's thought. And then an intermediate valve range where either valve is acceptable. In practice, there's been growing use of bioprosthetic valves. This is -- in this case, as a surgical bioprosthetic valves from -- Great Britain, particularly driven by more use in younger patients. These are data from the U.S., from the Northern New England database, patients aged 50 to 65. And you can see over time, a gradual increase in the use of bioprosthetic valves replacing mechanical heart valves for -- mostly for aortic stenosis. Now I'm most interested in the anti-thrombotic therapy that goes along with these valves. So transcatheter valves are typically treated with 2 anti-platelet drugs, aspirin and clopidogrel. Bioprosthetic valves are typically treated with aspirin with a short period, usually 3 months or either none or 3 months of a vitamin K antagonist, that's the drug that needs an INR to monitor it. And mechanical valves require vitamin K antagonist plus or minus aspirin. There's controversy over which patients need aspirin. Now it's really important to recognize that FDA approval of these devices requires a reasonable assurance of safety and effectiveness. And prosthetic valves are developed with an antithrombotic regimen that is arrived at through guess or extrapolation or historical what's worked for other valves. And the valve and antithrombotic regimen are evaluated together to have a reasonable assurance of safety and effectiveness. And there's typically no systematic evaluation and no requirement for developing an optimal antithrombotic regimen for each valve. And I started this, I mentioned previously that there's some obvious differences between these valves. Now it's also very important, as you've already heard, recognize that antithrombotic options are a major factor in surgeon and patient valve choice. And I think there's really 3 factors here. One that's driven this move from mechanical to tissue AVRs over time. One is a percutaneous option. I mean if patients can avoid surgery and get their aortic valve replaced, that's been intuitively attractive to patients. The second is short-term bias that most patients, when they're thinking about getting their valve replaced are thinking of now. I have a problem now. They're not thinking about 10, 15, 20 years in the future. Bioprosthetic valves typically last 10 to 15 years, we think. They're evolving faster than we can study them however, and mechanical valves typically last longer than the rest of the patients, so forever. And then the third one, which has been really instrumental in thinking about anticoagulants is what I term the worry associated with warfarin. And mechanical valves to date have all required anticoagulation with warfarin. So these are the guidelines for mechanical heart valves and anticoagulation. And in patients with a mechanical valve anticoagulation with a vitamin K antagonist that's warfarin is recommended. It is interesting that the most recent guidelines have started to tease out differences among the mechanical valves. There are older generation and newer generation valves that are highlighted. And the On-X valve there in that fourth row, as you heard from John, has a guideline indication for a lower target INR based on the PROACT mitral data. So this is just a slide about warfarin and why people are so worried about it. You get a valve and you'd like to -- you get a new valve and you'd like to forget about it. But warfarin makes you not forget about it. So you have to worry about the risk of bleeding. Warfarin has a relatively narrow therapeutic window where low INR is associated with thrombotic risk and a high INR associated with bleeding. There are more than 100 drugs that interact with warfarin and will change your INR as well as diet, particularly green leafy vegetables that we're all encouraging our patients to take. And so this all means that you have to have your INR checked monthly or more frequently forever. So that prevents you from forgetting about your new valve. This is not the case with bioprosthetic valves. So you've already heard about the On-X mechanical valve and why it might be different in terms of its thromboembolic risk. This is the PROACT Xa trial, which John alluded to, that studied patients who are considered at low risk with an AVR patient -- a cohort of patients who are at higher risk with a aortic valve replacement in a cohort of patients with On-X mitral valve and randomized them to different antithrombotic regimens. In the low-risk AVR that was clopidogrel and aspirin. Those are 2 antiplatelet drugs versus warfarin with an INR of 2 to 3. In the high-risk AVR, it was warfarin with an INR of 1.5 to 2 versus warfarin with an INR of 2 to 3. And then in the mitral cohort, INR of 2 to 2.5 versus 2.5 to 3.5. And this is the 2 AVR cohorts primary results. Shown on the left is the high-risk AVR cohort. Those first 2 bars are the primary endpoint, which is a composite of bleeding and thromboembolic events. You can see there's more than a 50% reduction in bleeding with the lower INR and no real increase in thromboembolic events. So those are the data that John showed you previously. In the low-risk AVR cohort you see something slightly different. There's more bleeding, first of all, with clopidogrel, showing that antiplatelet therapies is not really safe and you do need an anticoagulant. So antiplatelet therapy alone with aspirin plus clopidogrel does not prevent thromboembolic events. That yellow bar is substantially higher than that blue bar in the low-risk AVR cohort. So as you all probably know, there have been 4 new oral anticoagulants that have been developed, dabigatran, a factor II inhibitor and rivaroxaban, apixaban and edoxaban, factor X inhibitors. These drugs have been around for more than a decade now. I was very involved in the development of apixaban. It now has something like $10 billion a year in sales and is the predominant anticoagulant use for preventing blood clots in people with atrial fibrillation and venous thromboembolic disease. There has been some work done with apixaban in animal models of -- with mechanical heart valves. This is one study that was done suggesting that apixaban might provide adequate anticoagulation for patients with mechanical heart valve compared to standard warfarin. But animal models all have limitations. And so a couple of years ago now, Pat and others from then CryoLife now Artivion we met and put together the PROACT Xa trial. We're taking patients who have an On-X valve in the aortic position at least 3 months out from surgery. So everybody is getting warfarin for those first 3 months. We're going to enroll a 1,000 patients and randomize them to continued warfarin with an INR goal of 2 to 3, not the lower INR, but the higher INR. We can talk about that if you'd like, or to apixaban 5 milligrams twice a day, which is the standard apixaban dose that's used in patients with atrial fibrillation. We're going to follow the last patient enrolled for 2 years and accumulate more than 800 patient years of follow-up in each arm. Our primary endpoint is a valve thrombosis or valve-related thromboembolism. What we want to know is apixaban adequate to prevent thrombosis in people with an On-X valve. Secondary endpoint will include components of that and major bleeding. And we need to show that apixaban is at least as good as warfarin. So we have 2 co-primary analysis, one is a noninferiority analysis with an absolute margin of 1.7% per patient year, and the other one is a comparison of the apixaban event rate compared to an OPC criteria that is typically used for mechanical heart valves. So the status of PROACT Xa. We enrolled our first patient in May 2020, just around the time the COVID-19 pandemic was starting. PROACT Xa though is designed well to be enrolled during a pandemic and that it can almost all be done remotely. We have 56 U.S. sites opened. 52 are enrolling. We're just opening up the last 4 sites now. We were originally planning on going to Canada, but we ran into some challenges with that, so haven't. We have 627 participants enrolled as of a couple of days ago. It was 632 as of last night out of our 1,000 enrolled. Remember, these patients can be out from their aortic valve surgery. So about 44% are less than a year out, more than 3 months and less than a year out from their AVR and 56% more than a year out from their AVR. Our top enrolling site is the Mayo Clinic, but we have a number of other high enrolling sites from around the country. They are the same sites that put in a lot of aortic valves. And we currently have more than 450 patient years of follow-up. Our DSMB -- We have a DSMB that's looking at unblinded data. They last met in November. They will next meet in May. And so far, they've been telling us to continue the trial as planned. So I think that's it. I'd be happy to take any questions during the Q&A period. Thank you for your attention.

Thanks, John Davis and, Dr. Alexander. We've now got some time for questions, either on my topic -- the topics I covered, on On-X that John Davis covered or what Dr. Alexander just covered. We've got mics because this is being webcast.

If you have a question, just raise your hand and we'll get a mic to you, so you can ask away. We got one up here from Mike Matson.

Mike Matson, Needham & Company. A question for Dr. Alexander about PROACT Xa. So just given the pandemic, can you see any way that the pandemic potentially Covid infections and things like that could potentially interfere with the results. I mean if you control trials, you think it would kind of effect both arms equally in theory, but…

So the pandemic has obviously slowed us down a little operationally in enrolling the patients. I don't think there's any way it will meaningfully impact the results. We're collecting COVID infections as an adverse event. But we're -- and we're avoiding obviously, enrolling patients who have an active current COVID infection. But other than slowing us down a little bit from our original projections, I don't think so.

Okay. Got it. And then I think there was a comment made about PROACT Xa potentially already driving some increased utilization of On-X. So just wondering if both of you could comment on that.

Okay. Yes. I think that what's happening is that physicians are looking at this and saying that a few have said literally to me that I have a rough time imagining the conversation with a patient that I put in a non On-X valve in today with awareness of this trial. Because if it is successful, what I have done by putting in a competitive valve is I have relegated that patient to a life of Coumadin for sure. Whereas all I had to do was put in your valve and the possibility exists that they will no longer be on Coumadin, no longer have that issue. That's what's driving it now. It's just the awareness of it. We're not out promoting the trial, but at the same time, they're fully aware of it. They understand it. And it's that conversation that's driving.

Yes. And I want to make it clear, we obviously don't off-label promote. We're doing the trial because we need the data to get the indication to get the approval. But every meeting we go to it's on the podium and everyone is talking about it. So I think what John said is -- and it's hard, we can't measure it. They don't call us up when they implant a valve and say, I put this one in because of that trial, right? But clearly, people are thinking about it. Two other quick comments. One is we're enrolling people 3 months out from their surgery, right, in the trial. So the first 3 months are the same as standard care. So there are sites that are saying, "Look, this trial exists. I'm going to put this valve, and we'll talk about it again in 3 months." And so it's -- because it's an option for patients 3 months out from surgery. It's also an option, though out years from surgery. And one of the things about the way PROACT Xa is designed is you could have your valve implanted by a surgeon who's not a site and still be in the trial. We would just have to refer that patient to a site, but the trial can all be done remotely. And so there is some of that going on that sites that are not participating in the trial are still having their patients referred to the trial.

Suraj from Oppenheimer. Dr. Alexander or Dr. Davis, in the real world, do you envision risk stratification when, let's say, Eliquis becomes mainstream, is it for all with MHVs? Or do you see a world where there would be, Suraj is not most likely to have major events, and I would switch him to Eliquis, keep Coumadin for majority of the others.

So Dr. Alexander, why don't you take that.

So I -- we are studying people with an On-X valve in the aortic position with or without an aortic conduit. And we have very broad inclusion criteria. So I think if the trial is successful that this will support use of apixaban with the On-X valve in the aortic position in almost everybody. There will clearly be patients. Apixaban is not going to result in zero events. And so there'll be patients who have events on apixaban down the road presumably. And some of those might get switched back to warfarin. Warfarin will be used in everybody for the first 3 months, and there are some scientific reasons to think that might be necessary. The other -- it's also used in the first 3 months after bioprosthetic valve. It's used some of the time. It's advised by the guidelines to be used and it's probably used about half the time after a bioprosthetic valve. What -- I'll just extrapolate your question just a little. There are 2 other factor X inhibitors and I -- we won't know whether they are equally as good. That would presumably require some additional trials. These drugs will all be becoming generic in the next several years. So that will have a big impact on the cost. And then this is -- I do think that there's reason I think the FDA and the guidelines are likely to say this was only for the On-X valve. And I think there's good scientific reason for that. But I wouldn't -- they're already people using the NOACs for mechanical valves with no data for a variety of reasons.

If I could just one additional question. I'll ask the same thing a slightly different way. So bear with me. So let's say, Suraj is on On-X for, I don't know, a year, right? He's readily available to switch to be randomized, right? There is a certain amount of acute events that have already happened with Suraj. There are a certain amount of long events that will happen. So now Suraj is randomized to whatever arm, right? So the question is, how would you advise when we look at the data, you have X number of patients that were for months on Coumadin and the [ events ]. How would you advise we stratify and look through the data and say, "Okay, this makes sense. This is how it -- Eliquis, how to read through the data". I hope my question makes sense.

I think so. I mean the thing that I do think is relevant that we will be looking at. I mean it's early -- patients who are earlier and patients who are later. And so we have a preplanned analysis looking at people who are less than a year out and more than a year out, and we have about half of patients in each of those groups. We will inevitably slice and dice that more finally as well the FDA to try to understand is 3 months really the right length of time? Or should we be going a little longer with warfarin. So those are sort of exploratory analysis that we will all be doing. We will certainly look at subgroups of patients, a variety of subgroups of patients in the trial to try to understand, are there groups where the main results don't apply. Yes. I hope that answers your question.

Cecilia Furlong, Morgan Stanley. I wanted to ask just in terms of what you're seeing today and pull forward in some respects in terms of operators wanting to implant the valve on the prospect of being able to use Eliquis in the future. But what you've incorporated, Pat, also in your projections for the next few years? And how you think about kind of post potential extended indication how that acceleration might shift? Just curious -- the near term as well...

Yes, I can take it from a -- I mean we don't project in the numbers we show -- in the revenue numbers we showed you, we aren't projecting any off-label sales from PROACT Xa. We just don't do it as a company. Those numbers are all driven off of the chart you saw from John where we've taken significant share over the last 5 years off of PROACT aortic. We will continue to take share in that segment. We're about to launch PROACT Mitral and you'll see the same thing happen with PROACT Mitral, which is a continued share in that segment. So the 2 of those together give us that 10% to 15% growth and we've seen already. When you get to PROACT, and we've done market research on this, and again, Dr. Alexander can comment. He was involved with ARISTOTLE, the ARISTOTLE trial, which got approval for apixaban, Eliquis in the U.S. for atrial fibrillation. We already know the answer to that bleeding question between Coumadin 2 to 3 INR and Eliquis. Eliquis wins every time. It was 18,000 patients setting -- Marshall Stanton is going to show you that trial. So we know we're going to win on bleeding. If we tie or roughly noninferior on thromboembolic events, the market research we have from surgeons and cardiologists is this is a rapid uptake. We take the entire mechanical market overnight, and we take a big chunk of the tissue valve market. So he can come in from a clinician set. Maybe you ask the question this way, why would anybody stay on Coumadin if Eliquis is approved from a mechanical valve standpoint.

Yes. So I won't -- I don't think I'll comment on the -- how the market will react. But I think -- but I mean there's no bleeding question. I mean, apixaban will be safer than warfarin with an INR of 2 to 3. Remember, we already know that warfarin with an INR of 1.5 to 2.5 has 60% less bleeding than an INR of 2 to 3. And that has driven some change in use. Apixaban that will have a similar reduction in bleeding -- and if it doesn't have an equal effect on thromboembolic events, it won't get approved. So the whole question is does it prevent thromboembolic events the same way that warfarin does. If it does, it's a twice-a-day pill that requires no monitoring, has no food or drug interactions. We've seen in the Afib market that 4 people who can afford apixaban, warfarin is almost not -- or one of the other NOACs. Warfarin is really not used. And I think how quickly that would happen, I don't know, but it would happen

Follow-up as well on On-X Mitral. What you've seen over the past several years, just from a share standpoint? How you think about and expanded INR indication? What that does for the field? And then also what you're incorporating as well from On-X Mitral specifically in your 3-year outlook?

Yes. So we think -- I mean, I think the chart that John showed, maybe you can -- I don't know [indiscernible] if you can go back to the market share slide because I think it's really telling of what PROACT aortic did when we launched it. And I would also comment while they're pulling that up. When we acquired On-X, our reps were used to selling BioGlue and tissue valve. They hadn't sold mechanical valves. They now have 5 years of experience selling a low INR aortic valve, and we've taken 30 points of market share. They know all the surgeons, they know the valve inside and out. And a lot of our mitral valves are already on the shelves and consignment. So it's just spreading it to more surgeons and taking more share. So I think once that gets approved, we expect to see the same trajectory. And our assumptions are just that we take share this slide, right? So we launched -- we acquired the company in 2016, and we started at the low 20s. And I think the most recent data is even higher. So that's what you're going to see with PROACT Mitral. You've already seen the playbook.

You also had a question about market share. We're currently #2 in the mitral valve segment, we have about 44% of the market and Abbott has the rest essentially. So we like that position based on this chart. We think [indiscernible] comment.

Maybe just to kind of further -- John showed you this on the PROACT mitral side, right, which is important, actually, if I go back here, this is a really important concept. That gray box that 2.5 to 3.5, look at the bleeding 2.5 to 3.5. It's even more significant to take the INR down in that segment. And it's not so much and Dr. Alexander mentioned this, lots of things interact with Coumadin. So this concept of overshooting, you get the valve, they put you on Coumadin, and you shoot way above it up to a 5. Look at the bleeding rate. So if you can keep someone at a lower INR, you prevent the overshooting. And that's the -- when we've shown this data to our surgeons, I just make -- the mitral freaks them out because of the higher INRs. So I think it's even more compelling on the PROACT Mitral side than it is on the aortic side. At least that's what our clinicians tell us and the research we do.

This is John McAulay from Rick Wise team at Stifel. My first question for Dr. Alexander. I'm just kind of wondering, we're talking about the longer-lasting benefits in mechanical valves. But can you also walk me through kind of patient and physician reaction to the more invasive nature of the procedure as opposed to a TAVR occasionally bioprosthetic valve and how they kind of balance those 2 aspects when talking to patients and for patients wanting mechanical valve?

Yes. I mean patients go through this journey, right? So they -- for -- let's talk about aortic. So they have aortic stenosis. It progresses gradually usually over years, they're talking to a cardiologist about it that they're eventually going to need to have their valve replaced. Then that -- they come to the place -- time where they need to have their valve replaced with TAVR that is creeping earlier because there's a less invasive option. And TAVR really has changed the -- for older -- particularly for older patients, TAVR really has changed the clinical environment because patients have a natural tendency to want to avoid surgery. I mean everybody -- heart surgery is a big operation, and the TAVR procedure is a much smaller procedure. And so there -- I think there is this natural tendency, where that's a problem is in younger people, where you're talking about not one procedure, but you're talking about 2 or 3. Now that second one is 10 years away or 8 years, 8 or 10 or 15 years away. So it's hard for people to wrap their heads around it. But most cardiologists are comfortable talking to patients about that. And when they're younger patients, they then -- it's another step to involve the surgeons, right? The surgeons are not involved in these patients' care until patients are referred for aortic valve or surgical aortic valve replacement. Now actually, in much of the U.S., and I don't know the rest of the world as well, there are heart teams that are made up of surgeons and cardiologists who are doing TAVR. So the TAVR is actually done fairly frequent -- not infrequently by surgeons rather than interventional or structural cardiologists. So that does get them some plugged into the surgeon. The other comment I was going to make about apixaban just for a second is that the cardiology and to a large extent, the patient community are all familiar with it already. I mean cardiologists are using apixaban widely. And so it won't -- they think about apixaban a lot more than they think about heart valves and the same thing with the patient community.

Yes. The other point I would make is, remember, John showed you -- John David showed you the -- our focus is under 70, right? I think there's a couple of key points. When people say open heart surgery, a lot of these aortic On-X valves are going in, in a minimally invasive procedure. They don't crack the chest open anymore. They go through a little incision in between the ribs. So this idea of massive open heart surgery just doesn't exist anymore. Number one. Number two, there's tons of data out there. Bioprosthetic valves don't last long in younger people. So we're not talking about -- I think TAVR is a great operation if you go over 70. We're talking about the under 70 population, where they have a 20-year life expectancy -- a 65-year-old has a 20-year life expectancy. If they get a tissue valve, they're looking at tissue, TAVR or TAVR, TAVR and go to the cardiac meetings. They're taking these things out. So I do think from our data the idea of having one minimally invasive aortic value put in and being on a benign kind of an Eliquis, which also protects you from atrial fibrillation and about 1/3 of those bioprosthetic patients are going to eventually get atrial fibrillation as well. So there's a lot of reasons why this is kind of a sweet spot between kind of 60 and 70 for On-X with Eliquis.

That's helpful. And one more, Pat, I just want to follow up on the Asia, Latin America expansion. Can you walk me through how big do you think the sales force needs to get there? What more do you need to add? And just a little more detail on maybe what products are driving the growth there?

So maybe Brian, if you can go to the channel slide. Yes, we -- actually, our Head of Regulatory is here right now. I mean we've got a number of approvals. So if you think about that portfolio I showed you. When I started with the company, we had 1 person in Asia Pacific and nobody in Latin America, right? So it's like -- it's literally a greenfield exercise. We've now got 25 in Asia and 10 in Latin America. The bigger investment is going to be in Asia Pacific. Latin America -- and we've got great leaders in both places. Latin America will probably add another 5, I guess, maybe get to 15%. Asia Pacific is going to double to like 50. And the reason is we keep getting approval. I mean last year, we had nothing in Australia. And we got all of our key products. We got our NEO approved, our E-nside approved. So we got to actually add the channel. We go direct in Thailand with 1 rep and he has the entire portfolio and the payback period is like a quarter. So and the guy who's running that -- worked for me at Medtronic and ran Asia for me, so he knows exactly what he's doing, is it's super aggressive. So it's really going to be more disproportionately weighted to Asia Pacific. But those 2 regions, we think are going to grow 25% to 30% on the backs of feet on the street and product approvals. Okay. We're going to -- we're kind of at our Q&A session. Dr. Alexander, thank you very much, John, thanks very much. If you can move me up to Karl's slide.

So I now have a pleasure to introduce Karl Will. Karl and I actually worked together. I ran Vascular for Medtronic in Europe 20 years ago, and Karl was my country manager for Germany. He's a -- he spent 22 years at Medtronic in their stent graft arena as well as their heart rhythm arena, a true sales pro. He's our Head of Sales and Marketing for all of Europe. We hired him in the middle of the pandemic, actually at the beginning of the pandemic. He started -- supposed to start on like March 13, 2020. So he's had his whole career with us under the pandemic and he's done a fabulous job. So without further ado, Karl, come on up.

Yes. Thank you very much, Pat. Yes, it's a great pleasure for me to show you our stent grafts and stent grafts portfolio today. Here we are. So as you already saw from Pat, we have the most comprehensive endovascular portfolio. And what do you see on the left side is the aorta and what you can see is we are the only company who has technology to treat the full aortic portfolio. Just to guide you a little bit through the endovascular discussion we have today, we divide in the blue segment above, you see the Aortic Arch Solutions, how we call them. By our products, AMDS, E-vita Open NEO, NEXUS and E-nya. And then we make the split to the abdominal solutions down below in the green, that's E-nside, E-tegra, E-liac, and E-ventus. Coming to the numbers, like you can see in 2017, we acquired JOTEC facility based in Hechingen. And in '19, we did the major investment for Endospan coming with the NEXUS device and then in the middle of the pandemic, which you can also see the dip, we acquired a Ascyrus Medical with the AMDS device. And you can see our journey just began. So a CAGR of 12% during the last years. And this is, as I said, like just the beginning of a great adventure. You see on the next slide now. We go a little bit more deeper into the pathologies. So we are now talking about Aortic Arch Solutions. And you can see on the left, AMDS, our recent acquisition. It's for acute type A dissections. So patients who need treatment time is very critical. So we have a very easy solution, quick solution. And we have the great pleasure today to listen to Professor Kempfert from the Berlin Heart Center, which is the biggest one in EMEA. He has treated most patients, about a little bit more than 100 patients already with AMDS. So we will have a deep dive later today for this game-changing technology for those patients. In the middle, you can see the frozen elephant trunk, the E-vita OPEN NEO device. JOTEC has been the innovator and founder for this technology back 20 years. So we are now talking about the third-generation, the E-vita OPEN NEO, and we also have the pleasure today to hear Professor Shrestha with more details. Professor Shrestha from the Medical School of Inova was one of the founders in cooperation with JOTEC for this great technology. And then on the right, you see the NEXUS device, which is the endovascular solution for the same patient. So we are talking about same patient group. We have all technology in our hands to treat all patient disease in the aortic arch. I think this is the most important part is the game-changing technology we have here. And this is the marketplace. So if you look at the marketplace, you see there's only 2 companies competing with us. It's Terumo and Cook. You can see AMDS, we are very alone in this market, which is great for us. It's a great, easy solution, a good technology, and we see for the first year, in the middle of pandemic, we have a growth rate of close to 60%. And given the regulatory hurdles, especially also in EMEA, we are -- we have 7, 8 years in advance of any competitor who can come to the market. Then we see the hybrid, frozen elephant trunk system. You see Terumo is the 1 company competing against us. It's an old technology. We are the leader in this technology. We could show a growth rate of 60% also in the middle of the pandemic to launch such a great device. And then on the right side, it's NEXUS, NEXUS is the endovascular approach. So no hybrid operation. You put it in via stent graft. We showed an 85% growth rate also during the pandemic. We have Terumo and Cook, both have technologies in this segment, but both of them cannot provide anything off the shelf. It's all custom made, which takes time. And I said, for those operations, time is critical. It's crucial. We have it off the shelf. Whenever a physician sees a patient, he gets the device immediately. So we can ship this device directly off the shelf. Now switching to the abdominal stent grafts by category. So if you now look, we are starting on the left side with the thoracoabdominal. We will show you a dedicated or Professor Resch, who is here from Copenhagen. He's the endovascular specialist worldwide. He will show you the E-nside results and we will have a deep dive later on, on this technology. It's worth mentioning from our perspective is we have precannulated stent graft which decreases the operation time. As I said, time is critical here. it's very easy and simple solution. We will have a deep dive from Professor Resch today. Then we also compete in abdominal space with E-tegra, our AAA system. And then we have E-liac, we can also treat iliac as well, as you can see. Now if you look at this market space, it's a little bit more crowded in the arch solutions. So we see Terumo, Medtronic, well known, Gore and Cook. And let's say, and start from the left side, the thoracoabdominal part. So we offer as I just said, E-nside off the shelf and the only company who can compete with us is Cook. They also have an off-the-shelf device for the AAA which is 10 years old. So we are in advance and we have here the precannulated wires, which will help us. And then on top of this, we have the tailor-made solutions for every patient. So custom-made for thoracoabdominal devices where also Cook is competing with us. You can see on the growth rate, we have 43% growth rate last year in those segments combined. It's the same patient, you can treat them either off the shelf or as a custom-made solution. And then you see the abdominal space E-tegra. We're also competing there. It's quite a busy place, but you can see we're growing 17%. We are gaining share there. Those key differentiating technologies open doors, which is very important. And then not to forget, iliac, E-liac is a great device for us, Gore and Cook in this area and we can treat all patients for the full aortic space. We just had a look on the technology we provide. And as I said, it's a core differentiated technology. What is also important is that we have a dedicated and very skilled play for us. So we have 32 cardiac reps and we have 66 vascular reps. They are well trained and certified to partner with our physicians and they provide good support, daily business there in the OR helping to get a good outcome for our patients. And as you can also see on the -- we are direct in all big markets. So all European markets, we have direct access to our sales force. And with that, I would like to introduce to you, Professor Kempfert from the Cardiac Center in Berlin. As I said, it's the biggest cardiac surgery center in EMEA. He has more than 20 years of experience in cardiac surgery. He has about a little bit more than 160 publications. He's the specialists for AMDS. He has treated the most patients worldwide with AMDS. And with that, up to you, over to you, Professor Kempfert.

Thank you. It's my privilege to take you through the details of the AMDS device. And before we do so, I think it would make sense to first focus on the disease that we are addressing here to get everybody on the same page. So what is actually an acute aortic dissection. Basically, it's a problem of the aorta, which is the main arterial vessel in the human body. And the problem originates from a tear in the inner wall of this vessel. This will lead to the blood flowing through the tear, and this is going to disrupt the aortic valve layer leading to the formation of 2 parallel flow patterns. And then we see 2 lumen. One is the good one, which is a native vessel lumen, and the other 1 is a bad guy, which we call the false lumen. But the incidences reported to be 2 to 16 cases per 100,000 persons per year, most likely the true incident is actually even higher. And the acute type A dissection is clearly an emergent disease. So the mortality without surgical intervention is 2% per hour. So in other words, after 48 hours, 50% of the patient not treated are going to be dead. And just in 2020, the CDC reported 12,000 Americans that have died due to an aortic dissection. So it has been known basically since ever. So King George was the first on autopsy to be found with acute dissection. There are the quite famous people who suffered from this John Ritter, Prince Diana due to a car accident that led to a tear of the aorta. And then also Michael DeBakey, which is one of the most famous cardiac surgeon that tragically spent his whole life treating these patients, also doing a lot of research on the aorta and then suffered the type A dissection himself. So why is the acute aortic dissection acute or deadly. So there are 2 mechanisms that are going to lead to death. One is aortic rupture. I think this is almost self-explanatory. When the tear in the wall gets transmural, the patients are either going to lead to death within minutes or they will die from a thing that is called pericardial tamponade, which is basically blood in the pericardial sac, which is going to compress the heart and prevent adequate filling of the heart. The other problem is the phenomenon called malperfusion. So this is going to be expected in the 30% to 55% of all acute type A patients, and this is going to lead to a 5 times higher mortality. So the mechanism that has been illustrated on the right is that the true lumen gets compressed by the membrane, so the new membrane that is now visible in the aorta and this is going to obstruct the lumen. So it will going to obstruct instruct the blood flow to vital organs. And this can basically affect any artery in the vascular tree. So if it is problem with the corona arteries, we are going to expect acute myocardial infarction. If it's the vessels feeding the brain, you'll get a stroke. If it's a visceral arteries, you're going to die from organ failure. And if it's a peripheral arteries, you're going to suffer from paresis. So what is actually the standard of care. So the surgical standard of care to treat acute aortic dissection. So typically, this is a procedure which we call hemiarch repair. And you can see the illustration on the right. Basically, the surgeon is going to replace a short segment of the aorta, the ascending aorta. And this is a life-saving procedure. However, and this is nicely visualized on this image here. It's only going to treat the proximal part and the rest is going to be left untouched. So the arch and the descending still have these 2 lumens supports in the true one. Based on the STS database, the problem in addition, is that an average American hospital is likely to perform 3 of those emergent procedures per year only. And only 11% of centers perform 10 or more cases. So the problem is the acute issue that needs urgent surgical repair. However, the expertise is not really there most of the time. So you're going to be faced with an emergent procedure that has to be done by whoever is on call, which most likely is not going to be a specialized aortic surgeon. Part of that explains why the mortality for these patients, even if surgically manages is still high. The literature usually reports number 17% to 26% here, and there's a clear correlation as in most diseases between the hospital experience and the mortality rates. Another problem that is adherent to the standard of care. It's something that we call DANE, the distal anastomotic new entry tear. And this is what is illustrated here on the upper right. This is basically a leaky anastomosis or a leaky connection between the surgical graft and the remnant of the dissected arch. And this is going to pressurize the false lumen and this is going to lead to problems down the road. So the fourth -- pitfall of this standard of care for the hemiarch procedure has been explained, the so-called DANE, the pressurization of the false lumen, which is going to lead to growth of the aorta and this is going to require second procedures. And also, it's a problem of the early unsolved malperfusion, which is going to lead to mortality. So here, you see a typical patient example, status post standard of care. So status post nonprotected hemiarch procedure and the DANE so the leaky anastomosis is going to pressure after false lumen, so consequently, the arch is going to grow, and this patient is going to require open heart redo arch replacement. This is the same phenomenon. And at this time, it's better visualized by a 3D construction of the CT scan. And altogether, you have to expect a 50% of the survivors of the initial procedure are going to either require reintervention or going to suffer from malperfusion or aortic growth. So definitely, the current solution that we have, the standard of care is not perfect. So what are the alternatives? The one option that is a very elegant technique is to be more aggressive and to replace more than just the tiny piece of the ascending aorta. So you need to take the whole arch and then put that hybrid prosthesis, so called frozen elephant to replace the arch and stent [indiscernible]. And so this is a beautiful and very effective procedure. It only can be done in highly specialized centers as this procedure is really technically complex. So it is not very well suited for the average patient that is going to come in the middle of the night or a weekend and has to be taken by whoever is on call and Professor Shrestha is going to give you more insight into this frozen elephant technique in a minute. So our algorithms in Berlin is that all the patients that we have to treat on an emergent basis for acute type 1 dissection. If the entry tear is in the ascending. This is 80% of all patients, we go the other route. We go for a standard procedure, but we add the AMDS, that we're going to show you in a minute. And only those that have a clear tear in the arch are going to receive that more aggressive frozen elephant trunk procedure. So this brings us to the frozen -- to the AMDS concept. So the idea of this device is that it's going to secure and expand the true lumen, so the good one to resolve acute malperfusion. It also should help you to seal the anastomosis or the connection between the surgical graft and the tissue to avoid a problem that is associated to the DANE. It definitely should cut complexity compared to frozen elephant trunk procedure to be suitable for emergent procedures, and it should hopefully induce positive remodeling, so it should avoid aortic growth down the road. So this is how it looks and is more schematic illustration on the left and an actual patient example on the right. So this nitinol stent is going to reopen the true lumen and it's going to seal in the arch and also going to help for the remodeling over time. So I would like to present you a case example of the AMDS usage. So this is a patient 65-year old truck driver that experienced sudden chest pain at work. And then he had acute syncope and he had left-sided hemiparesis. And on the CT scan, you can see that the carotid, so vessel feeding the head was occluded. You can see the device is the interoperative setting. We are already on pump. We opened, we dissected aorta. And you can see now the insertion of the device, which is relatively straightforward. So it's super easy to just insert device and then continue with the standard procedure, which is the usual hemiarch. So just a kind of an ascending replacement. Here, you can see how the device is inserted. Now in the next step, it is typically fixate at this desired position. This is done by a couple of standard self-supported sutures and then the only thing you need to do is to pull this green suture here, which is going to release the stent in the arch and the descending. Then the delivery is taken out. And now it is a standard procedure just continuing this suturing to complete the sandwich, how we'd like to call this. You can see the nicely opening of the stent relaminating the arch and from the inside. And now in the next step, the surgeon needs to suture a standard surgical graft. This is the usual step that everybody would do in a standard of care procedure. So now here, you can see the postoperative result. We had an immediate angiogram, so to check that now the head vessels are reopened again, and this shows very good results also in the CT we see a good result in relaminating the descending and also the arch looks pretty okay. Unfortunately, this patient had uneventful further course. Okay. So with this patient example I hope that you'll get a better idea on what this device actually is about and how easy it is to use. So let's focus on the time line and the current experience so far. So the first patient was implanted in Canada 2017, then after that it was the so called DARTS trials. So the DARTS trials was prospective trial that aimed at market approval was conducted in Canada and Europe. And then finally, 2019, the device received CE Mark Approval for Europe. Then the DARTS follow-up patients or the data has been published very recently and also the 2 years and 3 years data are now going to be presented. And this promising result creates a real noise within the community and everybody got interested in this new option. Obviously, at that time, CryoLife acquired the device. And now very recently, the FDA approved the upcoming PERSEVERE trial aiming at approval for the U.S. market. So just let me show a little bit of a comparison of the data that we have so far. On the right side, you see the data from that DARTS trial. And on the left, you see the typical outcome that is reported in the literature with the standard procedures. On the left is the standard procedure from standard of care; on the right, the data from the AMDS DARTS trial. So the patients were very relatively comparable in regard to the preoperative status. You can see malperfusion. 56% of patients had that, that were enrolled in the DARTS trial to quite sick patients, obviously, they all had acute type A type 1 dissection. So the overall operative mortality was quite acceptable with 13% given the nature of the disease. Especially promising was the malperfusion-related mortality, which was only in 7.7%. And this, obviously, is due to the fact that 95% of patients could be treated in a single-stage approach to resolve their ongoing malperfusion issues. Now coming to the experience that we have now in Berlin. So since these early days, this procedure has become basically a routine approach in our program. And now we have more than [ 120 ] implantation so far. And what is important that there's not only a very few -- a small group of dedicated surgeons that use the device basically, everybody who is on call and has to take on these emergent procedures happy to use the device as it is very easy to use as it has been tried to demonstrate it, and it has become a routine procedure since then. So this data that we have now collected with this device has been presented at the STS, in general, very recently. So the key outcomes are that we again have seen a high percentage of resolution of the malperfusion issues and also a high percentage of patients on the CT follow-up to demonstrates the full false lumen thrombosis. So in other words, the bad version of that lumen is thrombosed and only the true lumen is patent. So in our experience, we can say that the hybrid arch AMDS repair is a procedure that is quite safe. And most importantly, it's reproducible and very easy to teach or to start with. And this is due to the fact that it really does not have much technical complexity to the standard of care. So in other words, it only will take you 10 minutes longer compared to what you have been used to do the last 20 years. So there is going to be a DARTS post market registry. So this is ongoing, and we expect to include up to 100 patients from Europe and Canada. And obviously, this registry is going to follow up with the usual endpoints and the follow-up is going to be planned up to 5 years, including yearly CT-based imaging. Now the U.S. trial is going to start very soon. So this one obviously is meant to assess the safety and the efficacy of the device in the acute type A setting. It's a prospective non-randomized, single-arm, multicenter study. They plan to include 25 sites in the U.S. and the National PI, you can see here from the University of Pennsylvania, and a target at enrollment of up to 100 patients. And the objective, obviously, is to demonstrate a clinical meaningful reduction or improvement in the early and also midterm 1-year outcome compared to published literature of the standard repair, which is obviously the hemiarch procedure. With that, I would like to thank you for your attention. You can see all the references that I have used here in the hand out as we're going to have in the PDF version later on. Thank you.

Yes. Thank you very much, Professor Kempfert. And now I have the pleasure to introduce to you, Professor Malakh Shrestha from the Medical School of Hannover. He is one of the pioneers of frozen elephant trunk technique. He is 20 years in this business. He has more than 180 publications on this topic. And he will move during this year to the Mayo Clinic in Rochester. Professor Shrestha, we are very happy to hear you. Unfortunately, you are not here in person, some issues with the traveling. So over to you, Professor Shrestha.

Thank you very much, Karl. So very good morning from Germany. So I'm Malakh Shrestha. So I'm going to talk about the E-vita NEO frozen elephant trunk hybrid graft. So I do not have any disclosures for this presentation. As Karl said, presently, I'm Professor and Director of Aortic Surgery in Hannover Medical School as well as the Vice Chairman of the Department here in the University. As of fall, I'll be joining the Mayo Clinic in Rochester as Professor of Surgery and Director of Aortic Surgery there. So when we talk about the diseases of the aortic arch, so Joerg Kempfert just told you about acute aortic dissections. So basically, there can be 3 types of diseases in the aortic arch, which is the main artery coming out of the heart here. So 1 could be the dissection, which is the tear acutely, but if some of the patients do survive this acute phase. And later on, it becomes chronic. So this is 2 diseases. The third one is dilatation which means that normally, aorta is about 2.5 to 3 centimeters in diameter, but in some of these patients due to congenital diseases or hypertension it can go on to become 5 or 6 centimeters and then the danger of rupture occurs. So the indications for replacement of the aortic arch would be in acute dissections because that's Professor Kempfert already talked about, 80% of patients die within the first 2 days if they are not operated. And of course, in acute -- chronic dissection, the same thing and in acute, in any reason, if the diameter becomes more than 5 centimeters, the danger of rupture occurs, so have to operate them. But if you look at this data coming out of Japan, acute aortic dissection is more common than previously thought. So the CT scans in postmortem -- CT scans in patients who died, who were thought of the death being due to cardiac arrest turned out to be acute dissections in 8% of these patients. So this is more common than we generally see in literature. And aortic arch aneurysm the dilatation of the arch is at least about 5 to 10 per 100,000 person years. So this is also -- although it's not that very common, but still also a significant number. If you go back in history, the first ever heart surgery was done by Dr. DeBakey and Dr. Cooley way back in the 50s in Houston. In those times, the mortality of the perioperative stage was about 50%. Of course, it has been a lot better now. There are different ways to treat the arch. A lot of surgeons have their own ideas. So this is a list of the different techniques that you can do. I'll go through them very quickly. One of them is the so-called trying to replace the whole of the ascending arch and the descending aorta through this huge incision. This technique was proposed by Dr. Kouchoukos, he was in St. Louis. But his excellent results have not been able to be reproduced by any other surgeon in the world. So that's why this technique has not gained much widespread use. The other technique is so-called the 2-stage procedures with the elephant trunk procedure. It was started in Hannover about 40 years ago, but the patient needed to operate it twice, once from the in front replacing their ascending in the heart. And then in the second stage from the side, besides the lungs, we had to replace the whole descending. What we found out that was way back in 2011 when I did this study following the 30-year results of all the patients that had ever been operated in Hannover, we found that during the first days of operation, the mortality was more than 17%. And in between the 2 stages, of course, we lost several patients, and then you had to operate again from the left side. And again, the mortality was 7%. So altogether, you have 25% to 30% mortality. So that's why in 2001, as a first in man worldwide in Hannover. We did the first so-called frozen elephant trunk technique. This is a special graft. In those days, we did not have any prefabricated graft. So these were custom-made grafts, where we -- this graft had partly. The first part was not stented. It's so the Dacron graft, and the second part was stented. So in certain group of patients where there was this dilatation of the descending order, which you can see in these diagrams that you could operate from front and treat the patients as a single-stage procedure. So later on, of course, different grafts came. And here, the JOTEC, which was bought by CryoLife, which is Artivion now, developed the first-ever prefabricated graft and needs to revolutionize our -- the way that we could treat the patients. Several years ago, we also published our data over the last 15 years from 2001 to 2015 with all the patients we had ever done, and it shows that the in-hospital mortality has gone down to 11%. Mind you, it used to be more than 50% in the [ 15 ], but this was until 2015. We also found out that in aortic dissections, which Joerg Kempfert previously spoke about, if you do with a frozen elephant trunk, then you can see that in the postoperative CT scans, the disease was totally eradicated in all of the survivors. But having said that, as Professor Kempfert said that for doing a frozen elephant trunk in acute dissections demands a high level of technical skill. That's why usually this type of surgery is done only in big centers. But having said that also, if a large number of patients do come to these big centers and here, we can offer them this type of surgery because we know that the elimination of false lumen is 100% in this group of patients if you use the frozen elephant trunk. That's why now the European Association of Cardio-Thoracic Surgery brought out this position paper where I was first author several years back, has been also proposing now that one can do a frozen elephant trunk in acute dissection in selected patients. A couple of years later, again, the European -- together with the European Society for Vascular Surgery, ESVS, has again brought off the second position statement. Here also now the frozen elephant trunk has been proposed as -- where to treat the patients in acute dissections in certain patients also. Earlier, last year, the EACTS brought out this position paper about the treatment of acute aortic dissection. This is the first-ever paper that has been published by any society about acute aortic dissection. And I was honored to be part of it. I was the only -- European surgeon in this group. There was one other Japanese surgeon. Otherwise, most of the surgeons were from U.S. or Canada. In this paper, it's clearly now that -- said that in acute dissections in certain group of patients, you can see #2 here that frozen elephant trunk maybe reasonable to be used in acute dissections. But having said that, I want to show you this picture for Mount Everest. This is a true picture from top of the Mount Everest, where about 200 to 300 people now can climb Mount Everest, which is almost 30,000 feet. And this guy has climbed the Mount Everest for more than 25 times. And he says that he's working to bring normal people, not a highly skilled climber, but normal people top of the Mount Everest and bring them down alive. The way he does this is try to standardize everything, putting ropes and ladders all the way up. So this is similar to what we try to do to standardize everything and try to reduce the mortality, which used to be about 50% 50 years ago, now it's down to 5%. And this is only possible because we have devices like -- can you please show me the other slide, please? Yes. Thank you. So you have these new devices, the E-vita NEO, which came up about 3 years ago, which has really revolutionized our -- the way that we treat the patients. You can see that the graft, this is the stented part on the upper side. On the lower side, it's the unstented part. It has 3 branches for the 3 branches of the [ superior ] vessels, the right and the left outreach to the brain and the left artery to the left arm. And there's another 1/4 for the heart-lung machine to perfuse the whole body. This is a special branch in the sense that the proximal- and the distal-centered parts can -- are available in different sizes. For the surgeons, it's important that there's a sewing color, which simplifies the suturing of the distal anastomosis. It's very important nowadays in the days of COVID, that there are no animal products are used, which is used in the graft made by the competitor, by Terumo. And we always had a problem that after 2 to 3 days, the patients used to have fever, and we were never knew whether it was due to the reaction of the body to the animal products or it was due to infection. This has been eliminated in this graft. So this is a big plus point, for me at least. And the second is that the stent itself, it's a best-in-class. The stent is way better than the other graft. That's why actually I was one of the, I would say, co-inventors of the other graft, which was brought out by Terumo. But since -- as of last year, I totally switched to this graft in Hannover. Can you go back? Now please show the video, please. So in the video, you'll see that -- because we -- can you show the video? It shows how innovative it is, how easy it is to deploy this stent. Can you please show the video, please? Hello?

The video is playing now. [Presentation]

Okay. So in conclusion, I have to say that, of course, there is no technique that can reduce mortality to 0% in this type of complex surgeries. But in complex aneurysms, E-vita NEO frozen elephant trunk procedure potentially allows for a one-stage repair. And if we do need a second-stage procedure because of this innovative stent, even endovascular repairs are possible, which Dr. Resch is going to talk about later on. And in acute dissections, the frozen elephant trunk would really eliminate any redo surgeries in the heart and descending. But having said that, of course, this involves a high level of technical skill. In chronic dissections also, the first lumen thrombosis is also favored by the stent, and it really helps in treating these patients. But for us, as certain, the E-vita NEO has really added to the armamentarium to treat complex aortic heart diseases. As of now, of course, this graft is only available in Europe and outside of U.S., I'm hoping that once I join the Mayo Clinic in fall, hopefully, that we will be able to do clinical trial and get the FDA approval as soon as possible because I really believe that this graft is the best-in-class right now. Thank you very much. I'm happy to take your questions.

Yes. Thank you very much, Professor Shrestha, for this impressive presentation. I'm now really happy. We are leaving now the cardiac surgery area. So we are now going to the abdominal space. I'm really happy to introduce to you Professor Tim Resch from Copenhagen. He worked at Cleveland Clinic as well as in Sweden. He is the specialist for endovascular techniques, and he has more than 200 publications on this one and more than 20 years of experience in this area. Tim, please come up. Thank you.

Good morning, everybody. Thanks for having me here today. This is the first picture of me in a tie that I've seen in almost a decade, clearly photoshopped. It's a pleasure to be here today. And I'm going to talk a little bit about the E-nside TAAA device and little broadly about complex aortic aneurysms. These are my disclosures relevant for this. And for those of you who are feeling that lunch is approaching rapidly, this is the sleep summary. So this is the take home of the whole shebang. The complex erotic aneurysms are increasing in frequency and the current surgical therapies, as I will show you, are not minimally but actually maximally invasive, but mainly invasive. And vascular repair offers a lot of benefits and off-the-shelf interbranch endograft is a versatile solution in this field. So about 40,000 cases of abdominal aortic aneurysms occur in the U.S. annually. That's about 10,000 to 100,000 a year, and that's actually the 13th leading cause of death for males, up -- in the U.S., about 15,000 deaths a year. If one of these things rapture, the survival rate -- even if you do come to the hospital and have surgery, the survival rate is only about 5% to 10% in the total cohort. There are many causes of abdominal aortic aneurysm and thoracoabdominal aortic aneurysms that are slightly different from what we've heard in the thoracic arena. Obviously, comorbidities were an [ elderly ] population. So the mean age of our patients now that we treat for this is 77, 78 years old with significant comorbid conditions. A lot of them are heavy smokers. Obviously, there is a genetic component to this as well. You inherit good things from your parents, but also things that are less good. And then there's always the roll of the dice if you're the unlucky one in the field. What we do know for thoracic and for complex aortic disease is that it seems to be increasing over time, specifically in females actually in this arena, but also in males. And this is the study out of Canada a few years back. So what is complex aortic aneurysm? Well, we sort of define it as everything of the aorta involving a branching vessel. All the straight segments of the aorta are reasonably simple to deal with, if you want to put it in that perspective. The ascending aorta, as we've heard of it, you only have to deal with it and not the next vessels or the thoracoabdominal segment, where all the visual vessels are involved. And for the thoracoabdominal segment, this is the classification we normally use for this, and this is based off of the Crawford classification 1 through 5 actually now that is relevant, where type 2 is the most extensive encompassing the whole thoracic and as well as the abdominal aorta and then to various degrees. So the treatment options available to us and our patients for these complex aortic thoracoabdominal aneurysms are basically 3. You can do best medical management, which means treat all the other diseases but not the thoracoabdominal aneurysm, because there is no best medical management for these patients. You can do open repair, and we'll go through a little bit of that. And then the main topic here, of course, endovascular repair. So what affects what treatment you choose for your specific patient? Well, obviously, the morbidity and mortality of the procedure that you're offering to patients both in the short and the long term and also the durability of the procedure. Even though most patients are mostly interested in getting out of the hospital are not so interested in what's going to happen in 5 or 10 years with these. So best medical management in this setting is basically controlling blood pressure. And we know from studies, this is Crawford, the man behind the classification, who already in 1986 published this with this very extensive experience that the 2-year survival in TAAA patients with conservative or best medical management was only about 24%. So a very dismal prognosis. And this is has been repeated and shown several times. This is a study actually out of Scotland, 200 patients, where half of them are unsuitable for open repair, half of them didn't want a repair. After 11 month follow-up, 1/4 of the patients were dead and half of those patients due to aneurysm ruptured. So a very lethal event. And we do know for AAAs less benign that an unoperated cohort of patients, the survival is significantly less than in a match population without an aneurysm. So open repair for thoracoabdominal aneurysms. Some you might want to close your eyes, but this is what we're currently offering our patients, and this is the standard of care in this field. So to reach the thoracoabdominal aorta, you basically have to make an incision from the pubic bone up to the left scapula of the patient and then left lateral to cubital position as you see here. So this is massive, massive surgery. These images that I show you here are actually from Joe Coselli, probably the most experienced open surgical -- open surgeon in this in the world at the Texas Heart Institute. And you can see the magnitude of this incision. As a vascular surgeon, you would like to think this is a beautiful operation when it works. But in the best of hands, and Joe's hands are the best, this is a 10% mortality for these patients when they come off the table for these most extensive aneurysms, plus about a 10% spinal cord ischemia rate leaving the patients paraplegic. This is from Mark Schepens out of Belgium, one of the most experienced operators for open repair in Europe. And he's shown that if you can actually sustain the initial hit, your life expectancy is still significantly less than a matched population as shown in this slide. So what about endovascular repair? Well, why do we need it? I think it's pretty clear that too -- a lot of patients are just too high risk for open surgery. They just can't sustain it. Even in the best of hands, as I said, 10% mortality in a highly selected cohort of patients. And even if you survive surgery, it's very high morbidity and very high mortality. The rupture risk is excessively high with medical therapy alone. So it's only for patients that actually can't have anything done. And we know from thoracic TVAR repairs and EVAR repairs in the admin that EVAR provides an [indiscernible], lesser trauma and less ischemia time, quicker recovery and much fewer complications, at least in the short term. And the principles are very easy. We do these procedures percutaneously. There is no clamping, there is no incision. There is -- doesn't have to be general anesthesia. And we actually put the system together inside the patient. So we customize it on-site sort of when we're in the patient just as we do with open repair. This is just one example. Just to give you a vivid picture, this gentleman came to my hospital about 10 years ago, actually or even more now. I'm getting old. He's a Jehovah's witness. I have his permission to publish his picture on postoperative day 3. We had a ruptured aortic arch aneurysm but refused blood transfusion. He was life-flighted through past 2 thoracic departments because they wouldn't operate him if you didn't take any blood. So we did this total arch repair on him. And he's now 10 years out after surgery, doing very well. And this is postoperative day 3. And I challenge anybody to show a patient like that after open arch repair. So this is the image to keep in mind when you think endovascular. And we know with these complex repairs, and you will recognize this chart that we actually do increase life expectancy for these patients. So they survive -- not only do they survive their operations better, but they actually do better in the long run. They're not -- they're sick people. So they still do less well than the general population, but intervention impacts survival positively. As been mentioned before, we know that experience and practice makes perfect. That's very relevant for open repair, as you can see here. Not only the hospital volume but also the surgical volume when it comes to open repair and definitely for these very extensive repairs is very, very important. And you have to keep in mind that 95% of these historical abdominal repairs that are done open are done in single-case institutions in the U.S. So only 5% of the repairs are done in institutions where they do more than 10 cases a year. Luckily, with endovascular repair, you don't have to be as skilled. They had a fellow who came back and told him that that's the proof that endovascular works is that anybody can do it without killing the patient. But in all honesty, the learning curve is much shorter, so you can do less harm in the surgical setting with these patients. And this is just a comparative chart for open surgical repair versus TVAR for descending aortic aneurysms. One of the problems, though, is in vascular repair for these complex devices is that it requires a lot of imaging and planning to be able to do these procedures safely with the current technology we have available. You have to have experience in doing this. And 80% of the operation takes place before we actually go to the operating room. And it's very challenging to do that. Plus in the U.S., there is a lack of devices to do this. So basically only 10 places in the U.S. that can offer endovascular thoracoabdominal repair with customized devices, which leads to a lot of invention among physicians treating patients in every kind of way they should or shouldn't do. And this rule always applies. Just because you can do something doesn't necessarily mean you should do something. And it's very true for complex aortic disease within the vascular. We call it endo trash, and we spent a lot of time repairing those types of repairs. So when we do have these customized or off-the-shelf devices for patients, basically just to grasp of the technology, we can use fenestrations, which are windows or just holes in the graft that we customize for the patient to fit the individual patient, as you can see on the image on the left. Branches are different. They're cuffs that sit on the main body of a device. And the image on the left there shows that they're a little bit more versatile. You get more reach with the branch to find your target vessel. That means your planning doesn't have to be that precise, and it offers an easier perspective for off-the-shelf solutions. And off-the-shelf solutions is really what we want to be able to provide for most of our patients most of the time, and a lot of these solutions have been fought. But it sort of come down to these branch solutions being much more versatile. And also in the setting, again, single institution -- or single-case institutions, you want something that's familiar to most people so they can put a device in without doing too much harm. In Europe, we have this device up until about a little while ago. And now this is the E-nside device that just jumped on the market a few years ago, and it's a little bit different. So it has these interbranch devices as -- and the cuffs are on the inside of the device, the main body device, as opposed to being on the outside. And that's especially usable in the emergency setting or in the off-the-shelf setting because sometimes you're treating patients, they're a little bit out of the scope for the device. So if you have deal with vasculature angulation or narrow per visual aortas, it becomes a little bit easier when you have interbranch devices. I'll just show you this one case. This is a 78-year old gentleman as it was that came in with this 83-millimeter symptomatic aneurysm. He we was clearly not a candidate for open repair and was not interested in being operated with -- in the acute setting with the 20%, 25% mortality. So we took this E-nside device that we have on the shelf, and it's a nice little device that makes with obviously Artivion's own portfolio, but also any other device that you sort of have on the shelf for standard descending or infrarenal repairs. It has these preloaded catheters that go through all these branches, making it easier for the operator to spend less time on this repair because time is critical to get these patients off the table as quickly as possible. So this is the device in place. You see the black outline is just an angiogram of the aorta. Very clear markers on this device. So you can see the orientation. You know your branches are in the right place. Then we just take them down one by one. That's actually done completely transfemoraly. You can see the sheet coming up and over into the left renal artery and replacing bridging stents out to these. And this is the superior mesenteric artery, everything done from the groin. This case took about 2 hours, and you can see here the final imaging. And this is the patient when he came back to my office. 2 months later, he's doing really well. I'm very happy, of course, that we excluded his aneurysm. So in summary, thoracoabdominal aneurysms, potentially a ticking bomb. I think there are a lot of patients out there that never get treated because the treatment is just too invasive as we see it today. Luckily, we now have options and they're coming more and more, and we've done this now for very many years. And this is a very good addition to the portfolio. So we can send our patients so like this instead, so they can go on living their life. All right. Thanks.

Thank you, Dr. Resch. So we're in our next Q&A session. So we should have our 3 surgeon presenters on the line, Dr. Kempfert on AMDS, Dr. Shrestha on our NEO device, and obviously, Dr. Resch is here with the E-nside device. So I'll open the floor for questions.

Yes, Suraj.

Suraj, Oppenheimer. So for any of the physicians, how should we think about operator technique and device design as it relates to type 1, type 2 leaks for any of the grafts for that matter? Because that is one of the critical things that across the board, people talk about. Maybe if you could shed some light on that.

Dr. Resch, you want to take that?

So these type 2 leaks, just for the -- perhaps those of you who are not into the endoleak classification. So we sort of divide leaks when these devices don't seal the aneurysm that we're treating properly. You have direct unleased, those we call type 1. And they're usually an effect of incorrect planting of the devices. And I showed you a couple of these things. So I think that in a branch device setting, you have much more leeway when you implant for the physician to implant a device without having these type 1 leaks. Now type 2 leaks are totally different. Those are indirect flow endoleaks that you don't treat endovascularly. You just leave them or you embolize them beforehand. So I think that from a physician perspective, especially if you have less experience, the branch devices and the off-the-shelf devices help you because there is no -- not that much planning involved. So there's -- the procedures, as we heard before, are much more standardized in that sense. So I don't know if that answers your question but...

Can I -- this is Dr. Shrestha. Can I add to your statement, please?

Sure.

Yes. So in case of the frozen elephant trunk, the endoleaks do not occur because we are suturing the graft to the native aorta. So there is no endoleak at all.

Is device migration also an issue or not?

So for extensive thoracoabdominal repairs, it's actually quite uncommon because they're so extensive. Device migrations are totally dependent on, again, finding appropriate fixation zones for the device. And I think that the problem with migration is much less. If you limit yourself to devices that are less complex, you'll see more problems in the mid- to long-term because you're not treating the disease appropriately. But if you use these complex repairs -- and that's what we've clearly seen over time appropriately than sealing zone or fixation zone issues with migrations really don't exist.

In fact, I think the cases he showed you with E-nside, if you think about it, we launched the first AAA when I was -- 20 years ago. You still got a tube in the aorta, and it would potentially kind of slide down. The thoracoabdominal he showed you has 4 branches going into individual vessels. It's fixated above, it's fixated to 4 vessels, and it sits on top of a bifurcation. So you have almost like 6 fixation points on the device versus a single tube in an aorta.

I think just -- we know this from open repair as well. If we do -- in less experienced hands, if you choose to do a less complex procedure to try to get away with it, you're going to suffer downstream. So incomplete repairs lead to more complications. So with these devices that allow us to do more complex repairs, if we get the appropriate procedure done, so less complications during follow-up.

Mike?

So it sounded like there's some overlap between AMDS and frozen elephant trunk. So can you maybe comment on to what degree the AMDS product can maybe cannibalize frozen elephant trunk?

So I'll let Professor Shrestha and Kempfert because I -- basically, what we've -- in our research and our discussions with physicians, and they even both said it. So you have to split the diseases up, right? So if you think about an acute type A dissection, the beauty of AMDS is it can be used by any cardiac surgeon. And you saw the issue is these acute type A or emergency that you have a mortality of 2% per hour. So you got to get treated immediately. That device can be put in by anybody. So we think 80% of acute type A dissections can be treated with the AMDS. If they get to Hannover or Berlin, they will -- they could choose to treat an acute type A dissection with a frozen elephant trunk. That cannot be done everywhere, and it will never be done everywhere, at least in the next decade. But then you go into chronic dissections and aneurysms, that's all frozen elephant trunk. So you have to kind of separate the acute type As from the chronic dissections and the aneurysm. Maybe Professor Kemper or Shrestha, you could comment on what I just said.

Yes. From my side, actually, you hit the nail on the head, actually. That's exactly how it's going to be.

Okay. And then just as a follow-up, how does NEXUS fit in relative to the open, I guess, options?

Yes. And it's great to have Professor Resch here at the same time, right, because you have the cardiac and vascular surgeon perspective. These are -- I think one of the things that we're -- it's a very serious disease we're talking about here. When you have an aneurysm or dissection in your arch, you saw the mortality rates. They're off the charts, right? So we've got kind of 3 shots on goal, if you will. We've got the AMDS for acute type A dissections. We think that will be used in 80% of the cases. Frozen elephant trunk will be used 20% for acute type As, and then they'll use for aneurysms in chronic dissections. Then you have this new player, this endovascular treatment, just what Dr. Resch showed you for the thoracoabdominal. That patient we showed you was actually in the arch. It was an endovascular treatment of the arch with somebody -- 2 cardiac centers turned the patient away because he couldn't take blood, you die on the table. It's an emerging technology, right? So I've been in this field for -- in the [ stent-graft ] for 20 years. It's very new. It's just come out. So I think, over time, it probably will not be used in acute type A dissections just because of all that's involved in that. But for chronic dissections and aneurysms, which is where the trial is, I think it's a newcomer to that field. And in all the benefits that Dr. Resch kind of talked about with open versus endo in the abdominal region also apply to the thoracic aorta. But as I work with our cardiac surgeons, I was at a meeting in Frankfurt a couple of weeks ago, I mean that's a tall order to be putting catheters up into the arch. And it's going to happen. It's just in the early days. Again, maybe Dr. Resch and some -- Professor Shrestha or Kempfert can comment on the endovascular option for the chronic dissections in the aneurysm.

Yes. So what we've seen is that the biggest obstacle now for vascular repair in the arch is the ascending and coronaries. We don't have an endobentol solution, which means that for most of these repairs, I would say 90% of them need to be done by open means, so is that frozen elephant trunk or arch placements or hybrid repairs and whatnot. Right now, at our institution, many institutions, the biggest patient cohort that we treat endovascular arch solutions are those that have had previous ascending arch repairs for acute dissections.

So they're chronics.

So now they become chronic. And now the patient is 6, 7 years out. They're a little bit sicker, and they need a reduced sternotomy. They have a complication, and they're actually the best candidates for us to treat by endovascular means. So at this time point, they're very -- it's very rare that they're competitive, but they're actually complementary. So yes.

Yes. Professor Shrestha or Kempfert, you want to comment on that, the question about how you see endovascular treatment for the arch when you have an AMDS and a frozen elephant trunk?

No. What I see is that -- yes. What I see is that personally that I think these are complementary. And every patient should be seen in -- by both an endovascular surgeon as well as an open surgeon to decide which technique would be best for the patient, depending on the age and the patient's condition. And like Dr. Resch said, if the ascending aorta is not involved, and of course, then one could think about an endovascular treatment for the arch only. So I think that in the future, it will be more and more. As better devices come and there's more cooperation between the doctors open surgeons and the neurovascular surgeons, I think there will be the -- this 9%, 10%, what he said, is going to go more towards endovascular also.

And it's important to note this comment that was just made about the heart team, the collaboration between the cardiac surgeon and the vascular surgeon. Number one, you saw Karl sales force. We have -- we focus on cardiac surgeons and vascular surgeons. Our TRIOMPHE trial, which is the NEXUS trial, has a cardiac surgeon PI and a vascular surgeon PI. They work together. Because when you get into the arch, you're in a whole another ZIP code. That is the most sophisticated procedures that are done, and they're life-saving, life-threatening. And again, it needs -- these guys who've got all the experience to here, what's the best treatment for that patient. Cecilia?

Cecilia Furlong, Morgan Stanley. I wanted to follow up on AMDS, what you've seen both from an awareness standpoint as well as kind of current penetration geographically and as well as expectations over the next several years in terms of where you could see penetration OUS ahead of U.S. market entry.

Maybe, I guess, Dr. Kempfert -- or Professor Kempfert can comment on -- I mean you saw at his center. It's the technology's kind of spread just like it was designed to, right? All 13 cardiac surgeons that take a Q type A dissection call are using the technology. And maybe, Karl, you can comment on what you've seen in Europe. I will say that launching this product in a pandemic is not the easiest thing to do, both from a -- we aren't -- surgeons haven't been to conferences. We can't do training sessions. And a lot of these centers, people got to get tested to go into a hospital. So we've also done extremely well with this, right? We've opened up a bunch of centers, we grew 60% last year. But maybe, Karl, you can comment on kind of how you see that unfolding?

Yes. Exactly like you said, Pat. We're launching this product in the middle of the pandemic. The most important part is everybody is interested in this device because it's a solution for a severe situation in those hospitals. The challenge we saw like during the pandemic is like getting them trained, becoming at a routinely used product. That's a little bit the drawback. But the interest is very, very high. And also, you see that reflected in those numbers. And I think with the Berlin Heart Center, you see like what we are doing currently is like we start focusing on those emergency things. And it's just like it takes a while until you train the full team. Those cases happen Friday night, 1 p.m. or 1 a.m., and then somebody comes in and then they -- to change this routine takes a while, but we are progressing very well.

Yes. I think another important point is there has been no -- Professor Kempfert showed you the standard of care, which is a hemiarch. They basically just go in and fix the tear in ascending aorta. There's been no technology in the field for 50 years. This is the first of its kind. I think the second thing that's going to really start to accelerate this is the start of the U.S. clinical trial. We're expecting to start that trial very soon. It's in the top 25 aortic centers with the top aortic physicians. There's a surgeon here in town who was in the Canadian center and now is here. He's a true believer in the AMDS technology. So I think the more you see patients, the impact that this device can have on patients with malperfusion and mortality and paralysis is just going to continue to take hold. And we actually think this will become the standard of care for acute type A dissections around the world, which is 80% of all acute type A dissections, which is a $540 million market.

Great. And if I could follow up just on that last point as well. If you think about the trajectory toward 80%, I mean, how do you think about that, one, in Europe today, adding on U.S. longer term? And really how long it will take to get to 80% or what percent really makes sense over time?

Yes. I think the part -- again, maybe Professor Kempfert, you can comment. I mean I know a lot of people ask him. He's basically done the U.S. trial in his center. He's already done 100 patients. That is the U.S. trial. And they obviously believe strongly in it. So I think this is the typical market development. We're the only ones, which is great, but also there's no one else talking about it. So I think that it is a market development effort. So getting the data out, training the physicians, peer-to-peer type things that we always do. I don't know Professor Kempfert, are you still there?

Yes. So from my perspective, also the very first implants happened in Canada with Michael Moon's center. And also, he has experienced exactly the same as what we have seen in Berlin. So he was the first one to use the device in his center. And then over a very brief period of time, the other colleagues when they were on call and had a Type A, they call him whether or not they could use this new device. And he helped them maybe once or maximum thrice in the cases and then became independent surgeon and kind of relied on this technology the next case they had to take on. So it's basically really you see one, it could even be a video, and you can help with a more experienced colleague once and that's how easy technique is to basically -- to have it in the daily routine.

Yes. I think for Europe, we talked about the basic market development-type things that we always do, right? So it's getting the data out, training physicians, opening accounts, basically creating the noise around the technology. And then behind that is this U.S. clinical trial. When that trial enrolls even along the way, it's going to get a lot of attention by those users as they talk in their different conferences. But you asked about the U.S., I mean this will be a late breaker at STS and potentially a New England Journal publication. And I expect that technology to be adopted rapidly in the U.S. We've got one question up here, John, up here. Well, I guess you can go to Jeff.

Jeff Cohen from Ladenburg. So Dr. Resch, could you talk about the AAA market a little bit and talk a little about the E-nside? I'm assuming that, that was done endovascular, not open. And then talk about some of the fenestration and branches available for you to pop out from the E-nside device.

Yes. So the E-nside is for -- it's a thoracoabdominal graft, a 4-branch device. It's endovascular, totally percutaneous. And then I suspect you're talking about the bridging stents, the actual stents that we put out in the target vessels. So there is a stent -- E-ventus stent that comes with the device. We -- in clinical practice, we often try to make whatever stent we have to match the anatomy. So depending on tortuosity, depending on the anatomical requirements with regards to radio force and tortuousity, we might choose between 2 or 3 different stents. But it's approved for use for the E-ventus bridging stent.

We had a question up here.

So Pat, just generally on -- you had a slide earlier where you kind of showed the whole Artivion offering of aortic products. I mean, can you just kind of talk us through -- are you the only company with an offering this broad? How does that help you in centers with hospitals be overall.

Brian, maybe you can go to the competitive slide. You just show the kind of our position in the marketplace. And it's unique because again, we -- if you look at that chart, we're really the only ones that have therapies from the aortic valve all the way down to the iliac artery. And we have various people we compete with in each of the segments. What's interesting -- Karl showed you a number -- so here it is if you populate that whole thing, right? So you have to pick a segment. So if you look at the stents and stent grafts we talked, there is no competition for AMDS. In the frozen elephant trunk, you heard Professor Shrestha talk that he used to use the competitive device, and he switched all the way to -- is all to NEO. And we're taking share and growing 60%. You heard Professor Resch talk about the E-nside device. There's a couple of competitors. Both have of -- only one has an off-the-shelf device, and they don't have an interbranch device. So and we're taking share in that segment. We're the #2 player in Europe, and we're taking share there. So when you dive into one of those kind of categories, you can quickly check and see how we perform. In almost every one of these categories, we're either the #1 or 2 player, and we're taking share if we're not. So hopefully, that gives you kind of a perspective as you look across this.

That's helpful. And then one for maybe Dr. Resch or Dr. Shrestha. You guys talked about going through your slides, kind of make your life easier for the procedure. But I'd just like a little more color there. Could you kind of go into -- I mean, is the procedure shorter? Is it easier on you? I just want to kind of shake out where that could get for U.S. adoption, utilization or other positions.

Yes. So for the thoracoabdominal, I think -- there are a couple of things. I think when you venture onto these very complex procedures, it requires a certain amount of safety in the operator to say that I can do this, I can perform this safely for the patient. If you have a branch device like the E-nside, for instance, which you do percutaneously, you put the device up, there's actually -- unless, of course, the aneurysm is ruptured. But even in a semi-emergent setting, there is more room for error. So it gives you safety. The branches are preloaded. So you know you'll find the branches even though you're not -- I joke with Karl, I said I don't need those whiles. I'll find them anyway because I've done so many -- in so many cases. But that's not the case if you only do 2 or 3 cases a year. The other thing that's amazing -- it's always one of the things I teach my sells within vascular procedures like historical, if you end up in buying an elective patient and you can't complete the procedure totally with a bridging stent, you can actually stop the procedure and come back another day. Call another guy and say, obviously not in a ruptured situation but in those situations. So you -- and we utilize that actually in elective settings to stage the procedures to even further bring down complication rates for these patients. And the reason they do so well, apart from the fact that there are no incisions because big incisions hurt the patients, but the other thing that makes the patients do much better is that you never clamp the aorta. So you never interrupt flow. Everything is done in full flow. So there's no cardiac pressure in the same setting as with open repair, where you actually have to stop all the blood flow to the heart or cool the patient down, have heart-lung machines. And that's the reason why we do these procedures, even if they take 4 hours. Even if it's a complex operation, it takes 6 hours. The patient -- next day I come up on the board, the patient's having breakfast. And they wondering if they can go home. And there were complaint is that it actually hurts in their groin. And that puts a smile on my face because then you know that this is a good procedure for these patients. So I think there's a lot of safety. And plus, if you just look at what surrounds one of these procedures, if you do an open repair, the requirement on the rest of the staff on the hospital on the ICU to take care of these patients for days on end compared to endovascular repair, which is -- it requires much less resources around the patient. So I think it's...

I think just a couple of points that are consistent with Dr. Resch was saying. We try to develop simple, elegant solutions. And it's not because we wanted to be a win some award. It's because time is morbidity and mortality in what these guys do. So your first thoracoabdominal cases at the Cleveland Clinic and Avashley, how long did they take?

Can I say that?

Yes. Yes.

So I remember doing the first cases with Dr. Greenberg, who is a pioneer in this. And we would do a thoracoabdominal case, they would take somewhere between 10 and 12 hours.

And what was your last E-nside case?

I think it was an hour, 45 minutes.

So time is morbidity and mortality. And if you talk to Dr. Shrestha and Dr. Kempfert, the simplicity and the elegance of AMDS is any cardiac surgeon can do that in less than 10 minutes. Because when you're on the clamp in the patients on the heart-lung machine, time is death and morbidity. The frozen elephant trunk, the new device that Professor Shrestha just showed you, simple and elegant. It's got a new delivery system. It's got an easy branch system. The faster they get off the circulatory arrest, the better the outcomes. So that's our whole mantra is improving outcomes with simplicity and ease of use, which is a huge deal in this field.

Yes. I agree to that. Actually, when you are operating on the aortic arch -- this is Dr. Shrestha here, in the aortic arch, you have to cool down the patient and stop the circulation to the brain. So not even minute counts there. So you could see that in our -- the video I showed that the deployment of this graft takes about 10 seconds. And because the branches are designed in such a way that I can finish the whole operation now in 4 hours case. Actually, one of my fastest was 3 hours. If usually takes 7-8 hours before. So this is what makes this device so elegant.

President on the Neuro division. So he's not just a clinical guy. He's got the whole package. He's going to run you through the pipeline. So Marshall.

Thank you, Pat. This is an exciting time to be at Artivion. We have 6 PMA trials that are in different phases to bring new products and new indications to the market. And these are going to open up large market opportunities that are going to drive revenue growth and margin expansion in the short term, the midterm and the long term. I'm going to go over each of these and highlight some things. But first, let me just sort of give you the big picture. And the easy way to look, you've got a lot of trials there, a lot of different opportunities. You've got PerClot, which you know that we divested, but they're still in -- we are responsible for delivering on approval in the U.S. The next 2 are our On-X valve for the mitral position and for the aortic position. I'll go into more detail on that. And the next 3 we've just been talking a lot about are for the aortic arch. And this really emphasizes the broad and market-leading portfolio that we have in Europe that we're going to be bringing to the United States. So it's a lot of work that's going to be going on there. And why should you be confident that we're going to be able to deliver on this? Well, first off, we're going to be increasing our -- the size of our clinical department in Artivion up to 75 people from the 50 that are there right now. We supplement the internal expertise with external clinical research organizations, CROs, such as DCRI, the Duke Clinical Research Institute, where Dr. John Alexander works. We have DCRI and Dr. John Alexander, partnering with us on the PROACT Xa trial. We engaged top key opinion leaders from around the world, many of whom you've just heard from. And we are funded for success. Thank you, Ashley. And our Head of Regulatory, our Vice President of Regulatory, Drew Green is an ex-FDA official. And lastly, Pat gave you a brief introduction on myself. I had 21 years at Medtronic, a number of those years running very large clinical research organizations, such as for the Cardiac Rhythm business as well as for the entire Cardiac and Vascular Group of businesses, which was an $8 billion business at the time. I have a lot of experience bringing trials to FDA and to CMS. Some of you may remember the SCUDHEF trial that opened up primary prevention to prevent sudden death. And you also may remember the MIRACLE trial, which was the first trial to bring a product with cardiac resynchronization therapy for heart failure. I was on Pat's staff there. And I can tell you that one of the main reasons that I joined Artivion was because of Pat. So let's go over these one at a time relatively briefly. As I said, you all should know that we have divested the PerClot product line. But we still are responsible for delivering on approval in the United States of the PMA. And when we get that PMA approved before the end of this year, that triggers a $25 million payment to us. The results have not been presented publicly yet, but I can tell you that they've been accepted for presentation at the American College of Surgeons in October of this year. We are confident in the results, which we have submitted to FDA. We submitted those as our PMA in the second half of this past year, and we anticipate approval coming up in Q4 of this year. You heard John Davis talk about our PROACT study portfolio. That was PROACT Aortic, there was PROACT Mitral, this PROACT Xa. PROACT Aortic resulted in a labeling change that we already have for running the INR, the anticoagulation, at a lower rate. And this is one of the many factors that has driven the share gains that you saw that On-X has had. So this is a similar trial for the On-X Mitral valve. The PMA was submitted and is under review at FDA. We're responding to their questions. And we anticipate having relabeling of the On-X mitral label for use with a lower INR later this calendar year. We've spent a bit of time talking about the PROACT Xa trial. This is a very important trial, a very large trial. We've committed a lot of resources to it. And again, this is looking at our On-X aortic valve and in a randomized trial with 1,000 patients comparing the standard use of Coumadin, warfarin versus apixaban. Apixaban, remember, does not need to have blood tests done on a regular basis. You just simply stay on a dose. Also, you don't have to worry about changes in your diet. With warfarin changes in your diet can affect your anticoagulation status. We're in the enrollment phase. And as you heard, we have 632 patients enrolled as of yesterday, on our way to 1,000, which we anticipate having sometime in the middle of this calendar year. There's then up to 2 years of follow-up, which brings us into 2024, and then about a year for approval. So we'd anticipate having approval in 2025. One thing to keep in mind, if you remember, Dr. Alexander talked about how there's a DSMB, a Data Safety and Monitoring Board, that keeps an eye on the trial to make sure it's safe to continue it. And they meet every 6 months. Every time they have met, they have said continue the trial as is. They have not recommended any modification to the study protocol or the conduct of the trial. You should think of that as a derisking of the trial as we go forward in time. Every time that they meet, they look at the unblinded data, which none of the rest of us get to see. -- so they know exactly what's going on in the people on apixaban and what's going on in the people on Coumadin. And every time they meet and the trial continues, that is derisking the trial and meaning that we're heading likely towards a positive outcome. These are interesting data to look at from the ARISTOTLE trial, which Dr. Alexander was involved in. He was second author on it. And this is what gives me the confidence of why this trial was set up the way it is. And the likelihood, can't guarantee it, but the likelihood it is going to be positive. The upper graph there shows the occurrence of stroke or thromboembolism in the ARISTOTLE trial. This was in patients with atrial fibrillation. Blood clots can form in that. Blood clots can form on valves. Maybe similar, may be different. So it's not an exact parallel, but you can think of it as similar. And what the upper graph shows is that stroke and thromboembolism were decreased by 21% for patients taking apixaban compared to those taking warfarin. The lower graph shows that major bleeding episodes were reduced by 31% for those who took -- were randomized to apixaban compared to warfarin, again, for the treatment of atrial fibrillation. But this gives me increasing confidence that this is the right drug to be using in this trial and makes me feel like we're going to have a positive outcome. So what is that going to do in the marketplace? This is interesting to look at what did the ARISTOTLE trial do to apixaban's place in the marketplace. Apixaban was approved in the end of 2012, so really launched the beginning of 2013. So you can see the, I guess, reddish line that starts at 0 on the bottom left is apixaban brand name Eliquis. And the top one on the left is Coumadin. Now in between our 2 other what's called NOACs, which are novel oral anticoagulant, so not Coumadin but in the same category as apixaban. So what happened? After 2 years on the market, apixaban took over as the #1 novel oral anticoagulant. And a year later, it took over the market leadership from Coumadin. So this emphasizes to me that I think we're going to see the same thing. First off, the left side of those graphs give us confidence of a positive Xa trial. And the right side shows the appeal of apixaban compared to Coumadin. And that's going to really drive On-X use and, I think, demand from patients for it. We heard Professor Kempfert talking about AMDS. I'll just briefly remind you, this is for acute type A Type 1 DeBakey dissections in the ascending aorta, a very highly -- a highly morbid, highly mortal disease without treatment. 50% of patients are dead in 2 days. We have submitted and gotten approval for the IDE from FDA. We are in the process of activating our centers, and we anticipate starting enrollment in the second quarter of this year. And we'll be focused on trying to fulfill enrollment by the end of this year. There'll then be 1 year of follow-up. That takes us to the end of 2023 and then submission in early 2024. And we'd anticipate approval in early 2025. For those of you interested in seeing some more data, an abstract with up to 4 years of data with AMDS has been accepted for presentation at the AATF meeting in Boston in May. NEXUS, just to remind you, is from a company called Endospan that we have a partnership with. We are distributing the product in Europe, and we have funded their clinical trial in the United States. Remember from the previous presentations that the NEXUS device is implanted endovascularly. So you don't have to open up the chest. It is used for chronic dissection and aneurysm. So not acute, doesn't compete directly with AMDS. And that trial is ongoing and is enrolling. Should finish enrollment in the middle of 2023, 1 year of follow-up into 2024 and then approval likely in 2025. I will point out that there's a competitor -- competitive device that is being trialed not on the market. And a year ago, some early results were presented at the AATS meeting from that, and it showed a 50% stroke rate with that device. As you can see here, early data from NEXUS showed a 7% stroke rate at 1 year. Lastly, I'll mention our NEO device. The NEO 2.0, which is under development, will be our third-generation frozen elephant trunk device. And as you saw from the previous presentations, we have the leading portfolio for the arch available now in Europe. We're bringing that portfolio to the United States. And I want to point out also that there is no frozen elephant trunk device on the market in the U.S. as of now. So we're very excited about this portfolio. You can see all the products that we have in Europe. It is our intent to bring most, if not all, of those products to the United States. We have strategically chosen which ones we're coming forward with first and very much look forward to speaking to all of you in the future about the other products that we'll be bringing to the U.S. And with that, I'm going to turn things over to Ashley Lee. Ashley is our Chief Operating Officer and Chief Financial Officer.

Thank you, Marshall. I'm going to walk you through our financial outlook through 2024. And we're going to start with revenues, which we anticipate growing 10% on a compounded annual basis through 2024, culminating in revenues of approximately $400 million. That growth is going to be driven by existing products, continued strength in On-X, as you've heard, as well as our stent and stent-graft programs. In addition to that, we expect significant growth outside of the U.S. and in particular, Asia Pacific and Latin America. And we expect both of those regions to generate 25-plus percent growth over the time frame. Another thing that we're going to be working on is regulatory approvals in 2022. We expect both approvals in both PROACT Mitral as well as PerClot. And the other thing is channel enhancement. As we continue to expand internationally, we are using that as an opportunity to selectively change out distributors. And as part of that process, we are able to capture pricing. And in addition to that, we are going to be going direct in certain markets around the globe. And as part of that, that will obviously help with pricing as well. Next is gross margin. We're expecting gross margins to expand about 200 basis points in '24 compared to '22, going from roughly 66% to about 68%. There are a few things that we're going to be working on to drive margin higher. The first is product mix. A lot of our growth over the next 3 years is going to be coming from our higher-margin projects, many that you have heard about earlier today. The second thing is the channel enhancement, which I've just talked on briefly when I spoke about revenues. And the last thing is cost-down initiatives. Whether that's a combination of strategic purchasing, process improvement or volume increases, all of those over a 3-year time frame we expect to drive down unit costs, which will obviously have a positive impact on gross margins going forward. Moving on to adjusted EBITDA. We ended 2021 at about $44.1 million in adjusted EBITDA. We expect that to expand to about $75 million to $80 million over the 3-year forecast period. Obviously, with increasing revenues and expanding margin, we're obviously expecting some nice increases in adjusted EBITDA. But in addition to that, as we exit '23 and move into '24, we think that the bulk of our investment in our channels in Asia Pacific and Latin America are going to start to level off. And those, again, should start to decrease at that time frame. In addition to that, our SG&A expenses excluding business development are going to be running anywhere from increases from mid-single digits to high single digits over that time frame, which is below our expected revenue growth rate. And then finally, R&D expenses. We expect those to be anywhere from 13% to 11% of revenues over the forecast period. And we obviously expect those to decrease as our revenue base increases going forward. And then moving on to net leverage. So a couple of assumptions that we've made about net leverage is in 2024, our convert and our term loan B are going to remain in our capital structure. The other thing, that assumption that we've made, is that any cash that we have has been netted against our term loan B in calculating net leverage. So if you look at 2021, we exited that period at 5.9x adjusted EBITDA for leverage. And as we moved into 2024, we expect that number to decrease to less than 3x adjusted EBITDA. So again, we're expecting over this forecast period to build cash substantially and decrease net leverage. And then finally, Pat showed a version of this slide a little bit earlier in his presentation. But again, just comparing 2024 to 2021, just a snapshot. You can see that over that time frame, we're expecting an incremental approximately $100 million in revenue and let's call it, close to $70 million in adjusted EBIT -- in gross margin. And we believe that we can hand back 50% of that incremental gross margin to our shareholders in the form of adjusted EBITDA. And as we exit 2024, I think that sets us up very well into '25 and beyond to significantly accelerate our cash flow generation as well as our profitability. So that's my last slide, and I'm going to turn it back over to Pat, who's got like one slide to close with.

Thanks, Ashley. And thanks for your attention today. Hopefully, this has been a worthwhile session for you. Let me just wrap up with a sneak peak of what's to come in 2025. So based on what Ashley just showed you, we would finish 2024 with around $400 million in revenue. Our gross margin would be around 68%. Our EBITDA would be between $75 million and $80 million, and our net leverage would be under 3. You just heard from Marshall that we expect AMDS, PROACT Xa and NEXUS to get approved in 2025. The various timing of each one of those, obviously, we'll see as they come. But let me walk you through what this will do to those 4 lines. We will rapidly accelerate our revenue post 2024 as we launch 3 PMAs worth $1.3 billion. Second, we will rapidly accelerate our gross margin because every one of those products carries a 90% gross margin. We will rapidly accelerate our EBITDA because as Ashley said, not only are we going to drive our top line faster and expand our margin faster, but there aren't going to be any more spending going on. Our channels are fixed, our R&D pipeline is going to come down, and we're going to leverage the organization that we've built. And what that leaves you with is just significant drop-through right to the bottom line. Investors will finally realize the investment we've made, this $700 million, in creating this worldwide aortic franchise. It all comes to you in a big way starting in 2025. But don't wait until then folks. We just showed you a great plan over the next 3 years to deliver top line double-digit growth, expanding gross margin, growing EBITDA and significantly deleveraging the company. So I want to thank you for your attention here.

This is our final Q&A session. I've got Marshall up here for the pipeline; Ashley, for the financials, and we're happy to take any questions in this last segment. Suraj?

First question for Dr. Stanton. Dr. Stanton, given your vast experience and do the best you can say right now, what would you consider as the weakest link in PROACT Xa? Would it be time and therapeutic range? As you look -- I understand the DSMB aspect of it. But at the same time, when you talk about risk mitigation and when you guys think internally, how do you think about risk mitigation? And what's the weakest link that we got to pay attention to this?

Well, I think a lot of the mitigation was done upfront in the planning of the trial. And one of the differences -- one thing that was done was the 3 months of anticoagulation in patients who are getting a valve, a de novo valve, a new valve, and there's reasons for that. I'm not -- other than the vagaries that can happen in the clinical trial, there's nothing that jumps out to me that I'm very concerned about. I've already told Pat, I'm very confident that this trial is going to be positive. I showed you a lot of my rationale for it there. But you have to run the trial, and we'll see what it shows.

And I'll leave it for either Ashley or Pat. Pat, you talked about ASP, the impact of ASPs, for example, after On-X -- or after PROACT Xa On-X. Maybe if you could just reiterate again. Beyond '25, 2025, how do you see the impact of ASPs? And Ashley, as you talk about FY '24, the 10% CAGR until 2024, how have you internally absorbed the current spillover effects from all the geopolitical issues, everything going on? Any color? Obviously, it's somewhat vague science, I get it. But just help us understand how you'll have thought through this and how you'll have mitigated it just from an outlook perspective.

Yes. So maybe looking at the first 2 lines there, right? So one of those PMAs in the revenue, if we get PROACT Xa approved in 2025, that valve is already a 90% gross margin valve today. It's already on our customer selves. If this trial is successful, we will significantly raise the price. I'm not going to comment on exactly what it's going to be. But based on the fact that it will provide a lifelong therapy with a different anticoagulant, we will be the only ones. We will be raising the price on the On-X valve for the PROACT Xa indication. Maybe you can show the -- Brian, maybe you can show the revenue slide. I think it's like Slide 10 in my deck, Slide 10 or 12 for the second question for Ashley. Your question was around how do you look at the revenue with all the puts and takes going on. I mean I'll give you an example. Russia, Ukraine, obviously, very challenging situation from a humanitarian standpoint. It's less than 0.5% of our revenue in 2021. So from a business perspective, it's not that big of an impact. We've given pretty specific -- it's not guidance. Again, this is like, again, giving you a range of what we think is going to happen. We think our stents and stent-grafts are going to grow high teens to 20, and we've got a phenomenal portfolio. We took you through all of it. On-X, we're about to -- we're going to continue to get PROACT Aortic share. We're going to about to launch PROACT Mitral, and we're going to enroll PROACT Xa. So I think the 10 to low teens is doable. So you can kind of go right down the list of things. I mean we didn't even talk about our tissue preservation services. There's been a massive uptake in the Ross procedure. There was a new paper that just came out showing how beneficial that is. I mean we've got significant demand on that valve as well. So I think -- we give a range of guidance. We can absorb some shocks along the way. And I've been running businesses for 25 years. It's never a straight line. But I mean we feel pretty comfortable and confident in what we've got here. If something kind of goes down a little bit, then something else is going to go up a little bit. So I think -- I don't know, Ash, if you'd add anything to that.

I would just add on a macroeconomic level from a cost standpoint, we've contemplated 4-plus percent inflation in all of the projections that we've given. So I think that hopefully covers us from a labor standpoint and a material standpoint. The things that we really don't have a good grasp on, and I don't think anybody else has either, is supply chain. Anything could happen there. We pretty well managed that over the last couple of years, and it hasn't had a big impact on our business. And we're just going to try to manage that as best as we can going forward. And from a geopolitical standpoint and what's going on with the events in Russia and Ukraine right now and any spillover effect that, that could have, I think it's kind of anybody's guess right now.

Okay. Other questions? Yes, Cecilia?

Cecilia Furlong, Morgan Stanley. I wanted to ask just on the core, on the legacy tissue preservation business. You talked about one growth driver. But as you think about the next several years, mid-single-digit growth, what other factors should we be thinking about? And then kind of tied in from a gross margin standpoint, is any of the gross margin expansion that you laid out tied to further enhancements, improvements in the tissue preservation business?

Yes. I think about 70% of the incremental revenue and gross margin comes from On-X and stents and stent-grafts. The tissue preservation product line is -- was at the roots of when the company started. It's a good business. The margins are obviously lower. I don't think there's going to be a lot of improvement on that side of things. We've got a lot of costs from the way that whole business model works. But it's very profitable, and it funds our R&D pipeline and our channels. So I think it's -- in the basketball analogy since we're in the NCAA, it gets a lot of rebounds. May not be the leading score, but it gets a lot of rebounds. So I think for the next 3 years, it's an important business for us. I think beyond that, I think we can talk about it at that point. But it definitely is a very strong business. It's a high demand. We treat little babies with heart disease, young patients with aortic valve problems. I mean it's a very important business. But I don't think there's a ton of room on -- we always try to refine and improve the processes, but we've been at this for 30 years. I don't think we're going to see a lot of benefit there on the margin side.

Great. And then just on R&D and thinking through the cadence through the period that you laid out. Just curious that 9% to 11% -- or 11% to 9% range, how do you think about just the different clinical trials in the U.S. specifically rolling into that as well as kind of the long-term outlook for the business around R&D as a percentage of sales?

So it was -- it's 13% to 11%. Just...

Yes. Right here, bottom line.

Just so we're clear, 13% to 11%. And it's -- we obviously have a very robust pipeline, as Dr. Stanton just laid out there. But we have a lot of programs that are going to be rolling off over time as new programs roll on. So for instance, most of the spending for PROACT Mitral as well as BioGlue China, which...

PerClot.

Yes, PerClot. All of those are going to be rolling off. You've got PROACT Xa, which we anticipate getting approval in hopefully sometime in early 2025. And at that point, you should expect a significant portion of that cost to roll off. AMDS, we hope to complete enrollment this year and this year a follow-up, but that should roll off. And as all of those roll off, we're going to be bringing in other programs with potentially E-nside and NEO as well. So that's why we feel pretty strongly that once our R&D spending gets nominally up into the between $40 million and $50 million range that it should level off and as a percentage of revenue decrease over time.

Yes. I think the other thing is from this slide, I mean, we're stacked in '25. I mean we literally have $1.3 billion coming out of 90% gross margin revenue with very little competition, if any. So I can manage the R&D pipeline, right? Our revenues grow up to $400 million. I can get that R&D line down to the lower end of that range, like a 10%, 11% range. I can feather stuff in as I need it. And again, we've got stuff to keep us rolling this thing for years to come after this as well, but we'll keep it focused here for now. Got a question? Yes, John?

John McAulay from Stifel. Just one for me. I just want to clarify some of the language you mentioned with PROACT Mitral and PerClot. You said later this year, if I remember correctly, previously, it was maybe more of a 1H time line. Has anything changed there? Has there been any delays or am I just...

So PerClot, we've said all along, we thought that was going to be a late '22 because we filed that PMA in October. And the typical PMA takes 12 months, so it's Q4. I think PROACT Mitral, we filed that in the end of July. So if you do your typical 12 months, that puts you in the second half. So we're saying '22. I mean, again, we're in discussions with back and forth on -- with the FDA on both of those as we speak. So until you get more clarity, you're kind of in the process and trying to pin down a quarter for regulatory approvals is a dangerous game in this business. So -- okay. Any other questions? Well, listen, I want to thank you all for coming. We finished 12 minutes early. But there's a lot thrown at you today, but I'm extremely confident in what Artivion represents as an opportunity both pay and into the future. And I want to really thank you all for being a part of it and look forward to speaking to you on our quarterly earnings calls and future investor presentation. So thank you for attending.