Cytosorbents Corporation (CTSO) Earnings Call Transcript & Summary

Good morning, and welcome to the Cytosorbents Virtual KOL and Analyst Investor Day. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Cytosorbents website following the conclusion of the event. I'd now like to turn the call over to Dr. Deliargyris, Chief Medical Officer of Cytosorbents. Please go ahead.

Welcome, everyone, to the Cytosorbents Virtual Key Opinion Leader and Analyst Investor Day. Good morning to those participating in the Americas, and good afternoon and good evening to our international participants. My name is Efthymios Deliargyris, I'm the Chief Medical Officer of Cytosorbents and I will also be the moderator for today's event. Approximately 4 years ago, we held a similar event to introduce you to the application of antithrombotic removal and to show you how this novel therapeutic intervention can be made possible by our unique polymer B technology. We also reviewed at the time the rationale as to why this application was the right one to lead our efforts in opening the North American markets. Well, a lot has happened since then, including completion of our pivotal trial, and today is a perfect opportunity to bring you up to date on all the great progress that we have made. We are privileged to be joined today by an esteemed faculty panel, including the three STAR-T principal investigators, Doctors Michael Mack, Mike Gibson and Richard Whitlock and also by Professor Michael Schmoeckel, who is a true pioneer in the field of antithrombotic removal and also serves as the principal investigator of the International STAR Registry. Let's now review the agenda for today's call. Leading off is Dr. Gibson, who will discuss how the antithrombotic landscape is evolving and how both the unmet medical need, but also the need for innovation is greater today than ever before. Unfortunately, Dr. Gibson is not able to join us live today, but was kind enough to record his presentations. Any questions relating to this presentation will be covered by the rest of the panel. Next will be Dr. Michael Mack, who will be reviewing the top line results of the pivotal STAR-T trial that were presented approximately a week ago at the 104th Annual American Association of Thoracic Surgery Meeting in Toronto, Canada. I suspect that for our callers who were not present in Toronto, there is a lot of excitement to learn about this data. Following the first 2 presentations, there will be a 10- to 15-minute Q&A session. Please enter questions to your chat room. The third lecture will be by Dr. Richard Whitlock, who will review the key issues faced by cardiac surgeons today when managing patients on antithrombotic, the serious consequences of severe bleeding after surgery, and who will also discuss the Canadian experience in the STAR-T trial. Our final lecture will be given by Professor Schmoeckel, who will review how antithrombotic removal is changing European practice in cardiac surgery. Also the growing evidence base that supports its use and will provide an update on the great progress of the International STAR Registry. Following the completion of these lectures, I will then take a few minutes to review our plans going forward by outlining both the regulatory strategy and the associated time lines. The event will conclude with another 10- to 15-minute Q&A session. However, prior to turning it over to Dr. Gibson, let's review the regulatory status of the technology that will be discussed today. First, for DrugSorb ATR, this is an investigational device. That means that it's limited in the U.S. by federal law to investigational use only. This investigational device has not been evaluated by the FDA, Health Canada or by any other global regulatory agency. This investigational device is not yet cleared or approved by FDA, Health Canada or by any other global regulatory agency, and it is not commercially available for sale. The proposed indication for its use is to reduce the severity of perioperative bleeding in patients under coronary artery bypass grafting within 2 days of ticagrelor discontinuation. In relation to CytoSorb, please note that it is a CE Mark approved in Europe for the following approved indications: Cytokine removal, bilirubin and myoglobin removal and also ticagrelor and rivaroxaban removal during cardiothoracic surgery. CytoSorb is not yet cleared or approved by the FDA or Health Canada. Thank you for participating, and welcome once again. Now let's listen to the first lecture by Dr. Michael Gibson.

Hi, I'm Mike Gibson, an interventional cardiologist, medical trialist and Professor of Medicine here at Harvard Medical School. Thanks for having me join today. I think the honor of being involved in the development of numerous anticoagulants and antiplatelets over the past 40 years, we've built better and better drugs over time. Think of it as successive cars. We've gone from Fords to BMWs to Ferraris. They're better and better and they're faster and faster. But everyone always wants to know is, how do you put the breaks on when anticoagulation or antiplatelet therapy goes a ride? So we're here to talk about today is putting the brakes on, well, we need to put the brakes on when antiplatelets and antithrombotic are in there and lead to delays in care. My disclosures are shown here. I do have research grant support from Cytosorbents, the sponsor of today's call. Well, this is the anticoagulation and antiplatelet pathways, very complicated, lots of arrows here. Drug companies have targeted all these different arrows with drugs to prevent clotting and then they've targeted these different arrows to begin reverse that risk. We have risk when people come in to the hospital and need surgery, and we may need to prevent bleeding as well as reverse bleeding. There are a lot of patients out there nowadays on antiplatelets and anticoagulants. Back in 2019, it was estimated that about 6 million people are on anticoagulants, and about 4 million were on antiplatelets. Now that gets rid of aspirin use. The number is much higher, probably double that if you include aspirin use. That number is probably much higher now, and it's expected to be closer to 12 million by 2030. It just keeps going up because our population is aging. And as the population ages, they have more and more of the diseases that we're treating. Things like acute coronary syndromes. Things like stable disease in their coronaries, their carotids, their peripheral vessels. After you put a stent in, you're going to need to be on one of these drugs. And after bypass surgery, you're on these drugs. Atrial fibrillation, a regular beating of the heart is going up as the population ages and they're on anticoagulants as well. More strokes out there as the population ages. They're on antiplatelets or anticoagulants. And finally, we have more and more patients in the hospital, and we're going to need to prevent and treat deep vein thrombosis or clotting in the legs. Now the good news is we have better therapies. The bad news is as we introduce more and more of these therapies, there's a greater and greater risk in the population as a whole for bleeding or a need to stop bleeding or prevent bleeding in surgery. While over on the left-hand side, you see some of the numbers we've been talking about, the antiplatelet numbers have been stable at about 10 million patients on antiplatelets. About half of those are on aspirin. On the right-hand side, you see how the field is changing with respect to which of the super aspirins or thienopyridines people are on. What is happening is ticagrelor in blue continues to gain market share. It's up to 60% now. Some of the other drugs in this class, like clopidrogrel and prasugrel are going down. Some of this is because clopidrogrel has resistance. As many of you know, ticagrelor does not and you see that this is before ticagrelor comes off patent. And once it does later this year, I expect those numbers to grow. So expanding use of thienopyridines, there's more and more data out there comparing aspirin monotherapy to ticagrelor monotherapy showing that ticagrelor monotherapy is probably superior to aspirin monotherapy. So I think you're going to see a reduction in aspirin use in the future because it causes GI bleeding and a continued growth in, say, ticagrelor therapy over time. That's the antiplatelet side. This is the anticoagulant side. And what you see is that warfarin use is going down over time and it's being replaced more and more by the novel oral anticoagulants like rivaroxaban and apixaban. When you look over on the right-hand graph, you see that there is expanded use of anticoagulants. The whole market itself is expanding when you lump together warfarin plus the DOACs. So antiplatelet therapy kind of constant, a lot of people on it, anticoagulant market growing, largely driven by apixaban and rivaroxaban. The good news is we have better thrombotic outcomes. The bad news is we have more and more patients on these drugs who are at risk of bleeding or who do bleed. The 2 big issues are sometimes someone comes in on these drugs, and we're worried that they're going to go to surgery or have an intervention while on the drugs, and that may cause bleeding. And that gives us a lot of hesitation, as you'll see. The other problem, which is less frequent is that they come into the hospital bleeding, and we've got to reverse that bleeding. Bleeding is not just painful for patients and frightening to them. What it does is it also causes them, in many cases, to back off on the medicines that they're on. They say, well, I don't know whether it was the blue pill, the yellow pill or the red pill, something is causing me to bleed, I'm going to stop all those different pills to prevent bleeding. And what it does is it costs them to fall off the pathway of evidence-based medicine. So aside from just the bleeding complication itself, there's also a withdrawal of a lot of good evidence-based therapies when you bleed. Now aside from overt bleeding, we also have the problem of people coming in, for example, with a broken hip and they're on an anticoagulant and the surgeon is scared to operate and rightfully so because they're worried about bleeding complications. So they delay care. And those delays in care, as we're going to see, can be very, very costly. So our unmet need is this, we need to reduce the high cost associated with bleeding, we'll look at some of those, and we also need to make care more efficient. Hospitals are at 100% capacity. We need to keep people out of the hospital to make room for other patients. So we really need to improve the efficacy or efficiency of our hospital care. Last time we were together, I showed this slide and it showed that as the use of anticoagulants goes up, the number of adverse drug effects related to anticoagulants has gone up tremendously. Likewise, for antiplatelets. You can see over the years, those numbers have climbed as well. When you put together anticoagulants and antiplatelets, they account for the most adverse drug effects that cause someone come to the emergency room. Well, let's fast forward now to 2016 to 2020. As the use of these drugs goes up, the number of ED visits in patients on these drugs go up. Here you can see the numbers in red going up to almost 200,000 ED visits in people on anticoagulants at this point and about 100,000 of those or about half of them will be hospitalized. So they're in the hospital and they may need surgery or intervention where they're bleeding and this is a big, big management issue for us clinicians. Let's look at one kind of bleeding in particular, that's bypass surgery bleeding. I'm an interventional cardiologist, and I'm highly focused on this as a clinician. Here is the usual rate of bleeding when someone has probably most often an elective surgery. You see most of the surgeries are coronary artery bypass grafting surgeries, about half or more than half of them, and the risk of bleeding with bypass surgery is about a 5% risk of major bleeding or a rate of reoperation for bleeding or one out of 300 patients. Now that's the uncomplicated elective case. What happens when you throw antiplatelets and antithrombotics into the mix? And this is current data that comes from an E-CABG registry, being on Brilinta or clopidogrel triples the risk of bleeding. And what you see over on the right-hand side is that the risk of bleeding is time dependent. So if you go to the OR within the first 2 days after having adjusted one of these 2 drugs, you have about a 15% or greater risk of bleeding. So that is very high, and it gives the surgeons a lot of, lot of hesitancy to take someone to the OR if they have taken clopidogrel or ticagrelor within the past 2 days. And this is a conversation I have all the time with my surgeon friends, when we have a sick patient, and I want them to take them to the OR urgently. They cite this data and they cite their concern about bleeding. Well, this is a snapshot of my life as an interventional cardiologist. People come in. They're having a heart attack or an acute coronary syndrome. Bring them to the cath lab and then we find a problem that needs to be fixed, not by me putting a stent in, but needs to be fixed by the bypass surgery and the tension is always this. They have an acute problem that needs to be treated acutely, and on the other hand, they're now on an antiplatelet or an anticoagulant, and the surgical team is hesitant, and rightly so, because of the risk of bleeding. So this is a tension. There's an acute problem that needs acute treatment, but there is an acute risk, an acute risk of bleeding. And what we need is a strategy that can get them to the OR quicker to minimize that risk of acute thrombotic complications but at the same time allow us to do it safely. Let me tell you about a case I saw recently. A gentleman came in, he was touching his chest, having chest pain, came into our emergency room, was seen, was diagnosed as having a heart attack. As usual, got put on aspirin and ticagrelor in the emergency room immediately, was brought upstairs to the cath lab where I did a cath. The person was found to have a totally blocked right coronary artery and a severe blockage over on the other side of the heart of the left main artery that supplies most of the blood flow to the heart. Now ordinarily, we would do what you see on the right-hand side of the screen here, we would put a stent in, but given the extent of disease in this patient, we called our surgical colleagues to come, evaluate the patient. This happens in 5% to 10% of our cases. But in this case, it was really an urgency. Now what would have been optimal would be to stent the patient. But again, they needed bypass surgery. Our surgeons are very concerned about bleeding and frequently, what we have to do is we have to take a detour. We have to send that patient to an area of the hospital where they can let the drug wash out over the next 4 or 5 days whether it's ticagrelor or clopidogrel. They sit in the hospital bed for 4 or 5 days waiting for the ticagrelor or clopidogrel to washout. Then we bring them over to the operating room where the bypass surgery can be done with less bleeding at that time. So we need innovation. We need innovation because in many of these patients we don't have the luxury of waiting. Time is muscle. In this case, it was a heart attack and the patient really needed to go to the operating room sooner than later. That's why we need innovation. The innovation we need is shown here, which is antithrombotic removal strategies. Now let me talk to you about the focus of today's discussion, and that's polymer bead hemoadsorption. The technology consists of a cartridge filled with these biocompatible polymer beads that have a very, very large surface area. The beads are small, but they have a very large surface area. And they are put into the bypass circuit itself. These beads adsorb to molecules that are under 60 kilodaltons and adsorb drugs like the antiplatelets and the antithrombins, in particular, ticagrelor. Now, the beads have a CE Mark for approval for removal of cytokines, myoglobin, bilirubin, ticagrelor and rivaroxaban. The beads are also emergency authorized for COVID-19 for cytokine removal in both the U.S. and Canada. There had been 230,000 treatments to date without any unanticipated adverse device effects. Well, let's talk about the p-value. There's the p-value that applies to the statistics in the trial. The most important p-value is the patient value. Really, I think patients want the safest route possible that minimizes their pain and suffering. There's also the p-value for the payer, and that is very important in 2024. What we looked at in the STAR-T trial that you'll hear from Dr. Mack about was we looked at big drivers of cost. Two of those big drivers are transfusion and probably one of the bigger ones is ICU length of stay. Now as you'll note, we looked at bleeding very, very carefully in this trial. The greater the bleeding, in particular, the greater the severe bleeding, the greater the need and volume of transfusions, which can be costly. Also, you'll see that the greater the bleeding, the greater the ICU length of stay. Now you'll see we broke it down into hours here because the ICU isn't like a hotel room. We don't say, tomorrow morning at 11, you're going to be discharged. We try and get people out of the ICU as quick as possible because it is a big, big driver of cost. It's also kind of a bad place to be in because there's a lot of sick people in there, a lot of competing needs and we try and get people out of the ICU as quickly as possible, big driver of cost. Now one of the endpoints you'll see today is chest tube drainage, chest tube drainage. The greater the chest tube drainage, the greater the length of stay, again, a potential major driver of costs. We also did a survey in STAR-T to see how long were people waiting and where were they waiting during that washout period. In the U.S., they're waiting about 4 days for washout. In Canada, waiting 3.7 days for washout. Where were they waiting? They were waiting in some pretty costly areas like in the ICU or the step-down unit, which is a transitional care unit, but with a lot of labor-intensive care. And over on the right-hand side, you see that if you implemented the STAR-T strategy, there was a cost savings of about $8,800 in the U.S., about $6,300 in Canada. And if you just look at the daily implementation of the strategy, $3,700 of cost saving in the U.S. and $3,000 of cost savings in Canada. Well, it's been really invigorating over the past 40 years to be involved in the development of more and more potent antithrombins and antiplatelets. That's the good news. The bad news is sometimes we need to put the brakes on. And this is a big problem for me as a clinician. We have to balance the need for getting someone to the OR for intervention quickly with the risk of bleeding. This is a dilemma I face multiple times a week. I'm so excited to be involved in a trial where we're evaluating a technology that may allow us to bridge this gap. And now, I'm going to turn things over to the other investigators to talk about the results of the STAR-T trial, particularly Dr. Michael Mack. Thanks for allowing me to speak today.

Well, just as a reminder, Dr. Gibson is not live with us today. So any questions related to his presentation the panel will try to address during the Q&A. But next is Dr. Mack discussing the STAR-T trial pivotal trial top line results. Dr. Mack?

Thank you, Dr. Mike Gibson. And I think that you heard very well from Dr. Gibson, the clinical conundrum that we face not rarely but frequently and maybe not on a daily basis, but at least weekly in terms of caring for patients who have recently been admitted with a heart attack. So the trial we conducted was the STAR-T trial, which is a pivotal randomized sham-controlled trial examining the safety and efficacy of intraoperative removal of ticagrelor in patients undergoing urgent cardiac surgery. This is my conflict of interest disclosure. I have been in the leadership of a number of trials involving cardiac surgery. So by background, as you've heard from Dr. Gibson, ticagrelor is a potent P2Y12 inhibitor, which is used as first-line therapy in the management of patients who are admitted with a heart attack and are potential candidates for stents. There was a trial called the PLATO trial that showed that patients undergoing a heart attack on ticagrelor and required bypass surgery have a high risk of severe bleeding complications if operated within the first 3 days after the dose. And because of the results of this trial, the guidelines that we all follow in clinical practice recommend that we wait 3 days before proceeding with surgery so that the drug can be washed out naturally by the body's own systems. However, this 3-day benign period -- this 3-day period is not benign because there are complications associated with just waiting on an unstable patient. And until now, there are no available solutions that allow more timely surgery without excessive bleeding occurring. So you heard about the DrugSorb ATR bead technology from Dr. Gibson and it can remove ticagrelor, and early evidence specifically from Europe that you're going to hear subsequently suggests that reduced perioperative bleeding with intraoperative use occurs before the 3-day washout. Now the FDA recognized the unmet need here and granted breakthrough device designation for this and that resulted in the STAR-T trial as you're going to hear the results from now. So again, this is the device. I'm not going to go through again what Dr. Gibson did about how it works. But what you see on the lower right is the diagram of how this is set up into the circuit of the heart-lung machine, which is used in all of these operations. It's important to note that this is one of the few sham-controlled trials that I've had the opportunity to participate in. And what that means is this device that you see on the right, the DrugSorb device, is either an active device or a sham controlled. So nobody in the operating room, including surgeon, perfusionist, anesthesiologists knew whether the patient was actually getting the device treatment or a fake or dummy one, nor did anybody recording the results after surgery know whether the patient had received the active device or not. So truly an objective evidence-based trial. Now there's a couple of ways that we define bleeding after surgery. The first is the universal definition of perioperative bleeding, or UDPB, and there's 5 criteria, as you can see, on the left side of this slide. 0 is no bleeding, 1 is mild, 2 is moderate, 3 is severe and 4 is massive. And these categories are based on 2 separate factors. One is the amount of chest tube drainage, and chest tube drainage means how much blood comes out of a chest tube that we placed around the heart during time of surgery. Some amount of bleeding is expected. However, the more bleeding you have, the more it's associated with complications. As you can see on the right side of the slide here, it goes from 0 to 500 cc of blood in 24 hours on the left to over 2 liters of blood on the right. Now another component of this definition is the blood products that are -- that the patient actually receives or transfusions and there's a number of different components of transfusions as you can see listed on the slide. For purposes of this trial, we're going to focus on UDPB 2 which is moderate bleeding and level 3, which is severe or massive bleeding. And those were part of the endpoints that we used for the trial. So this is the design of the trial. The objectives were to evaluate the safety and the intraoperative use and then evaluate the efficacy in terms of reducing postoperative bleeding. There are 140 patients randomized it was -- the total trial duration was 30 days. The safety endpoint was adverse event rates assessed by an independent data and safety monitoring board and there were 2 efficacy endpoints, the primary one was a composite of fatal bleeding, moderate to severe bleeding and 24-hour chest tube drainage. Composite number two was any fatal bleeding, severe bleeding only and 24-hour chest tube drainage. And we used a statistical method called the hierarchical win ratio of these 3 components. So there were a number of prespecified populations. The results for safety and efficacy were analyzed in 3 study populations. The safety population was all patients who actually received the device which was 132 patients out of the 140 patients. Efficacy was analyzed in 2 populations. One is overall population of patients that received all surgery inclusive of protocol deviations, which was 132 patients. And the second was patients who underwent isolated CABG without protocol deviations, which represented about 92% of the patients in the whole study. This is the baseline characteristics between patients that received the device and those that receive the sham-control, and there is no difference in any of the parameters on this slide. Now as I mentioned, about 92% of the patients were isolated CABG. And there are a number of other surgeries that were included. Now we did not know at the beginning of this trial, what the exact composition of this was going to be and what patients would be randomized. And as I said, it turned out that 92% were CABG. But there were a number of other operations performed including aortic valve replacement, aortic route replacement and more complex surgeries. And as you can see by the P-values highlighted on the right side here, all were associated with greater duration of surgery, greater duration on the heart-lung machine, higher risk ahead of time. And all of this is important because of these sicker patients that had more bleeding I think partially obscured an efficacy signal here. So this is the safety results. This was determined by the Data Safety Monitoring Board, which reviewed all patients that were enrolled at predefined intervals of 40 patients, 80 patients and the complete 140 patients and found that there were no safety concerns present and that the study met its primary end point. There, you can see on the bottom left, the adverse events in the population and there was no difference between drug and control, and these are typical adverse events that we see after cardiac surgery. There were three deaths in the population in the study. As are shown in the graph on the lower right. One patient died -- underwent CABG and died at 5 days afterwards, and that was a patient that was randomized to the controlled device. A second patient underwent did a complicated aortic route, and the aortic valve replacement did receive the device but dies of complications on day 17. This was adjudicated as a cardiac death, but not device-related. And the third one was a patient that underwent coronary bypass and double valve replacement and did not receive either device. This is the prespecified efficacy endpoint analyzed by the win ratio. And on the top is the overall population and the first composite is moderate -- includes moderate to severe bleeding and there was no difference between treatment group and control group nor was there any difference in terms of severe bleeding with a win ratio that was not statistically significant. However, if we look at the isolated CABG per protocol population for patients that had moderate or severe bleeding the win ratio was 1.33, which again is not statistically significant. But if we look at only those patients that had severe bleeding, there was a statistically significant win ratio of 1.59, and we'll go into this in some detail as we look at this isolated population. So this is the hierarchical win ratio, which looks at every patient and pairs them with every other patient in the trial, resulting in 3,060 payers. And the most important complication, of course, is death or fatal bleeding. And there was no incidence of this in either population. The next most important in the hierarchy is UDPB 3 bleeding, and that was in favor of DrugSorb, which won 14% of the time versus only 5% of the time in the control group. And then if we look at the amount of blood coming out of chest tube over the first 24 hours, again, that was favorable for the device compared to the control of 46.9% versus 33.5%. So it ended up in 61% of wins for the device and 38.5% of the control, which ends up at a win ratio of 1.59, which is statistically significant. Now if we look at these specific events and look at the component of those in the CABG population, you can see that there were 6 -- UDPB 2 or greater, there is about an equal number in both. If you want to, UDPB 3, there were 15% of events in control and -- I'm sorry, 9 events in the control and 3 in the DrugSorb. If we look down at the bottom left of the components of severe bleeding. There were 4 patients in the control that had excessive bleeding in the first 12 hours. 4 compared to 2 that underwent reoperation for bleeding and 1 patient that had to have their chest left open control group because of excessive bleeding. If we look at moderate bleeding, there was no real difference between the 2, except there was less -- 1 patient less bleeding in the device group and 7 patients received no blood transfusion, but still were characterized as moderate bleeding. If we look at the transfusions per se, so packed red blood cells is basically concentrated blood, and that was down 51% with device compared to control. The platelets, which help prevent bleeding or that use was down 24%. Fresh frozen plasma and cryoprecipitate, which are other factors in the blood that help prevent bleeding was down 70% and 55%. So that overall, there was a 50% reduction of blood usage with the device compared to control. There is also -- so -- and this was statistically significant at a P-value of 0.25. If we look at a sensitivity analysis, there are actually some patients that received blood transfusions, but had no or minimal evidence of bleeding by their chest tube, yet they met the standard definition. So the 3 principal investigators underwent a blinding review of these patients and found out -- and found that there were 9 patients that actually by the classification had leading events, but we couldn't find any evidence of bleeding. If we then look at this population, you can see that the win ratios for both moderate to severe and severe bleeding were statistically significant. If we look at just 24-hour chest tube drainage alone, you can see that, again, there is a benefit in favor of the DrugSorb device with a low amount of bleeding, less than 800 of being 75% of patients receiving the device versus 53% with the control, which is statistically significant. And on the right side here, if we look at the highest quartile of bleeding, again, there were much fewer patients in the drug group -- DrugSorb group compared to the control. Looking at it one other way as what's categorized as major bleeding. We found that there was a 73% decrease in the number of patients undergoing severe bleeding events with an absolute risk reduction of -- from 22% to 16%. So the number of patients needed to be treated to prevent a major bleeding event was 6.3 patients. So I know that this is a lot of data because we analyze this in many different ways. But we concluded from all this that the primary safety endpoint was met. The primary efficacy endpoint was not met in the all-comer population. The severe bleeding efficacy endpoint, which was prespecified, was that in the isolated CABG population, which represented about 92% of the patients in this isolated CABG population, the use of the device was associated with reduced bleeding severity by either grade or chest tube volume. The number of patients needed to be treated was 6 to prevent a major bleeding event and there is an overall favorable benefit risk profile. So on the basis of these trial results, the sponsor is planning a regulatory submission to the FDA under the breakthrough device designation and to Health Canada for the use of the DrugSorb ATR in patients undergoing isolated CABG within 2 days of ticagrelor discontinuation. And this is the study leadership and oversight of the trial top sites. As Makis mentioned, myself, Dr. Gibson and Dr. Whitlock, we're the co-principal investigators of the trial, a number of luminaries in cardiology, blood experts and surgery comprised the executive committee. You can see the Data Safety Monitoring Board and Clinical Events Committee and then the top enrolling sites was London Health Sciences Center in Canada. Maryland, New York University in the United States, and you can see the rest of them there. And with that, I will stop the presentation and turn it over to Makis for question and answers.

Thank you, Dr. Mack. And actually, I'm going to turn it over to Tara. Tara, do we have any questions coming in?

Yes, we do. So please hold for a brief moment. So we're going to begin the Q&A session with some verbal questions from research analysts, and then I'll turn it back over to you, Dr. Deliargyris for any written questions. So the first question comes from Brandon Carney at B. Riley. Brandon.

Yes, Tara we're not getting a question in. Is there anyone else waiting for a question?

Yes. So we'll just go to the next analyst, Sean Lee at H.C. Wainwright.

This is Sean. So my first question is on the differences that we see between the high CABG Group plant as well versus the other surgeries group. So what do you think explains the discrepancies we see in the leading results between the two patient populations?

So perhaps I can take this first and then have Richard a weigh in here. I think that there was so much bleeding that occurred in the higher risk, more complicated population that it obscured any benefit that may have been seen when you look at just the isolated CABG only. I think that, that -- there's too much background noise associated with these higher risk patients to detect the signal benefit in the overall population Richard?

Yes, I agree, Michael. So bleeding in other cardiac surgery, the non-cardiac surgery is quite complex. So you have surgeries like aortic surgery, aortic dissections, where you have prolonged cardiopulmonary bypass time, you often will lower the patient's temperature in order to safely perform surgery on vessels going to the head and other parts of the body that really is a heterogeneous population with multifactorial cause of bleeding, whereas the CABG patients, which is the predominant population that the drug ticagrelor is used in it's either you have a surgical problem that is rapidly fixed, or you have some type of inhibitor specifically a drug that's causing bleeding. And I think that's why it's a more homogenous group. There's -- it's less multifactorial and really, I think, focusing on that the CABG population really focuses on the cause of bleeding in this case, which was predominantly drug.

Great. My last question is on the clinical benefit of what we see in these results. So based on what I -- maybe correct me if I'm wrong, but based on what I'm seeing is DrugSorb ATR seems to have the most effect on the severe bleeding patients. So for these patients, how much of an clinical relevance is there for -- to improve them from severe to moderate bleeding, for example?

I think there's two answers to that. One is the less bleeding and the less transfusion you have, there's benefit to it. It's a continuum. It isn't an off-on switch. Or a dichotomist variable. It's suffice it to say the less bleeding you have, the better. But I think the biggest clinical benefit here will be in not -- and clinicians feeling comfortable not having to wait 3 days in the hospital and being able to know that if they have this device, they can feel more comfortable moving ahead earlier and not delaying the patient, taking up beds, taking the risk of complications happen by waiting. Richard, your thoughts?

Yes. I share those 2 same thoughts. But I would even say there's a third component here. There's a patient-centered and I will show in the slides coming up that as Michael said, this is not a binary thing. This is somewhat almost a linear relationship between bleeding and bad outcomes and bleeding by any definition. Secondly, health care resource focused blood is a limited resource. the less we use, the better because we have a limited number of donors and this is not just red blood cells, but this is plasma. These are -- so -- if we can shift people from severe to moderate or to mild, it's great for the health care systems. And lastly, as Michael alluded to, is not only getting the patients to the operating room sooner, but also once that patient has a bleeding event, it tends to cause a longer length of state post-op of. Now this STAR-T was not powered to look at this. That is also a very complex variable that is fairly difficult to study. But I can assure you, when I have patients who bleed excessively, they have increased rates of atrial fibrillation. They have increased length of ICU stay, hospital stay respiratory complications, so again, they occupy health care resource, hospital resource for longer.

Tara looks like Brandon is ready to ask his question.

Yes. Brandon, you may now mute your line.

And sorry about that. Can I just ask about the -- it looks like there was 10 I-CABG patients that were not included in the per protocol analysis. Can I just ask about why those weren't -- those patients weren't included?

Sure. I believe, and Makis can correct me if I'm wrong here, there is a technique that is used in cardiac surgery to help prevent what's called hemodilution or patients becoming anemic during surgery. And what's happened is an amount of the patient's blood is drawn off before they go on the heart-lung machine and save. It's a procedure called ANH and at the end of that procedure, that blood is then transfused back into the patient. And this is a technique that we use to help prevent what's called hemodilution and the need for blood transfusion. . However, it was not allowed in this trial because of the fact that, that blood that you remove has active ticagrelor drug in it. It's not exposed to the device and then it's transfused back into the patient afterwards. So any potential benefit you would receive from removing ticagrelor would be offset by infusing blood with active drug back in it at the end of the procedure. And despite this being a protocol violation, we realized part way through the trial that there are actually some patients that had this, and they were not included in the analysis for that reason. Makis, anything to add?

No. That was perfect. That was the vast majority of protocol -- major protocol deviations were related to A and H.

Okay. And then I wanted to also ask about those 9 patients. You were talking about that were classified as bleeding events on the protocol analysis, but then you did the reanalysis and didn't find any evidence of bleeding. Can you give us some more details about those 9 patients, what the differences were between those 2 analyses?

Yes. Absolutely. So what we did was it was a blinded review. So we had no idea whether these patients were in-- had received the device or not. and look at the amount of chest tube drainage they had, the number of transfusions they received, what happened to their hemoglobin and hematocrit afterwards as well as their platelet count. We also looked at the time that they received the blood transfusions. Some of the patients actually received the transfusions before they ever left the operating room. So in other words, they didn't have a chance to bleed, but the surgeon or anesthesiologists was concerned enough on the front end that they just went ahead and gave the patient platelets. In 2 of the patients, it looked like it was standard protocol within -- with this particular surgeon or institution to go ahead and give platelets afterwards. I think all of these patients had less than 800 CCs of chest tube bleeding or a couple of patients look like they had it just because they had no chest tube drainage, but their blood count. And these were women that started anemic went quite low afterwards, and the clinical care team felt it was the best -- in interest of the patient to give a blood transfusion. And again, this probably occurred due to fluid they received around the time of surgery that caused dilution of the blood but was not due to bleeding per se. Richard, other thoughts.

Yes. So this is quite a complex issue. I'll highlight my talk, I run a lot of clinical trials with tens of thousands of patients in cardiac surgery. Right now, in another trial, we're facing a very similar issue dealing with defining -- appropriately defining bleeding at the cardiac surgery and pigeonholing it into a definition can be complex. As Michael alluded to, some patients get transfusion because they already have some of the -- a baseline anemia, the hemodilution by putting them on the heart-lung machine with a prime or a crystalloid solution, a non-blood solution that occupies all the tubing and filters, it dilutes them and suddenly get a transfusion, and then they get a protocolized platelet administration and suddenly they need a definition. What we really wanted to do is to ensure that we are capturing the spirit of the trial in trying to prevent bleeding that was visible and obvious, meaning the actual visualization of blood loss along with those definitions of transfusions. And when we did that in a blinded way, some of the events that -- if one was just solely focused on purely -- purest approach, they met the definition really with not what we were trying to capture. So that was a sensitivity analysis that we did in a blinded fashion that demonstrates some of these events were not true bleeding events, but rather dilutional or protocolized care.

So thank you both. We're running a little behind. So we're going to move on to the next -- that was perfect, for you Rich. To start with your lecture here. Some of the questions in the chat, just -- we've been reviewing them, they will be answered as part of the sponsor's remarks at the end in relation to the regulatory path forward and the time lines. And then we'll use whatever time we have left for Q&A. Rich?

Great. Thanks so much for the invitation. It was my pleasure to participate in the STAR-T trial. Canada and myself came in a little bit later, as I was discussing with the leadership team, the proportion of Canadian patients that are exposed to ticagrelor was significant, and we are having a significant problem with this. So I'm going to talk to this from a Canadian perspective. Just -- sorry, about that -- just so you're aware, so I am a lead investigator at McMaster University, a popular Health Research Institute. I have a lot of experience with clinical trials. The clinical trials that I have led out of PHRI. I've randomized probably the most number of cardiac surgery patients in the world, through trials that led to a lot of experience, and I was very pleased to see the sponsor take up this blinded, randomized trial to generate robust evidence in a field that has previously been dominated by single armed studies or observational studies indeed. I do have these disclosures, I am a co-principal investigator of this trial. I also have grants from other industry partners that I feel are trying to better outcomes for patients. I'm going to breeze through these slides, again, to allow further discussion. But it just is that -- there are several categories of antiplatelet agents. The ones that we are focused on here is one of the P2Y12 inhibitors that works on the ADP receptor, and that is ticagrelor, and it basically prevents activation of platelets. So this came in -- Michael Mack earlier, and I believe also Michael Gibson alluded to the PLATO trial, where that trial compared ticagrelor to the more common drug that was added on top of app at the time clopidogrel. And what was very powerful about this trial is this shows a forced plot, the smaller inset here is time from procedure in months and the y-axis is the cumulative endpoint include death, but there was a significant reduction of death in cardiovascular events compared to Plavix. And therefore, ticagrelor is -- has been supported in the Canadian guidelines as basically the go-to drug when you have a stent or an acute coronary syndrome, such as a heart attack or add on top of aspirin. So we see this used a lot. And then we get into, it's a great drug for preventing events, just as Michael Gibson's alluded to, but what happens when suddenly that patient who is loaded with this drug needs to have surgery urgently or they start bleeding. So again, commonly used in Canada, we're not sure what to do with it, and it certainly delayed care. And this is the recruitment graph from STAR-T. And the reason I highlight this is I discussed probably at the end of 2022 with the team about bringing Canada on board said that Canada will be a major contributor of patients in this. And you can see that when we activated Canada in February 2023, there was a sudden increase or uptick in terms of the recruitment rate and proportionally Canada did extremely well in this trial, not only because we have centralized care, a lot of patients taken care of at a single institution. But because our cardiologists particularly are very evidence-based, and they follow the guidelines very closely. So many of our patients with coronary artery disease or signs that they're having a heart attack or myocardial infection get loaded with this drug. So let's speak specifically to the P2Y12 inhibitors, of which ticagrelor is and the perioperative management. We know clopidogrel. We have a lot of experience in that. Generally, you wait about 5 to 7 days, ideally 10, however, Plavix or clopidogrel responds very well to platelet transfusion because it basically is permanently bound to the platelet and you can just overwhelm the drug by the administration of additional platelets. Same with prasugrel, we do not see prasugrel used in Canada anymore. However, ticagrelor, a very potent drug, ideally, you wait 3 to 5 days postponing surgery. But if you need to go sooner, platelet transfusions do not work well with this drug because this drug is irreversibly bound and it just bounces on and off platelets, messing platelets up. So you give platelet transfusions and that drug is floating between platelets and messing each of these platelets up. It's very hard to overwhelm this drug. When we first started seeing this drug used in our center, all of a sudden, I got a call from one of our head hematologists and say, "Hey, what is going on? We're seeing these massive bleeding events with you guys. And I'm really, really worried about this drug." That was Ted Warkentin. I remember that call extremely well. He's one of the world renowned hematologist, one of the best published hematologists around heparin-induced thrombocytopenia and transfusion around cardiac surgery, and to get that call was a bit shocking. So indeed, this is a real problem. The second thing is that not only do we start delaying surgeries, but speaking earlier, the comment about shifting patients from severe to moderate, moderate to mild. If you look at any definition of bleeding, so the universal definition of perioperative bleeding, chest tube outputs on the right here, over 24 hours. If you look at a number of packed red blood cells administered platelets administered, there is a continuous relationship, an almost linear relationship with very bad outcomes. The more bleeding, the more transfusions the worst patients do in terms of morbidities and mortality. And this is highlighted again in this graph from Karkouti, who's a very experienced and well-known researcher at the University of Toronto, who looked at the number of red blood cells transfused and mortality. And you can see this almost linear relationship when you look at liberal transfusion in this forest plot, liberal to the left, restrictive to the right, if you are restrictive in your transfusions, you tend to save patients and indeed, we proved that in a trial that I led with David Mazer out of Toronto called TRICS III. So this is why I really believe these results were important. And when we look at the spirit of the trial, as I mentioned, I'm not going to go back and review all of the trial results. But those patients that had significant bleeding and those patients who are isolated with CABG, which is truly the focused population or the population that this drug is intended to, we have a win ratio of 1.59 and a p-value of 0.04. The data suggests that you have better outcomes with the treatment group as opposed to a control group. And again, this is the per protocol CABG population, the sensitivity analysis. And when you look at moderate to severe bleeding, the worst type of bleeding, the one that is associated with the greatest morbidity and mortality, you have a win ratio of 1.65, a p-value of 0.02. If you look at severe bleeding lone, again, similar win ratio of rounds off to 1.6, the p-value of 0.04. So these results from these STAR-T trial suggests that the group that received treatment was favorable as compared to the control group. So thank you so much.

Thank you, Rich, and we look forward to the Q&A session. Potentially some questions in the Canadian perspective will be very interesting. And now on to Professional Michael Schmoeckel. Joining us this evening from Munich, Germany. Michael, take it away.

Hello. Can you hear me?

Yes.

Okay. Great. Next slide, please. Unfortunately, I can't move it at the moment. So if you could move it for me, that would be nice, actually. Okay. So this is my disclosures. I'm actually together with Rob Storey from Sheffield, one of the PIs of the European STAR Registry, which I'm going to present to you in the upcoming slides. Next, please. How did it start? Actually, about 10 years ago, we were facing more and more patients that were on rivaroxaban or apixaban, the DOACs, when they underwent cardiac surgery. And the manufacturers of these 2 drugs have recommended that we should stop these drugs 48 to 72 hours before surgery. However, we realized that there is still more bleeding even if we discontinue the drugs for 48 to 72 hours and actually our recommendation after our own data was that we should actually wait for up to 10 days before you are down to the normal bleeding rates that you would expect without these 2 drugs. So this becomes true especially in patients that have a reduced kidney function, and that's actually not a rare event in cardiac surgery patients. Next slide, please. Then we read a paper in 2017 of Angheloiu, who did a [ MOX ] circulation where he was actually able to remove both ticagrelor and rivaroxaban from a MOX circulation with the help of the CytoSorb absorber, and that was actually quite effective in this experimental setting. So we decided at that time that since the CytoSorb absorber was actually already CE marked for cytokine removal in Germany and in Europe in general, that we should use this CytoSorb absorber for the removal of these 2 drugs, both ticagrelor and rivaroxaban. And in fact, next slide, please, the first experience was quite promising. On the left-hand side, you see the ticagrelor group, there was 43 patients was published in 2019, actually, where we had a significant reduction of operation time. Since we had less time for hemostasis necessary, we had less chest tube drainage and actually no re-thoracotomy at all. And in the rivaroxaban group there was only 12 patients. We could even show that we had a reduction in time on the ICU and in total hospital stay. Next slide, please. This shows you again the reduction of the chest tube drainage in these 2 groups. So they came down from 600 mills to 390 in the rivaroxaban group. And from 890 to 350 in the ticagrelor group. So next, please. We actually then expanded our experience to remove apixaban in a clinical setting. And we also used it not only in isolated CABG, but also in acute aortic dissection, which is the middle paper. And last not least, I was able to present at the AATS meeting in Los Angeles last year that if you run the blood of the patient through the CytoSorb absorber for about 1.5 hours in a study and you measure the levels of ticagrelor, you are able to reduce these ticagrelor levels by 67% in these patient groups and thereby reducing bleeding. So next, please. In Europe, we then decided that we should even expand our small little local experience in Hamburg to a more generalized European experience, and we started a registry together with Rob Storey from Sheffield. And the objective was to generate high-quality data, both on the clinical outcome and on health economics. And these -- we were actually able to include quite a substantial amount of centers. If you look at the next slide, please. We are now, as of today, up to 5 countries: Germany, the U.K., Austria, Belgium and Sweden with 23 participating sites and we have now enrolled 453 patients since April 2022. And this is steadily increasing, as you can see on the right-hand side of the slide, actually, if you press the button, then you see all the countries. Next, next and next. And on the slide here, you can see the enrollment of the registry, which is quite steadily growing, and I am actually quite optimistic that we will reach about 500 patients quite soon. Next slide, please. Last year, on the European Association of Cardiothoracic Surgery meeting, I was able to present some of the data, preliminary data of this registry. And actually, as of today, they've just been published in the Journal of Thrombosis and Thrombolysis. So if you're interested in detail, you can read it up there. Just briefly, at that time, when I presented this data, we had included 165 patients, 2/3 of them had a P2Y12 inhibitor, mostly in 77% ticagrelor and some of them together with us and some also clopidogrel and prasugrel, although I, myself, I'm not really a believer that it will help in this subgroup of patients because clopidogrel usually binds irreversibly to the platelets. And we had 1/3 of patients, namely 51 who were in DOACs, mainly apixaban, the yellow group, 47% and 27% on rivaroxaban and the others are dabigatran and edoxaban. And if you look at the next slide, please. You can see that actually the bleeding was what you would expect like a moderate bleeding, not a severe bleeding. It was again kind of a difference between 2 groups. Those on ticagrelor underwent mainly isolated CABG. And those who were under DOACs had more complex surgery, which is reflected by the yellow or orange bar on the bottom on the right side. because you had more bleeding due to these more complex procedures in the DOAC group. But still, it was actually quite moderate and all the centers actually I have spoken to, they were very enthusiastic about continuing with this form of therapy. Next slide. And in parallel to the STAR-T trial that has just been referred to by Dr. Mack. Rob Storey from our registry will present the data, isolated CABG just with ticagrelor in this registry on the EuroPCR meeting in Paris, just in about 10 days' time. And so you will hear about, I think, more or less a similar data set in this registry if compared to the STAR-T randomized trial. The next slide, please. There have been also some new applications of the device. So it's not only used during cardiopulmonary bypass during surgery. But also in patients that are operated by CABG but off pump. So without the use of a heart, lung machine. And in this case, my colleague here in -- at the Utimate clinic in Munich, he used the device using a apheresis pump, before surgery, and he actually put this patient on an apheresis pump via a venous return access, and he could actually remove successfully, again, ticagrelor and DOACs to reduce bleeding events in this specific patient group. The next, please. So just to sum up what we know so far about the anti-thrombotic removal is that it's a significant unmet need, and this was referred to in the very first talk. And this is now also validated in the STAR Registry. We can perform our surgery timely, which means a patient doesn't have to wait. There is the usual washout period of about at least 72 hours. And we have, therefore, a significant saving in health day resource costs and utilization of hospital costs. And even we think that we can reduce operation times and ICU times, which is actually kind of a bottleneck in our health system because we don't have enough ICU beds and not enough operation capacity because of personal resources problems. So all this drives actually quite an enthusiasm to introduce the CytoSorb absorber and this indication as a standard of care. The next slide shows you that even the guidelines have now incorporated this into their -- is this the next slide actually?. Yes, yes. Okay. into the recommendations. So in patients on ticagrelor, rivaroxaban, the European Society of Anesthesiology and intensive care has given it a 2C recommendation to use the CytoSorb absorber as an adjuvant therapy to reduce bleeding complications. And on the very last slide, I would like to leave you with a -- with the sum of these testimonials most of them actually are participants in our Registry who are quite enthusiastic about continuing use this kind of therapy, which has already been CE marked in Europe for the indication of removal of rivaroxaban and ticagrelor from blood of the patients who are -- who undergo cardiac surgery. And this is a more and more common feature that it's actually used in more and more centers and the interest is still high to include more patients into this Registry. Thank you very much for your attention.

Thank you very much, Professor Schmoeckel. So to the audience, hopefully, the 4 lectures that you already listened to today provide you with a detailed update as to where we stand today. In relation to the unmet need we are trying to serve, the clinical data on safety and efficacy from our pivotal randomized double-blind STAR-T trial, and the growing experience and evidence with the increasing adoption of anti-thrombotic removal in the European Union. But as many of you are thinking of what happens next? Well, what happens next are the regulatory submissions and we're moving full steam ahead with submissions both to FDA and Health Canada. And in the next few minutes, I'd like to give you a little bit more visibility around our strategy and the time lines related to that. So first off, let's remember that DrugSorb ATR is a breakthrough device. The FDA has actually granted 2 breakthrough device designation for DrugSorb ATR. In 2020, for the removal of ticagrelor during emergent urgent cardiothoracic surgery. And in 2021, a second breakthrough designation for the removal of apixaban and rivaroxaban. The breakthrough device designation program provides timely access to medical devices by speeding up development, assessment and review for premarket approval of 510(k) and de novo authorization. The devices need to meet 2 criteria. The first criterion, device needs to provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or condition. And the second criteria where the device must meet at least 1 of the 4 listed below, eager to represent a breakthrough technology or to be indicated for use with no other approved or cleared alternatives exist, to offer significant advantages over existing approved or clear alternatives and device availability to be the best interest of patients. Obviously, DrugSorb ATR has met those criteria, that's why we were granted those 2 breakthrough device designations. Since 2015, the FDA has granted 192 such designations to cardiovascular devices, which is our population of interest, as you saw from the STAR-T trial, and to 83 GI or urology devices and diagnostics. The reason that number is improved because that's the review branch that was going to be reviewing the DrugSorb ATR submissions. The breakthrough devices must meet the FDA's rigorous standards for device safety and effectiveness to be authorized for marketing. And breakthrough device marketing submissions received prior to review. So that's an important backdrop to consider, as we discuss the next steps. This is one of our external regulatory experts that we've been working with and is advising us on how to proceed, Mr. Mark DuVal, President and CEO of Duval & Associates. And here's his quote, "we have been working with CytoSorbents on the development of the regulatory strategy for the DrugSorb ATR device. Based on the data the company has shared with us and the extensive experience we have in the preparation of de novo submission, it is our opinion this device is appropriate for the de novo pathway. The de novo pathway is for low to moderate risk devices for which special controls, in our case, our clinical trial data, provide reasonable assurance of safety and effectiveness, but there is no approved predicate device. There's a heavy emphasis during these reviews on the probable benefit and risk of the device in the intended population. Breakthrough devices receive priority review on device marketing submission and in the recent analysis led to a more rapid review of de novo applications by 25%. So having a breakthrough designation is important. Accordingly, we are targeting parallel de novo submission to FDA and also regulatory submission to Health Canada in Q3 of this year. The time lines by the FDA for de novo reviews are listed at 150 days. However, post-COVID reviewed times have been closer to about a year. So to summarize, ticagrelor is an FDA approved drug, widely used as standard of care, both in the United States and Canada but does compare serious risk of perioperative bleeding for patients requiring urgent surgical treatment. DrugSorb ATR has FDA breakthrough status for this application highlighting the large unmet medical need and the lack of available alternatives. We believe that the STAR-T data support a favorable benefit to risk profile for DrugSorb ATR in reducing the risk of severe perioperative bleeding in patients undergoing cabinet surgery. Based on a favorable benefit to risk profile observed in STAR-T, our regulatory experts recommend that we submit to the FDA for DrugSorb ATR, use in CABG surgery under the de novo pathway. Therefore, we plan on parallel FDA and Health Canada submissions to cure in Q3 2024 under the combined mutual e-STAR program. Pending FDA agreement of the de novo pathway submission. Breakthrough designation is expected to facilitate a priority review with a potential FDA decision between 6 to 12 months following submission. So that concludes our prepared remarks for today. Thank you again for participating to the CytoSorbents Virtual KOL and analyst investor event. Now I'm going to turn it over for a second Q&A session. Let's see if we have any live questions and then we'll turn to the questions that have been the chat. Tara, do we have anyone calling in?

Yes. So our first question of our second Q&A session will come from Brandon Carney at B. Riley.

I guess my first one is for Dr. Whitlock, do you expect any difference in how the Canadian regulatory agency will interpret the data and the application compared to the U.S. agency just based on the differential usage of ticagrelor in Canada versus U.S.?

I don't think so. I mean I certainly don't have a crystal ball, but I think there is certainly is a strong back story here in terms of the problem and the magnitude again, this is geographic. We're a country of just over 35 million, slightly more concentrated in terms of our centers. But there are also areas within the states where there is heavy use. So I don't think that will lead to any sort of differential decisions between the 2 agencies.

Okay. And then for Dr. Schmoeckel, what is the data like in the EU for the ticagrelor i CABG patients versus those with the more complicated surgeries? Do you see a difference like we have in the STAR-T trial? And how has that affected usage? Are physicians there still using the device for more complicated surgeries?

Actually, we do. I think that we don't get this significant because, as it was already mentioned in these complicated cases, you have a mixture of coagulation bleedings due to correlation disorders. And you have due to the very -- a lot of wound problems and bleeding for surgical reasons. So it's difficult to differentiate where it's coming from. But however, if you can get rid of the coagulation disorder bleeding and you are just left with the surgical bleeding, it still makes a difference. And so that's the reason we would still continue to use that also in the complicated case, although it's not significant in this specific study because sometimes it's just an effect of these numbers. You have some single patients that bleed a lot, and that will kill your whole statistics then. But we think we -- we believe that it works because we have shown that it reduces both the levels of ticagrelor and the DOACs and so it's a mechanistic thing if you can get rid of maybe 70% to 80% of the ticagrelor or the DOACs, it should have an effect.