Heart Valve Insights Summit Originally Broadcast November 12, 2020
Valve Choice is a shared decision between the Cardiologist, Surgeon, and Patient. Dr. Maurice Sarano, Dr. Marc Gerdisch, Dr. Mohanakrishnan Sathyamoorthy, and Dr. Tracy Y. Wang engaged in a meaningful conversation about the present and future of aortic valve replacement and the potential game-changer in the choice of AVR with the PROACT Xa Clinical Trial. Watch Today!
TAVR vs. SAVR and VIV in Young Patients: Valve Survival, Patient Survival & Eventual Need for Anticoagulation Maurice Sarano, MD | Minneapolis, MN
SAVR, TAVR, ViV – Life in the Fast Lane: Who, What, When Marc Gerdisch, MD | St. Francis Health
Blood Thinning in 2020 and Beyond: Impact on AVR Patients and Artificial Prosthesis Selection Mohanakrishnan Sathyamoorthy, MD | TCU & UNTHSC School of Medicine
A Potential Game Changer in the Choice of AVR: PROACT Xa Tracy Y. Wang, MD | Duke University
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I am very excited to welcome all of you to this symposium tonight. I'm not going to spend too much time on the introduction here. We have a fantastic agenda with experts, both medically and surgically on valvular heart disease. Each of these speakers will keep their comments to about 10 minutes. Um and then we will have a Q and a session for a few minutes after that. Without further ado, I am going to introduce Dr Marie Serrano. I know Dr Serrano now for a couple of years. He is a professor of medicine at Mayo Clinic, and he directs the valvular heart disease clinic at the Mayo Clinic. And his research really focuses on innovative treatments of valvular heart disease. So Maurice is going to get us started on Taber versus Sabir versus valve in valve in young patients showing us some data on valve survival, patient survival as well as the eventual need for anti coagulation. So, Maurice, why don't you get us started? The discussion constantly for the about is is what are we gonna do? What are we going to choose for the patient mechanical bio procedures and now bio prosthesis by implantation off TVR and evidently were as position we're concerned about. Trumbo's is and bleeding off patients with mechanical procedures and structural about the generation off biological prosthesis. And the guidelines have been very limited in what they're saying. If you're less than 50 years, put a mechanical valve. If you're more than 70 put a biological value in between. We don't we don't know, really. But we give you some elements off preference. Andi And so the complexity that we face is that we have to advise patients based on the multiplicity of factors. So we have to do in our brain of multi factorial analysis and projecting how the patient is gonna be in 5, 10, 15 years later. And so with that and the immediate fear off the Trumbo sis and anti coagulation, the mechanical prosthesis has gone from 25% off the market in 2000 and 6 to 15% only in 2000 and 10, and the decline continues. And it's understandable because this is a distribution of age, all the Arctic cyanosis, and you realize that the mean age is 75,000,077 Onley, 10% are younger than 60 and and 15% are between 60 and 70 so there is a justification of age. But some would like everybody to have a tissue valve, possibly by TVR. And the current fashionable statement is used only by your procedures. We can do valve in valve in the future, and you don't have to worry about structural about the generation in that discussion. The issue is what are the facts and and do we have randomized trial to to guide us? There are a few, but there are quite old. This is the Scottish trial that was done and published years ago, and and the mechanical versus tissue valve at the time. Surgical Val was not different in terms of survival, but survival with intact prosthesis was way better with mechanical than tissue. And then they did a re analysis going up to 20 years. And although there was a little trend for better survival with with a mechanical valve over the 20 years, there was no significant difference. But again, there was a confirmation with a very large difference the mechanical valve having um or survival without prosthetic dysfunction than than the porcine bio prosthesis. The other clinical trial was in the US, the Veterans Trial. And in their first publication in 1993. There was no difference in survival after a VR between biological and tissue valve and and mechanical valves, and and that was the same for mitral valve replacement. But then, when they're republished, when they did a second publication at 15 years off, follow up. Then you can see that the surprise was that the people with aortic valve replacement live longer than the people with the biological valve prosthesis, mechanical vs biological and this waas a surprise finding. And you see what is interesting is the third randomized trial was very small. You see the small number of patients. But although it waas non significant the mechanical valves where better than the bio prosthetic valves, there was a trend for better outcome, so we haven't resolved. But But there is an alarm ringing saying, Oh, mechanical may be better for these patients. So do we have observational course telling us something about these difference in a controversies? My former colleagues wreckage history and the hearts Will Shaft sort of showed the experience that Mayo Clinic showing that people were younger than 70 the mechanical valves as a much better survival, even when you do a matching. There is a better survival with mechanical valve than with bio prosthetic, though, but this is one institution. And then there was a Siri's off publication from much larger samples. Here is the example that the the experience of New York state that showed no difference in survival between mechanical and bio prosthesis. But there was the usual similar stroke rate, higher re operation rated by a prestigious and higher bleeding with mechanical valve. This was not really conclusive in the 50 to 69 years. But then there was this study coming from all California residents Cocoa organized by Goldstone. And what they saw is that there was a trend for benefit for the mechanical valve with less complication, less mortality particularly significant in the 45 to 54 years of age, but with a trend in people who are between 55 64. So the the the here. What is very interesting is that the, uh, the um the the Age where it becomes equal is, um, around 60 to 65 close to 65 but below the mechanical as a benefit as compared to the to the biological valve. So here we had a similar signal than the veterans trial of a benefit for our mechanical valves. And and then there was the study from Europe on the study from Europe was striking. This was not just a community, it was all of Sweden showing that the patients operated in Sweden for Ev Er, between 50 and 69 had a significant difference in survival, with a better survival with mechanical, mechanical valve and biological. And what is interesting is that when you analyze, you do a propensity score matching. You see that the make the biological have have a risk of increased by 30% and whatever adjustment you do in the whole cohort, you see, it's all around 30% increased risk. So what we have learned from this cohort is that not all studies are positive. But there is a consistent trend for a better survival with mechanical prosthesis in that age range of 50 to 78 years old. What about a more dynamic deterioration? The here is an old slide off different types of prostheses is showing that over time there is structural valve. The generation uh that goes a different speed between different studies performed. But but there is a sort of precipitous decline after a few years off these patients now, more recently, there has been this study done in Quebec and and showing that after surgery for aortic valve replacement, there is quite a bit off mortality. Half of the patients are dead at 10 years, and there is a small percentage off people dying from structural valve degeneration. But what is interesting is that to consider all structural valve the generation, this is not time. This is different subgroups, and you see the deterioration of Imo dynamics in this subgroup off clinically relevant structural valve disease. But but the important fact is that there is a clinically relevant symptomatic the generation at 6.6% and 30% more subclinical. So So this is a new, interesting fact, and this fact was confirming study from the same group. But looking at time where there is accumulation off the generation and overall, their percentage off prosthetic valve degeneration reached 30% in that study with different type of the generation over time, and the, uh, and what is important is that when you have about the generation, the IT impacts mortality. You multiply mortality by two, so it's a high risk element. More recently, uh, the there is a paper on T A V, R versus surgical biological valve, and this was kind of interesting in looking at the rate off the generation per year. So the percentage is a rate off structural degeneration per year, and and the older version off the SAPIEN XT valve showed a high rate off the generation, and the this rate was much higher than the surgical. So TVR versus surgical was a much higher rates significant rate. But you see the SAPIEN three year, the rate of structural that degeneration with biometric but with bio prosthesis valve failure is double. And when you do an analysis by about, by weighing these these you see that it's significant. So so there is a slight difference in the rate of the generation mawr in the patients with TVR than structural valve disease than than surgical valve implantation. And so this has to at long term, to impact the outcome off this patient. So what are the facts? Recent data suggests? Ah, high frequency of a more dynamic deterioration over time, particularly with TVR and increasing precipitously over time. So we have seen these things, these elements off the literature that are going against the grain of what you hear every day from some surgeons and really the clinician need to consider facts and not advertisement in advising patients regarding prosthesis type. We need to minimize bleeding through improved anti coagulation. And we need to obtain new data on structural valve disease in clinical practice, uh, to to make our own clinical decision making with individual patients. Thank you very much for your attention. Great. Well, we do have a couple of questions coming in through the Q and A. The first question, which I think is a fantastic question, is what potentially confounding variables may have weighed in the initial mechanical versus bio prosthetic valve decision in these retrospectively studied cohorts. Maurice, I think you have presented some great data from different parts of the U. S. And actually also different parts of the world. What do you think is your response to something like this? Yeah, it is. It is a That's a very good point because people will have may have some co mobility that weighed on the on the valve implantation. So So it is very difficult to include all factors in the adjustment on That's a good point. And this is why we need to see um, Mawr studies done on on the comparison of mechanical and and biological valve to see if this trend goes in the same direction. So the Goldstone California study shows a little difference. The Swedish study shows a bigger difference. The New York State shows no riel difference in terms of survival, and we have to integrate all that to say, Okay, what is what is the average effect? And when you look at the experience of Mayo too, you can see that this is not the story that we heard that biological value that we perceive because we don't give anti coagulation is better. I think that the there is mawr and and the and the outcome of patients with a mechanical valve in our experience has been pretty, uh, pretty good, uh, in particular with the most recent valves. And, you know, while I'm I'm also gonna ask Mark and Mo to weigh in on this question. Um, And while they're answering, I'm gonna ask the audience. If you use your chat function, I'd be great to sort of scare what? You're going to kind of pull you guys a little bit in this day and age. If we have had a healthy patient, relatively low surgical risk or bleeding risk, I should say, uh, let's say, between the age of 50 and 70 years old, can we random? Can we do an RCT randomized clinical trial randomize ing to a tissue valve versus a mechanical valve? I mean, what Mark and Mo, Do you have any opinions on this and the audience? Um, if you'd like to go into the chat function, give us a yes or no. Do you have equal poise, or would you be willing to randomize someone to a tissue versus biomechanical tissue versus, um, uh, metallic valve? I think it would be tough. I'm gonna go and and then let the other speak. I think it would be tough. You see, the veterans trial was 15 years to give you an answer. That's the major. That's the major point. And and and then everybody says, Oh, but your comparison is from 15 years ago. It's not valid today. Now we use anti calcification and this and that. And and so it's more difficult study to do now. And so maybe what should be done should be an analysis of what happens in routine practice and compare what? What? What we have. But I let, uh, let the other speaker Well, briefly, I will cover some of it, of course, when I speak. But I would agree with Maurice e think that the most interesting data at this point, because everything is moving so quickly, is to I think, if we could understand the algorithm that's being applied, if we could gather data on how patients are moving through any given system and then develop some kind of cohesive vision of how we manage this type of disease in the United States, I think that would be spectacular because we're better at getting that information from places that do have more cohesive programs that they harvest their data easily. He talked about the Swedish data. I'm gonna talk about the finish data, and we have less good, high quality data from these kind of 30,000 ft views that have multiple institutions on enrolling their data, you know, some well and some not so well. So if we could really refine that understanding what the algorithm is in the country, I think that would be really helpful. Modi have anything to add to that? Yeah, Maurice is always illuminating talk, and and I think, if I could, if I could just draw everyone's attention. Thio Maurice's comments and slide, uh, discussing the partner to data and the difference that's already being witnessed. A five year sampling time between trans catheter implants and surgical sort of tissue by prosthetics. Surgical implants. This should be alarming and should really, fundamentally asked the question. Biomechanically, What's the difference from bio materials perspective? What's the difference? What's happening in terms of accelerated decay? It's being seen at five years. They should really start influencing the way we think about patient selection. So in this gray zone of 50 to 70 the concept of a trans catheter valve is This Data is emerging, gives me fear because we're almost looking at repeat interventions, and I think Mark is going to get into this in terms of the risk of valve and valve operations, etcetera. I can't wait to see this data, but but that's the one point I would make is that should really draw attention. Thio Age and valve type selection. Yeah, and a couple of audience members responded through the Q and A function to say that they would have a hard time with that trial. So I think that answers that question here. Here's another question for you, Maurice. Was the valve deterioration of five years any better with SAPIEN three compared with previous safety inversions, any any any information on sort of self expanding valves? I know this is kind of getting into some of the later talks, but maybe you could just do a quick answer. There it is. Absolutely. The city in three has better, better result than the X t previous version, and it's difficult to understand exactly why. Why there is that improvement. Maybe it's the treatment of the tissue. Maybe the explanation In the papers, they say, Oh, there are bigger valves. We don't need to do re inflation off balloon, and we don't affect the tissue of the valve because we have a better sizing. Um, maybe it's true. Or maybe the crimping off the valve is something that explains some off the alteration ISAT benign to crimp valve and then to inflate it. I don't know long term. Do we affect the tissue? It's very difficult to know the cause. Yes, the CPN three was much better than the CPN X T, but there was a trend for a slight difference with the surgically implanted valve where the valve was not crimped when it was implanted. So you and it's from the same company, so the tissue should be the same. So so that little trend is worrying me. And it's within five years. So it's not when things accelerate. And so, um, it's a it's something, and it's in people who are 80 years old. So so the older population with a lot of mortality. So we may not see the people reaching the end point off five years because of that age factor. So so. But what happens at 70? What happens at 55? Because few patients in those trial with a mean age of 80 were in that age range. So so we we have. We have many, many questions remaining on durability before we jump to doing a TVR to everybody and projecting a valve involve in five years and another one, and there are many, many, many questions, and we have to really way and give the options to the patients. Well, thank you, Maurice and I really want to thank our attendees for jumping right in and sending us questions. So keep doing that in the interest of time. Let's move on to the next speaker, and Maurice will go into the Q and A and try to address some of the questions that are still in there. So don't worry. So our next speaker is gonna be Dr Mark Kurdish. Mark is the chief of cardiovascular and thoracic surgery on co director of Heart Valve Center at Franciscan ST Francis Health in Indianapolis. And I think, um, one of the things I've really admired about Mark is that he's been the first in so many areas. He's been the first in the US to use the Edwards SAPIEN XT trans catheter aortic valve. He's also one of the first to implant the onyx aortic valve. And so Mark is gonna talk us. Talk to us about life in the fast lane who, what when is it relates to Savage tavern valve valve? And I think we'll continue the conversation we've been having so far. Mark, take us away. First. My disclaimer is in the form of just liking all of this stuff. I am absolutely thrilled with the direction of heart valve disease management, and I'm involved in all of it. And I still do plenty of surgical aortic valve, but do tappers as well and expanding practice of aortic valve repair. So given that, you know, we're talking about Tabar a little bit and Maurice was the perfect set up for me because there are some things were gonna overlap on. I'm just gonna add a little bit too, and we will will develop a little pattern. I think of thought so back to trans catheter bells. This ship has already sailed. This is the best thing that ever happened to really high risk patients. Older folks who need an aortic valve replacement whom ah, lot of whom we never saw and and many of whom we didn't want to operate on now have that opportunity. This has been a real blessing. You know, we can debate about men doing better than women or women doing better than men or what the implications are but high risk patients older, high risk patients. This was a great, great thing to happen in medicine. We get into intermediate risk and it's still great because there are a group of patients in the intermediate risk stratification and STS that you know, there's the saying of the eyeball test. You know, there's the intermediate risk that you want to operate with, and there's the intermediate risk that you really don't feel like you're gonna prove their life. And so this also was a real gift to us. And as a heart team, we make decisions for these patients and it becomes a little bit more elegant conversation. It becomes a little bit more algorithmic. And it's important to remember, though, that we're starting to acquire some longer term data on the intermediate group, and we're seeing that the outcomes differ over time. So although there might be that initial bump in surgery as you get out further in time, you get out to five years. They separate more people go back to the hospital or the trans Catherine developed. If they lived, Thio be to have five more years, and in fact they have more complications such as rehospitalization. They have. In fact, this is interesting. They have a little bit more into code itis, although it doesn't show up statistically, I'm gonna get back to that in a minute. But they have more re intervention, substantially more re intervention. And this becomes important when we look at those re interventions because they're coming back in because the vowels were failing. So this isn't a group of people who have a mean age of 82 and the main reason they come back into the hospital is because the devices they're failing now most of them get another Taber. But if we go back and we look at those endocarditis cases, they never got touch. So those people, the people get into credits and taverns typically don't get treated. The folks in surgical valves that get out of the car tow endocarditis do get treated in this cohort. Unfortunately, three out of the four died, but the point being that we don't see much in the way of structural deterioration in five years, they're not going back to or we replace surgical valves and I may get to a little bit about that later. As far as what I think the key roles are. But the point is that we see that deterioration importantly every time there's a meta analysis, whatever could be done to look at Sarah versus Tavern once you get out past two years, and certainly once you get past three years, you start to see this for everything. The trend goes positive toward surgical vows. Now that doesn't mean that everybody is supposed to get a surgical valve. It just means that we have to understand what it is in the context of the human being that we're seeing their longevity and what the implications are for them and the effect on their lives. Low risk. We talked about this briefly. This is actually important study. We want to know what's gonna happen. Patients at low risk because we have patients of low risk Sometimes that we want to offer a trans catheter valve. Thio STS risk is not the be all and end all. That said. It's important to recognize that this is the forward facing part of this study for the general population, that there's a random ization of 1000 patients, although the truth is if you look at the forward facing version that we received as physicians. There were 50 over 1500 patients that were enrolled, but there have been a third of them are excluded. So what's going on here? Why are a third of them out of the studies? Because they either have a small Angeles. They're big Angeles, thereby husband. They have a I. They have severe left and digger dysfunction. They have a lot of calcification, the aortic valvular complex and the outflow track. These are all things that are not a problem in surgery, whether you're low risk or high risk. And in fact, so if you look at this highly selected group of patients that were perfect for transform, Taber, perfect for transform whatever with a mean age of 74 did better. On the short end, there's no difference in all cause mortality. One year we're seeing some changes in, uh, involved, uh, function over time. But there's nothing dramatic. It is important that there's some AI and 30% of those taverns, and I don't think that a I is a big deal when it's mild. But I do think that a I is a signal that the valve is not perfectly deployed that it is not round. And we know that around tavern doesn't last as long is a not round. So two thirds of the patients that were excluded were by husbands. So you can see why these aren't great for whatever we do do Tavern by husbands and they do okay most of the time. Most of the time isn't good enough in surgery and aortic valve replaced in the low risk patient. So when you're dealing with this, we cut the valve out. We put a new valve in. Furthermore, for those bicuspid patients, it's very important that we be cognizant of their aorta. So the younger the patient, the more important any enlargement in the order becomes, especially if we think they have a long game so that they're gonna live a long time because we will address that a or at smaller and smaller dimensions based on their longevity. We actually have an app for that. This is a great app that the guys in Montreal developed for us. It has everybody's guidelines, so we can always have a cogent discussion with the patient. What if the test group were minimally invasive para sternal surgical aortic valve replacement if we selected patients with good, angular dimensions. So that's solid size or even really big. They can have all the AI you want. They can have by customers valves. They just have to have good federal access for per close formal cancelation the orders in a good position. What if we get to choose? Well, I suspect, then that Sabir is gonna look better than ever, because even those bicuspid valve we're gonna have to be randomized. So the reality of it is, there's a There's an application for all these devices, and we have to look at who the human being is and what the consequences consequences are. We could do this through a small incision. We can do it through a little incision without touching the sternum, and the patient has a rapid recovery, and it affects their lives very little. So earlier we talked about the Swedish data. Here's the finish data mechanical versus biologic prosthesis. 50 to 70 years of age and people always say to me, Well, you know, that's the finish date, and finally a great health care. They can manage I in hours so we could see that that's true, right? because their mortality is better with mechanical valves. There re operations, Of course, they're better with mechanical valves are much less They're bleeding, is the same. Why is that is because they have a lot of home and are monitoring the monitor their anticoagulants shin perhaps better than we do as an entire nation. Stroke incidence is the same. It's always the same. So when people say, well, you know, stroke incidences higher from mechanical valves that's not true. A mechanical valve, Santa coagulated or a tissue valve. They carry the same stroke incidence overall. So long term, you know, again, as I said, if you look at that and say, Well, that's the finish experience, they have things well controlled. I think this paper is very important. Diaz he they took everybody all of the relevant good studies. So all the match studies and the one randomized control study that was fairly recent, which was mentioned earlier status so and they showed that in fact, mechanical valves and 52 7 years of old age were associated with a longer, long term survival. Now people are still gonna say it's inconvenient. You gotta be another coagulation, maybe their lifestyle issues. We're still gonna talk about that. But the reality of it is that there are several studies demonstrating early mid and long term survival benefit with mechanical battles were so biologicals. There are several studies demonstrating no difference in survival. But there are none that show that biologic valves have a survival advantage. That is not something you can offer in the conversation. But like politics, medicine is local. Patient management will differ both subtle and obvious ways across institutions and even within them. And this is just the truth about the wild West of valve disease. So, Val choice in the modern era, what are we accountable for? How do we generate a valid lands? Okay, we have to know the patient schools. We have to provide them legitimate feedback to what their thoughts are. Persons telling you gonna live 30 years, you know they're not. Or if you have thio, they have to change course in their life, and they can deliver on that. Then you make the deal with them. But you have to think about what their long term survival is with the quality of their life is and what's the Internet? What the internal milieu of their body. How will impact the valve? I'm gonna show you some really interesting stuff about that. No patient prosthesis. Mismatch. This is an absolute. So if someone is in a valve center of excellence, they should never leave that institution with wrong sides valve. And it doesn't matter what kind of elopement yet. So how do we develop this framework of discussing valve durability Based on what we know what we expect in the context of that particular human beings so match the long term performance of the device of the longevity of the person. What do we know? Well, you know, I wake up on September 20 27th. Last year. I open my favorite, uh, journal. And what's that? What does it say? It says that when it planted correctly, a safety in three could last 25 years. And this is absolute baloney. That headline should not be there. What are they looking at? They're looking at a perfectly circular safety and three in a bio testing device that has sailing in it and just opens and closes the valve a billion times. Sure, that might work, but in a human being, it's not the same thing. Structural valve deterioration is unavoidable, and we don't really appreciate the full problem prevalence of because we lack of full definition is, Dr Serrano showed earlier. We could look at it in subclinical framework or the clinical framework and other symptomatic. But either way, that valve is changing. So certain is a biologic valve was in. It starts to change my favorite paper on this subject. Handcuffed to buy operas. Thesis Goldstein doctor Dr David followed all of his patients prospectively 1134 patients with perspective follow, including Echo. This is the best study looking at tissue valve durability 1982 to 2004. What does he show us? He shows us The doctor is a very good valve. Mean age of 67. Patients do okay. He also shows us that without doubt, the most important variable is the patient's age. So age determines durability. Why is it is because of the younger you are, the more vigorous your immune responses. Conclusions Hancock to is a good valve. Patient age is the most powerful predictor of valve durability, and for him, the most important thing was that although they identified structural valve deterioration. 87 patients on Lee, 74 re operated because of remaining 13 were deemed inoperable. What is driving some of that in the outside of the age? And the other major factor is the active milieu. Inside the patient is a great paper from People Rose Group. Looking at the impact of this metabolic profiling, we're all familiar with the central and a posse insulin resistance, thes air patients we see all the time. And what did they see that once there was a signal of it? Once there was a signal of impact on the valve. The deterioration accelerates dramatically, and it's a function of the dis metabolic syndrome in the patients. So it's that internal million. Yeah, they will accelerate the alliteration. So that means not only a young patient might be better with mechanical valve, but somebody middle aged with this metabolic syndrome and coronary disease might actually do better with a mechanical valve. It's not just the younger patient it that drives that lives longer. It's because of the opportunities due to the sexual valve. Deterioration creates excess morbidity and mortality. My point here is that those valves start to change as soon as they're in the patient. And this is an important paper that Dr Serrano showed earlier. There is another paper that's very similar to this sub clinical and clinical impact. Basically, what it tells you, though, is the Grady int rises on these valves. The effective orifice area goes down, so these vows start to deteriorate to start to tighten over time. This is is, of course, mostly pericardial valves. But that patient will live with a moderately disease valve for several years before it's time to replace it. Or it's time to do a valve valve. So why does surgeons think that these valves last a long time? They get the impression that they're gonna be 15, 19 years. Almost 40% of the surgeons thought that because they see these types of communiques that talk about 20 year function of these valves, durability of the valves. The reality of it is, though, that data does not include these young folks. You put young folks in there, you're not gonna get the durability of the valve. So his anti calcification treatment changed it all. I could spend an hour just on this. I spent a lot of time researching this reading the papers. There's nothing clinically evident that shows us for sure that any authentic calcification process is better. And unfortunately, the inspiration valve, which I do implant in the under. Folks that demanded tissue valves doesn't have any real data other than eight sheep out to eight months where they showed in the mitral position. The calcification was lessened in the belly but still occurred at the Commerce shares will wait to see if that translates into a better long term effect. Sometimes good values go bad. A random valve can fail in a tissue valve. Uh, this sometimes a trans catheter valve will fail. Very early is a woman who only 20 months earlier it had a 20 millimeter SAPIEN. Put it, This is a person. This is a young man who had chronic renal failure when, when he first had his valve implanted, who is in bad shape, He came back to us, and we took that out and put a mechanical valve in him. But you could see the accelerated wearing this valve from chronic renal failure. Just as we know it happens in surgical. Now, this metabolic syndrome 64 year old woman, 3.5 year old valve, this metabolic syndrome, as I showed you earlier effects the valve 50 year old man who is six years out from a magna Now, by the time we get to this valve, there's a left ventricular hypertrophy is bad diastolic dysfunction. He's had the disease of modern Europe stenosis for a long time. How do we decide to go sooner on any symptomatic patient who is suffering the consequences of a moderately cyanotic belt? This lady was 82. She finally had obstruction due to Panis in growth. She might be better off than the 50 year old because she got 25 years of good valve function until we put her tissue about it. When we look at an onyx valve on, Lee sees the outflow tract sees pure carbon and it comes out to the order. This is an important point for this valve because it seems to be immune to Panis and growth. No one wants to be an equivalent unless it saves their extends their life, and they're still not happy about it. But we still have to tell him the truth. People with with tappers, they're often antiquated, 30% of taverns, antiquated tissue, a tissue. Aortic valves are often antiquated. And remember that patients that are free of atrial fibrillation at age 55. By the time they grow old, they're at a for approximately 40% chance of getting agent tribulation needing an accumulation. So have a tissue valve. Doesn't mean you're not gonna be an equivalent. It should buy a prosthetic valves, be routinely at quake again. For people. It was a beautiful paper that outlines the fact that if we really are paying attention to our patients, we should be in coagulating. A lot of them is a lot of them have an indication for it. I'm gonna go back to this chain paper that Dr Serrano mentioned before 4000 patients New York database. And I think the important signal here is that strokes the same re operations more on bio prosthetics. Major bleeding is more now re operations. They're dangerous, right? 9% mortality. Maybe we've improved that with Val. Val, we don't know yet because we don't know how durable these are. And we know that bleeding is a problem. So if I can fix one thing on here, if I could make this go away, then mechanical valves or the clear winner. Maybe we're changing the risk of redo with valve, valve valve fractured, which we do a lot of, and we're actually participating in a registry for that. But what we really after we're after coming up with a appropriate decision for the patient that allows them to make a have a cogent understanding of what's gonna happen to them after they have their valve replaced. It's worth noting that the onyx valve is pure carbon. So 17 years ago I met Jack Buck Gross, the guy who invented the silicon alloy paralytic carbon that's on every mechanical valve on the planet, and his goal even then was to come up with this, and he had just discovered it. He had just made Onyx Carmen. He had just brought it into the valve field, and you can see how much smoother it is and less likely to be thrown eugenic the the structure of the valve. This is important because, as you know, we're moving into a very exciting trial that Tracy's gonna talk about. But the mechanics of the valve allow for better washing the of the hinge point, the hinge. Point moves up and down in this socket and gives a three way purge. And the valve leaflet doesn't have to fall as far when it closes, so it requires a smaller closing volume that then, then the additional closing volume could be spent washing the leaflet or washing the hinge. Sorry, it opens to 90 degrees to a 90 degree angle. It's the only valve that really gives the opportunity for true laminar flow. And this is what I was talking about before with the motion of the leaflet in the Hinge Point in the frame of the valve, this is a taller valve. It has a fairing that drops down into the outflow track. That's the reason that we don't see panacea growth because the pianist we have to go down around the carbon faring. The housing is designed so that it sits inside the outflow track and prevents that, like I said, that's the Achilles heel of mechanical valve. The blood only sees the outflow track and the valve, and this is a unique property of this fell. It's laminar flow a larger, too restore normal flow. Our goal in these patients, especially the younger folks is to re couple their heart with the vasculature in a normal fashion. Who can we do? Well, how can we do that? We could do that with a home, a graft or freestyle and onyx, you know. In fact, it shows that replacement the replacement flow pattern for valves is different for the various devices. Whether that's a mechanical valve, stateless valve or standard valve, the pattern is different and in fact, for an onyx valve, it's very much the same as a normal, healthy volunteer. So this is a normal aortic valve flow pattern. This is an onyx felt laminar flow, normal vertical flow into the vortices, perf using the coronary arteries. We showed, of course, that with Pheonix felt we could we could run it at a lower dose of blood thinner. And this was This was, of course, the pivotal study. And the most important thing that came from the lower in a coagulation study was that we could move the ion our point down. We found that the sweet spot for the onyx valve was a lower dose of Coumadin with an eye on our of 1.5 to 2, and that resulted in a 65% reduction in bleeding events so that in the at the in the end analysis for our primary end points it was significantly less for the lower end of coagulation protocol. So we change this. We changed the ability that we change the bleeding risk for the valve. And we provided patients with a durable valve that would not provide them. Then with that increased risk of bleeding in whom should we consider mechanical valve? Those that we don't want a high likelihood of re intervention if they're young, chronic, logically physiologic age and the talking about, Like I said that this metabolic syndrome and the more complex scenario thank you very much. Hey, Mark, that was great. Every time I listen to you talk, I get so immersed and everything you say and I lose track of time. Uh, just a quick question here and we'll have you answer some more of the questions online. But I thought this was an interesting one that maybe you could answer quickly. 60 year old decent Health Tavern Feasible good size Angeles, but absolutely refuses anti coagulation to which option which you consider Sava now with a valve in valve. Hopefully, in a decades. I'm, you know, assuming abroad. Prosthetic now versus with a velvet valve later on or tavern now and then surgery in a decade. What do you think? Yeah, this is an interesting topic that's come up kind of recently. I think I'm solidly in the minimally invasive Sabur, uh, department. It depends a little bit on the anatomy of the of the Ordo annular complex and making certain that we can offer them a solid valve valve later. And that's actually important consideration and no patient rights. Thesis mismatch. Development of opportunity later. But that same 60 year old, you know, if it's 70 when they need another valve, then you do. There's valve valve and they get to be 80 then your valve valve valve on. That is doable, but it's not great. You know, we've done Tavern Taber plenty of Alvin Valve, and we do Val fracture for that often, so we have to talk about them about to them about the entire continuum. But I just had that patient the other day and did a minimally invasive sand reform. Well, that's good. And we we just have time for that One question and so we'll move on to the next presentation. But there is a question, uh, some for you to answer in the Q and A Well, while Mo is speaking here. Great. So thank you for that. Next, I'm going to introduce Dr Most Satya Murthy, who's the professor and chair of the Department of Medicine at T C u N u n th s s c School of medicine who is our thrombosis expert and is going to be talking about blood thinning in 2020 and beyond. What this means for our a v r patients as well as how do we collaborate with surgeons thinking about artificial prosthesis selection somo. Thank you very much. Well, thank you. Again again, Tracy. In front of them organizing this in such a nice way online during the pandemic. My best wishes to everyone for safety during this very challenging year. For for you and yours. Um, really, in a brief period of time, I'd like to get through valve selection with regards to the choice based on your assessment of present versus future from metabolic risk. Why is this platform that we're all very experienced with, uh so helpful and why they reduced I and R and then is there any experience with with dough acts? Of course. We call these dough acts now a supposed to know acts and application thio throughout metabolism reduction in mechanical valve prosthesis. So I think both Mark and Maurice covered this already. We understand that the global phenomenon for valvular heart disease, secondary toe structural valve deterioration keeps increasing in time that to 2050 projection probably is under what we're probably going to see. Probably closer toe 909 150 million patients will need found replacement. Um, you know, the geographic international distribution between mechanical versus tissue about prosthetic is quite different, with data favoring tissue by prosthetic implementation here in the United States is compared to other countries around the world. So way understand the scope of the problem. We're all here because we're very interested in having the heart disease for cardiologists that air joining us this evening for decades passed. We got very interested in the physical examination, the clinical correlation of symptoms, as opposed Thio. Where about would stand in terms of its systematic predict progression? Um and then we would engage your assertion surgeons to a certain extent in terms of FINA type decision making, if you will mechanical versus prosthetic by a prosthetic but typically would stop there Rarely would a Cardiologists B, I think, deeply engaged in a specific platform of choice on DWhite. Is that well, as I mentioned, those of us that get really interested in ingredients might have an interest in one particular particular mechanical valve platform versus the other. And for those that are really interested in post implant human dynamics, you know, avoidance of this very dreaded outcome of poor, uh, a selection of Valentina Top can lead Thio ppm patient prosthesis mismatch. So a long held belief and mark just touched on this with that outstanding slide about the likelihood of tissue about thrombosis. This is really going up. And so you can see here some four dimensional CT data published not too long ago the journal about the likelihood of formation of micro thrombosis, one of the I think important determinants of short term surgical valve deterioration. Now again, why? Okay, So So we We really start with this conversation. Mechanical tissue radiance and avoidance of of patient processes mismatch. So, as I mentioned, typically, we would have really been interested in just the concept of a mechanical valve, right? And so for those of us interesting McGrady ins, we we kind of chased radiance and have a conversation with surgeons. However, the reason why I think it's very important for us to consider really being engaged without surgical partners now, especially with this Monix prosthesis that's available, is we, as the managing cardiologists, will have a long term longitudinal relationship with our patients and will largely be responsible for their anti coagulation for the balance of their life. So if the I R goal is typically 2.5 to 3.5 for 3 to 3.5, depending on co verities, etcetera, most of us were typically not have a huge role in and engage in a surgeon on valve selection. So it really doesn't make a whole lot of difference to my management, right? So that's I think that's one of the reasons why traditionally, we may have stepped back and let our surgical partners decide which fouled. We will re except the patient or practice after post operative recovery and then managed to sign our because everything is about the same here. One of the reasons why we may elect tissue valves and patients is the promise of of delivering them freedom from anti coagulation. But Mark just showed you even more contemporary data. This is a little bit older data, but the likelihood of a patient developing a need for long term 84 regulation is quite high. You know, approaching 65% in the mitral position and in the aortic position, typically very to 40% will require some form of systemic anti coagulation post implant through the balance of their life. So the promise of delivering a valve replacement for management of symptomatic Eric Ballard disease and stenosis with freedom from anti coagulation with a tissue by a prosthetic valve might not entirely be accurate for the patient. Uh, now, why is that Mark touched on? This is well, it's because of two motor lying comb over conditions that track with many of our patients. Eight different relation and being a Strongbow embolism. So what if we told you that a particular valve and we're talking about the Onyx valve was different? Andi was very different from its other brethren in the phenotype. What would you. What would you think about this? In fact, what if we were to share with you? Data and evidence a smart did briefly about a lower anti coagulation burden is reflected in a nine are of 1.5 to 2. I would ask all the cardiologists that are with us this evening whether we can think of any evidence based support for a I and our goal of 20.5 to 2 point. Oh, in clinical practice. And if you think about this and reflect on it for a moment, we simply don't have that evidence for any other disease states. So what if I told you we had a valve that could accomplish this? Well, this is the onyx file that we're talking about this evening. The FDA allowed for Thea the lower IR in April of 2015, 1.5 to 2.0, after the 1st 90 days of standard therapy three the These have also then, of course, found themselves into the a c A c c h A guidelines. Well, is there any real world data? That's cohort observational registry type That might, uh, that might suggest why this is the case. Why there's a lower IR this required. So I draw you to Dr Williams outstanding work that really launched incredible interest in this field, probably nearly a decade ago. This is presented at the Society of Heart Valve Disease in 2011 at the annual meeting. This was a 10 year study of very poorly controlled anticoagulant patients in South Africa with the target and are set of 1.5 to 2. There was a This is a 906 patient, your fault. It's a really incredible accomplishment for a study. That's that's that's that's really good in the surgical of Outfield, 42% of these patients were entirely non compliant or kind of loss to follow up. Well, if you look at the morbid events associated with the things that we really worry about thrown globalism or val thrombosis, the likelihood in the aortic position was exceptionally low, very low T ray, no thrombosis of the onyx valve with a relatively low bleeding likelihood as well. So really extremely hypothesis provoking. This was then further, I think, accentuated in a study presented a couple of years later, Uh, this was a clinical event rates with the Onyx Mechanical Valve Multi center experience follow above 12 years. 691 patients almost 3600 patient years. Look at these events. The total TV events for for the on expanding the aortic position 0.6% major bleeds 0.4%. If you go into double valves, it's still incredibly, um, low thrombosis events. So again, very hypothesis stimulating eso a mechanical valve that requires us anti coagulation. Why? I want to quickly cover three important concepts and Mark already shared this slide. Jack glucose is incredibly important. Discovery of a material, uh, physics to material engineering process allows for the production of pure onyx carbon without any silica lol silica particulates that are embedded leading to a very smooth surface. This then from an engineering perspective, allows one to take theon x pure carbon and shape it in a way that mimics our aortic valve, the mammalian aortic valve, the human aortic valve, and allows for the accomplishment of these six very important endpoints. Um, okay. This then has an impact on flow characteristics and fluid dynamics and flow in terms of laminar versus turbulent flow. And as we know the more turbulence. The Mawr sharing themselves, the more activation off all the all the trouble makers in your circulation that eventually leads to micro thrombosis problems with Excursion Panis development etcetera. You can see then also that the Grady INTs related to the to the Onyx valve are quite low nine millimeters mercury on average across almost all the valve sizes. So the hypothesis generating studies that I demonstrated led to the formulation proact study. And because we have a relatively small time today, I won't go through the entire construct the trial. Suffice to say, the null hypothesis was, could we identify patient population of high risk patients? Uh, status post a VR was from the high risk a BR group and on anti coagulate them to a lower and lower and are then compare this to the standard therapeutic range that we've all followed for many years and the outcome was significant. So this is published by Dr Poskus and colleagues. Um, a number of years ago now there was a significant reduction in bleeding 50% reduction bleeding, with no significant increase in the stroke rate versus the standard of care arm, if you will. The sweet spot er optimal range for the Onyx hire Ex patients is in that 1.5 or two point arrange and mark show toe. Really nice slide. I have a much less elegant home brewed slide that I'm not going to share because it simply won't stand next toe marks elegant side that he showed a few moments ago. But just remember, the sweet spot is 1.5 to point out eyes their guidelines. Support for you is a practicing cardiologists. You better bet your bottom dollar. As I noted earlier, you have guidelines support to use the 1.52 point oh plus 81 mg asked for long term. You see the reference range for anti coagulation for other valves and remember is we keep moving that curve and shift that curve in terms of the therapeutic range. The t p R. For for forgiven, uh, clinical indication, the more likelihood there is bleeding because the likelihood of exceeding that margin and getting into the i r. 4 4.5 5 will result in higher bleeding rates. So the last couple of minutes I wish Thio bring back wonderful memories for everyone here, which is the coagulation cascade something that I dream about every night because this is something I personally, really enjoy and we investigate in our laboratory. So if you love this in medical school, you're just like me. You were a bow tie, and you're not considered normal by those that are closest to you. Hematologist. And I won't take a fence to that comment because I'm being self deprecating. Uh, let's just simplify the cascade factor. 10 days converted a factor. Three factor 10 to 10 A. This allows for cleavage of the damage in Prothro Month Roman, which then allows fiber engine to be converted to five run and fiber and ultimately, is what allows our our favorite little sticky cells to do their thing view of the phone program receptor. How do anticoagulants work? They work essentially all the ones that were typically used to using the Hepburn Hepburn oId Loma like awaits happens etcetera. By serving as a catalyst, they essentially allow anti thrombin, which is your endogenous anticoagulant, to bind with a very high affinity inability to this five Penta sacha right sequence, which then allows for a much greater enzymatic reaction, allowing for binding to factor 10 a and thrombin and then release of these in circulation from the circulation through the reticulated the legal system. Eso This is what led then. Of course, Thio colleagues developing low molecular weight have have been a much smaller protein. 68 kill adults in size and in the Penta sack correct sequence, which is commercially numb as Fondo para Noora extra how thio direct oral anticoagulants work, it skips the concept of requiring anti common three to bind and binds directly to a very specific binding pocket directly in factor. Tentative leads directly to inhibition off that without any Cadillac catalytic action, if you will. With regard to Ryan, are even in the very best, uh, warfarin clinics that are nursing and pharmacists adjudicated physician supervised the likelihood of accomplishing a therapeutic I and our is only about 60%. So despite all the effort we put into this, we're really not great at maintaining patients in a therapeutic range. So this led Thio very important trial, which we participated in when I was at Vanderbilt Kodak trial. That was the very first n i h funded pharmacogenetics trial. 12 centers were involved in this. The question being Can we buy by stratify ing the war from prescription based on the presence or absence of a Lilic density To be course C one or C two c nine? Could this have an impact on the end point in terms of patients Events related to the I R thrown globalism, bleeding, etcetera. Unfortunately, this was published by Kimmel all in the journal A number of years ago. Didn't the null hypothesis not satisfied? This once again shows the complexity off farm Homogenic trials. Yeah, so have no acts been studied for management of thrombin ma'lik risk in the aortic position. Uh, the answer is yes to bigotry and was examined. And I think everyone here we could skip through this knows exactly how this drug works what it is. It's a direct thrombin inhibitor that's taking an aural form. The first of its kind. It's US label is for prophylaxis of a tra formulation. Uh, now, this is extended tiu some other applications as well in the subsequent years since I made the slide. But this was the first dough act studied in the balance space. So in the realigned trial, I'm gonna kind of quickly take you through this, you can take a moment and and study this slide. But ultimately it was a fairly large trial that looked at minimizing patients either to either toe warfarin or to the bigotry and dose between 2. 20 and 300 mg B i b with a typical, uh, study endpoints that way. Assess in these types of mechanical valve 80 coagulation trials. What was the outcome? Well, the outcome No, I don't know where that slide when I think it disappeared. The outcome was not good. There was a slide that I had here that seems to have disappeared. Uh, there was there were excess, uh, pre specified events in this trial that led to the data safety monitoring port, uh, prematurely or stopping the trial early. And no movement has taken into space since a t least until now. And Tracy, in a few moments, is going to go through this exciting, important development related thio, a direct oral anticoagulants and the on expel. So in summary, this'll eyes a valid that in our experience, and our program here in Texas has improved long term outcomes related thio anti coagulation gives you a very fine radiance. Very low likely that every operation with minimal if no Panis has a very low adverse event rate. And it's the Proact trial demonstrated a significant reduction in bleeding without a significant increase in trouble, embolism and its guidelines supported. Now that was fantastic. Thank you very much for taking us through this. I think there was definitely interest from the attendees, especially on that South African study that showed poor anti coagulation. There was a question about whether or not this was a peer reviewed study. It was, in fact, a peer reviewed study and published in the official journal of the of L Disease Group here. But here's here a couple of questions about antiquated regulation that I'd love to get the three of your thoughts on. So maybe you can start on this one, and then Marcus, a surgeon you can weigh in. So is the in our goal for a composite onyx valve graft for mental. The same is just a VR alone within within onyx valve mode. Any any thoughts on that from a medical from both the standpoint? Yeah, so I think I think, uh, just say from up from up from a risk perspective, at the moment we started manipulating the aorta thing. Equation changes a bit in terms of the proact data. This was not something that was addressed. Perspectively retrial. What defined high risk was a very large left atrium, low ejection fraction presence of from Ophelia, you know, etcetera, etcetera. But, you know, I would probably apply this data in practice more towards just the straight valve replacement patient, if you will. But I love. I love Mark's thoughts on that. I don't know how he manages that this practice. So curious. Mark. Yeah, so it's a super important question for for a couple of reasons. One is that we didn't include them in the study, and it was more a matter of kind of a hurdle with the FDA at the time. And I think it really hurt us because we use that conduit so much on. We have not gone ahead and changed our practice for them because we don't have that FDA clearance. That said, if we have somebody who has the conduit and develops a bleeding complication, then we go ahead and drop them down. But and justified in the documentation, it's also important to note as you're going to describe that We we made sure that in this next generation, the next study that we include them because in actuality and mo, I appreciate your input. In actuality, though, if we look at the great, the greater data on on the matter we can't find any complications with respect to trump symbolic events related specifically to those graphs. Yeah, And then here's another question and again reflects sort of this uncertainty about i n our target. If you've got a valve that's got a lower flow so maybe a low ejection fraction or L V O t. Issue here, um, you know, would you be still be comfortable using that Lower I and our target range in these patients? Um, so maybe mo and Maurice, You guys might both weigh in on this one or isa e. I did use the law and are you know, all the trials of high versus low showed that the you didn't increase. But by having low i n r. You didn't increase the Trumbo anabolic events and you decrease theme or agit complications. So my whole practice was fighting with the coagulation clinic because I was insisting on the low i n r. And they were telling the patient, but you're not within guidelines. And that concept that we should increase the anti coagulation is gonna beam or effective in preventing Trumbo anabolic complication, I think is completely wrong. And and so I'm looking forward to the clinical trial that you're gonna be doing to sort of change that completely to say, Okay, we we don't have to have an extreme anti coagulation in particular with patients who have isolated the aortic valve. Prosthesis flow is high by defect prosthesis. You know, in in the past we mixed the started words procedures with by leaflet and the started words multiply the risk of Tom Gamble A complication by five. So no, I'm completely that what I was telling my patients, If you have an eye on our of two, you're fine with an isolated mechanical aortic valve, and I think it's even truer, as has been demonstrated with the with the Onyx, because because these people have a flow that is really an A material, which is which is, uh, off high quality. So So it's different, but all by leaflet prolapse by deflector prosthesis. Warranty calculations fine. One quick final question before we move on to my talk, which is if someone has triple vessel cardiac coronary disease, does that affect your valve choice in the intermediate age group? I mean, that's someone who may potentially need PC. I later who might need anti platelet therapy on top of anti coagulant therapy. Mo your thoughts there? Cancer? Yeah, this is This is a tough one, because really, you know, ultimately, I think the way we view this is the way I think all four of us have talked about this type of complex decision making. This is something that's best done with your surgical partners in terms of how best to get the most facile result for the patient in one setting, if it's possible. And so there's data that we have now that supports three use of an anticoagulant with, for instance, a single anti platelet agent post PC, etcetera. So though the waters are less money than they were about five years ago, my personal preference is a integrated surgical solution when it presents itself because that's that's probably going to give our patients the best long term, um, outcome from a revascularization perspective and clearly from, From about perspective. Mark Oh, thank you so much. I think there's a super important question. I think that patient is best served quite honestly. If we're serious about the science with an onyx valve and coronary bypass surgery, because the patient then would have the benefit of LoDo Santa Coagulation, which is probably protective, and people who have extensive atherosclerotic disease it's not confined their corn age. They would have the most definitive therapy for their their for their coronary disease. Uh, obviously, people make the argument that by a prosthetic valve would serve them better. Because again, like you say, eventually they may need stents and then you end up with triple therapy, but that I think that's kind of, you know, down the road kind of thought. And I think that those same patients have a shorter durability, their bio prosthetic valves. So it's a conversation to be had. Well, that's a great question you have. Sorry. Go ahead. You know, the question you had was is very critical. That triple triple therapy is a killer. You know, it's the only cerebral hemorrhage I've seen in young, relatively young patients with mechanical procedures. When when they are on triple therapy, so we should resist that as much as we can, because we're gonna have a nexus s rate off hemorrhagic complication. And and if we need to do, ah, coronary intervention that you cannot foresee before you implant the vow. Well, maybe be not as much anti platelet therapy and maybe a single single medication. Also, the newer stents only require a month of anti platelet therapy. So in the science stents taken, stop the Plavix after a month on Lee, if it's done in the elective setting, I think very little data and acute coronary setting. So we do have to be careful there and many of the trials looking at dual anti from biotic therapy. You know, a single anti platelet plus an anti coagulant have mostly been done in the A fib population. They have excluded patients with mechanical valves. So again, some caution with pulling over that literature. Well, thanks for the Q and a session. Um, I have to give myself some time to talk here, So, uh, just a quick introduction. I have the privilege of being the principal investigator of the proactive in a trial, and I hope to use the next few minutes to really convince you that this is a potential game changer in the choice of erratic valves. So I'm a non invasive cardiologists at Duke. Uh, just a quick disclosure. This is a trial that is sponsored by CryoLife. And here are my other disclosures. So we've been dealing with this issue, which is, um, people don't like anticoagulants on. We've actually seen tissue valve implants increasing over time, especially in that younger demographic between 50 and 65. And this is really reflecting that. I think, uh, this, uh, disinclination thio Thio use anticoagulants, Onda coagulants like warfarin. Uh, this is what's currently recommended for patients with mechanical prosthetic valves. It's the Onley approved anti coagulant. As you all know, this requires continuous IR monitoring and dose adjustment. It often results. It has a lot of different limitations to it. It's got a long onset of action, hangs around for a while. It's got a long, uh uh, variable half life here. So it's just a really tough drug thio to manage. There are numerous drug interactions. For example, someone who requires an antibiotic may sometimes need to get Iran are monitoring more frequently my patients hate the next part, which is about diet. They just they have to control their diet. They can't be spontaneous on DSO. This is something that really requires a lot off. Um, patients Time Clinicians, Time Healthcare System Resource is to manage optimally. So there have been numerous alternatives to war from therapy that have mostly been explored in the atrial fib relation and Venus Rommel embolism type of environment here. This slide, which I am not going to go over, really just outlines the many options there are. There's the bigger trend that came out first, uh, then study data related to River Rocks Fan, which has the advantage of being daily and then a picks, a ban, which is given twice daily and the latest one of Doc's a fan which hasn't had a whole lot of market share in the US But many of these trials were designed as non inferiority. Many of them proved themselves to be great alternatives to war foreign in terms of non impurity, so no increased risk of stroke or throw emblem bolic outcomes with ease. And actually many of these have also shown a better safety profile and to Maurice's point about intracranial hemorrhage. That's where ah lot of these agents really have the most advantageous profiles in that there is a lower risk of intracranial hemorrhage with these, uh, doh acts or no acts compared with traditional warfarin rather than going into all of these trials. This is a summary slide that basically puts these studies, um, and categorizes them into the four quadrants based on on the X axis stroke and systemic Ebola symbolic risk and on the y Axis bleeding risk. So the most favorable drugs should be in the bottom left quadrant, the one that's highlighted in green here, where there's the fewest number of strokes and also the fewest number of bleeds. And we find that among these, perhaps some of the better safety profiles are things like a picks. A band that green dot down here, which really has a really good efficacy profile as well as a fantastic safety profile. Um, this is one of the few that actually proved a mortality benefit. Um, and so that's how we decided to pick this particular agent to do R R C T. Now mo alluded to this, and I almost wonder if I had managed to jinx his presentation because he couldn't show the slide. But I happened to have it in my deck here. These are the results here for the realign trial not going to go over it in detail, but this was a trial that was discontinued a prematurely. It was discontinued about a year after the first patient was enrolled because you started seeing those curves diverged early in the D. S. M B said no. This is not something we feel good about continuing. But I think there are a couple of key issues that might have led to these results, and I'm highlighting two of them. There are others. One is that patients were randomized immediately after valve implantation. And many of you who are surgeons in the audience know that that's also are high risk, highest risk, period in terms of a rumble anabolic event occurring. The second issue is that they picked a big a trend. Now, if you ask me as a medical cardiologists, um, in terms of which Doha core no act I would reach for in an 1/5 patient. I would say that the big A trend now is pretty low in terms of my priority, in part because of the side effect profile, but also because many of these patients required dose adjustment. And we saw that in the study and the study, almost a third of patients required a dose adjustment or a discontinuation because of the characteristics of the drug itself and how the protocol was written. So I think these are two key factors that probably led to the bigotry and really being not a great option to study and the results of the realign trial. So I would say that we really needed to try again. We can't just say this is done. There is some great in vitro data for a picks a band compared with war friend here. This is a porcine valve model here looking at thrombosis burden buildup on these on these valves and you can see that a picks abandoned warfarin had very similar in vitro results, and that gave us courage to think about Well, how about we try this in humans? And so, after a couple years of discussion with the FDA and with our leadership committee, we decided to test the following hypothesis, which is in patients who have the Onyx mechanical valve and is, uh, Mark pointed out this is the valve that really has a very nice flow dynamic profiles, that is, um, less Toronto genic. So we take the mechanical valve that that that we hope it's the least from a genic and match that up against the picks a band, which is one of the better efficacy safety profiles that I've shown you earlier between these two things can we maintain the patients safely with this valve with a picks, a band compared to standard warfarin and so are try A, which is now in progress, is going to randomize 1000 patients. This is one of the largest valve trials that we're going to be doing here. We are focusing on patients who are three months out from their surgery. So we're not looking at the highest risk period. We're trying to make sure people are safe at least three months later. That's when we're gonna randomize patients to either continuing the warfarin or going on a picks. Urban. And you might have noticed that we're going for a night in our goal of 2 to 3 here, and you might ask, Well, why, given that these are patients that have been safely demonstrated to do 1.5 to 2 before. Well, this was an FDA requirement. They wanted to really do a head to head comparison without giving a picks, a ban, any advantage here. And so this will be a pivotal trial for dough ax in this mechanical valve setting. It is comparing a pixie bands head to head with warfarin at a goal of 2 to 3, and we're gonna follow these patients for two years. The inclusion criterias I'll show in the next slide, um, is and the exclusion criteria. The endpoints are really trying to demonstrate efficacy as well a safety. So on efficacy side, there's a head to head comparison a picks up and should be non inferior warfarin. But we're also gonna make sure that the patients we recruit into the trial are similar to the patients we are treating in real world practice. And so there's a second efficacy comparison that will compare to objective performance criteria. So, historical data here and then finally, we wanna actually show that a picks a band is superior to war friend in terms of preventing leading because this is something that was seen in the A fib and the VT trials as well. So the inclusion criteria is a valve implanted at least three months ago. They are able to take warfarin with that I and our target of 2 to 3. And this next criteria something that's also a little controversial, which is in our trial. The patients either have to be taking a 75 to 100 mg. So in the U. S. That's 81 mg daily of aspirin because current guidelines tell us that they need to. But the guidelines may be changing or if a patient has a contra indication there okay to still be included in the trial. But this is something that I wanted to highlight. There is well, and the exclusion criteria there a couple in there that are really designed to make sure that this is a safe tri ALS for our patients, that we're answering the questions that were trying to answer on gay. Maybe for patients who have a low crapping clearance where a picks a ban is, um, dozing is a little uncertain. We've excluded those patients and, of course, patients who blood recently. These are patients we do not want, um, in the trial as well. We also want to make sure we're able to have the war from be a good control arms. So these are the patients who are going to continue doing their monthly I and our testing. And as you know, prior trials there have been home testing this one, we're allowing all sorts of testing Azaz long as their I n r is within range. Our primary efficacy endpoint is a familiar one. This is one that's sort of a composite of valve from Moses or valve related Trumbull embolism or valve thrombosis related mortality so very hard and points here, and the primary, the secondary appoints are the components of this as well as the risk of major bleeding. We want to make sure that these therapies are safe here, and this is my final slide. But this slide, I'm very excited to know that we've got several sites up and running. These stars represent where these sites are across the U. S. Where we're hoping that unfortunately, this does not look anything like an electoral map that you guys have been looking at lately. But We're hoping to get good geographic representation across the U. S. Andi patients who are managed both in an urban setting as well as a rural setting here is well so that we're really getting, ah, population that is representative of our valve population. So with that, I will stop and see if we have any questions in the Q and A it looks like, uh oh, good. I've seen not a question that I'm seeing a comment that you've got a few patients with in on itself and you want to enroll them. Come talk to me, email me. We'll get you in the trial. My email S t r a C y dot W A N g at duke dot e d u. There's a question. Can we enroll outside of North America? I'd love to say yes, but we are currently limited in which countries were able to recruit in again, reach out to me. We'll see what we can do here. But right now, uh, this trial is North America on Lee. Um, so I'm going Thio, say thank you to all of our phenomenal speakers. Um you know, I think this is every time I I hear these talks, I feel like we I'm learning something new and I hope you are too eso Thank you very much for your time and your attention. Thank you. Excellent. Super fun. Appreciate it.