Alright, welcome everyone to the Heart Failure Society of America's latest episode in our educational webinar series. My name is Scott Longren. I'm one of the heart failure cardiologists at the University of Nebraska Medical Center and I thank everyone for your attendance today. Today's topic involves updates in advanced heart failure, how to take care of this population and latest advancements in this area. We are very grateful for our educational support from Abbott Laboratories that made today's event possible. Again, I'm Scott Longren and I appreciate the support and the help from Dr. Laura Peters at the University of Colorado, Dr. Ian Hollis at the University of North Carolina for helping put together today's presentations. We have some great speakers lined up for you to talk about multiple aspects of advanced heart failure in this population. So Dr. Brian Houston from Medical University South Carolina, Jacob Schroeder is our cardiothoracic surgery representation from Duke University and then Pollock Shaw, another heart failure transplant cardiologist from Inova will join us as well. Our learning objectives today are threefold. So we want to describe the current strategies, predict, prevent and diagnose and manage heart failure, especially in kind of the post LVAD population is our specific topic for today. Review the current evidence and clinical trial data for the medical management of left ventricular assist devices in patients with advanced heart failure. So this will include medical management as well as anticoagulation management with updates specifically on anticoagulant management and anti-platelet management in that population. And then we're going to discuss the different methodologies for donation after circulatory death with a specific focus on procurement and preservation of these organs as we get them from donor to recipient centers. So here's our agenda for today. We'll have Dr. Schroeder talk first, followed by Dr. Shaw and Dr. Houston, and then we'll have plenty of time at the end for panel discussion. So feel free to put your questions into the chat using that Q&A tab so that we can have kind of a good facilitated discussion later in the talk. To claim credit for this, make sure you go to HPSA website to complete your course evaluation. So you'll go to HPSA.org, go to the Learning Center, and it will be available at the conclusion of this event as well as the on-demand access. So if you miss any parts of the talk, feel free to go to the Learning Center and watch the on-demand access for what you missed. So that ends our opening remarks. I'll stop sharing my screen here. And our first speaker today is Dr. Jacob Schroeder, fresh off a heart transplant already, so even better for our topic of discussion, cardiothoracic surgeon at Duke University. And again, happy to have him here. Thanks for taking time out of the OR. Thanks, Scott. And I want to thank all the organizers and HFSA for having me. Can you guys see my slide? Yep. Okay, perfect. So I'm Jacob Schroeder. I'm the surgical director of the heart transplant program at Duke. A lot of amazing things have happened over the last, I don't know, sort of 5 to 10 years in heart transplant. And I was initially asked to discuss something, sorry. And then Scott asked me to sort of broaden and both hone it a little bit, both, and talk about outcomes, DCD, and preservation. And then last week, I spent the week in Prague at ISHLT. That's a view from my hotel room, which was quite nice. And what I realized is that one of the, there's a lot of great stuff about DCD, but one of the other things that really is coming to fruition is research into different methods of organ preservation and perfusion. And so instead, I decided I would talk about organ recovery, preservation, and perfusion. And I don't know, some of you may remember back in the early 2000s, a skit from SNL, but it always makes me think about this, and we're going to call it heart in a box rather than what it was called on Saturday Night Live. If you don't remember this skit, you can just imagine that being me and Rob Metz dancing in our early 90s boy band days. So the first thing is step one, cut a hole in the box, but we have to rewind a little bit and ask, well, what is the box? And I'm going to discuss all these four methods of organ preservation and transportation and perfusion. So you have the igloo chest filled with ice, which is the classic method, which worked totally great for many, many, many years. Below that, you have the paragonic Sherpa pack, which is a temperature controlled cooler essentially. On the top right, you have the Transmedics Organ Care System, which is a warm perfusion device. And then below that, you have the ex vivo hypothermic oxygenated perfusion device. So cold static storage, again, the gold standard for many, many years in this country and around the world. The problem with cold static storage is when you put the heart to sleep in a donor, you start the clock and there's definitely a time dependent organ injury. And that was fine 20 years ago when the average donor age was 25. But now that we use a lot more extended criteria donors, that's changed. Even back when the donors were young, there was a definite sort of number of cases of primary graft dysfunction. And really, once you hit about sort of three and a half, four hours, the rates of primary graft dysfunction and increased mortality went up. Once you put the heart in this bag and then throw it in the ice, you have no ability to do anything to the heart. You just get on the plane and fall asleep and go back to wherever you came from. And this is ischemic time and the risk of primary graft dysfunction and mortality really limited the utilization of potentially viable organs. And as I said, you know, this risk of PGD. So you know, the temperature empirically is zero degrees. But we know that when you throw a heart in ice, that the temperature of the actual heart is also not uniform. I got interested in transmedics as an aside when I was a fellow, I don't know, 13, 12, 13, 14 years ago, because I wanted to go to Puerto Rico because we would get offers from Puerto Rico. But, you know, coming back, depending on which way the wind was blowing, that can be a four hour flight. And that was that was really a no go back then. So step two, put the heart in a box. The thing that has changed from the one of the things that's changed from just a box of ice is the use of this paragonic Sherpa pack. And what this is, is you can see it's sort of two inner canisters and you fill it with the preservation solution. And then it has cooling packs that you put around it. And this really can deliver a more uniform temperature to the heart and sort of temperature control. And because we know that when the heart freezes, that it's not good for the myocardium. There's very good research showing that the myocardial cells don't do well when you actually freeze them. So the goal of the Sherpa pack is really to keep it between sort of four and eight degrees. It also hangs the heart so it's not flopping around, banging against the ice. And it's also it's isobaric pressure isolation. So this is actually presented by Dave D'Alessandro at ISHLT this year. And this is all from the Guardian Registry, which again, it's not a randomized controlled trial, but there are thousands of patients in this registry now. We've got some excellent data about this issue of temperature and temperature control. And if you look, these are sort of matched groups. The gray line is cold static storage with ice. The pink line is cold static storage with the Sherpa pack. So the pink is the one we're more interested in. And you see that when all comers from this group that say go out to four hours, that the risk of probability of severe primary graft dysfunction is half at that sort of time point at four hours. And as you see, frankly, that not many hearts were preserved at six hour above six hours with ice, as opposed to the Sherpa pack where people were going out to seven and a half, almost eight hours. I know we have gone flown from Durham, North Carolina to Los Angeles using the Sherpa pack, which was about eight hours. If you actually look, if you sensor out the hearts that were sort of slightly out of temperature range and you only had the hearts in the right graft that were temperature between four and eight degrees, the results are even better. And as you go out, so 10% PGD for the ice group was really at about three hours, which 10% is probably, you know, classically about what we would see at both centers, maybe a little higher. But you don't reach 10% PGD with the Sherpa pack until over six hours. And so this has really changed the way we do things, frankly. And I know here at Duke that we use the Sherpa pack for almost all sort of standard organ recoveries. And so this is really exciting data. And I know the company is looking at other devices that they are going to try and produce to make this even better. So again, temperature range in 48 degrees in Sherpa pack. The most significant improvement is between six and eight degrees. So that's the optimal. And they actually calculate in the third sense, they calculate the best results are at 6.4 degrees. I'm not sure if we'll ever get quite to being able to manipulate the temperature with that device, especially to 6.4 degrees. But again, very, very good data supporting the use of temperature control, not just throwing the heart on ice. So step three, open the box. We talked about a cooler, and we've talked about essentially a cooler, but a temperature control cooler. And so there are some very exciting data coming out about other devices. And some of you may have used this, some of you may have seen it. So the TransMedix organ care system is a essentially it's a miniaturized heart lung machine. And you see the heart. This is the best, of course, right? Everybody loves this because you get to see the heartbeat. And so I should just put slides over this and stop talking. But you know, basically what it does, it has an oxygenator and a pump, just like a heart lung machine has a reservoir and it perfuses into the aorta and the perfusate and blood then go through the coronaries, go through the myocardium, drains out the coronary sinus. And then when you do it like this, you actually occlude the SVC and IVC. And then you see there's a sort of bigger cannula or tube shaped like a C that's in the pulmonary artery. And you can measure coronary flow, you can measure different metabolic parameters. The company sort of hung their hat on measuring lactates to judge the health. And so, again, this is compared to the two previous methods. This does offer you some ability to actually monitor the heart. One, you can see it. And I can look at that heart. We've done this probably about 300 times at Duke using this device for both brain dead and DCD donors. And I can look at that heart and say, yeah, that looks really good, actually. The heart is actually backwards. So the left side of the heart is on the left side of the screen. But you see all segments of the heart are moving. But you can do some other things. We've tried some epicardial echo. You can't volume load the heart. So that's a little bit of a limitation. But we've also actually taken the device to the cath lab. And it was really painful and hard. But we've actually injected dye into the root and actually shot the coronary. So for donors where you don't have a cath, and you need that information, say for, you know, a 55 or 60 year old donor with risk factors, if you wanted to do coronary angiograms, you could. So does this thing work? There's still people who don't think it does. But I'll tell you, we just published the EXPAND trial in Jack heart failure. And this was a single arm trial of what we call extended criteria donor heart. So hearts that were really far away, older donors, donors with left ventricular hypertrophy, donors with some non-flow limiting coronary disease, things like that, things that historically were not used often. And we then compared it to a control arm of 1800 sort of standard transplants done at the same centers. And if you see those red and blue lines, they're essentially exactly the same. So in a higher risk donor population, these hearts work as well as lower risk donor hearts in a sort of similar recipient population. So the device definitely works for extended criteria donors. The other thing that is nice about this device is there's certain cases that we do that where you may need extra time. Things like the Fontan transplant, LVADX plants. It makes it very, very nice. I think some people think that we're gonna be able to make heart transplant a daytime endeavor. I actually don't really support that because I think we have an elective schedule here at Duke that we need to really keep working. So I don't mind doing this in the middle of the night. But again, there are different benefits to doing this. The company has put decades of work into this. And the only problem I have with the device, frankly, is we don't really know how to make it better yet. And they're gonna work on that. Many people are working. But what biologic agents, what pharmacologic agents, what genetic modifications could we do to donor hearts and actually make them recover from the ischemia reperfusion event that occurs? And all this stuff is very easy to do. It's like the perfect platform for research. It is an isolated circuit that only perfuses the heart. And so there are a lot of people around the world who are working on that. So next, we'll talk about DCD. Again, I was supposed to talk about DCD, but I get that talk all the time. So I thought I'd talk about something different. Anyway, so donation after circulatory death is different than our standard sort of historical brain-dead donor. So before December 1st, 2019, in the adult world, all the transplants done were brain-dead donors. So in this country, when you're declared brain-dead, you are medically, legally, and ethically dead. And so you would then go and evaluate all the organs for recovery. And when ready, then perfuse the organs and remove them and transport them back. The problem is that there are a number of patients who don't qualify for brain death. And that could be because the rules are so strict in terms of what you have to do to declare brain death. And then some donors actually cannot undergo brain death testing. So before December 1st of 2019, we couldn't use any of these hearts. Now, liver, kidney, and lung had started using them, but we didn't have a great method to actually preserve them and transport the heart. So in 2014, the group at St. Vincent's, including the surgeon Kumuditol, implemented the first DCD heart transplant using the Transmedics OCS. And then here you see in December 1st, my senior partner, Carmela Milano and I doing the first one in North America. You know, I think there's another method of DCD, which again, I won't talk about, called normal thermic regional perfusion, but this is a very simple method. You know, the donor, the ICU team taking care of them, so not the transplant teams at all, withdraw life support the way they would normally in the ICU. And that can be in the ICU, it can be in the PACU, it can be in the OR. Then the donor suffers cardiorespiratory arrest. So they die. Then they wait some period of time, most places five minutes. And then after five minutes, they're actually declared dead. And then it's a very rapid organ recovery. Basically for the heart, you do a sternotomy. You put a cannula in the aorta to perfuse the heart, put the cross clamp on and perfuse the heart with a preservation solution. And then on the back table, you take the heart out. And then on the back table, you instrument and put it on the device like this. And so that has revolutionized the way we did this. And does this work? Well, last year we published the USDCD trial. And again, I'm not gonna go into a lot of detail about this, but it was actually a randomized control trial. You know, if you think about areas that are difficult to do randomized control trials, transplant is one of them, as is evidenced by the EXPAND trial where it was a single arm trial, which no one loved. But this is a randomized control trial comparing outcomes, DCD heart transplant outcomes using the OCS versus sort of a standard of care arm or control arm. And if you look at this, you know, actually the results for the DCD arm are excellent. And, you know, you could say, is it better? Well, we aren't gonna know for a while if it's better. But what I will say is that DCD heart transplant is equivalent to standard of care heart transplant. And really importantly, DCD heart transplant should be available for all potential heart transplant recipients in this country. And people have called me patients and I've said, listen, if you aren't at a center that offers this, you should go to one. Because this is actively expanding the donor pool. Again, before 2019, no DCD. I mean, we did, you know, a banner number of transplants last year, like 4,000 some, you know, mainly courtesy of the Sackler family and Purdue Pharma. But, you know, other than the opiate epidemic, we haven't expanded the donor pool until this. And this is, I think is the biggest thing to happen in heart transplant really, since we started doing heart transplant. So excellent results. So let's open the box further. Because there have been groups around the world who have been working on perfusion devices. And there's this debate, is cold perfusion better, is warm perfusion better? This is the ex vivo perfusion device. And it is a cold perfusion device. It is very simple compared to the OCS. It is a very simple circuit. It is a low pressure, low flow system. Very similarly perfuses the perfusate and blood into the aorta. And then it just circulates it through. And it is, you know, cold and low pressure. And the question is, well, is this better? Who knows? And what I will say is also at ISHLT that Philip Rega from Europe as the lead investigator for our European group presented this, which they call NHIP 2019. Basically a trial that looked at the use of this ex vivo machine in both standard of care and extended criteria donors. Now, what you have to realize is that in Europe and in Australia, that most donors are what we would consider extended criteria donors. So pretty much this is truly an extended criteria donor trial. You see the 15 centers. They did an amazing job of enrolling and accruing patients using this device. And this is probably the most important evidence that this, again, cold perfusion also exceedingly effective. You look at the graft on the left and that is the incidence of primary graft dysfunction. So again, where the heart doesn't work, they need to go on ECMO after transplant, which is a huge risk for morbidity, mortality, hospitalization, decreased length of survival, et cetera. And if you look at that, the risk of PGD was 28.2% in the standard or control arm and 10.9% in the ex vivo arm. And additionally, overall, if you looked at their composite primary endpoints, definitely better in the ex vivo arm. And that was again, mainly due to this significant decrease in primary graft dysfunction. It was a tremendous trial. The Europeans and the Australians have done a lot of great work using these perfusion devices and advancing the field of transplantation. So in the United States, we're actually now enrolling in the ex vivo preserve trial. You know, this is similar to the EXPAND trial. It's similar to the European trial. It's really a trial for extended criteria donor trial. So for the donor to be eligible, the cross-clamp time or time ischemic time that the heart is not being perfused has to be over four hours, which again, we recognize as a risk factor for PGD. Or the cross-clamp time has to be some modest time over two hours, which is pretty much everywhere these days. And at least one of the other qualifiers, which is age greater than 50, which makes me sad because I'm now a extended criteria donor, reduced EF, extended downtime, left ventricular hypertrophy or coronary disease. Importantly, unlike EXPAND, the FDA recognized the importance of the USDCD trial and they actually asked ex vivo to add a donation after circulatory death arm to the trial. And I think that is the FDA, you know, again, recognizing how important these technologies are to the transplant community and potential recipients. Now that can only be normothermic regional perfusion, which again, I'm not gonna discuss today, but that is a different method of organ recovery. So, conclusions. So it isn't 1985 anymore. And, you know, the Igloo chest filled with ice is really not a great method that should be used anymore. For cold sac storage, temperature really matters. And between 6.8 and eight degrees appears to be ideal from the Guardian registry. Machine perfusion improves outcomes in both extended criteria donors and DCD donors, and is here to stay. We need more research. We need to understand what these devices are doing and what we can do to the hearts to make them better. And, you know, again, when we need to compare the two methods, we need to compare the devices. We'll have five years from now, we're gonna know a lot more about what we're doing, not just doing it like we, as much as we can. One thing I didn't address is the cost of all these things. And that is gonna take some, somebody who actually understands a real financial analysis to do. But what I will say is what we've shown here at Duke is that we decrease our time on the wait list. We decrease our preoperative time in the hospital. We have decreased our length of stay. That saves money. Now, when you go to your administration and say, I wanna use this device that costs $100,000, they say that costs $100,000. But I think when you do this, I think you have to start thinking about the true cost savings. And I wanna thank you all. This is actually one of the most profound moments of my actual career, that I did a surprise organ recovery in Raleigh. And our recipient actually came from Charlotte. And I arrived back from Raleigh as he was arriving at the hospital, and he was in a clinic. So I'm like smoking and joking and drinking a cup of coffee. And I walked back to see him, and his name is actually John Smith. And with permission, he's allowed me to tell the story and show this picture. But I said, hey, Mr. Smith, do you wanna see your heart? And he said, what do you mean? And I said, well, I mean, it's in the other room. And so I start wheeling it back and the pre-op nurses are going crazy, telling me I can't do it. And I kept saying, it's his heart. He can see it. And I actually got to show Mr. Smith his own heart. And I think that's maybe the only time ever that that's occurred. But I can envision a time in 20 plus years where it's gonna be almost like Amazon Prime. We will have machine perfusion much better. There'll be centralized locations where hearts go, they get rehabbed, and then they go out. Anyway, I'm done. And I wanna thank you all for your attention. I can't wait for any questions that you might have. Awesome, thanks, Jacob. We appreciate your insight into this, especially from a surgical standpoint. Because you're right, there's so much that's changed over the last few years and that's gonna be changing in the near future. So we're gonna move on to our next speaker. Dr. Pollack Shah is a heart failure transplant cardiologist at Inova, and he's gonna touch base on some medical management, anticoagulation management in our LVAD population. Thanks for joining us, Pollack. Great, thanks, Scott. And to the Heart Failure Society of America for having me here. I'm gonna get my slides up and we can get started here. All right, great, thank you. So I guess we'll shift framework a little bit and start talking a little bit about left ventricular assist devices. The goal here is to really focus on the intermediate and long-term management of patients who are on LVAD support, kind of skipping some of the early perioperative management and ICU management immediately after LVAD implant. Here are my disclosures. And I think we'll start with the first polling question. And the question here for the group is, if you have a patient who's getting a left ventricular assist device today or tomorrow at your institution, what is the expected median survival for that patient getting a contemporary LVAD? I'll give people a couple more minutes here and then we'll go to the next question. Okay. So these were the, I guess, the results. I'm not sure if that'll share, but those are the results, and then we'll cover that a little bit. Go to the next question, which is here. So you have another patient at your program that is getting a left ventricular assist device, and you're debating what antithrombotic drug regimen to put that patient on. And so your options include 81 milligrams of aspirin, heparin, warfarin for an INR goal of 2 to 3, 325 of aspirin, heparin, warfarin again for an INR goal of 2 to 3, no aspirin, let's say heparin, warfarin for an INR goal of 2 to 3, no aspirin, no heparin, and just start apixaban at 5 milligrams twice daily. Great. So we'll go over those at the end, and hopefully people have learned a few things from the talk. All right. So I'll start with the answer to, I guess, question number one, and really highlight the contemporary survival for patients getting a left ventricular assist device. This is data from the Momentum clinical trials, and you can see that the fully magnetically levitated centrifugal flow pump, or the HeartMate 3, has a median survival that exceeds five years, and the five-year survival, estimated survival, is about 58 percent. You may be thinking, well, this is a clinical trial patient population, and patients in clinical trials do better, but the reality is that if you look at the Intermax data as well, the group with the dashed green line is also the patients who are getting a fully magnetically levitated pump outside of the clinical trial setting, and their estimated survival is about the same. As we, as a community, start taking care of these patients on LVAD support for a longer period of time, it's important for us to recognize heart failure and really think about how these patients are optimized, and I'll tell you a little bit about why. So, you know, for the first kind of 10 years of LVAD support, we were really focused on the left side of the screen, hemodynamic or hemocompatibility-related adverse events, device thrombosis, stroke, gastrointestinal bleeding, etc., and as the device technology has improved, those adverse events are really not as common, especially as you get further and further away from the perioperative setting. On the other hand, the stuff on the right side, these hemodynamic-related adverse events, have become more and more common, and our management of them is quite critical. That includes things like both right and left-sided heart failure, aortic insufficiency, hypertension, etc., and this concept of hemodynamic-related adverse events was introduced by Jonathan Grinstein and a group of authors in this JAK state-of-the-art review. And why is heart failure important? So these are different adverse events that our patients can experience after LVAD support, and you can see that, in general, with the HeartMate 3, most of the things have gotten better, especially with respect to hemocompatibility-related adverse events, but the one thing that doesn't necessarily favor the HeartMate 3 right now is readmissions for heart failure-related syndromes, and importantly, when you look at the survival of patients who have been admitted for heart failure after LVAD implantation, those patients have inferior survival compared to patients who are free of heart failure after LVAD implant, suggesting that this is an important therapeutic goal to reduce in our patient population. I really like this schematic because I think we often see heart failure, but it creates a nice framework for how you should be thinking about it. A lot of us think about the left-sided dominant kind of heart failure, where the pump speed is inadequately titrated. There may be aortic insufficiency, and I think many of us have gotten used to kind of diagnosing that. There's obviously right heart failure, which could be related to primary RV dysfunction or potentially RV dysfunction that we're inducing by really either inadequately unloading the patient or potentially unloading the patient too much and changing the RV geometry. There's pump-related issues in terms of outflow graft or inflow graft or potentially hypertension, and then, of course, extracardiac causes of kind of heart failure symptoms. This is some work that we did about six or seven years ago, and it highlights the importance of surveillance right heart catheterizations, where about one-third of your kind of ambulatory LVAD patient population often comes back into the cath lab with kind of either abnormal hemodynamics, and you can see that these patients either are congested or potentially have a reduced cardiac output, and with some speed titration and pump optimization, you're able to get the majority of patients kind of into the normal perfusion, normal hemodynamics quadrant. This has been followed up by the INTELLECT2 investigators that published this data last year, which took about 100 patients receiving either the HeartMate 2 or HeartMate 3 who had a cardiomyopathy, and the patients who achieved kind of hemodynamic optimization defined as a PA diastolic less than 20 millimeters of mercury had, you can see, improved functional capacity, and importantly, if you look at the bottom, had a reduced readmission rate for heart failure compared to the patients who are not optimized, suggesting that either chronic monitoring of hemodynamics may be potentially beneficial for our patient population. You don't just need hemodynamics to do this. All of us can do this by echocardiography as well. You know, this is an ambulatory HeartMate 2 patient from, you know, a few years back, and you can see that although the patient was doing well, good end organ function, feeling well, not in the hospital, you can see that that LV is still dilated. There's still at least moderate mitral regurgitation, and this is a patient who may potentially benefit from further hemodynamic optimization, and this guideline from the American Society of Echocardiography is a nice resource to think about how to do proper LVAD echoes and then how to read them and then potentially titrate pump speed. I'll shift now to guideline-directed medical therapy and reverse remodeling. Notice I'm not necessarily talking only about myocardial recovery. This is a really great paper from the Yale group that took the Intermax data and looked at the use of guideline-directed medical therapy and its effect on patient survival, and what they did is they blanked out for that first kind of six-month period after LVAD implantation where a lot of post-surgical complications may occur, and they looked at the utilization of guideline-directed medical therapy, and you can see that the patients who get triple guideline-directed medical therapy, that kind of bluish line at the top, really had the best adjusted survival long-term compared to patients who were being treated without guideline-directed medical therapy, and this is some of the best evidence we have in the absence of randomized controlled clinical trials that supports the utilization as tolerated of guideline-directed medical therapy in our LVAD patient population. This does not need to be that complicated. This is an algorithm for how we think a little bit about use of these medications, optimization of patients. In our program, we have a therapeutic goal of myocardial recovery and ideally in the ideal candidate device explantation, but even if your goal is not to take out the device, this is a nice framework for how to think about optimizing the patient using echocardiography, hemodynamics, as well as biomarkers, and then also how to be thinking about the use of guideline-directed medical therapy to promote some reverse remodeling, even if you don't want to take the pump out. What happens if you do take the pump out? This is some work from the VAD-WEIN registry. It's an international consortium of about 50 sites and 600 patients who have had their device explanted or decommissioned, etc., and this was work that was presented recently at the ICHLT, and you can see that after device explant or decommissioning, the patient survival at 10 years is 50%. The group of investigators actually did a propensity matching where they picked patients from the ICHLT registry based on certain characteristics, and you can see that the survival is non-significant in terms of the patients who were explanted versus the patients who were transplanted. They had great long-term survival free of LVAD or transplant. Even if you don't want to take out the pump, it's important to reverse remodel the patients, and this is data from the Duke group where they had 300 or so LVAD patients who were unselected. They weren't necessarily as part of some sort of recovery protocol, and you could see that more than half of them had an ischemic cardiomyopathy. They had about 10% of their patients who we would define as responders, meaning their LVEF was less than 40% and their LVIDD was less than 6 centimeters, and then a group of patients who were also partial responders where their ejection fraction improved from, let's say, 5 to 10% but didn't improve to greater than 40%. Why is this important? What you can see here is that the patients who had some degree of reverse remodeling and recovery really had a great freedom from events on follow-up compared to the patients who were non-responders who potentially did not improve their ejection fraction, and so this suggests that even if you don't want to take out the device, the fact that that EF improves, let's say, about 10% with guideline-directed medical therapy and loading really can help that patient survive on long-term LVAD support. For the last kind of portion of my talk here, I'm going to talk and provide some updates about antithrombotic therapy because there's been a lot of work in this space of the past few months. So I'll present initially the results of the ARES trial. This was presented at the AHA meeting in November and published simultaneously, but this was an international multi-center prospective randomized controlled clinical trial, double-blind, placebo-controlled, and the hypothesis here was that exclusion of aspirin would be safe and tolerated in patients receiving a HeartMate 3 left ventricular assist device. So the primary endpoint was freedom from non-thrombotic non-surgical hemocompatibility-related adverse events at one year, and you can see that the patient strata was as such, where patients received either aspirin at 100 milligrams daily plus a vitamin K antagonist for an INR goal of 2 to 3 versus a matching placebo for aspirin and then vitamin K antagonist for an INR goal of 2 to 3. Here's a primary endpoint. You can see that in the aspirin arm, this is the event rate for hemocompatibility-related adverse events at both one and two years, and you can see a statistically significant reduction in that event rate for patients who received placebo plus warfarin compared to aspirin versus warfarin. Importantly, if you look at the primary-secondary endpoint, the bleeding rates in patients who received aspirin were at about the same rate as those who received aspirin, were about 30% at one year and 42% at two years. On the other hand, the bleeding rates with the placebo arm were significantly lower, approaching 30% at actually two years instead. As with all studies, when we're withholding antithrombotic therapy, it's important to make sure that there's no safety signal, and importantly, there was no excess in strokes or pump thrombosis or mortality in patients who received placebo as opposed to aspirin. And this data really supports that for new patients receiving a left ventricular assist device in the contemporary era, we can withhold aspirin as part of that initial antithrombotic therapy. I'll now present a little bit of data that is coming out and has been covered at both the THT meeting recently as well as ISHLT on some initial safety kind of feasibility data around the direct oral anticoagulants. If you recall, about six or seven years ago, there was a study done using dabigatran, where patients were randomized to a warfarin-like agent versus dabigatran, and the trial was stopped early because there was an excess of thromboembolic complications in the dabigatran arm. Christopher Hayward and the group in Australia did some work with mock loop studies using the old HVAD device, and they identified that apixaban seemed to effectively prevent thrombus formation. And when you look outside of the LVAD patient population in afib, apixaban is the only direct oral anticoagulant that not only reduces thromboembolic events but also seems to reduce major bleeding. So we designed the DOAC LVAD study. This was to evaluate the safety of apixaban as compared to warfarin in patients receiving a left ventricular assist device. This was the study schematic where patients were randomized to warfarin for an INR goal of 2 to 2.5, which is our institutional goal, apixaban at a dose of 5 milligrams twice daily, and the primary endpoint was freedom from hemocompatibility-related adverse events at 24 weeks. Over a period of 18 months, we assessed 82 patients for eligibility. We excluded 52 patients of that. 12 patients said, you know what, I'm happy with warfarin, I'm going to stay on warfarin. We had 40 other patients who were excluded predominantly because they had already had a hemocompatibility-related adverse event after an LVAD implant or they had a non-HeartMate 3 LVAD. We randomized 30 patients. 14 patients received warfarin for an INR goal of 2 to 2.5. All of those patients were followed up at 24 weeks, and then another 16 patients received apixaban at a dose of 5 milligrams twice daily. They were all followed up for 24 weeks. We did have one patient who had their device explanted for recovery at 20 weeks, but that patient continued to follow up afterwards. Here are the patient characteristics. Overall, you can see that the median time from LVAD implantation to randomization was 115 days, so we're getting patients early but not really early after LVAD implant, and a majority of these patients had an indication for anticoagulation outside of their LVAD, including AFib or prior DVT. Here's the primary endpoint data. What you can see here is that in the warfarin group, we had two patients who had gastrointestinal bleeding. One of those patients had a repeat bleeding episode, and then on the apixaban arm, we had no patients who had an event through 24 weeks follow-up. Importantly, there were no thromboembolic events in the apixaban arm. In summary, I hope I have instilled on you that heart failure is an important thing to be monitoring our patients for after LVAD implantation. It's an important cause of not only readmission but patient mortality long-term after LVAD implant, and you should be thinking about how to optimize pump settings as much as possible in the ambulatory setting. Even though the data is not from randomized controlled clinical trials, randomized controlled clinical trials, I think the use of guideline-directed medical therapy is tolerated, is critical for this patient population, especially as they're on support for longer periods of time. Even if you don't want to take out the pump, I think partial recovery is certainly a good thing. For your patients receiving a device now, they should be withholding aspirin unless there's a non-LVAD indication for aspirin. At least the apixaban right now seems to be feasible in all that patients, but we really need to wait for appropriately powered clinical trials before we can make claims about safety and or efficacy, so I would not recommend clinical implementation yet. So I think, Scott, thank you to you and as well as the other organizers for this opportunity. I think I have a post-calling question, and hopefully I've taught you a few things and will improve our statistics here. Look at that. I'm learning stuff. Thanks, Pollack, again for covering this topic, especially so succinctly in a short period of time. I appreciate it. Great. So it looks like people did really well and learned a few things. So yes, the estimated survival now for a patient receiving a left ventricular assist device is 58 percent, so median survival is beyond five years now. And then the next question I'll get to... All right. So this one, I guess people were maybe a little bit more excited about apixaban and not as excited about using warfarin as we have. You know, I think if we gave this talk in another four or five years, I think number four would be the right answer, potentially after we have appropriately powered clinical trials. But really right now, the answer is three, right? We really need to be, there's data now from appropriately powered clinical trials to say we can withhold aspirin in the majority of these patients. But the heparin bridge and warfarin is still the standard of care for this patient population. And I remind everybody that, you know, if you look at apixaban in the non-LVAD patient population, there have been clinical trials that have been done that have stopped after about 85% of the patient population was enrolled with the onyx valve before they decided that there was a safety signal that prevented the safe utilization of apixaban. And so I would discourage use of apixaban at this juncture until we have appropriately powered clinical trials. So thank you guys. Thanks again, Dr. Shah. We appreciate it. Kind of bringing us home with today's seminar is Dr. Brian Houston, another heart failure and transplant cardiologist out of Medical University of South Carolina in Charleston. He's going to be speaking to us today on some RV failure post-LVAD. Brian, appreciate you being here and great recording your talk. Awesome, Scott. Yeah, thanks. I have the distinct pleasure of listening to myself give a presentation. So I turn it over to the HFSA folks. Okay, good morning or good afternoon or evening, depending on where you are and when you watch this. I would like to thank the Heart Failure Society of America for inviting me to give a talk on identifying and managing RV failure after LVAD. I have no relevant disclosures, and my general disclosures are listed below. They've asked me to start with two polling questions, which we'll then repeat at the end of the talk and discuss the answers and why they're correct. So polling question one, I'll read to you here. Which of the following is true about the RV in the post-LVAD patient? Choice one, pulmonary affective arterial elastance or RV afterload increases after LVAD. Question two, the right ventricle becomes much more sensitive to afterload after the LVAD. Choice three, septal contribution to RV contractility increases after LVAD. Or choice four, turning up the pump speed will fix RV failure after LVAD. Let you think about that for a second. Then we'll move on to polling question two. Again, I ask which of the following is true about treatment of RV failure post-LVAD. Choice one, prolonging intubation can help prevent post-operative RV failure. Choice two, upfront utilization of RV temporary mechanical circulatory support is associated with better outcomes than delayed RV temporary mechanical circulatory support. Choice three, sildenafil is universally associated with a reduced risk of RV failure post-LVAD. In choice four, the RV is preload dependent and so diuresis will worsen RV physiology post-LVAD. So with that, we'll move on to the objectives. Our objectives are to define early post-LVAD RV failure, including early and late versions of RV failure. We'll discuss the prognosis, pathophysiology, and predictors of RV failure, and treatment options. So of course, to identify a disease, we must first define it. And we can lean on physiology here and give a very general physiologic definition. According to Braunwald, failure of the right heart to generate blood flow through the pulmonary vasculature and into the left heart, leading to reduced cardiac output, or in our setting, perhaps LVAD flow, commensurate to the requirements of the metabolizing tissues, or the ability to do so only at elevated right heart filling pressures. This is RV failure. Now, of course, this may not work in our LVAD population, or at least doesn't give us much granular to hang our hat on if we ask, does this patient have right heart failure? And we're helped here by the recent academic research consortium definition. Now, there hadn't been multiple iterations of right heart failure definitions throughout the years, but this is the most recent and updated one. And there are a lot of points on this slide and that we can cognitively compress them in just a few ideas. The first idea is that if you need an RVAD, you have right heart failure. And it depends on when you get it as to how it's defined. If you get it during your surgery, you have early acute right heart failure. If you get it within 30 days after your implant, you have early post-implant right heart failure. And after 30 days, it's late right heart failure. The other idea is that if you have a prolonged need for inotropes or inhaled pulmonary basal dilators, you have right heart failure. If you need them for more than 14 days, you have early post-implant. If you need them after 30 days, if you have to restart or re-administer either inotropes or IV diuretics after 30 days, then you have late right heart failure. Now, you also have to have signs or symptoms of congestion and malperfusion or low flow to meet the criteria. So a lot of points, but pretty simple. If you need an RVAD, if you need inotropes or inhaled basal dilators for a long time with signs or symptoms of congestion and low flow or malperfusion, then you have right heart failure. So we've defined it. We need to ask ourself, is it common? And yes, it is, but it depends on which paper you read from what era and what definition they use. Early postoperative RV failure is 25 to 38% of patients. RV failure requiring upfront RVAD, 4 to 8% of patients. And late RV failure, a disease that we probably under-recognize, still as high as 8 to 10% of patients. So it's common. Is it bad? And the answer is unequivocally yes. No matter what definition you use, it portends a bad prognosis. Early acute RV failure in the current definition portends up to a 44% one-year mortality. You can see here, based on the recent Intermax data over the course of a decade, if you ended up with a VYVAD in the green dashed line, you did significantly worse than the LVAD alone patients. Early RV failure, your patients with prolonged need for inotropes or vasodilators, still a 25% one-year mortality versus 7 to 10% of patients who don't have RV failure. And late RV failure may be even worse. A one-year mortality as high as 28%, but the three-year mortality as high as 60%. These patients do not just have an elevated mortality, but a higher rate of morbidity as well with higher rates of strokes and GI bleeds. So why does this happen? Again, we'll start with a general physiologic idea that there are really only four main determinants of RV function, afterload, preload, contractility, and leucotropy, or diastolic stiffness. Now this is summarized here in the recent New England Journal review, and you can see how these main determinants are not independent of each other, but can feed back in a kind of a spiral sometimes. Now we're going to discuss really just afterload, preload, and contractility because no one knows how to interact with leucotropy. So what does this look like after LVAD? There are multiple changes that the right heart undergoes that are deleterious after an LVAD. Pictured here from our review in 2017, you can see the post-LVAD heart on the right. The right ventricular contractile pattern changes from being largely a longitudinal or base-to-apex sort of a contractility pattern, to a latitudinal or lateral free wall dependent contractility pattern. This occurs partially because the septum is the driver of that good or early longitudinal contractile pattern, but it gets shifted over to the left and can no longer contribute in that way, or at least as much. The loss of pericardial constraint may also play a role, and the reduction in left ventricular force generation with unloading also plays a role, recalling that left ventricular force generation is transmitted to the right ventricle through septal interaction. And finally, patients may have anatomic or geometric changes such as chest wall adherence, or malpositioning of the LVAD with tethering that may contribute to reduced RV contractility and right heart failure. So what happens to our physiologic variables such as afterload, preload, and contractility after LVAD? Well, it's distinctly true and very well shown that afterload declines early after LVAD. Here you can see the PVR, effective arterial elastance, and compliance all improved early after LVAD. Despite this reduction in afterload, the right heart still fails, and it's largely due to a reduction in contractility or RVPA uncoupling. Here you can see the Paul Scheel and Steve Sue's work using pressure volume loops, showing a much lower EES to EE ratio, or a measure of how well the RV is coupled to its afterload after LVAD. And it's markedly worse than the non-LVAD heart failure controls, showing that even with a reduction in the afterload, RV contractility has a larger decrement and becomes uncoupled from that load. So if you said, you know, Houston, can you summarize post LVAD RV failure pathophys? RV afterload declines usually, almost always after VAD. Unless you have severe fixed pulmonary hypertension or some other physiologic insult. If you unload the left heart markedly with an LVAD, if you're successful with that, RV afterload will decline. RV preload remains about the same. The CVP post LVAD is about the same as pre, but RV contractility, or if you want to call it load adaptation or RVPA coupling markedly declines. Another way to think about this is the right ventricle becomes very sensitive, even more sensitive to load, both preload and afterload. And this occurs due to all of those mechanisms we saw in the previous figure. You can see this depicted graphically looking at the blue and black lines here. The blue is the relationship of right atrial pressure to RV load pre-VAD. You can see a nice shallow relationship there where rises in afterload cause very small increases in right atrial pressure, as opposed to the post-VAD line where the relationship is quite steep. Okay, so we know that it's common. We see it a lot. We know why it happens mostly. Surely we can predict it. And the answer is not really, or at least not very well. Here are five different scores, which have been validated to at least carry some predictive value prior to, for a right heart failure prior to LVAD. And I'll focus your attention to the bottom of the slide, the area under the curve, or a way to think about this is accuracy in the validation cohorts range between 0.53 and 0.65, or 53 to 65% accurate. Another way to say it is 60% of the time, these scores work every time. Now, they may not be perfect, but I think we can employ some common sense predictors and derived from these scores, there's a lot of overlap and they tend to focus around these areas. The idea is that the best predictor of post-operative RV failure is pre-operative RV failure. So if a patient goes in with an elevated right atrial pressure or an elevated right atrial to wedge ratio, that is not a good sign. If a patient has a reduced poppy or pulmonary artery pulsatility index, that ratio of pulmonary pulse pressure to right atrial pressure, that's not good. Or if pre-elevate, they need high dose inotropes, a percutaneous RVAD or ECMO, that portends a bad prognosis for RV failure. Other organs can tell you the tale as well, such as hepatic or renal dysfunction, leukopenia or thrombocytopenia, and ventilatory failure can also predict the future. If your patient has sick lungs going in and is requiring mechanical ventilation, it's gonna be a rocky ride as that RV has to fight against those sick lungs and prolonged intubation coming out. Intubation and positive pressure ventilation is tough on the right ventricle. All right, so we've talked about predicting it. How about, how do we manage it? And I first wanna take a tangent and say, the first thing you need to do is include that the thing you think that is RV failure isn't actually pericardial or mediastinal tamponade because they can look very similar. In elevated CVPs, end-organ congestion and worsening function, low cardiac output and or LVAD flow and systemic hypotension. So make sure you get an imaging study and look to say, is there a compressive hematoma or pericardial effusion that may be mimicking RV failure because the treatment of these two entities is of course, very, very different. Okay, so you've gotten your echo. You know, this is RV failure or we're in it. What do you do? So step one, I want you to hop in your time machine and go back in time and avoid it. It's really that simple. So of course not, right? We don't have time machines, but there are some important things you can do pre-VAD to try and avoid or at least risk mitigate post-VAD RV failure. Again, the first thing is decongest that right ventricle. If you go in with the right ventricle congested with high CVP, you're really gonna struggle post. Optimize organs, including pulmonary function. I think this is probably overlooked. Our patients lay flat on their back, have a lot of atelectasis and respiratory failure coming out and intraoperatively, now I'm not a surgeon, but the literature teaches us that avoiding cross clamp and cardiac arrest if possible is good for the right ventricle. Don't flood the heart if you can help it. There's a growing body of literature that lateral thoracotomy may help preserve RV contractility and get the inflow cannula right, meaning mostly pointed to the left, away from that interventricular septum and if possible towards the mitral valve inflow. All right, so of course we don't have a time machine. We're post-VAD and we're in a post-VAD world now. What do we do? So optimize preload, right? That should be step one. Or you're doing all these things at the same time, but don't forget, optimize preload and that means almost always reduce preload. This idea that the RV is preload dependent, that goes away after all that. This congested RV is really behind and stretched out with lots of TR and you gotta try and decongest it and move that septum back over to the right. If the diuretics aren't working, don't fear ultrafiltration. Avoid or minimize afterload increasers such as hypoxia or hypercarbia. Multiple transfusions, admittedly, they're needed in bleeding patients, but try not to overdo it. And remember that the pulmonary vasculature is a vascular VAD and responds to vasopressors. And so indiscriminate use of pure vasopressors may harm you. You can reduce afterload with inhaled nitric oxide or epiprostanol. And of course, almost every patient after VAD needs some version of contractility augmentation, usually done with inotropes such as dibutamine, milrinone or epinephrine. And I think it's important to recognize that avoiding systemic hypotension is crucial. Remember that LV force generation is RV force generation to some extent. And if you have hypotension, the LV is generating less force. All right, you've done all the right things. You're doing all the things we just talked about. What now? If you're still in trouble, don't wait too late for RV mechanical circulatory support. Delay leads to worsening RV function. It just spirals down. You get worsening end-organ perfusion and worse outcomes. One of my co-presenters, Dr. Shaw, showed that contemporaneous versus staged VADs had shorter ICU length of stay, better long-term end-organ function and better survival. So if you got an early RVAD, you did better than a delayed RVAD. And remember that many, I'll say most patients in my experience can eventually be separated from RV support. And we have a growing menu options for improving temporary MCS options for RVs. All right, so you don't need an RVAD, but you're in the situation where the days are getting long, you can't get off inotropes. What should you do? So the first thing is make sure you don't have an afterload problem. Make sure you're adequately unloading that left heart, you've reduced the wedge pressure, pulmonary venous pressure is down, and you don't have another reason for fixed pre-capillary pulmonary hypertension. In that situation, focus on RV preload. If you're trying to wean the inotropes with a congested right ventricle, that's a recipe for a failed inotrope wean. So get that CVP down. Phosphodesterase-5 inhibitors are controversial. They may maintain a role in select patients with persistently elevated PBR. I think they're falling out of favor as some studies have shown an elevated bleeding risk, particularly if you go into your LVAD on a phosphodesterase-5 inhibitor. And please avoid the inclination to just indiscriminately turn up the pump speed. This study by Michael Brenner that was recently published showed us that some patients' right ventricles may respond favorably to increased pump speed, but many can get worse, and it's actually very difficult to predict which will be which. So in summary, even in the modern era, post-LVAD RV failure remains common, deadly, and hard to predict. It can be avoided or at least risk attenuated with careful patient selection, optimization, an operative approach, and post-operative management. Focus on preload and afterload reduction, knowing that the LVAD is quite an effective afterload reducer, and you really need to decongest that RV while supporting its contractility, and don't delay right ventricular temporary mechanical circulatory support if you need it. The longer you wait, the worse things will go. All right, so thank you very much, and we'll turn back to our polling questions and see what we've learned. So again, I'll read the question, and we'll go through the answers and talk about why they're correct or incorrect. Which of the following is true about the right ventricle in the post-LVAD patient? So choice one, pulmonary effective arterial elastance or RV afterload increases after LVAD. Two, the right ventricle becomes more sensitive to afterload after LVAD. Three, septal contribution to RV contractility increases after LVAD. Or four, turning up the pump speed will fix RV failure after LVAD. I'll give you a second to respond. So hopefully no one chose four after the talk. It's certainly true that some patients may need a higher pump speed than they come out at, but that's generally not true for all patients. The correct answer is number two. The right ventricle becomes more sensitive to afterload after LVAD due to all the mechanisms we talked about leading to a reduction in contractility or RVPA coupling. Choice one, by and large, RV afterload decreases after LVAD and septal contribution to RV contractility also decreases, that's choice three. All right, polling question two. Which of the following is true about the treatment of RV failure post-LVAD? Choice one, prolonging intubation can help prevent post-operative RV failure. Choice two, upfront utilization of RV temporary MCS is associated with better outcomes than delayed RV temporary MCS. Choice three, sildenafil is consistently associated with reduced risk of RV failure post-VAD. And choice four, the RV is preload dependent and so diuresis will worsen RV physiology post-VAD. Again, I'll give you a second to key in an answer or think about these. All right, so the answer is choice two. Upfront utilization of RV temporary MCS is associated with better outcomes than delayed RV temporary MCS. Of course, this is in patients who need RV temporary MCS. It's better if you don't need it, but for those who do, early initiation is better than late. For choice one, we know that prolonging intubation is actually bad for right matricular failure. There are multiple physiologic reasons for this, but patients who remain on mechanical ventilation do poorly. Sildenafil, as I mentioned, is not consistently associated with the reduced risk of RV failure post-VAD. Recent studies have indicated, if anything, equipoise there and maybe a signal for harm. There are occasionally patients with persistently elevated PVR where you might consider a phosphodesterase-5 inhibitor. And then for choice four, the RV is preload dependent and so diuresis will worsen RV physiology. This is not true. Most right ventricles coming out of LVAD that are struggling will benefit from diuresis, getting that CVP and right atrial pressure, right heart filling pressure is down, and decongesting the heart, moving the septum back to the right, reducing tricuspid regurgitation. So I think that wraps it up. Again, thank you to HFSA for allowing me to do this and looking forward to the rest of the talks. Awesome. Great job, Brian. I know it's always tough listening to yourself. Yeah, thank you. Yeah, that was particularly not fun for me, but hopefully folks learned stuff. No, I think it looks like people learned a lot because there's no questions in our Q&A panel. So I was hoping to get all speakers back on. Pollack's still available. I know he said he had a couple of meetings, but Laura and Ian are joining us for a little bit of some time for a panel discussion. I was gonna start with a question for Pollack, but I'm gonna direct it your way first, Jacob. So some talks about utilizing Eliquis post-LVAD, which I think a lot of us are excited about. We hate fluctuations in INR and admission for bridging and all that kind of stuff. Is there a time point post-LVAD that you would feel most comfortable starting Eliquis? So what's that kind of post-operative time point? Again, assuming patient's stable and no bleeding, all that kind of stuff. Yeah, it's a great question. I mean, the great thing about the newer, well, the only device we can use, the HeartMate 3, is that it's designed such that it washes really well, right? You know, the pulse utility and the actual pump design means that pump thrombosis is, you know, essentially 1%. And so I think from a surgeon standpoint, you know, probably five days, something like that. I mean, you have to worry, you know, it's just, it's nice with the current device, no aspirin. You know, I don't start heparin until the next day. Sometimes we wait longer. And so the only thing I would be, I wouldn't be concerned about the pump, but I would be concerned about other bleeding. And so maybe three to five days, depending. I think that would be reasonable. But it is an exciting thing for patients to be able to transition, hopefully, off of Warfarin. Yeah, no, I agree. I think it'll be interesting to see some of the, to come larger randomized trials, especially again, I think in the early post-operative period I'm glad Paul did their study with a small patient population, but I know some of their patients were further out. So I think that early post-operative period is still gonna be critical time. Brian, I've got a question you mentioned. I think we all know that timing of RVAT is important for outcomes post-LVAD. You discussed that really well. Do you have a preference on RVAD type? Protect Duo, ImpellaFlex, what's your experience and do you have a go-to at your institution? Yeah, gosh, that's a good question, Scott. So, I think there's still equipoise and I would guess if you asked even my partners here at this institution, three of them, you might get three or four different answers. I think you probably have to, one, match it to the patient. So we've had experiences where, for example, the Protech, you get these big dilated RVs and that cannula just keeps falling back into the right ventricle. And that can be really harmful, right? Now you're pumping three, four liters instead of into the pulmonary artery, you're pumping it into the right ventricle. I always really enjoy when my surgeons put a graft on the PA, tunnel it out and do a surgical RVAD that way that can be decannulated without having to reopen the chest. That's a really stable platform and I find performs well. We get pretty enamored of the percutaneous devices but I think that's probably avoiding the surgical RVADs which are really, really well done by our surgical colleagues. I think one lesson I've learned in this space and this fits as well in the temporary MCS LV, on the LV side as well is, find what you do and do it well. You don't have to use every option on the menu but find a couple of things that will serve almost all your patients and then really hone down on doing it well. So personally, I like the stability of the surgical RVADs, my favorite. And then probably Protech is our next most used device here at MUSC though, you know, we've had some anatomic difficulties with a couple of really big dilated RVs. No, I think you're right, especially for those patients that you're thinking need an RVAD in advance. I think a surgical RVAD is a great option as well, especially, you know, bigger cannulas, you can flow them better with lower pump speeds, help decrease risk of, you know, hemolysis and all that kind of stuff. So I agree, I think that's a great option. Laurie and do you guys have any questions for Jacob? I'll jump in. I have, this question was loaded up for Palak but he dipped out, so I'll have to ask Jacob. In light of the ARIES trial and obviously the results with, you know, withholding aspirin, Palak was kind of hedging. He said, you know, it's okay to withhold aspirin in patients who don't have other compelling indications or, you know, I think he said, you can withhold it in most patients with a HeartMate 3 but I'm curious, like your thoughts, is it okay to just go ahead and withhold it in everyone? Are there targeted patients where you're still using aspirin? How have you managed this at your institution? Yeah, we pretty much withhold it in everybody. I mean, obviously they have a compelling reason but most of these patients, the most compelling thing about them is their heart failure and, you know, the risk of GI bleeds and other things is still significant. So we hold it in pretty much everybody, honestly. We're the same way, Ian. So we called, I would say 90% of our patients the day after the trial came out and stopped their aspirin. We have a couple of carve-outs for like very recent PCI, although, you know, with the DAPT data coming out now, like we keep carving that time further and further back. You know, if you have severe peripheral vascular disease with stents or cerebrovascular accidents that are thrombotic and not embolic, but other than that, you know, we've largely separated from aspirin. I think philosophically, the question for the HeartMate 3 device is like, how low can you go, right? So now we're done with antiplatelets. Is an INR of two to three really necessary? Can you do 1.5 to 2.5? Is full dose of pixaban really gonna be the deal or can you do half dose? I think that's the next frontier of questions that should be answered in serial clinical trials. I'm sure we all have patients out there who've had enough GI bleeds that they're off all anticoagulation. And I mean, I don't, we haven't had a, I think we have a fair number of those. No, I mean, not a huge number, but we have enough of them and none of them have had pumped thrombosis. So it definitely is true. There's hopefully in the next few years we'll learn even more and can continue to drop that INR goal or switch to something more patient friendly. Yeah, that's a good segue. I was gonna ask Block, but I'll ask you guys here. Is there any reason to think that a pixaban won't work out? Like as this data progresses and we get more experience, is there any reason to think this isn't gonna work out? Is there anything that could go sideways here as we get more data? I think people got pretty sketched out by the dabigatran trial, right? Like that really threw some cold water on DOACs. And I think it's important to remember, and you know much better than I do Ian, like these are not equivalent medications in any other application that we use them in. We don't see equivalent outcomes between dabigatran and pixaban. I think what makes, I'll speak for a heart failure cardiologist nervous is the difficulty in reversing. Now we've come a long way obviously since then, but our patients have enough GI bleeds. And then the big bugaboo is a brain bleed, right? You can really get in trouble. I'll be honest, I think it's gonna be fine. I think it's going to be a well-tolerated medication when we look at, again, other kind of non-MCS applications that pixaban does very well. But I'll share Pollack's caution that we shouldn't go switching everyone yet. We should do the trials. We owe it to our patients to get that answer before we switch them. No, I agree. I think it's gonna, I think the trials are gonna turn out successful, but we need more data. But I think one thing I like about Eliquis, I agree with you, Brian, some concern about reversibility, although we have more agents for that, but I've seen a handful of these VAD patients on Coumadin that get such super therapeutic INRs and have spontaneous brain bleeds. So I think hopefully a little bit more consistency in anticoagulation and those levels with pixaban will be helpful to maybe avert some of those episodes as well. There's a question from Dr. Modi that came directly to me. She was wondering a little bit about why there's reduced thrombotic complications with these new devices. Brian, I didn't know if you'd be willing to take that. Yeah, I can give you the answer that we've been given. I think the short answer is we think we know, and there's maybe lots of different reasons. The company says the larger gaps between the rotor and the pump housing makes a difference. The built-in speed modulation where the HeartMate 3 slows down and then speeds up every couple of seconds provides washing of those areas of stasis. There may be changes in the inflow cannula flow path as well. Those are the main reasons that we're given. Without really getting down into the nitty-gritty of the thrombotic pathway, I think it's tough to know. But it's clear that whatever was changed between the last generation of device and this one, it's worked. As Jacob said, it's to the point now that if I get called and a patient has an elevated LDH, I say, yeah, that's not real. Draw it again. Whereas in my HeartMate 2 era, I said, bring him into the hospital, put him on heparin, get the pump exchange scheduled for tomorrow. It's really nice to live without that level of anxiety. No, I agree. Dr. Mori asked a little bit about driveline infections as well. I think from what I've known, no significant changes in rates, but it all kind of depends on the patient, right? So we know morbidly obese patients are going to be at higher risk for driveline infections. Those that don't wear a band, they don't wear their dressing. And we've had a lot of luck, probably like you guys, that if they wear an anchor, that significantly helps decrease trauma to the driveline site and decreases driveline infections. So rates haven't changed, just the patients, I think, for the most part, had patient selection and how they manage their driveline in terms of determining infection risk. Jacob, you said several times in your talk, you didn't want to talk about NRP. Can I ask your thoughts about NRP, direct procurement to OCS versus NRP? Do you have thoughts? Well, we are very agnostic here, and so we do, but we actually don't do either ourselves anymore because we don't have the bodies, perfusionists, but we believe in both methods. I think we'll learn more and hopefully understand what is better when, but we're not going to go to Wyoming and do NRP and then fly the heart back four and a half hours. So there's definitely benefits. There are benefits to both. I mean, NRP theoretically could be a lot cheaper if you do it yourself. But again, most centers in the country are not going to be able to do that. You can't have a whole team of people and call 365 days a year. I think that there's a definite signal that NRP may be better for the other organ systems when you immediately reperfuse in the body. I mean, let's be honest. There's all these debates about what is better. I mean, even a body that has undergone significant issues like cardiorespiratory arrest, it's probably still better to resuscitate organs in a system that has other organs that are working, like a liver and kidneys and enzymatic processes, all those things. So there are going to be benefits to NRP over direct procurement and preservation with either ex vivo or OCS. But we'll find out, you know, and hopefully we do the studies to really understand what is better when. But, you know, we've done both. They both work. Go ahead, Laura. Oh, as a follow-up question to that, I was thinking from an ethical perspective, I feel like there's a lot of conversation around DCD donation. And as a transplant center, it's really exciting to see organ availability increase in ways I think that are safe for our recipients. I'm just curious, the conversations around NRP versus like ex vivo, et cetera, and how you support your patients and families or the questions that are received, or if those are sort of conversations that you don't really have to kind of worry about. Well, so for those of you who don't, so NRP, I wasn't trying to get, this is like, we could have like a six-day. Sorry. Six-day webinar on DCD and the difference. So NRP is where the donor suffers cardiorespiratory arrest. You very quickly go in, and we call it thoracodontal NRP. You cannulate the aorta and the right atrium, and then either go on ECMO or cardiopulmonary bypass, but you occlude the arch vessels. So you don't reperfuse the brain. And there's a lot of ethical debate about this still. You know, they aren't allowed to do it in Australia. They were doing it for a while in England. They made them stop. Like Belgium, you know, they had this whole product. They did some, and then they made them stop. Now they're going to be able to do it again because they have data. So there's a lot of ethical debate. And the discussions we have with patients, frankly, I mean, you know, these heart failure patients, most of them are really sick and want to get transplanted, you know? And so the ethical discussions don't really occur at that level. They just don't. We tell them that there are these two methods and the differences, and they don't really care, and I don't frankly blame them. It's really a societal question. The bigger problem that we have, frankly, is that one of the biggest problems with the whole system is that not only are the, you know, doing one versus the other in Durham is different than doing it in Raleigh at a different hospital, that the rules on how we do this and what we get to do are dependent upon not the U.S. government, not UNOS, not the OPOs. It is the donor hospitals. They make the rules. So if you go to a Catholic hospital in Indiana, you're not doing NRP because they ethically don't believe it's right. Or, you know, and there are other reasons. The OPOs, the way the OPOs are run and organized, there's a lot of stuff that goes on that we don't know about that's probably not right. But again, I think what we have to do is there are a couple of things in terms of DCD donation that need to occur. The critical care societies in this country need to. come up with a standardization for withdrawal of life-sustaining therapies, because it varies from, again, not just even hospital to hospital, but which team is actually withdrawing life-sustaining therapies. It could be an intensivist one day, and if they time out, another intensivist could do it differently. So that should be standardized. Even simple things like the standoff period should be standardized. And so that we can take a lot of these sort of just the way things vary for no good reason out of the picture, and really do our best for our transplant recipients. I think I have one more question, and maybe Ian can weigh in as well as Brian. So, you know, Darsha was talking about, you know, GDMT use and our LVAD population in our center. We're very heavy with quadruple therapy, and we're a recovery center, so we try to get all of our patients, but I was wondering if you guys have thoughts on timing of GDMT initiation post-LVAD. So we do a lot in hospital at that initial index submission. I know there's some centers that, you know, try to get their LVAD patients out as quick as possible, and then do some of that optimization post. You guys, we'll start with Brian, if you have thoughts on timing and GDMT initiation. Yeah, so I think this is another space where, you know, we're lacking in prospective data. We have some pretty compelling retrospective data, right? There's the very well-known, I think it's in JAMA cardiology paper, that showed that if you got on four agents, you know, all four agents, your mortality, you know, was much better. We all know the foibles of retrospective studies there, right? Like maybe you didn't start the beta blocker because you didn't believe in the RV, and maybe you were right, so you're self-selecting out a population that's not going to do great. You know, I think it's incumbent on us, again, to like get the data. Nonetheless, I think the pendulum has swung, and it's now, you know, recommended by expert consensus to try and maximize, you know, four-pillar GDMT. So I think personally, just like in the heart failure world, you know, we can port that data over and say as soon as possible. You know, there are clearly patients where their kidneys are struggling, and maybe you don't want to hit them with an angiotensin antagonist early on, or their RV's struggling, and maybe you're not super comfortable with a beta blocker. But as soon as you can, you want to try and layer those in. Some medications are really well-tolerated. SGLT2 inhibitors are well-tolerated. So are mineralocorticoid antagonists. Those are medications that are pretty ubiquitous that the patient leaves the hospital on as long as they've got renal function for either one. We try and get them on, you know, within the first month in the outpatient setting. Again, like I don't want to close the book on this question, though, as a field. Like I think we still don't have a definitive answer. Ian, I'd be curious to see what you think about that. Yeah, I think our practice has been, well, if you ask me personally, I like Ras inhibition frontline based on some of the salutary benefits from Dr. Houston's papers and some others about potential GI bleed reduction. So that's kind of my preference for the first one that we try to get on board if a patient is a good candidate. SGLT2 inhibitors are pretty easy to throw on prior to the index discharge as well. So I think at a minimum, we try to get people out the door on at least, you know, maybe a Ras inhibition, even at low dose, plus minus an SGLT2. We're sort of conservative with beta blockade in the early post-operative period. I think based on a lot of what Brian just described about RV failure, I think we're probably on this, you know, if you looked at multiple institutions, we're probably on the very delayed onset of beta blocker side of that curve. I think we do a lot of that at the post-discharge clinic visits. And it's a rare LVAD patient that goes home from our institution on beta blockade from the index hospitalization. But again, I, we may just be more conservative than other institutions. The one thing I'll throw in too, is we've been doing some work on early IV iron replacement and management of iron deficiency anemia immediately after all that. And so we put a protocol in place. We let them get out of the ICU and out to the floor, check an iron panel. And if they're candidates, we try to replete the IV iron before they go home from that index discharge. We've got some data that shows that it reverses the laboratory parameters of iron deficiency. We couldn't really correlate that to clinical outcomes because they're getting better because of the VAD in the first three months. And so it's just hopelessly clouded, but I think at least theoretically, there's a benefit to correcting the iron deficiency straight away and not letting that go on for months after the LVAD. And so that's, that's something we've been trying to do as well. All right. Well, I think we're getting to the end of our 90 minutes. I'd like to thank our speakers, especially Dr. Houston is the only one that's made it through this whole 90 minutes with us. And co-planners Ian and Laura, thank you for helping put this together. Remember to go to hsa.org, to the learning center and fill out the questionnaire to get your CME for this, this seminar today. And please stay, keep on the lookout for additional HFSA seminars coming in the future. Thanks everyone again for your attendance and participation. Have a good evening.

Heart Failure Society of America

educational webinar

Dr. Scott Longren

advanced heart failure management

LVAD

organ donation after circulatory death

heart transplant preservation

LVAD settings optimization

guideline-directed medical therapy

aspirin therapy

anticoagulation therapy

RV failure post-LVAD