Dr. Bil O'Neill describes the randomized trial to assess the impact of primary unloading with Impella CP® heart pump prior to revascularization on infarct size in patients with anterior wall STEMI.
William W. O'Neill, M.D. Medical Director, Structural Heart
So this morning, I'll go over uh basically, uh what you guys pretty much already know. It's kind of like bringing coal to Newcastle to tell you about how to do a heart attack program. But I really want to tell you some of the stuff going forward and then hopefully appear into the future. So can I have the next slide, please? So this is the basic and if you think about this slide, this kind of tells the whole story in a nutshell. This is the first canine model of occlusion reperfusion that Reimer and Jennings did at Duke University was published in the early seventies. And what they did is they took an animal, they occlu to the coronary artery for various periods of time and then they reperfus. So that on the far left, 40 minutes of occlusion in the middle three hours of occlusion and then at the end 96 hours of occlusion. So we know that the battle is kind of gain or lost right now between 40 minutes and three hours. And that's why the whole initiative have been to try to get patients to the Cath lab and get them reperfus as soon as possible and where the magic of the 90 minute do a balloon time comes in. Um, the, the average person takes about 1.6 hours from the incident, chest pain to get into the emergency room. And so the minutes that we spend, uh, with that, uh, you know, really are critically important. But unfortunately, truthfully, the large number, more than 80% of the patients are coming in after three hours of symptom onset. So, so we have what we've been trying to do really basically for the last 20 years is try to figure out how we can extend the opportunity to have reperfusion, allow my car to salvage. So we've done an incredible job and you guys have helped us all the, all the way through these trials to show what we've done with acute my car in park. And the in hospital mortality has dropped enormously before we started reperfusion. If you came in with a sta you had a 13% mortality. If it was an anterior sting, you had a 20% mortality. So think of that, if you come into the hospital with a, with an anterior i in 1970 you had a one in five chance of dying. It was almost like Russian roulette. In terms of mortality. We've driven that down initially with thrombolytics, but more importantly, recently with, with primary PC PTCA and with, and with stunting and the mortality overall for patients with an with a non shock is under 2%. If you take a look even further at the subsets, whether it's angioplasty, whether it's angioplasty with a, with a two B, three A agent, a stent or A with two B three H at the mortality rate was really under 1%. So a lot of people have kind of declared victory and we've had a little bit of a sense of, of, of, of satisfaction that we're doing a great job. And truthfully one of the moderns, one of the modern miracles of American medicine has been how angioplasty has been so widely adopted, whether you're in Norfolk, Virginia or Atlanta, where I am today or in Hong Kong or in Brussel, you're treated exactly the same way. And that's because we've proven overwhelmingly that this is the ideal choice for treating patients with ST segment elevation on Carolyn Park. Is that, is that all all rosy though? And really what I want to give you is sort of a sense, let's get rid of this complacency because there still is a big challenge. This is data that we collected back in 2005. Looking at the size of in spas of anterior versus non anterior. And you see that in the, in the orange mark, those are patients that have inferior mice, they ended up, they have a very small amount of myocardium that ends up being an inf FARC less than 10%. And there's a lot of data showing that if you have an infarct, that's less than 10% that's long term survival is actually very good. However, with a, with a larger infarct, you end up with a much worse outcome. And we found was that with, if we want to do my Caro salvage studies, we have to treat the highest risk patients. You can see that in red patients have a huge infarct and it is, it is time to depend it out to about three hours after that, it's more dependent on the collaterals. The other thing I just want to point out to you is take a look at that 90 minute. The number that says 27 the standard deviation there of infarcts as between nine and 43%. So there's a huge individual variability and, and that's the thing we have to really recognize. You can say, well, patients in four hours out five hours, there's no point but it's really not true there, a lot of other factors including collateral flow really tell you that there's an enormous amount of inter inter patient variability in the final size of infarction, but clearly antes are much worse than inferiors. And if you had to choose if you have two patients in the emergency room and only one cat that available, you should actually prefer the or put the answer in my in front because the inferior I still are going to do pretty well in a time independent manner of my carl salvage. So, so this is now specifically on tech techni system of imaging. And we're taking a look again at anterior I only and you can see that when a patient comes in within less than two hours of symptoms, that they end up with a very small infarction. And so for the DT trial, remember, the inclusion criteria is presenting less than one hour from symptoms. That is an exclusion. Those patients are hyper acute, you should really break down the barriers. Treat those patients like a stab wound to the heart, get them to the cath lab, break everything, get the artery open as soon as you can. And, and that's the most likely thing that's going to cause myocardial salvage in those patients that are hyper hyper acute one hour though it's less dependent on time. And you can see that after about three hours, there's really no time dependency, but there is a lot of individual variation. And so that's what we're really trying to do is we're trying to enhance the ability of reperfusion to salvage myocardium in patients that are presenting between two and six hours. And that's why we're doing the DT trial. And again, I can't thank you guys so much for being actively involved with this. And I'm just a thrilled to have you on board as partners. So, so why is that bad? Why is a big heart attack bad? And this is a nice schematic. That kind of tells the tale. If you look on the far left, you have the apex that's involved. When the, when the ventricle or the anterior segment and the septal segment becomes involved, then that area becomes a kinetic that area thins out. And then at the far right, the ventricle now becomes globular. And that's what we've seen in. We've actually created a whole myriad of patients throughout the United States right now that have been reperfus they're alive, but their ventricle is slowly remodeling adversely. And you guys see these patients all the time. A patient had an infarct 10 years ago. Now, they're coming in with heart failure with ischemic mi regurgitation, with arrhythmias, with the heart block, needing CRT therapy and all the wonderful heart failure medications that we have. Now, if, if a patient is, is 90 that might be ok. But imagine if this patient was 40 years old and came in with his first M I and, and his, his whole trajectory of his, the rest of his life is going to be dictated by what we do in the first hours to see whether or not we can salvage myocardium. So that's really the uh the gauntlet, the mission to you. That what the thing that's been driving my passion to try to do something to decrease in size for the last 20 years is that we can't ignore these patients. And, and so often what happens is that your patient comes in with an T I. The arteries is occluded. You open up the vessel T three flow looks great. Pata in the back. Good patient goes home in three days. But what we don't see is brewing is that the anterior wall is dead and that patient is going to come in maybe not tomorrow, but in a few months and a couple of years with ischemic heart congestive heart failure. So that's really the drive and the passion and the goal that we have for this. So it also affects mortality. This is data from Greg Stone looking at infarcts. That is a classic article depending on the size of the eye. If you see on the red, the patients have a small infarct, less than 8% of LV mass, there's very low mortality. Whereas in the patients that have larger infarct sizes, the mortality is much higher. I'm going to show you some data. And I want to, I want you to get a new number in the back of your mind. We've talked about one of the targets for reperfusion is timmy three flow and we want to get timmy three flow more than 95% if we're successful. But the next step is really how big a heart attack was caused at the into this when we do all this stuff within the first day, what do you end up with? You have to sort of have a battle plan to decide whether or not they have a small M I or a large M I. And I'll show you some data from CMR which is really pretty, pretty astounding. So this is, this is basically the construct. And again, you guys have been actively involved with this next slide. And so the DT trial, the reason mechanistically why, why we think that we're going to decrease infarct size on the left. What we're doing is resting the ventricles. So there's an enormous amount of decrease in myocardial stress, decreased myocardial oxygen consumption. And basically, we're decreasing the infarct by decreasing demand at the ischemic zone of the heart. There have been some nuclear studies in the middle where when you put a patient on impala, you actually get reperfusion through thespian collateral. So you're probably already quickly reperfus the heart. And the proof is in the pudding because we have this thing called the impala snooze. When we take in these patients with anterior mind, they're having a lot of chest pain, they go in and they get a randomized impala. As soon as the impala gets turned on, the chest pain starts going away and the segments start to resolve. So there does appear to be a mechanistic reason by by how we're decreasing infarct size. In addition, Naveen Kapoor has demonstrated that survival kinas are released and the myocardium, the muscle becomes more resilient and less chance of having apoptosis. So there's another mechanistic way of decreasing myocardial salvage. I'm sorry of increasing Carol Salvi. And I think that those are kind of like the three reasons that I can give for mechanistically why this should work. But again, the proof is in the pudding. And so we were really concerned when we did the pilot that people really couldn't stand there. So the arteries are closed, patients having chest pain, you know, got open, got open, we were afraid that people were going to bail early. But on the, on the, on the upper panel is the ones that had delayed reperfusion. And in those, none of those patients had to have their, their artery open abruptly and, and we didn't uh we didn't eliminate it. We said, look, if you feel like you have to, you have to. So none of the, none of the operators felt that they had to open. So that was the main reason was the safety and feasibility and we proved that it was very safe to do therapy and it's quite feasible. So that's why we're in the pivotal trial right now. Next slide. Yeah. And we unload it for 3 30 minutes and and unload it for 11 minutes in the immediate reperfusion. So now this is this is the data and you're looking at the myocardial salvage. So this is the amount of salvage that you can and remember different people have different sizes of mis. And that's one of the difficulty if you have a small distal led inclusion versus a proximal led inclusion or the collaterals are sufficient. There's just a huge amount of individual variability to get rid of the variability. We look at the size of the inc as the area at risk initially and then the size of the infarct is. So that's considered myocardial salvage. And you can see that going across when you, when you have immediate reperfusion, the myocardial salvage is about 40% which is, which is OK. But when we, when we delay the reperfusion, especially in the patients that have large infarct, the myocardial salvage index is very large and the P value was significant. Now, that's not that this is just a hypothesis generating, it was never sampled to be large enough. And so now that's why we're doing this mega trial right now. And, and you know, believe me, it's an international trial that's, that's garnered an enormous amount of momentum. Yesterday alone, we had four patients that were recruited from throughout the country. Canada is now involved that Europe is now involved. And I think we are aiming to have this study completed by the end of the year. And we think that this is going to be a revolutionary trial from everything we've seen so far, we're pretty convinced that we're going to have a dramatic reduction of in park size when we place the patients with the, with the impala catheter. And so what we're trying to do uh uh schematically if you take a look on the left, you take a look at the myocardial salvage and you can see that the quicker you get the patient into the study, the more likely you are to reperfus. But we're trying, what we're trying to do is we're trying to extend this sort of duration of their so that we can get more patient salvaged. And you can see that on the right when we, when we unloaded, the patient delayed opening, we actually decreased in for exercise. So that's what we're hoping to do is they're hoping to get a lot more patients with anti M I that will get my Carol salvage, that is time independent. So I want to show you some, some data from the CMR and this has actually become very intriguing again, again, this is sort of a post hoc analysis, but it's got some really interesting data. So we took it, we took 39 patients that had ac Mr uh uh half of them had, had delayed and half of them had immediate opening. And, and we looked at the CMR data and what we found is so taking everybody all the comers. So at the end of the day, at 3 to 5 days, what happens? And on the left, we can see the ejection fraction. If the infarct size is less than 25% of LV mass, the ejection fraction significantly increases from about 45 to about 60% on this on the AC Mr and then on the echo, the ejection fraction also increases. So and, and that all makes sense. If this heart attack is small, the ejection fraction is gonna increase, the ventricle is gonna normalize. However, if the heart attack is large, meaning greater than 25% of LV mass, uh the ejection fraction stays, stays static both on the CMR and the echo. This is, this slide is a little bit complicated, but I want to tear you a little bit on this because it's got an enormous amount of information. So when we looked at as the, as at the echoes, the sequential echoes at 3 to 5 days and at 90 days and then looked specifically at the anterior wall. So we're looking at the basal, the mid cavity and the apical segments. Now on the left, you can see that in the patients are divided as to whether or not they have a kinetic hypokinetic or normal segments. So black is black is bad. Is, is, is it kinetic and gray is in between, which is hypokinetic and then look at the segment. So now divided between the large or small heart attacks. And you can see that on the left of each panel is the small infarct and on the right is the large. Now, the infarct rarely involves the base. It does involve the mid cavity and primarily it involves the apical segment. So you can see that in the apical segment in the patients that had large infarcts, the the area was, was very akinetic. Now, we always hope that this would improve. But then if you take a look at exactly the same thing at 90 days on the far right, you can see that the area of the inf FARC is a kinetic. So unfortunately, if they have a big infarct, the area remains a kinetic and and similar in the middle in the mid cafeteria is markedly hypokinetic. So, so we know that there's a significant amount of my car damage that occurs. And what I would urge you to do is take a look at the predischarge echo on these anti my patients that you're treating. Because if you see that the the anterior wall is a kinetic, unfortunately, it's really not very likely to improve. And those are the patients that you really want to look at very carefully to make sure that start getting hooked up into heart failure clinics. And someone is going to follow those patients closely because they're not going to have a very good prognosis. And so now this is data from CMR looking at infarct size and a very large pool of patients that were treated in Europe. And you can see and this slide is, is, is, is freedom from mortality based on the size of the infarct that happens with CMR and anti my patients. And as you go across, you can see that if the inf FARC is small, less than 10% great outcome up until you get to about 25% which is exactly the same that we found. And then when the infarct starts, becomes larger than 25% the mortality significantly increases. And this is the same thing for mace. Now, there's another concept called microvascular obstruction and we don't have time to get into that in detail, but it really, that demonstrates how much blood is actually getting into the myocardium. Now, if the patients have no microvascular obstruction and a small infarct at the top line, the black, they're, they're outstanding. If they have a large infarct, have a substantial amount of microvascular obstruction, they have a very poor outcome and you can see that the mortality of three years is almost 50%. So, so this now allows us to use a lot of prognostic indications. And we're going to be looking at this in detail in the semi D two trial because I'm predicting that CMR is going to become the next quality marker for a semi program. If you don't have CMR, it was not available. I think an echo is a poor man, CMR and looking at the anterior wall is really going to be very important and very prognostic. And then I just want to show you where we are with stir right now. Uh On this weekend, we recruited our 4/100 patient in the randomized portion of the trial And uh and we fully expect that we're going to be able to uh enroll this patients in complete enrollment by the end of the year. We love to have you guys reactivate. I know you're really interested in your screening and I can't tell you how thankful we are because we need centers like yours that are good, that are technically excellent, that can follow the protocol and get the patients uh followed appropriately in order for us to complete this trial. And again, hopeful dreaming, we're hoping that this is going to change the paradigm for treating anterior my patients. And there is a pressing need to do that because many patients with anterior I are going home with with dead anterior walls and their outcome is just not going to be very good. Long term. We're also doing the Protect four study. I'll talk a little bit about that and then the CP trial, which is actually quite an interesting study. So I'm just going to concentrate then on the Protect for trial. So this is this is a slide that is a data from a registry from Europe. 14,000 patients with myocardial infarction were treated. And you can see on the on the blue line if they don't have shock. So stummy without shock does wonderfully across the country across Europe, across the world. And so that's not in terms of hospital mortality, that's really not a problem. On the other hand, if the patients have shock whether they have cardiac arrest or not, still a 50% mortality. Now, this data was published in 2018. So very recent current data shows that, that we're doing great with non shack. We're not doing any better with shack than we did 40 years ago. So this is data from 1985 from the University of Michigan. This is when we first did our original A QM my card shack trial, the first one that was done at Multi Center four sites in Europe and the US. And we were able to achieve a 50% survival which is dramatically better than the 80% mortality that was present before. So, so this is data was published in circulation in 1987. This is now data from 2017. So 30 years later, this is from the uh culprit shock trial. Mortality of 50% is still reported. And now this is data from the recent ECLS. This is using ECMO. And again, you can see that's still a 50% mortality. So, so from 20 from 1987 to 2023 a 50% survival for cariogenic shock. And that's really why I've been looking for other approaches. And, and we've been really looking at at impel a and to see whether or not mechanical circulatory, suppose it was going to change this outcome. So this is this is data from safety and the thing that's underappreciated about ECMO is that the patients actually do very poorly and they have moderate severe bleeding, a quarter of the patients have moderate or severe bleeding. And I think this is one of the reasons why the mortality actually is not any better. Early survival may be slightly better. But the patients end up with these massive complications with strokes and bleeding, which limits the efficacy of, of, of, of a, of ECMO. Although this is still, there's still a great deal of enthusiasm throughout the United States for using Ecol for S patients. We'll go to the next one. Ok. So this is so, so how today in the United States are we treating patients? A few centers are using ECMO, but primarily we're using vasopressors. If patients come into the emergency room, blood pressure, big anterior my blood pressure. 70. The first thing that the our physicians do is to start the patients on norepinephrine and that's appropriate and that's indicated. But the problem is that the more inotropes you use the worse the outcome. And, and I'll show you some data suggesting that inotropes, the more inotropes are actually harmful rather than helpful. And then on the right use a balloon pump. And so those two therapies are the mainstay of therapy besides angioplasty for, besides PC for opening up the target artery. And, and so there's really, we haven't had anything new that's shown any sign of being an improvement. And that's why I've been looking at, at, at Impala for the last few years. And, and you guys know all the range of catheters that the current new kid on the block is this Impala 55 is put in by a surgical cut down. Uh And as I go around the country, I've heard enormous amount of enthusiasm from the heart failure community and from the cardiac surgeons using this device. And it really appears to be a game changer and more to follow on that. But this is the whole family of catheters. I don't, I don't have the current RP flex on the right. We have the RP device in which is provides right sided support. So with this family of catheters, you can get left sided support or biventricular support. And I think that we can now mechanically support the patients in the vast of cases. So, so why, why could mechanistically why could impala be helpful? And these are the hemodynamics from the early shock experience. The cardiac index goes from 1.9 to 2.7. Arter pressure goes from 60 to 90. The SVR drops from 2000 to 1500 the wedge pressure drops. So these patients come in congested severely vasal cons poor per perfusion, poor blood pressure and all of it can be turned around with use of impala. So from a chemo dynamic standpoint, this provides a great deal of benefit. Well, how do we do? And and this is data that we got in the registry, all the patients treated with impala between 2007 and 2016 were put together and we had 16,000 patients that are treated around the country on card and shock. What we found was that the mortality was about 50% really no better than we're doing for the last 30 years. But what we found interesting is that there were differences in sites, some sites had a very low survival, some sites had a very high survival. And so we, we queried further to try to see what were the, what were the features that were associated with an improvement in survival. And so what, what we found was when we look at the survival of X plant, the things obviously age and gender is very important. But the one thing that that is, is critically important is use of the P A Catholic and using hemodynamics to drive to drive changes. If there's one thing that I would suggest that you hear about from me about K and shock. Well, two things, one is early impelling. The second thing is that you want to use a P A catheter and we'll go through why that might matter. So we put this algorithm and this is the National Car Shock Initiative. We initially in Detroit found that we had an excellent survival and, and then we took this nationwide Mike Hackle was on the phone actually was, was a huge driver of all this and helped us and go activate all these sites. So again, very briefly, just to go over the detail, there's three to the stool here to improve survival. First is that you have to identify the patients and get them treated early. So the door to the door to support is really crucial and not door to balloon is door to support, to get the patients on support and get them out of shock. The second thing is after the patients are supported on the right, you do the angioplasty and then you use the right hard cat to drive hemodynamics. If you go down this this treatment algorithm and you go over to the right. OK. So now we look at the CPO and Pappy, the CPO is normal, the Papy is normal, those patients can go to the go to the CC and actually are going to have a very good outcome on the left is where the problem is that and more than 30% of the patients are still in shock. So if you want to treat shock, you have to treat shock, you got to get the patients out of shock. And if you, if they go upstairs still in shock, then they're not going to do very well. And I'll show you that data. But so why are they still in shock? It could be a right sided problem, left sided problem or combined. And that's where we use the Pappy and, and we want to calculate those numbers. And I think you're all familiar with that. If the Pappy is low, certainly less than one, then they have severe RV shock. And you've got to support the right ventricle because if you don't support the right ventricle, no, no amount of left sided support is going to help you. And what I see on under appreciation is kind of an under recognition of patients with RV shock On on on the right side of that, if the, if the path is normal, so the right Ben is OK, but the left side is still poor, then you've got to upgrade and and mechanism. Methods of upgrading the support include the use of ECMO in the kind of configuration called Ella or the use of the 55 device of as pure left sided support. But you have to kind of come up and at Centa you guys have to kind of decide amongst yourself, OK. We treated the patient the impala in, they're still not doing well. What's the next step? Because if you don't do that, then they're not going to do very well. So why, why, why care about the right ventricle will 50% of the patients in the acute my shock have some component of right ventricle dysfunction in the shock trial and the shock registry. And you can see that these patients a minority have failure, but a very large number have RV dysfunction and what happens if they have RV, dysfunction is if you put an impala on the left side, remember the cardiac outputs from the right and left have to match. So if, if the, if the cardiac output, say for instance, was 2.0 on the left, then you get 2.0 on the right, then you put an appellant in on the left and now the, the cardiac output goes up to four, the right side can't keep up. And so then you start getting section alarms on the left side of the pell a catheter and it doesn't work very well. So we really have to pay attention to the right heart when we're providing left sided support. OK? So this is, this is how you can start doing that. So we took a look at this instruction alarms. So end diastolic sectional arms mean that an end dial, the ventricle doesn't have enough volume. So it's relatively hypovolemic. And in those patients, if they, if they continue with that, then the left side is not going to work. Well, remember the RP number will turn down so that you don't get, you don't get a very much suction. And then you'll see that the patient's forward flow really decreases and the left side really isn't working very well. And the answer to that is to either provide more fluid or to provide RV support. And what we found is that you can get dramatic 30 or 40% I'm sorry, 30 or 40 millimeter increase in blood pressure just by putting in the RV support device. So this is something that, that really is very important. And then the other, the other thing is that you can just with the patient on ECMO and ECMO does provide right sided bypass and it oxygenates and then sends oxygenated blood on the left side. So you can't significantly improve hemodynamics that way. And there's nothing wrong with that. It's just that it could cause a great deal of morbidity. And I don't think that the patient needs the oxygenator to provide right and left side. Most of these patients that are coming in with acute and my car shock do not have any problems with their lungs, they have problems with their heart. And so in a, in a sense, the oxygenation really is not necessary. And what happens is that if you just oxygenate without unloading, you do flood the lungs and then the patients do need oxygenation. And so we looked at this and this is data that now is ready for publication, the survival based on the duration of suction alarms. You can see that the more the suction alarms happen on the right, the worse the outcome and the lower the survival. So this is a very simple way of looking at it. And, and I would just urge that when you, when you, after you're done with the patient and they're kind of getting ready to go upstairs, Terry a while in the Cath lab, sort of just keep an eye on them to make sure that you're not getting a lot of suction alarms because if you are, then you have to take a look at the right side and, and, and, and believe me, it's just a lot easier to put it in an RP impala before they go upstairs than to have them come back down three or four hours later. So we did this in Detroit. And, and I think we've talked about this before. We did an initiative with all the hospitals in our institution, a region wide program with all the major institutions involved. And and this is Mike Hackler again, a shout out to him to Barbara Besir who was a CO P I with us. And that is, is, is, is the chief national promise with uh prominence with, with development of this and others in our organization. And again, very quickly the activation, our algorithm rapidly identify the patients. Get into the Cath lab femoral axis with sonic site, get a pigtail catheter if the, if the LVDP is elevated, uh then you can, the diagnosis is confirmed and you get the patient supported. And this is the group 400 patients around around the country. There were 48 there were 80 centers, 32 were academic and 48 were communities. So basically the 48 were hospitals just like Sana that were involved in treating these patients, you don't have to have like a huge transplant program to do this. You can, this can be done in any community hospital that has experience using impellent and these are the outcomes. So this is if you take a look at the patients in the patients that were in Sky Group C and D at 77% survival when we include the E which is including all the patients, including those that had cardiac arrest, a 68% 1 month survival. So they've done very well. And this is in comparison to the other trials. The original trial is on the bottom. So 44% survival without reperfusion, a 52% survival. And that's what's given the, the one B indication for an plus is this this delta of eight points at 30 days survival? And you can see how much better we're doing with similar kind of patients in the NC SI. And so then the other big thing that's come recently is, is one of the problems with, with looking at registry is that kind of a lot of it does depend on patients selection. If you're not treating a lot of sick patients, you're going to have a very good outcome. And everybody knows that the cardiac surgeons know that all the time whenever their mortality starts to creep up, they start really decreasing and clamping down on who they're operating on. And so what we wanted to have is sort of an apples to apples comparison. And this has been allowed by the, by the sky shot shot classification. And it's really a great, a great tool. We looked at that in NC SI and you can see that 60% of the patients were in class C but 30% were actually in class C. So this is, these are patients in extremists and in the middle, you can see that survival was great at it C and D and it wasn't as good but still almost 60% survival for patients in extremists. And I think that that's really wonderful and it shows that even with the sickest of the sick patients, we're getting very good outcomes. And so now this is data comparing other publications and you can see that we don't have any in class A. So I see if you have class A patients that are going to do very well in other publications. Uh in, in class B, you can see that we don't have any. So this is all kind of presho so classic shock class C. Uh our survival compared to the other publications. And you can see that even in class e our survival is much better than other publications that have used balloon pump or other techniques. So I think actually the the sicker, the patients are the more likely the grading of benefit. Uh If, if we put an impala in, in a patient in a in presho, it would be very hard to show a difference. But if the patients that are in extremist, that's really where the outcome is going to be improved. And so now just very quickly switching topics, I just want to kind of go over the the the inotrope story. So, so this is now from NC SI, we looked at the number of inotropes in the mortality and if the patients that leave the Cath lab with two or more inotropes, they've got a 60% mortality. And so what we really want to try to do is want to try to decrease the need for those inotropes by providing a mechanical support versus Ph logic support. If the patients are not on any vaso presses and 80% survival leaving the Cath lab. So this is really kind of where we want to get, where we're getting the patients towards barber. And, and our group is doing a study called the Ceramics trial where we have five centers that are really actively escalating to try to get the patients off of inotropes as soon as possible. And we'll have to demonstrate that, that, that, that, that, that does improve outcomes. And I think we're going to have a really story with that. So what we wanted to take a, take a look at on the left is the Finke CPO mortality, the classic mortality curve. And if you take a look at that curve, the inflection point kind of is at about 0.6. And that's why we've chosen as a definition for refractory shock. On the right now, we take in all of the NC SI patients and we divided those patients, basically those that have, have no vasopressors on the bottom and then 12 and three vasal presses. So take a look at the lower slide at the lower, at the lower curve. If you go to a 0.6 the patients are no vasal pressors have 90% survival. If they're on one vasal pressor, the survival dramatically decreases, mortality increases and then two or more. So, so this curve now what this does is it really kind of takes into account the amount of myocardial jeopardy that has occurred and the ventricle is not doing very well and you add more and more vasopressor, the mortality skyrockets. And so that's really the whole concept of trying to provide an escalation strategy. You can leave the patients on rocket fuel when they leave the Cath lab and their blood pressure, you know, 83 pressors, but they're not going to do very well because they're going to have persistent shock and profound gut ischemia, uh neurologic dysfunction and then peripheral ischemia, lactic acidosis. And is that lethal spiral that happens? So that's really the reason for trying to get the patients out of shock very early. So these are no outcome data based on the data that we have at 12 to 24 hours and also on lactate. So you get a story developing after about 12 hours. What is the trajectory of that patient early on if the trajectory is good, meaning that the cardiac power output is elevated and the lactates are washed out, those patients are going to do great. They have a 90% survival on the other side. If the patients have a low CPO and lactates remain persistently elevated, they're going to have a 70% mortality. And so this kind of helps us and the other two are kind of in the middle, but you can kind of figure out and what we suggest doing is rounding with the team at 12 to 24 hours and see how the patients are doing. If the patient's blood pressure is stable and their lactates are coming down and their CPO is ok, then they're going to do very well and you'll probably be able to wean those patients within a day or two. Conversely, if the patients are doing poorly, low urine output, high lactates need for pressors and a low CPO, then you have to decide whether or not those patients are survivable and you can do that right then at 12 to 24 hours. But don't wait until the patients are in refractory, acute renal failure and liver failure and all of that because the battle is done by then, if you're going to intervene in those patients, it should be done relatively early and then you have to kind of decide. All right, what is the, not only the on ramp but what is the off ramp if the patient is 90 years old? You know, maybe a little bit of neuro dysfunction, maybe a little bit of dementia. You're probably not gonna want to do anything more than that. Conversely, if the patient is 50 they're not doing well, those patients are absolutely viable and those are the patients that, that need to be escalated. Uh at your hospital at cent I think you guys are probably the regional referral center. So you, you're gonna be getting those calls from the other hospital, got the patient treated the blood pressures, et cetera. And then those, those really need to be transferred. But you can't just sort of watch them, you have to do something more active if they're going to have an improvement in survival. And then how, how much are the, are the inotropes. And so if you take a look in the patients that have a CPO greater than 0.8 they do extremely well with no inotropes and then there's a gradient and the more inotropes there are the worse their outcome. But more most importantly in the upper line, if the CPO is less than 0.6 and they have one inotrope versus two or more, you can see how dramatically the mortality increases. And so, so really the, the answer is if the CPO is still less than 0.6 problem solve and find out why it is is if a pure left sided support, they need left sided escalation. If it's combo, then maybe in an RP device to try to provide more rights sided support. But you can't leave the patients in this state because they will dwindle. They may not die right away. But they're going, you know, we all have seen this for years when the patients then have urine output, drops, their blood pressure stabilizes but continues to be low. And then you get all the complications with sepsis and ss and all the other things that ultimately cause the patients to die, but they die not right away, they linger and die over a long period of time. And that's why I think that really kind of making rapid decisions after you do the Gila in a 12 to 24 hours is really going to help you dictate how well these patients are going to do. So I just want to show you where we are with all of this. So on the left, you can see that the survival with only medical therapy is 17% in acute of my shock. And then in 1985 when we published our first data, we got the survival up to 50% and it's remained 50% for four decades. And even recently with the ECMO trial has been 50%. Conversely in the, in the in the Q I registry. So there's three large registers now that have been done. The NC SI has been done in Nova and Fairfax has got an excellent outcome with the same protocol. And then the entire country of Japan has, has gone from using ECMO to using Impala for shock. And in one year, they changed their survival from 30% to 77%. So this is now being replicated if and when the current guidelines get changed for shock, the current use using impelled mechanical circulatory support should have a two a indication. So we have, we're collecting a very robust series of patients. And I can say that today, currently, if you, if you're not in a trial, then this would be a very effective method of treating the patients, which will show you a significant improvement in survival over a very short period of time. And then I just want to conclude that that in my experience with 40 years of trials, uh people don't really change their treatments very much. They find all sorts of different excuses not to change because they don't want to because they don't believe the data et cetera until randomized trials are being done. So, in April at the American Heart, at the American College of Cardiology, the danger trial is going to be presented as a late breaking clinical trial from Denmark and Germany. 360 patients that were randomized to use of impala or control. And we're going to, this is going to be really the first large well done randomized trial of impella. And we're all anxiously kind of on pins and needles and waiting for the outcome. And I don't know the results yet either, but that's going to have an enormous impact, but we still need to do a second trial regardless of what that trial shows. And this is the recover for trial and this is now the therapy that, that we're randomizing. So basically, on the left side is the impala arm and we talk with you about what that would be and then the right side is control and, and, and it's going to take a lot of doctors sort of the courage to be able to participate in the trial because you're kind of worried about the control group. Now, the control group can be treated with whatever non impala support you want. So you can put them on, you can put them on a blue pump, you can put them on VSO presses, but you can't put them in impala. And this is honestly the only way that we're ever going to scientifically prove that impala not only works, but it should be the preferred therapy and it will drive the process. Well, you say, well, how are you ever going to do that across the country? I heard that in 1990 when we were doing primary PCI, the number one reason that people didn't think it would work was because well, you can't do it in small community hospitals and away from the major centers and you're going to bankrupt the system, et cetera, et cetera. Americans. American physicians. American cardiology are wonderful at taking these advances and really figuring out in, in the way with American ingenuity of how to, how to do this. And I can envision hub and smoke programs. You guys will be the hub of your smaller hospitals and then the my patients have come in there or you have to figure out transfer protocols, but we will get the job done and we will improve the survival. Right now. In the United States, there's probably about 80,000 patients a year that are presenting to hospitals with A Q to my shock and a 50% mortality. So that's, that's, that's, that's 40,000 patients a year, which almost is almost as many as dying in accidents. So I think that there still is a massive problem. I'm really looking forward to working with you folks with whatever mechanism you want to use, whether you want to stay in, whether you want to participate in an active register or want to participate and recover for. And we certainly love, I love working with you guys and I'm so thrilled to talk with you this morning. Thank you so much.
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