Talking Tall Rounds®: Heart Transplants at the Cleveland Clinic - 2000 and Counting

Dr. Eric Roselli and Dr. Amit Goyal discuss 2000 Heart Transplants at the Cleveland Clinic.

Enjoy the full Tall Rounds® & earn free CME

• Early Days of Heart Transplantation: James Young, MD
• Lessons learned over the Past 20 years: Randall Starling, MD, MPH
• Durable MCS use as a Bridge to Heart Transplant: Nicholas Smedira, MD
• Rejuvenating Heart Organs Using Ex-Vivo Heart Perfusion: Edward Soltesz, MD
• Multi-organ Heart Transplant Highlights: Michael Tong, MD
• The New Heart Transplant Allocation Systems: Jerry Estep , MD
• Contemporary Outcome after Heart Transplantation and Future Horizons: Eileen Hsich, MD
• Pediatric Heart Transplantation Highlights - Patient #2000: Hani Najm, MD

Transcript

Welcome to the Talking Tall Rounds Series, brought you to by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Eric Roselli:
Hello, everyone. Welcome to Talking Tall Rounds. I'm Eric Roselli and I'm here with soon to be really big papa, Amit Goyal. He's got two more kids on the way any day now, but he's making time to talk with us.

Amit Goyal:
Happy to be here, Dr. Roselli.

Eric Roselli:
Yeah, this is good. I'm glad we're doing this again. This has been really fun. Today, we're talking about the Tall Rounds that we did on August 26, 2020 when we were celebrating 2,000 transplants performed at the Cleveland Clinic and actually we were anticipating 2,000 and I think the case presented was 2,001.  Xingchen Mai, one of the fellows, presented a case of quite a typical patient from what we've kind of seen for many years as a 60 year old with coronary artery, representing sort of modern care this patient had. Couple of LVADs.

Amit Goyal:
Yeah that's right. And if we think about the number 2000 and on first glance is just a number, but each one of these individual numbers are a patient. And so this patient was a 60 year old man, a father, a husband, a son who developed end stage heart failure from coronary artery disease, ischemic cardiomyopathy and was at a crossroads. And it was back in 2010 who received the HeartMate II LVAD as destination therapy did very well, remarkably well for eight years, but subsequently started developing complications like a lower GI bleeding and driveline infections, which bumped him up into a transplant category. And he was transplanted as our 2001st patient.

Eric Roselli:
Yeah, it was really remarkable. I remember when I was a resident, I was involved a lot more with heart transplants. Those drive line infections just used to be so often insurmountable and this guy was able to fight through a whole bunch of that and he's got a new heart and it's just, it's fantastic news. Which was really great as part of the whole heart failure team was we led off with Jim Young, who is, the chief academic officer, used to be the head and actually is one of the founding or the person who helped to establish the Kaufman Center for Heart Failure, one of our very first centers of excellence. We now have over 50 centers of excellence in the heart vascular thoracic institute here, but that was one of the very first and still running strong, to celebrate the multidisciplinary work that happens in these centers of excellence. He gave us a really awesome firsthand I mean, truly firsthand experience about heart transplant and Jim's a great speaker and his energy is fantastic.

Amit Goyal:
Yeah. It was great to hear him speak, as you said, he's just one of the driving forces, that got our heart failure program to where it is today. And speaking of firsthand report, he showed a picture of one of the first heart transplants he was involved with, Debakey’s hand holding the heart it was incredible to see, the arc of his career. As a trainee, taking care of heart transplant patients, there's something miraculous about it. Dr. Young really went through a whirlwind tour of how he got here and you realize that the miracle that we experienced day in and day out today required the advancement and development of multiple domains, right? We are resting and operating on the shoulder of giants and it required advancements in the transplantation of other organs, like renal transplant, a lung transplant, forays into other areas like Xeno transplants. Device development for mechanical circulatory support to get our patients through the sickest of times, as well as innovations in immunosuppression, just to name a few.

Amit Goyal:
I would really encourage everyone to go and listen to the video lecture because this is a remarkable talk, but there's one thing I want to reflect on. In that when Dr. Young was thinking about the first Cleveland clinic transplant performed on September 4th, 1968, and just in considering the donors and donor families, he said he was reflecting on the and I quote, "the incredible heroism of donors and donor families." It's true love, a gift given. He takes us through the beginning of heart transplantation, the first transplant ever, the first transplant at Cleveland clinic and how this field really skyrocketed in the late 70s and 1980s. But again, these numbers that we talk about, they are individual patients, they're people who were given a remarkable gift to get themselves to that miracle. And so it's just such an honor and a privilege to have even a small role in them

Eric Roselli:
Yeah, absolutely. I went on many of those donor runs in training and it is a sort of a special sort of bond that everybody shares. It's part of this even when we're on the helicopter or the jet in the middle of the night going to do this, we always take time to hear the story of the person that's made the donation, reflect upon that. It's a certain kind of perspective that I consider a really a special privilege even to just been part of for a little while.

Amit Goyal:
It stays with you.

Eric Roselli:
Yeah. And Jim is really such a neat guy. It's great to have him as a guy with all the experience he has involved with the medical school, because it's fun for this very enthusiastic students to see a guy with his experience have the same kind of enthusiasm. And that's what we got from this lecture was great. And then we roll on, after he sets the stage. And of course, there's a lot of interesting bits in there about the Cleveland Clinic as well. The first dialysis machines being made with Maytag washers, that same group are the ones that sort of rolled over to other centers like helping Jarvik with the first artificial heart and everything else.

Amit Goyal:
Yeah. I had to listen with great pride just learning about our role as an institution with dialysis lines that eventually led to cardiopulmonary bypass, the first CABG, first stopped heart procedure, the origins of a total artificial heart. I mean, this is really incredible.

Eric Roselli:
Yeah. And everybody feels that. That's a part of this place. So we hear a little bit of that again from Nick Smedira later on as well because there is definitely an element of pride to it.

Amit Goyal:
Absolutely.

Eric Roselli:
And then we hear it from Randall Starling, who also has been involved with transplanting since its early days. And was the director of a heart failure center for quite a long time who shares with us, his lessons learned over 20 years and somehow he was able to fit that into his six or eight minute talk. And he talks a lot about what he learned about immunosuppression also in his typical way, humble as can be offers a lot of thanks to the people he worked with. And gets into some details about some of the papers and details can tell us a little more about.

Amit Goyal:
Yeah, absolutely. Talk about another luminary within the heart transplant realm. He took us through again, his first person's perspective of how things were shaped over the past 20 or so years. And he made a contrast in how we practiced the care of transplantation in 1995, compared to 2020. In 1995, we were doing biatrial anastomosis. And you can imagine all the complications, arrhythmia, et cetera thereof. Whereas, now we do bicaval anastomosis. Originally the immunosuppression in 1995 was cycles for a nasal thiopurine steroids. And today we use tacrolimus, mycophenolate, mofetil, and oftentimes no steroids. They talk about the story of induction immunotherapy, as well as how we've advanced or continue to advance and how we surveil these patients. We've moved from doing cardiac cath and biopsy almost exclusively to now we're doing fewer biopsies and more genetic testing and more noninvasive testing.

Amit Goyal:
And he went over some of the trials that got us here and how himself and many others here at the Cleveland Clinic have had an impact on like the 1998 paper by Kobashigawa et al showing the benefit of mycophenolic acid over azathioprine. The 1999 paper with David Taylor et al demonstrating the benefits of tacrolimus as a calcineurin inhibitor in this area, the work we did with everolimus having some better outcomes compared to azathioprine especially with regards to a cardiac allograft vasculopathy, but some of the nuances with regards to signals for decreased GFR and maybe increased mortality.

Eric Roselli:
Yeah. He shared the struggles they went through in this where they were questioned about IVIS as a valid end point. I thought that was really cool, personal touch slate being right at the front lines and delivering this message. That the whole time through the entire transplant story has been this idea of continuous improvement, even though there's times when they thought they had something new and I guess anticipated events redirected them. Then he just kind of charged along with the next story.

Amit Goyal:
This is incredible perspectives.

Eric Roselli:
Yeah, it was great. And then we jumped from a discussion about advances in the medical therapy of transplant to Nick Smedira, giving us that surgical perspective, really kind of the focus on mechanical circulatory support. Nick was right there all along when he came on early in his training, working alongside Jim Young and Pat McCarthy. And I remember when I went through my training, Nick was, Nick is still is, one of my important mentors. And I thought I was going to be a heart transplant guy after hanging out with Nick on a transplant rotation where I don't know we did, we had like a crazy streak at transplants in mechanical circulatory support devices. He's got a really great energy and shared with us a lot of the things that he had seen.

Amit Goyal:
Essentially being trained in the era where I take HeartMate III for granted, but he gave this incredible perspective of where we came from with Wilenkoff working on, dialysis and Suffolk subsequently cardiopulmonary bypass. How we had the beginnings of a total artificial heart that led to a Jarvik Heart. Later on developing continuous flow total artificial heart with a biomedical for short term support, but then evolving to improve durability with a max group pump and magnetic devices. And just he showed the evolution of devices and the iterative changes between them. The pneumatic HeartMate was enormous. I mean, it showed the module. It was as big as bigger than the patient himself or herself. And the Novacor pump was mechanical, electrical, more durable, but with a thromboembolic complications.

Amit Goyal:
And so the themes in his talk were there were several competing goals in this device innovation. The durability, the size, the mitigating complications in terms of how we arrived to where we are now. And it was great to see how the team here was so involved in exploring some of these complications and being actively involved with industry to improve the next generation of devices.

Eric Roselli:
Yeah. This was again, another cool part of this Tall Rounds that we talk about. I guess in the perspective of 2000 of them were talking a lot about sort of how we got where we are. We have other Tall Rounds, of course, where we focus on the use of mechanical circulatory support as you alluded to earlier. The use of those devices as a destination therapy versus bridge to transplant is all kind of a huge fascinating topic in and of itself. And one of the surgical leaders that runs our heart transplant or our heart failure center from a surgical standpoint now, Ed Soltesz. And Ed told me this morning that we have done 57 heart transplants at the Cleveland Clinic so far this year, ahead of our pace from last year, which is really cool in the pandemic.

Eric Roselli:
It also puts our total number to about 2020 ironically, at this point we want to pass that. We're going to go over that. Now we're going to be past 2020. And, Dr. Soltesz is hoping we might be as high as 70 transplants this year, but always with a focus on outcomes. And he talks about some of the advances that have happened in the actual heart transplant round from a surgical perspective.

Amit Goyal:
Yeah. Another fantastic talk by Dr. Soltesz, we've seen him on a number of these Tall Rounds, but he establishes a quandary that we're in right now, where there's an epidemiologic mismatch. There are a 100,000 to any where upwards of 300,000 patients with not just heartfelt, but advanced heart failure potentially in need of advanced heart failure therapies. But there are only maybe 3,400 hearts available in the year. And so you think that's not only an order of magnitude but there are two orders of magnitude indifference, so there's this mismatch. And how do you begin to bridge that? He talked about two primary mechanisms that we're working towards right now. One is expanding the donor pool and two is advancements in organ procurement so you can have a greater selection of hearts. In terms of expanding the donor pool, he talked about high-risk donors like HCV positive donors, which is just remarkable that we can take these patients. there's incredible innovations in medical therapy for antiviral therapy for hepatitis C virus.

Amit Goyal:
But then also DCD hearts, or donation after cardiac death organs. But right along side that is how do we procure the organ to begin with? These organs typically we harvest them and you know better than I do. we have the issues of cold ischemic time, which increase cellular edema acidosis, cause metabolic arrangements, endothelial injury that all with increasing time from procurement to implantation, cause adverse events down the road. And he said, the innovation there is ex vivo profusion of a heart, keep it beating with a warm environment to mitigate these adverse effects. And so he talked about his work with the Oregon care system, with the trans medics device, which is the only FDA approved device that allows physiologic preservation of the heart. Allows us to resuscitative capabilities, and expands the capability to receive organs from DCD patients.

Amit Goyal:
And so he went over a lot of the data there, the early feasibility and safety trial would proxy II that showed that look, you can expand the donor pool using the trans metics device with longer time from procurement to implantation without increase in adverse events. And the expand trial which shows established utility in the extended donor pool and then the ongoing DCD heart trials. So, really there's a need, there's a problem, but these are great advances in how to bridge that need.

Eric Roselli:
Yeah, absolutely. And we're seeing the same thing with lung transplant as well, this extra corporeal perfusion of the organs. It's important for all the reasons you've described. What I think is really remarkable is this idea that we prolong time for two reasons. One is we can resuscitate an organ, and all of us who take care of hearts know that sometimes all you need is time and the heart has this almost sometimes miraculous ability to recover from trauma. And a lot of these patients that are donating their organs have seen a catecholamine storm or something in the heart that will recover if it can be protected and resuscitated with some of these measures. The other advantage of time that I think is really critical here when we're talking about a limited pool of donors, is it also expands space?

Eric Roselli:
So geographically, we can go further. We can improve matches for difficult to match patients and make sure that any organ that is possibly is such an unbelievable valuable resource that it gets matched to the right patient, doesn't get wasted for logistical reasons. So this is a really great technology and I think is going to make a big impact on certainly many lives one at a time like you talked about earlier.

Amit Goyal:
Revolutionary.

Eric Roselli:
Yeah, absolutely. And then we hear again from another surgeon, Michael Tong, who is the surgical director of the transplant program works really closely alongside, Soltesz and Smedira and rest of the team. Who's talked about some of the advances on the surgical side with regards to doing multiorgan transplants. And this is also a really amazing area where as we've got technically butter, medically better, anesthesia teams have gotten better critical care teams have gotten better. We've been able to really expand what we can do with people with multi-organ failure.

Amit Goyal:
You know, I think we're all biased here in this room that we think the hardest is the most important organ. Without the heart for nothing else gets.

Eric Roselli:
For sure.

Amit Goyal:
But let's be fair. The heart doesn't beat in isolation of everything else. It's a part of a multi-organ system that is the person. and many patients who have heart disease also have concurrent lung disease, liver disease, kidney disease. You can imagine somebody with IPF who then develops end RV failure. You can imagine somebody with AL amyloidosis with end stage kidney and heart disease or a Fontan patient, or other amyloid patients with a heart and liver disease. And so how do we approach these patients? A heart transplant would be insufficient necessary, but insufficient. And so we have very active programs with our colleagues across the divide with active heart lung transplant program.

Amit Goyal:
A the time of this recording, we've done over 38 heart lung transplants. And the first one that was done is still alive. The outcomes have been incredible for these multi-organ transplants. 24 heart kidney transplants since 1992 and six heart liver transplants since 2006 with really tremendous outcomes. And that's a testament to the multi disciplinary collaborative efforts across the institution. He mentioned a couple of data points one, that for patients with GFR less than 30, they just did better when they got a simultaneous kidney, alongside the heart. So I think that really fueled the impetus for developing this heart kidney program. And as with the ex-vivo profusion of the heart, the life port device allows ex-vivo profusion of the kidneys. And if you do the kidney right away, right after the heart transplant what's going on?

Amit Goyal:
You've got coagulopathy, you got adverse hemodynamics, pressers, inotropes, you get ATN and bad outcomes with that new transplanted kidney. The life wear device allows us time to allow the transplanted heart to recover, the hemodynamics to recover, the coagulopathy to resolve so that now we've got this resuscitated kidney organ that can be transplanted at the best optimal time to improve the outcomes. And I think that's why we've seen that the outcomes for heart kidney as well as simultaneous lung transplants are all above national average in terms of the outcomes.

Eric Roselli:
Yeah. I mean, it's really awesome. We talk about it all the time in this place how we are building these team of teams, and this is one of the best examples that you could even imagine.

Amit Goyal:
Absolutely.

Eric Roselli:
And then what a great agenda we have here because we hear from Jerry Estep next who's just stepped up as a guy who was recruited here to help take over the new leadership of that section of heart failure and transplant. And is just an amazing guy that right away understood the culture of this place of with regards to this multidisciplinary teamwork. And is talking to us about what is so important in the field of heart failure and that's the transplant allocation systems.

Amit Goyal:
Dr. Estep he's been such a great addition as a terrific leader for the department, but he has this infectious energy about him and how he does everything he does. And he talked about the new allocation system that was launched back in 2018. And the new allocation decreases the median wait time for most medically urgent candidates by prioritizing the sickest of the sick. Then decreases the percent of patients bridge to heart transplant of the durable LVAD. So they can go directly to a transplant as opposed to going through the circuitous route. And it increases the donor heart regional and national sharing. Another way to help mitigate the epidemiologic mismatch. It increases the donor ischemic times, the heart transplant rates and the percent of patients bridge to transplant with temporary MCS devices, as opposed to durable MCS devices.

Amit Goyal:
The early data is a little bit perplexing, and I think we'll get a little bit more about why that may be with Dr. Hsich, but the UNOS registry, one of the earliest experiences showed the concerning trend of lower survival with a new allocation system. The opt-in committee in contrast did a six months survival that actually showed no difference between the new and the old allocation systems. Conversely, in our own experience, mostly with the status one, two and three patients, the survival of the 105 patients listed with the old system was 99%. And the survival with 68 patients that were listed and transplanted within the new construct have had 100% survival since October 2018. Including 40 patients that had at least six months of followup. So I think there's conflicting results. The two takeaways are one, we're still learning a lot about this new allocation system and how to optimize it and use it, but also that taking care of patients in experienced centers is of utmost importance.

Eric Roselli:
Yeah, I think the key is that it's adaptable because it needs to be fair. What used to be status 1A is now broken down into three groups, a very specific criteria which have evolved as the various kinds of mechanical circulatory support and other improved understanding of where these patients are when they're in this phase, where they stand. I think it's going to continue to be a dynamic thing that changes with time with data analysis. Yeah, the UNOS registry versus the opt-in sort of analysis that one is puzzling. And I'm sure that has looked a little closer underneath the data and get more granular with it. There'll be a better understanding of how to do that. And Eileen Hsich, who is a really active and super bright, investigator as well as, of course an excellent clinician talks about how risk prediction and maybe even some novel tools, with better computing, AI and other statistical methods will help us to understand better what's happening here.

Amit Goyal:
Yeah. You know, she helped us start to break down some of these differences that we're seeing in outcomes. And she says, 'Okay, well, this is all of our risk prediction, but what are the determinants of risk?" And she broke that down into four aspects. First, what's your cohort? The UNOS registry and the opt-in experience were different cohorts with regards to how they were listed and transplanted, with the different systems. The second is what's a followup time? The opt-in registry had a longer follow-up time. And so of course your outcome will be different within that regard. Three is, what's a variable that you're looking for? Are we looking at early phase survival? Late phase survival? Different populations, different subsets may do differently with regards to what we're looking at here. She said black patients do worse in the constant phase after transplantation.

Amit Goyal:
And is that a socioeconomic concern or a physiologic disposition? And the fourth was the statistical method. How much of a deep dive are we doing to really understand where these differences lie? Are there complex interactions that we don't understand yet? And really the ultimate goal here is to improve the long-term survival. And we need to develop maybe an allocation score that helps us better stratify who's going to be the best candidate, but to do that first, we have to get nitty gritty with the data like she and many others are doing.

Eric Roselli:
Yeah, no doubt about it. And I think the question about socioeconomic concerns is a critical one because what she didn't talk a whole lot about. Which really just, we need to get a better grasp on is what about quality of life of these patients? We do our best to make sure they're informed about what they're about to take on. It's a real challenge to live with a VAD, with an organ transplant. Amazing that the first heart bond guy is around almost 40 years later. But some patients it's more than they bargained for. And that's another sort of aspect of all this that needs to be understood better. And I think we certainly will see a better understanding of kind of every aspect of that care and that we deliver.

Eric Roselli:
And then our next speaker in this group, and it was pretty awesome to see that everybody actually stayed pretty much on track because it covered a lot of things in a short period of time was Hani Najm from, pediatric and congenital heart surgery to give us an update on what's happening with the pediatric transplant program. Which has seen a lot of growth, and a better understanding of how to use this treatment option for young patients with congenital heart disease, including even mechanical circulatory support advances.

Amit Goyal:
You know, Doctor Roselli I think if heart transplantation in general is miraculous, then transplantation and the pediatric population just takes on a whole new meaning and a whole new set of challenges. The etiologies of heart failure are different. The technical requirements are different. The outcomes are different, but I was really happy to see that our pediatric transplant program here, has been very active. Was established in 1985 amongst the first of its kind and year to date had done 178 transplantations at the time of Tall Rounds recording. With a growing population of congenital heart disease patients along the way the three-year survival has been 95% above the benchmark national average of 89%. But again, as a recurring theme, you can't talk about transplant without talking about mechanical circulatory support.

Amit Goyal:
So you talked about the forays of what's available to the pediatric population, much of what's available to our adult patients, but also the pediatric only Berlin EXCOR LVAD. And he also described over the duration of heart transplant program. There's the era effect that we see in so many of other programs that the survival has improved as we learned more and more about how to take care of these patients, both within the dilated cardiomyopathy and non-dilated cardiomyopathy patients in the experience here. In the pediatric population especially talked about the issue of longer wait lists. And so the inextricable need of durable LVADs to help support these patients and get them to the transplant once it's available. And so we talked a lot about their experience with the Berlin device and how they transition over to using bivalirudin as opposed to heparin the improved outcomes there.

Amit Goyal:
And he ended off with talking about our 2000th patient as an institution, which came from the pediatric side child with AML, with anthracycline induced cardiomyopathy. Who initially had a mitral valve repair as a bridge to transplant, later ended up getting a temporary LVAD that developed circled three clots with a stroke and left hemiparesis converted later to a central mag LVAD. Required a pump change along the way, and with grace ended up getting a transplant on August 4th of 2020. And as a father, I'm just thinking through everything that this child has gone through, and the gift that she was given by another person.

Eric Roselli:
Yeah. It's remarkable by another child really. Yeah certainly that case gives everybody pause. But none of this is possible without having just not only the teams of many, many people all led by each one of the leaders that we heard of speaking during this agenda. But even other teams that are behind the scenes and that really make a really critical impact on success of a program like this. A program that's continuing to grow and will continue to grow. And even in a crazy year like 2020 is on track. Great. And in this Tall Rounds, after listening to us, we have the opportunity to listen to a couple of our speakers. And of course we always encourage our listeners to go online and watch these for yourself.

Eric Roselli:
These talks are all wonderful, but they're even better when you can see the face of the person speaking and read their sign language, their body language. You can see in their eyes and hear in their voice and share in their slides and other things with the version of Tall Rounds online that you can also get free CME for. So thank you for listening to us. And now I hope you enjoy listening to a couple of the lectures from the Tall rounds. We've selected the surgical director and medical director of the heart failure center. Dr. Ed Soltesz will be speaking to rejuvenating heart organs using ex-vivo heart perfusion.

Ed Soltesz:
Thank you for the opportunity to present. It's a fantastic team that we work with every day and it gives a reason to come into work and a reason to put all the effort that we do in some of these new devices and new therapies, going forward. I'm going to speak about how we are trying and thinking about rejuvenating heart organs, utilizing an ex-vivo heart profusion system. Everyone knows that the number of transplants that we're able to do is dependent upon the number of organs that we have available. And that has effectively plateaued, not only here in the U.S. but for that matter in the world over the last five to years. The problem of course, is that we have more patients on the transplant waiting list, and we have available hearts. And this leads to an epidemiological mismatch. The fact that we have anywhere between a 100,000 to 300,000 patients with advanced class 3B or four heart failure, who need advanced therapies, but only about 3,400 hearts available leads to this problem of access for patients.

Ed Soltesz:
We've certainly been able to implant LVADs in about 12 to 15,000 patients worldwide to account for this difference, but we still have a tremendous lack of access for advanced therapies for patients. We have certainly pushed the limits of organs over the last few years with the advancement of using hepatitis C organs for transplant. We've shown, as well as other centers have shown that the survival is effectively no different than non hepatitis C organs really due to the amazing opportunities afforded by the new treatments for hepatitis C. But there still is a tremendous opportunity that we have not capitalized on. And that is to say there are underutilized brain death organs, and also underutilized DCD organs. These are patients that have not necessarily died yet, but are in the process of dying. And we have not utilized these organs for the heart.

Ed Soltesz:
So this may be a slight overestimation of the significant under utilization or the donor pool opportunity that exists, but be that as it may, it still does show that we have opportunities available. Right now, our donor procurement relies on cold static storage. That is to say, we travel to another hospital usually, sometimes six, 700 miles away. We remove the donor heart, administer a dose of cardioplegia protection solution and put it in a cold cooler and transport as rapidly as we can back here to the implanting center. Now there's clearly problems with this paradigm, cold ischemic storage is known to have problems associated with it, including cellular edema, acidosis and endothelial injury. That really all leads to either immediate or delayed apoptosis and potentially results in problems long-term. This is not a displaying correctly, but cold ischemic times, correlates directly with mortality.

Ed Soltesz:
So the longer the ischemic time of the organ, the higher the mortality at three months and the higher the mortality at one year with the inflection point, really being at about four hours. We have a number of organ systems available or profusion systems available for organs that allow us to perfuse organs and keep them warm, and effectively, metabolically active while we transport them to the recipient center. And here's an example of the kidney profusion system and the lung profusion systems, which are available. This is the OCS heart. This is the trans medics organ care system, the example-vivo profusion system, the only FDA approved one right now for the heart. And you can see here, there's a wireless monitor, a console that displays the physiologic parameters of the heart while it's beating. The profusion module which is a sterile encapsulated device where the heart sits and beats, and then a heart solution set which contains some of the nutrients and vitamins and drugs that are used to regulate the physiologic parameters of the heart.

Ed Soltesz:
The advantages of such a system really would be to allow physiologic preservation of the heart. That is to say have a warm beating heart, that hopefully would improve the quality of the donor organ. So we would obviously subject that donor heart to much less cold ischemic time, and potentially expand both the time and the distance we can go to retrieve hearts. It also would allow us to resuscitate hearts that is to say, potentially take hearts that are not in the best quality at the donor, facility and resuscitate them and determine their suitability for organ transplantation. This may open up the donor pool even further. And finally, this provides a platform for actually performing DCD transplants. We can modify the donor heart resuscitate it, reanimate it and in the process also determine its suitability for transplant in a DCD setting.

Ed Soltesz:
So the OCS, the heart and the box system, you can see here, which has a gas exchanger in the system below, the reservoir, a pump and some tubing. And basically once the heart is ex-planted from the patient after standard a cardioplegic arrest, we can leave the aorta, connected up to the system, place an LV vent, coagulate the pulmonary artery, close off some of the left atrial connections, and this is what it looks like before the box is closed up. and then we started beating. And this is a picture unfortunately, again, it may not be displaying correctly, but this is from RO-RO 62 in 2014, when our devices, that we use the OCS as part of the trial. So the donor heart assessment really allows us, while the heart is beating and warm to determine its suitability for transplant.

Ed Soltesz:
We monitor hemodynamic parameters such as aortic pressure, coronary blood flow, and we closely monitor lactate level, the arterial venous difference as well as the absolute lactate level. And the threshold really is set at five from some preclinical data. That is to say, if you have a continuous absolute lactate level of five or greater, it's typically a heart we wouldn't necessarily want to use. And of course visual inspection is also important. This is the proceed II study, which is a prospective open-label multi-center randomized trial. That was a non-inferiority trial that we had a significant involvement in back between 2010 and 2013, then enrolled 130 patients. The primary endpoint of this was 30 day patient and graft survival. And it was a multi-center trial as I had said that, really looked to determine the safety and feasibility of the organ care system compared to cold storage.

Ed Soltesz:
You can see here the significant difference in the donor hearts in patients that underwent the organ care system, the example-vivo profusion system versus standard cold storage in total preservation time. And significantly less cold ischemic time in the organ care system, because obviously the heart was beating and warm for a majority of the transport to the recipient hospital. The outcomes showed no statistical difference in the cold storage group compared to the organ care system group, both in the primary end points, as well as the secondary end points. And this led to the statement that the organ care system, the heart in the box device was not inferior outcomes to standard cold storage. So this open the door to the potential to take advantage of this system, to use it both in extended criteria donor heart procurements as well as DCD hearts.

Ed Soltesz:
Well, over the course of time the cannula and coronary filling, and some other components of the system were optimized. There was a compliance chamber and the aortic root that was added and a new aortic cannula design was made much easier to coagulate at the donor hospital and an automated human dynamics system, that led to much easier titration of the medications regulating coronary blood flow and mini aortic root pressure. The next trial that came out of the organ and care system and transmetrics device was the expand trial. And you can see we had involvement in this as well, and this really showed that the OCS system was useful in extended criteria, donor heart transplantation. And led to successful transplantation of 81% of donor hearts that otherwise may not have been utilized for either distance from the donor facility, or because of low ejection fraction, or other components that would make it an extended criteria, donor definition.

Ed Soltesz:
And the patient survival was equivalent at 95% at 30 days after transplantation. This has now led to the DCD heart trial utilizing this device. And this is what we're involved in right now. The first DCD heart trial was performed, last year and the potential here is to hopefully increase the donor pool by about 30%. That is obviously data yet to come. We don't have much data on that. This is the picture of the first DCD heart case utilizing the OCS device. This is from Australia, and you can see there was a 16 minute time from withdrawal to circulatory arrest. That's effectively the warm ischemic time of total of 28 minutes. And then the heart was pumped. You can see the decline in the lactate levels up in the upper curves.

Ed Soltesz:
And then eventually the heart was transplanted with a total ischemic time of 90 minutes and a total OCS profusion time of 257 minutes. So clearly a device like the OCS, like the heart in the box, potentiates the opportunity for using many more DCD hearts. So this system really, has been brought to our use through a number of trials. As I had mentioned, to proceed to trial established a feasibility and safety of the device. The expand trial established a potential usefulness and extended criteria donor hearts. We have the DCD heart trial going, and the goal with this sort of a device really is to safely increase donor organ supply through both extended criteria donor hearts and DCD hearts. More to come over the next number of years. But I think this certainly has an opportunity to afford advanced therapies, to many, many more patients. Thank you.

Eric Roselli:
And now Dr. Jerry Estep, the section head of heart failure and transplantation, will talk about the new heart transplant allocation system in the early observations thereof.

Jerry Estep:
I want to highlight the new heart transplant allocation system and early observations. Here are my disclosures. In October 18th, 2018 was the launch of the new system. The old system comprised of a three tier. Now we have a six tiered system. The idea was to improve access to those that were sickest driven by underlying human dynamics to improve upon weightless mortality with a hope that post-transplant, there would not be a compromise in survival. And so now we have been transplanting patients predominantly in status one, two and three as listed. There've been two examinations about outcome with the new system. One was a review of the UNOS registry, which I had the privilege to be part of. The other is based on the most recent Optum committee or thoracic committee February 2020 report. And highlighted in red is outcome six month survival in the new system compared to prior.

Jerry Estep:
And when we looked at the UNOS registry in 539 patients listed and transplanted in the new system, a bit of a red flag. Six months survival at 77.9% compared to 93.4% survival, those listed and transplanted in the prior system. Understanding that one of the limitations there was not complete followup and sample size of 539. And based on the more recent Optum committee report with a larger sample size and more complete followup, encouraging that the six months survival is 92.8. Not significantly different compared to those that were listed and transplanted in the older system, with the thought that certainly moving forward programs need to take into consideration the implications associated with the new system. So I highlight last year's 51 adult heart transplants, and the majority roughly 78% were then status one, two and three. And we have expertise, both surgically and cardiology and transthoracic temporary support, extended use and support have a tremendous team in our Hoffman recovery unit and in our intensive care unit that allows us to bridge these patients to heart transplant.

Jerry Estep:
And we saw a significant reduction in median time, median four days for transplant status one and status two, a median of 11 days. And most importantly, when we look at all those transplants, 105, since the new system, include those that had been listed in the prior system, only one death, that's 99% survival. And when we look at the 68 adult patients listed and transplanted in a new system, really a reflection of the team effort. Want to highlight the 100% survival. So this is just tremendous quality outcome. And to summarize the observed changes in the new system they're listed here, and the increases relate, which was the spirit of the change an increase in donor, heart, regional and national sharing.

Jerry Estep:
We're very cognizant of going out further. There's been an increase in donor ischemic times for those that are sickest an increase in heart transplant rates. And there's been a four-fold increase in the use of temporary support to bridge this patient population. The decreases are noted above, including about a 40% reduction in durable LVAD use as a bridge to transplant. And the goal is to balance this programmatically to improve weightless mortality for those that are sickest but not at the compromise of longer-term post heart transplant survival. So certainly more to come with the new allocation system.

Thank you for listening. We hope you enjoyed the podcast. Like what you heard, visit Tall Rounds online at clevelandclinic.org/tallrounds and subscribe for free access to more education on the go.

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