Cytosorbents Corporation (CTSO) Earnings Call Transcript & Summary

Good morning and welcome to the CytoSorbents KOL call on the use of CytoSorb for antithrombotic drug removal. [Operator Instructions] As a reminder, this conference is being recorded, and a replay will be made available on the CytoSorbents website following the event. As another reminder, the company may make forward-looking statements during this event and a copy of the safe harbor statements can be found in the presentation, which will also be made available on the CytoSorbents website. At this time, I would like to turn the call over to Dr. Phillip Chan, CEO of CytoSorbents. Please go ahead, Phil.

Thank you, Jeremy, and welcome, everyone, and thank you for joining today. We're very excited to bring together a distinguished panel of speakers with Drs. Gibson, Storey and Schmoeckel to discuss CytoSorb removal of antithrombotic agents. Before handing it over to our Chief Medical Officer and host for today, Dr. Efthymios Deliargyris, otherwise known as Makis, I wanted to give you a brief background on the company. Next slide, please. Thank you. CytoSorbents is a U.S. NASDAQ-traded medical device company that specializes in treating life-threatening conditions with its blood purification technology. CytoSorb is EU approved, manufactured in the United States by CytoSorbents and commercialized in 65 countries as an extracorporeal cytokine adsorber to help treat hyperinflammatory conditions where cytokines are elevated, including cytokine storm, with more than 88,000 cumulative treatments to date. CytoSorb is also EU approved to remove ticagrelor, which is also called Brilinta; or rivaroxaban, which is also called Xarelto in cardiac surgery; as well as bilirubin in liver disease; and myoglobin in trauma as well. In the United States, CytoSorb is not yet FDA approved, but on a dual path for U.S. approval with FDA Breakthrough Designation to remove ticagrelor during cardiopulmonary bypass in urgent and emergent cardiothoracic surgery; as well as part of a U.S. REFRESH II-AKI trial, which is a pivotal trial at 25 U.S. centers using CytoSorb intraoperatively to try to reduce the risk of postoperative acute kidney injury. In this COVID-19 pandemic, CytoSorb has received U.S. FDA Emergency Use Authorization for use in critically ill adult COVID-19 patients with imminent or confirmed respiratory failure as a treatment of cytokine storm and has now been used in approximately 1,000 COVID-19 patients in 20 countries, including here in the United States. We have about 156 employees with an international footprint across 2 wholly-owned subsidiaries. CytoSorbents' medical headquarters is based out of New Jersey, just near Princeton, where we have our ISO 13485 certified manufacturing, our research and development, our management, accounting and other functions. And we also have a second office based out of Berlin, Germany that focuses on commercialization and sales and marketing. We've been very fortunate to have strong government support with approximately $33 million in grants, contracts and other non-dilutive funding. Next slide, please. First of all, CytoSorb is very easy to use because it is a plug-and-play compatible technology with the existing blood pump infrastructure found in hospitals today, whether or not it's with a dialysis or continuous renal replacement therapy, or CRRT machine in the upper left; a stand-alone treatment with a simple hemoperfusion machine in the lower left; or an extracorporeal membrane oxygenation machine, or ECMO, in the upper right. All these machines are used in the intensive care unit. Or that CytoSorb being used during cardiac surgery, where it can easily be integrated into a cardiopulmonary bypass blood circuit, in the lower right, which you'll hear more about today. Next slide, please. As I mentioned, CytoSorb is approved in the European Union and distributed in 65 countries worldwide. The therapy has accumulated more than 88,000 treatments to date. Of these, roughly 2/3 are in critical care to treat cytokine storm and diseases such as sepsis, COVID-19, ARDS, reversal of shock, trauma, liver failure and many other hyperinflammatory illnesses. And roughly 1/3 of treatments involve cardiac surgery, such as valve replacement for infective endocarditis, reversal of vasoplegia or shock following cardiac surgery procedures, complex cardiac surgery procedures, such as aortic reconstruction and valve replacement surgeries, postoperative inflammation and sepsis and of course, the topic for today, which is the removal of antithrombotic agents. We have a hybrid sales model selling direct in 10 countries that make up about 3/4 of our product sales and roughly 1/4 are through distributors and partners. Speaking of partners, we are very fortunate to have 3 very large and well-respected partners who are leaders in their verticals, including Fresenius Medical Care, the largest dialysis company in the world; Terumo Cardiovascular, one of the largest cardiac surgery companies in the world; and Biocon, the largest biopharmaceutical company in India. Next slide, please. So we are pleased to note that CytoSorb adoption and usage continues to grow as evidenced by the increases in our trailing 12-month product sales. In addition, because we manufacture the CytoSorb device ourselves, we're able to benefit from volume production and have driven our blended product gross margins that mixes higher-margin direct sales with lower-margin distributor and partner sales, to 76% in Q1 2020 and as high as 80% in the fourth quarter of 2019, while keeping the therapy very affordable. Next slide, please. Finally, we look forward to even stronger growth from existing and new clinical applications, particularly in critical care and cardiac surgery, driven by many of the macro trends in health care today. For example, the aging baby boomer generation is increasing the need for cardiac surgery due to coronary artery disease and long procedures for structural heart and aortic disease that create potentially damaging inflammation. Also, many of these patients are on blood thinners or antithrombotic agents due to atrial fibrillation, history of a heart attack or other heart disease or stroke or other reasons. The elderly are also highly prone to getting infection and sepsis as well as traumatic falls and other injuries that can cause a cytokine storm. And so today, these are all applications where CytoSorb is being used today. Another example is the opioid crisis that is driving a high incidence of valve replacement for infective endocarditis or infection of the heart valve, because of the use of dirty needles, where sepsis and hemodynamic instability in these patients are being managed with CytoSorb. There's also the liver disease pandemic that afflicts 1 out of every 11 people worldwide due to alcoholism; hepatitis; and NASH, also called fatty liver, due to the obesity epidemic. CytoSorb is being viewed by many as the next-generation liver dialysis therapy because it not only removes liver toxins, but it also removes cytokines, which are often responsible for the acute-on-chronic exacerbations of liver disease that are seen in hospitals and ICUs around the world. And finally, we live in a very dangerous world where millions of patients are hospitalized every year for everyday trauma like motor vehicle accidents, natural disasters as well as sepsis from epidemics and -- or pandemics like seasonal flu, COVID-19 and many others. So with that, let me now turn it over to Dr. Makis Deliargyris to give an overview of the technology. Next slide. Makis?

Thank you, Phil, and good morning to everyone, and thank you for joining our call today. Next slide. Today, we will review the science, clinical applications and the market opportunity associated with the ability of CytoSorb to remove antithrombotic drugs from the circulation. This is a new and a very exciting application for CytoSorb with the potential to save many lives and reduce the cost of hospitalizations for thousands of patients. We hope that after today, you will also share our enthusiasm about this opportunity. Next slide. Let's start off with some of the science which will help us better understand how drug removal works. The CytoSorb device is a hemoperfusion cartridge filled with biocompatible polymer beads. Approximately the size of a grain of salt, each bead has hundreds of thousands of tightly controlled pores and channels that are generated via suspension polymerization. These pores and channels enable the polymer beads to remove substances from circulation based on pore capture and surface adsorption. Substances with sizes under 60 kDa and with hydrophobic properties are preferentially removed from circulation. As shown on the slide, additional drug properties that also contribute to the extent of removal include the half-life of the drug, the fraction of free to protein-bound drug in the circulation and the overall volume of distribution. Next slide, please. In today's discussions, we will focus in large part for the use of CytoSorb for antithrombotic removal in patients undergoing cardiac surgery. As Phil described earlier, CytoSorb is plug-and-play, compatible with a number of extracorporeal flow systems. That includes the cardiopulmonary bypass circuits used in heart surgery where CytoSorb can be easily installed in just minutes. High flow rates up to 700 mL per minute can be achieved and maintained and no changes are required in systemic anticoagulation with heparin already being used in the surgeries. Most importantly, CytoSorb has already been used safely in thousands of heart operations without any serious device-related adverse events being reported to date. Next slide. Today, we will focus on ticagrelor, also known as Brilinta in the U.S. or Brilique in Europe; and rivaroxaban, also known as Xarelto worldwide. Bench studies early on suggested that CytoSorb is very effective in removing these agents from circulation. That observation was later confirmed in clinical practice. And later, we'll hear in detail from Professor Schmoeckel his clinical experience in this application. Earlier this year, we received CE Mark approval for the removal of both of these agents in patients undergoing cardiac surgery and we are now actively supporting this indication in Europe. Recent studies suggest that CytoSorb can also effectively remove dabigatran, also known as Pradaxa; and edoxaban, also known as Savaysa. Finally, based on the characteristics of apixaban or Eliquis, we believe that this is also removable by CytoSorb. Therefore, we view that CytoSorb in the future will be an effective removal solution for the whole novel oral anticoagulant class. Next slide. Today, we are pleased to be joined by 3 world-renowned experts in the treatment of patients with cardiovascular disease and especially as it relates to the use of antithrombotic agents. Hopefully, you had a chance to review the impressive bio notes that were included with the agenda that was circulated. Professor Storey will begin with a review of ticagrelor and the important implications that effective removal of this drug by CytoSorb can have in today's clinical practice. Professor Storey is Professor of Medicine at Sheffield in the United Kingdom and he's also Director of the Cardiovascular Research Unit. He has been involved from the very early stages of the development of ticagrelor and has been a part of the executive committees of the large pivotal trials supporting its approval. Then Professor Schmoeckel will present the experience from his institution with the use of CytoSorb removal for ticagrelor and rivaroxaban in patients undergoing cardiac surgery. Professor Schmoeckel is Chairman of the Department of Cardiac Surgery at the Asklepios-Klinik in Hamburg, Germany. He and his colleagues have been the pioneers of using CytoSorb in this indication and we are very pleased to have him in person presenting their clinical data. The final presentation will be by Professor Gibson, who will educate us on NOACs and present the exciting implication of a solution like CytoSorb for the hospital management in these patients. Professor Gibson is a Professor of Medicine at Harvard Medical School. He's also the Chief Executive Officer of the Baim Institute for Clinical Research and the Founder and Editor of wikidoc.org. Professor Gibson has been instrumental in the development of many of the NOACs and also has been involved closely with the development of the antidote Andexanet, that will also be part of day's discussion. Next slide. We hope that by the end of today's event, you will have a good idea of the unmet clinical need for antithrombotic removal, the safety and efficacy of CytoSorb in this indication and the size of the business opportunity and addressable market. Now it is my pleasure to hand this over to Professor Storey. Rob?

Thanks very much, Makis. So it's a pleasure to talk about this very exciting area, that CytoSorb has big implications for ticagrelor and vice versa. So it's an exciting area to discuss and look at some of the new science. Next slide, please. So ticagrelor is the first oral reversibly binding P2Y12 receptor antagonist. It belongs to a novel class, abbreviated CPTP. So it's a small molecule, orally active and binds reversibly to the platelet P2Y12 receptor, which is a very important pathway on platelets for amplifying platelet activation. It's a bit like the volume control on platelets, regulating the -- how marked is the response to platelet agonists. Next slide, please. So about 12 years ago, I did this study with Paul Gurbel, based in the U.S., of the onset and offset of ticagrelor compared to clopidogrel, which was the standard of care at the time for acute coronary syndromes. And this study on the left-hand side shows the onset of action of the 2 drugs and a loading dose over 24 hours, showing by half an hour after ticagrelor loading the onset of inhibition to nearly what was seen at peak with clopidogrel. And by 1 hour, a very high level of inhibition with ticagrelor and much higher than achieved with clopidogrel. And then with maintenance dosing over 6 weeks, that's maintained. And then on the right-hand side, we see the offset of action of the last maintenance dose. So ticagrelor and clopidogrel, you see a peak in the inhibition after the maintenance dose. And then with no further doses, the effects wear off. And because ticagrelor binds reversibly to P2Y12, as the plasma levels fall then the platelet function returns. On the other hand, clopidogrel, similar to prasugrel, they are very similar prodrugs, we see a more steady offset of action and taking longer for platelet function to recover, related to the irreversible action of clopidogrel. Next slide, please. In the PLATO study, which was the pivotal study that led to the indication of ticagrelor in acute coronary syndrome compared to clopidogrel, we did a platelet function study. And here, showing during maintenance therapy, with a VerifyNow system showing pre-dose on the left, that's a trough effect; and post maintenance dose on the right, the peak effect. With clopidogrel, we see this quite widely variable platelet reactivity. And about 30% of patients treated with clopidogrel have a high response; about 30% of patients have a poor or even no response to clopidogrel. That's because it's handled very differently between individuals as a prodrug. Ticagrelor, on the other hand, much more consistent because it doesn't need to be converted in the liver. At pre-dose, 1 or 2 outliers. Sometimes we've seen that's related to compliance in many cases. But after a maintenance dose, we see all the patients very effectively inhibited, with low platelet reactivity. So ticagrelor is a very effective and reliable P2Y12 inhibitor compared to very variable effects seen with clopidogrel. Next slide, please. And this really is the major explanation for why ticagrelor performed better than clopidogrel in acute coronary syndromes in the PLATO study. Shown on the left, the incidence of heart attack is lower over 1 year with ticagrelor versus clopidogrel. And with great impact, the cardiovascular death rates were lower with ticagrelor compared to clopidogrel, saving about 1 in 5 lives when we use ticagrelor instead of clopidogrel. And this led to recommendation for ticagrelor as first line therapy. And one of the things with PLATO, it was a broad population of patients. So it was non-ST-elevation ACS patients who are managed either medically or with PCI or went on for CABG surgery; and it was STEMI patients undergoing the standard treatment of primary PCI. So a broad population leading to broad recommendation in the guidelines for ticagrelor in preference to clopidogrel. Next slide, please. So my center is in Sheffield, it supplies the South Yorkshire region. In the U.K., we have large centers supplying the revascularization services to the surrounding population. So we've got a population -- we serve 1.8 million people and we're the only PCI and CABG surgery center supplying that population. So it allows us to get a real-world look at the representative population. Next slide, please. So we introduced prasugrel initially in 2010. And then when ticagrelor was approved and recommended by NICE in 2012, we used that as our first line therapy. And we were able in this analysis of over 10,000 patients consecutively managed to look at the outcomes. Next slide, please. Many of our patients are managed with PCI, about 80% of the patients. And here, we look at the stent thrombosis rates, adjusted for any differences in characteristics. And we saw after adjustment a halving of the stent thrombosis risk. Some early events still with ticagrelor and we've managed to eradicate many of those after realizing this was related to morphine delaying the absorption of P2Y12 inhibitors. And so we've been able to address that. And so we've almost abolished stent thrombosis as a problem in the ACS population, at least got it down to below 0.5% of patients, so phenomenal improvement in safety. Next slide, please. The -- in the U.K., we have the British Cardiovascular Intervention Society, manages an audit of adult interventional procedures. And we have the audit results from April 2018 to March 2019. Next slide, please. Looking at the indications for PCI, shown here. And what we've seen across the U.K. is that there's been progressive increase in the proportion of cases being performed for acute coronary syndrome and a fall in the number of cases of stable coronary disease managed with PCI. That's partly related to the evidence showing how PCI has a bigger prognostic impact in ACS patients compared to stable patients. Next slide, please. And here, we see over time an increase in the percentage of PCI procedures using ticagrelor. It's used mainly for ACS, although occasionally, it may be used in high-risk, stable CAB patients. Now there's been quite a big uptake after appreciation of the reduced stent thrombosis rates with ticagrelor compared to clopidogrel. Next slide, please. We also have a national audit of cardiac surgery. And shown here, like with PCI, the number of elective CABG surgery cases has declined over the years. On the other hand, the number of urgent CABG cases has remained remarkably constant, again, showing how revascularization is being focused on the ACS population. We do have a problem in the U.K., though, in that patients for what we call urgent CABG, that's acute coronary syndrome patients, still have to wait about 10 days without operation. The proportion treated within 7 days is about 34%. And only 4 hospitals in this time period managed to treat more than 50% within 7 days. And not a lot has changed over the years. And partly that relates to antiplatelet therapy. The patients are initially managed with dual antiplatelet therapy. They have their angiogram and then they have to wait until the P2Y12 inhibitor wears off. And so this leads to extended hospital stays and logistic challenges in terms of, if a slot comes up on the list, it may not be possible for the patient to use it because they have the P2Y12 inhibitor on board. Next slide, please. And the reason we wait is because of the evidence that P2Y12 inhibition, alongside aspirin treatment, is associated with substantially increased bleeding. We see here in the PLATO study of CABG surgery patients how the initial chest tube drainage was in the patients who were having surgery within a day of stopping their study drug, was very high and more so in the ticagrelor group, representing the -- reflecting the higher levels of platelet inhibition. And then over time, over 4 or 5 days after stopping drug, the amount of chest tube drainage, i.e. bleeding postoperatively, reduced. The next slide, please. And that reflects the offset of action of the drugs and falling levels of P2Y12 inhibition. Shown by a different measure, the fall in hemoglobin more than 50 grams per liter, we see an even marked change here. So by 5 days, much lower rates of the substantial fall in hemoglobin, with both ticagrelor and clopidogrel, compared to when patients go to surgery early. And we've also showed in PLATO that there is a risk. Patients, some patients died as a consequence or associated with the bleeding in the PLATO CABG study. So this is an important safety issue and why surgeons wait until the P2Y12 inhibitor has worn off. Next slide, please. We did a small pharmacodynamic study in ACS patients looking at platelet reactivity after ticagrelor discontinuation. And you can see that by 96 hours, i.e., 4 days, we're starting to get normalization of platelet reactivity; 5 days, complete normalization or almost complete. So it does take 4 or 5 days for the effects of ticagrelor to wear off, even though some observational studies suggest that by 3 days, it's a lot safer. But still in this pharmacodynamic study, we see 1 patient who's below the risk threshold for increased surgical bleeding at 72 hours. So waiting improves hemostasis. Next slide, please. I was part of a task force writing a position paper on how to manage antiplatelet therapy in patients undergoing CABG surgery. And it's quite a complex exercise because there's so many possible options and patients vary widely in terms of their bleeding risks with surgery as well as their thrombotic risk when they're taken off antiplatelet therapy. And so we classified patients as high or low bleeding risk, high or low thrombotic risk and gave different recommendations. And those recommendations included bridging therapy in those who are high thrombotic risk or just waiting for those drugs to wear off in those with low thrombotic risk. But bridging therapies are somewhat, to them, shaky evidence. People can use glycoprotein IIb/IIIa inhibitors. These have a narrow therapeutic window associated with increased bleeding. And so there's a fairly weak evidence base for using these as bridging and significant safety concerns. So it's not ideal. In the U.K., we do see occasionally patients who have taken off their P2Y12 inhibitor and whilst waiting for surgery have another heart attack; or patients who have bleeding problems because of bridging therapy. So there's no ideal solution with this strategy. Next slide, please. So the potential to exploit ticagrelor's reversibility is very exciting. And this bench study, as Makis mentioned, shows that ticagrelor can be removed. Here, the ticagrelor is added in vitro to a bag of human blood and then it was run through the CytoSorb system. And by 4 hours, more than 99% of the ticagrelor in blood had been removed, with a substantial proportion by 3 hours. So the efficiency of this system in removing the blood ticagrelor is very impressive. And of course, once ticagrelor is removed from the blood, it's removed from the platelet P2Y12 inhibitors and those platelet P2Y12 receptors, sorry, they recover function and so platelet reactivity is restored. Next slide, please. In this economic model, this group looked at the potential implications in terms of morbidity and also health economic implications if one has the CytoSorb system available for standard practice. Next slide, please. And the modeling in this study was based on a number of different clinical inputs: bleeding complications, repeat procedures for bleeding, transfused blood products, length of the stay and the incidence of myocardial infarction whilst waiting for ticagrelor to wear off, with some sensitivity analyses around the uncertainty within this model. Next slide, please. And in the case of patients undergoing emergent cardiac surgery, those who have to go straight to surgery before the drug effect can wear off, with CytoSorb, this showed significant reduction in red cell transfusion, major reduction in platelet transfusion, reduced operation time associated with a reduced rethoracotomy rate, reduced length of stay on intensive care and a reduction of 3 days in the hospital length of stay. Next slide, please. Alternatively, looking at using CytoSorb and immediately versus waiting for the drug to wear off and not using CytoSorb, this model shows similar use of blood products, but a reduction in length of stay with 5 days with the CytoSorb approach to remove the drug rather than wait for it to wear off. And so a saving of 5 days, that obviously has major implications in terms of hospital resource usage and cost. Next slide, please. In the U.K., we're running a TISORB study to look at the impact of the CytoSorb system in patients with acute coronary syndrome undergoing urgent cardiac surgery less than 48 hours since the last dose of ticagrelor. These are patients who have a significant thrombotic risk related to stopping ticagrelor and therefore, go to surgery and have the benefit of using the CytoSorb system. And the primary endpoint of this study is a pharmacodynamic measure using the multi-plate system, otherwise known as multiple electrode platelet aggregometry. It looks at platelet reactivity in whole blood, measuring platelet aggregation with this system. And this will show how the removal of ticagrelor allows an improvement in platelet reactivity to ADP and therefore, addresses the problem of platelet dysfunction and the blood loss and hemo dilution that go along with that and the use of additional drugs and platelet products -- blood products that are necessitated by the bleeding. Next slide, please. So this is in 8 sites across the U.K., Sheffield being one of them. And -- sorry, next slide. And different measures, time points. So there's 2 time points to look at, platelet reactivity before surgery, patients then have surgery on ticagrelor using the CytoSorb system with testing of platelet aggregation at the end of cardiopulmonary bypass and then the following day and follow-up. And we're going to be doing a pharmacodynamic substudy to look at multiple aspects of platelet function as well as inflammatory markers and bleeding time, a clear measure of hemostasis. So we're going to get a lot of scientific information as well as proof-of-concept from this study for U.K. patients. Next slide, please. Here representing the primary effectiveness endpoint, so removing ticagrelor from the blood with the CytoSorb system. We will then be able to see an increase in platelet reactivity from being low as many patients have on ticagrelor, a low response to ADP. And then after CytoSorb, we'll see this increase in platelet reactivity in response to ADP, reflecting the removal of ticagrelor from the blood. Next slide, please. So in summary, ACS has become the dominant reason for revascularization over the last decade, dual therapy with aspirin and ticagrelor as first line therapy has dramatically cut stent thrombosis rates in our patients. The level of P2Y12 inhibition has a critical effect on surgical blood loss and the risks associated with urgent CABG surgery. Ticagrelor has the advantage over irreversible P2Y12 inhibitors, such as clopidogrel or prasugrel, with its reversibility, allowing it to be removed from the blood and thereby, the effects to be also removed. And CytoSorb has the potential to transform the safety, timeliness, simplicity and cost effectiveness of CABG surgery in the ACS population. Thank you for your attention.

Well, thank you, Rob, for a wonderful presentation on the ticagrelor use in current practice for acute coronary syndrome patients and all the issues associated with managing the presence of this agent for those requiring surgical revascularization. Now we will move to our next speaker, Professor Michael Schmoeckel, from Hamburg to tell us about the clinical experience with CytoSorb approach in removing these agents during cardiac surgery. Michael?

Well, thank you very much for giving me the opportunity to present our data during this webinar. May I have the next slide, please? Cardiac surgeons increasingly have to face patients that have been put on -- of -- have been put on the treatment with novel oral anticoagulant drugs. And most of the companies, actually, in their recommendations tell us that we should stop these drugs between 24 and 72 hours before surgery. However, please, next slide, in our cohort of patients that we have operated on during the past years, we have seen that this is not always the case. It's not enough to stop the drug just 24 hours before surgery. If you want to be safe that your patient doesn't bleed more than it should be the case, you should at least wait up to 10 days before you operate on elective patients. That's why we gave -- we published these data like about 2 years ago in the Annals. And we are actually now postponing patients who are on novel oral anticoagulant drugs up to 10 days before we operate on them. Next, please. In Germany, and I think it's the same case in the U.K., the number of PCIs have increased over the past years quite a lot and now, it exceeds the number of CABG surgeries by the factor of 10, as you can see in this slide of the German figures. Next, please. This has been made possible by the advantages of the antiplatelet drugs, especially prasugrel and ticagrelor, that have been especially seen in the PLATO study that you have just heard about from the previous speaker. Next, please. And these 2 drugs are actually now in the European guidelines for patients that are undergoing ST elevation myocardial infarct, the guideline states that 1 of these 2 drugs should be given to the patient before or at latest at the time of PCI. And that means that if a patient who has got an ST elevation myocardial infarct and comes to the cath lab and the cardiologist has to state that he is unable to solve the problem with PCI, this patient will already have received the ticagrelor or the prasugrel. So if this patient needs to undergo cardiac surgery, he will be loaded with the full dose of ticagrelor. And that's our problem as cardiac surgeons, we know, and next slide, please, that the risk of bleeding is actually substantially increased in these patients. This is the data of a Swedish registry that shows us that if you don't stop the drug more than 24 hours before surgery, you will have a 38% risk of major bleeding during cardiac surgery. So this is quite important to us and that's why we were thinking about any measurements that could decrease this risk of major bleeding. Next, please. And there was this study published by Angheloiu in 2017. They were using a mock circulation, just circulating whole blood through the CytoSorb column. And they could show that after quite a long time, 10 hours, you could actually reduce the levels of ticagrelor by more than 99% and still 94% after 3 to 4 hours recirculation. And that made us come to the conclusion that we should actually try to use this column in our patients. Next slide, please. So our hypothesis was that the platelet transfusion is not a definitive solution in these patients because of the circulating ticagrelor binding to transfused platelets. And that by using the adsorber technology, we may be able to reduce bleeding complications in those patients who have been treated with ticagrelor before surgery. And similar effects may also be expected in patients treated with rivaroxaban, as stated in this paper by Angheloiu. Next slide, please. So we conducted a clinical prospective cohort study that patients who underwent emergency cardiac surgery, who were treated preoperatively with ticagrelor and rivaroxaban were included. Since we knew about the possibilities to use CytoSorb in the extracorporeal circulation, we routinely installed the column and this was about half of the time period that we looked at. So half -- about 16 patients were treated before this time point of the JACC paper, so without the CytoSorb; and about 36 patients were treated with it. Next slide, please. This gives you the details of the system during cardiac surgery. This is the cardiopulmonary bypass machine. And in the center of it, here, number one, you can see the CytoSorb filter that is just included into the extracorporeal circulation. And the blood is recirculated about 90 minutes during surgery. This is the average time we need cardiopulmonary bypass for a CABG surgery. So the blood recirculates about 90 minutes through this filter or the adsorber. However, the blood flow is substantially higher than in the experimental paper, it's not just 17 mLs per minute, but about 400 mLs per minute. So the efficacy is probably more or less the same. Next slide, please. This shows you again the overview of our study. About 25% of our patients who came to our department for emergency open-heart surgery were on ticagrelor or rivaroxaban. And until April 2017, we had 16 patients who didn't get CytoSorb adsorption because we didn't know about the possibility. And since then, we have the 39 patients who were on the adsorber. Next slide, please. The next few slides are here to show you that the groups essentially had no preoperative differences. So age and body mass index were comparable in both groups. The New York Heart Association class was comparable. The comorbidities and the number of patients who had renal impairment was more or less the same in both groups, with or without adsorption. Next, please. This slide shows you again that the pump function, the left ventricular ejection fraction was more or less the same in the groups that we compared. The underlying disease was comparable. If anything, the patients who were with CytoSorb adsorption were more complex. We had 3 aortic dissections. We had additional valve disease in a couple of patients. So if anything, they were a little bit more complex. And of course, all of these patients were emergency patients in both groups. Next, please. This shows you the surgical procedures that were performed. Basically, most of those were CABG procedures for myocardial infarct. We had 3 aortic dissections. We had some combination with valve replacement or valve repair. We also had some patients who were on atrial fibrillation surgery. So we did ablation and we occluded the left atrial appendage. And as you can see in the lower lines, that the procedure itself, the surgical procedure itself, the duration was more or less the same in both groups. We had cardiopulmonary bypass times of about 80 to 150 minutes. We had a cross clamp time that was between 64 and 81 minutes. So there was no statistically significant difference. However, the duration of the whole procedure was much longer in those patients who were not on the CytoSorb column. And of course, it's because of the extended time that was necessary to achieve hemostasis. Next slide, please. Here, you can see the further results. When these patients came to the ICU, the drainage volume was much higher in the 2 control groups with 600 to 900 mL during the first 24 hours compared to only 350 to 390 mL per 24 hours. The patients had to be in the ICU longer in the control group and the total stay in hospital was also longer in the control group. We had some rethoracotomies in the 2 control groups. In the 2 CytoSorb groups, there was no patient who had to be put back to theater. So these results were all statistically significant. Next, please. This shows you in a graph, again, the drainage volume that is much higher and I think Dr. Storey just showed similar results for the U.K. If you don't stop the drugs in time, you get, during the 24 hours -- the first 24 hours, you get a drainage volume about up to 1,000 mL and a significant reduction if we use the adsorber in these patients. Next, please. This is a summary, I'm almost ready, of our study. It shows again that the transfusion of platelets and red blood cells was significantly less in the adsorber group. Next slide, please. So our conclusion is that both medical and economic benefits are there. If we use CytoSorb in these ticagrelor and rivaroxaban-loaded patients, we have reduced operation times, a decrease of blood product use and it saves cost by faster discharge of the patients from the ICU. Next, please. The story continues. We have now used the CytoSorb adsorber in more than double of the patients and the results are more or less the same. There's no significant difference in the percentage of patients that had to be transfused or the length of stay in the ICU was more or less still the same. So I think these data are quite valid. And in the first 5 months of this year, we used the CytoSorb adsorption in 18% of all our patients that were put on cardiopulmonary bypass. So it's quite a common procedure in our hospital. Next, please. And so our vision is that we should use it as a routine. The alternatives are actually quite expensive. This is just briefly to show you that the antagonists that are on the market are much more expensive. The antagonist for ticagrelor is not still available, it's in Phase I. Dabigatran will cost you about USD 8,000. And apixaban and rivaroxaban antagonization is much more expensive and almost impossible to be reimbursed by the insurance companies. Next, please. So this is our default procedure now, CytoSorb adsorption in all ticagrelor and all NOAC-loaded patients during emergency cardiac surgery. Thank you very much for your attention and this is my last slide.

Thank you, Michael. That was terrific. And thank you for presenting this impressive data from real-world use of CytoSorb for this indication. The data that you presented, I would like to remind everyone that it were published in the Annals of Thoracic Surgery in 2019 and there's a PDF available for you should you desire to have it. And now we'll move on to our third presentation. We're going to turn it over to Professor Mike Gibson, who is going to educate us on the landscape or on the NOAC use in today's practice and how CytoSorb could be a game changer here. So with that, Mike?

Great. Well, thanks, Makis. And we've heard a lot about the use of this technology during bypass surgery. That's, of course, very exciting to us in interventional cardiology, but we also want to look at how we could use this technology outside of heart surgery, where you could use much smaller filters. Instead of a 100 cc or 300 cc filter, get that down to, say, 40 ccs and where we could use smaller pumps anywhere in the hospital. So we'll talk about how many people are getting NOACs, its projected growth and we'll talk about moving beyond the use of this device for just open heart surgery. Next slide. My disclosures are shown here. I have research grant support from all major manufacturers of antiplatelets and antithrombins and also had been an investigator of Andexanet. Next slide. Here is a full recitation of all of my disclosures. Next slide. While the novel oral anticoagulants have really taken off, they've really replaced warfarin in many scenarios, particularly in atrial fibrillation, their market continues to grow. It's probably the greatest use of the novel oral anticoagulant is in atrial fibrillation. A lot of people undergo knee or hip surgery. And these drugs are used to prevent a post-op clot in those patients, in pulmonary embolism. Recently, several trials have been done, one of which I led, looking at the use of these drugs for people who are just hospitalized for being medically ill. The MARINER trial, for instance, for rivaroxaban was one of these studies. Some patients already have a clot. We're not talking about preventing them. They already have a deep vein thrombosis or pulmonary embolism. These drugs are the mainstay now of treatment for those. And finally, outside the U.S., based upon a trial I led, these drugs can be used for acute coronary syndromes, particularly when you have the overlap of Afib and acute coronary syndromes. So we have a lot of patients out there who have both a stent and atrial fibrillation and they are at particularly high risk of bleeding. Next. Afib is a common condition and it's getting more and more common as our population ages. These are some projections on how many patients in millions there will be by 2050. You can see an estimate of about 12 million if there is no further increase in incidence, that's if the population just grows. But what happens if we have an older population, which I think we will? That number will more likely approximate 16 million. So lots of growth in the numbers, absolute numbers of Afib patients, probably a relative growth in the numbers because of the older population. Next. This slide shows that as you age, you have a higher risk of atrial fibrillation. So it goes from about 13% in people who are in their late 60s, all the way up to 2/3 of patients who are over 90. And again, our population is ending up at about 85 years of age now. That's the mean medium life expectancy. So you can expect half those patients to have atrial fibrillation. So becoming a pretty common disease. Next. How do we treat it? Well, Coumadin, an older anticoagulant or warfarin was the mainstay of therapy for many, many decades. But over the past 10 to 15 years, we've seen that drug be progressively replaced by the NOACs. They tended slightly to reduce the risk of ischemic stroke compared to warfarin. They clearly reduced the risk of hemorrhagic stroke by half. And the bottom line on this chart is you see compared with warfarin, the NOACs reduced mortality. And that has really driven physicians to prefer these drugs now over warfarin, particularly for new starts of the drugs. Next. A big advantage of the NOACs is a reduction in bleeding. Most bleeds are reduced, particularly those intracranial hemorrhages. Some bleeds where some drugs are increased, like GI bleeds. But overall, these drugs tend to be safer than warfarin. Next. So here you have a class of drugs that has reduced mortality. In general, tend to be safer, particularly with our most feared complication, intracranial bleeding, and that has led to their widespread recommendation by professional societies. Societies like the European Society of Cardiology, the American Heart Association, the American College of Cardiology, Chest really recommend these drugs now for both atrial fibrillation and venous thrombosis and their use has really expanded and continues to expand. Next. So given this favorable profile, given the better safety, given the lower mortality, the market share for these drugs has grown. It's a little over $30 billion, as all of you know very well right now, I don't need to tell you, you're the analysts. And the market share is projected to grow to $40 billion by the year 2026, so a growing marketplace. Next. So that's some of the good news promoting use of these drugs. Let's talk about some of the bad news, which is still an ongoing risk of bleeding. This slide shows what proportion of emergency room visits are due to adverse drug effects. And what I've highlighted for you in pink here is the growing proportion of hospitalizations due to NOACs. And this says anticoagulants, but we could show you the same slide for NOACs and you would see the same kind of increase. Again, many of these are GI bleeds and there are several thousand of them each year just in the United States. Next. These bleeds are not only dangerous, but they're costly. So if you come into the hospital with a major bleed and you're on a NOAC, your risk of dying is 4x higher than if you weren't on a NOAC. Your risk of coming back into the hospital is 2x higher and your length of stay is 1.25x longer. So worse outcomes for patients. But the economic impact is substantial. The mean cost of these bleeds is about $50,000. The top 15% cost over $100,000 to treat. So mortal, morbid and costly, not good. Next. So this was the impetus for the development of a couple of drugs to reverse these agents. Dabigatran or Pradaxa is not really a factor 10 inhibitor, it's a direct thrombin inhibitor, but it gets thrown in together with the novel oral anticoagulants. There's a drug to reverse it, Praxbind. You heard about that in the previous talk. It costs about $8,000 for a dose. The other anticoagulants, rivaroxaban and Eliquis, are reversed and are approved for reversal by Andexanet, also known as Andexxa. So this drug is available for those catastrophic bleeds. So again, this slide focuses on how do we manage someone who comes into the hospital with a major life-threatening bleed? It's not talking about preventing bleeds, it's talking about treating major bleeds. The difference here is when we talk about preventing bleeds. Next slide. So I also want to circle back on Andexanet. It's a good drug. It does reverse 92% of the drug levels. It is approved for ongoing life-threatening bleeding, but it's not approved to give to a patient who needs to go to surgery; just someone with active, ongoing life-threatening bleeds, not for prevention. The other thing we found is an excess of thrombotic events. In our first publication, the risk of a thrombotic event was 18%. In our expanded experience with a larger number of patients, about 350 patients, that number came down to 10%. But people should be aware there is a numeric excess of thrombotic events. It's not clear if it's due to the Andexanet or the natural history of stopping an anticoagulant. And as you heard earlier, there are cost barriers. I think you heard numbers cited between $25,000 and $50,000. Those numbers are obviously in a constant state of flux and renegotiation. Next. So again, at the beginning, we're just talking about treating catastrophic life-threatening bleed. Let's now shift over to preventing bleeding, a whole different issue, and that's where I think CytoSorb may play a major role here. There's probably a much bigger addressable market for preventing bleeding than stopping it once it's already begun. Kind of giving a drug like Andexanet and Praxbind, it's a little bit like putting your seat belt on after you've had a car accident. We want to prevent accidents in the first place. Next. So you've heard about the heart surgery use. And you've seen the data previously showing that there was a reduction in the number of transfusions of red cells and platelets, less quantitative chest tube drainage, less rates of coming back and opening up the chest and total length of stay was reduced. All these things are great. It's though for bypass surgery, open heart surgery, with that bigger cartridge, that 300 cc cartridge, and with higher flow states. I think you heard a number mentioned about 400 milliliters per minute. Now obviously, we don't want to have to bring a bypass surgery machine around the hospital to patients' rooms to deploy this in other settings. So what we would need would be to be a smaller cartridge at lower flow. And the question will be, can that be accomplished? Next. Let's talk about why we would need a solution like that. This slide shows how often do you undergo surgery after you've had a stent put in. Now time 0 here is when someone like me puts a stent in. And I got to tell you, when I'm doing the procedure, when I'm talking to a patient, one of the questions I ask them is, "Do you have any upcoming surgery?" And I got to be honest, a fair number of people say, "Oh, yes, I am getting this tooth extracted or I am having a colonoscopy." Or a host of other procedures. Well, what this slide shows is in red, about over 5 years, about 4% of people will have to have the open heart surgery we were just talking about. But look at this number, about 32% of people, the green line, about 32% of people will have noncardiac surgery by 5 years; 32% of people with a stent in will have some kind of noncardiac surgery. That's a lot of patients. Keep in mind, we're doing 1 million of these stenting procedures a year. So that's a large number of people who are going to go on and have to have surgery. Next. So as I said before, what can we do to make this device deployable throughout the hospital in patients' rooms, in the emergency rooms? Well, we have to have a different setup. We have to have probably a smaller filter, a simple infusion pump like a hemoperfusion pump, something that pumps not at 400 ccs per minute, but maybe 1/10 of that. And can we be successful? Well, what I'm going to show you is data for some of the drugs showing that the data suggests that this lower flow approach with a smaller filter can be quite successful in this kind of setting. So the first drug that we're talking about here is rivaroxaban, the one that CytoSorb is approved for in Europe. And using, again, a smaller filter and a hemoperfusion pump, 91.6% of the rivaroxaban was removed in an hour. And on this chart, you see the kinetics. Here, you can see, if you want to get the level below 300, that's a safer level, work your way over by eye from 300, you can see at about 30 minutes, you're probably going to get below that level, probably at most by 60 minutes. So somewhere between 30 and 60 minutes, you're going to get rid of 90% of the rivaroxaban, smaller filter, lower infusion ccs per minute. Next. So you don't have to be on a bypass pump, basically. Now here is an example of a patient. Patient stories are always great. This is a patient who had atrial fibrillation, that disease we're talking about, and they were on 3 drugs, 3 drugs to treat both the atrial fibrillation and their PCI. They're on the rivaroxaban for the Afib; they were on aspirin for Afib and a stent; and they were on ticagrelor and aspirin also for their acute coronary syndrome. So they were on a lot of drugs that cause bleeding. And it's a 58-year-old gentleman who had a tear developed in the main artery going down to the front of his heart, the left anterior ascending. He had ongoing chest pain. This is a complication of the procedure and he needed emergent surgery. So 3 drugs, high risk of bleeding. He didn't have to go like that second. And they gave the CytoSorb using the system we just talked about and they got rid of both the rivaroxaban and the ticagrelor successfully and he had no excess bleeding and he was doing well 6 months later. The theme that I want to point out here is this was not used, this was not used in the OR. This was used in the -- outside the OR. So you don't have to have, again, a heart bypass pump. You could use this outside the OR. Next. Again, another drug that's lumped in with the NOACs, it's a direct thrombin inhibitor, dabigatran. Here, they used that cartridge outside the body -- outside the OR and you can see that it didn't matter where they used a 40 cc cartridge, smaller than the one in the OR, or a 20 or 10 milliliter, all of these got 94% to 98% of the dabigatran removed very quickly. So you could get a much smaller cartridge to do the job as well. Next. And another factor Xa inhibitor is edoxaban. Here's a third example, where they used a cartridge to get rid of 99.5% of the edoxaban in just 30 minutes. So again, the potential to move this from the OR right into the ER, where we could be, hopefully, very, very successful. Next. So I think we've seen a lot of exciting data for the use of this in bypass surgery, but I'm very excited by the use of the drug in this expanded setting throughout the hospital, off-pump bypass surgery, EP procedures. I was recently called into the EP lab because they were doing the procedure. They perforated the heart and got a bleed into the sac surrounding the heart, something called tamponade, which can be fatal. And I was stuck having to try and reverse the agents there. So this could be a safer way to do those procedures. Brain surgery, obviously, that's something where you don't want bleeding because you have, again, a contained -- brain contained within the skull, and there's not a lot of room for blood in there, very dangerous. Sometimes, when you fall down and hit your head, you might drill a hole to get the blood out. But many times, they'll just watch the patient and see if it doesn't expand. If you could reverse a NOAC, you might be able to more safely observe those brain surgery patients. Acute stroke, more and more of those. One of the best treatments we have is a clot buster called t-PA. But if you're on a NOAC, that's a contraindication. Maybe we could reverse things so some people could get t-PA. Lot of falls in these older patients, a lot of broken hips. It could really use a clean surgical field with reversal before that. Lot of GI and cancer surgeries and GU surgeries could be safer. And finally, a lot of people have trauma and this could be, again, a better way to do those procedures and you have that golden hour to get someone to the OR, one of the biggest complications is bleeding in the trauma setting. Maybe we could reduce that risk with this deployment right in the ER before they go. Next. So to sum up, NOACs are really now the standard of care. They are progressively replacing warfarin. We have more and more older people. They are developing more and more atrial fibrillation. The NOAC use is good, but there are certain challenges due to the bleeding risk, particularly if you go to surgery. And CytoSorb is a potential strategy before you go to the OR, before you go to the OR, anywhere in the hospital, hopefully, that you could use this to prevent bleeding. We could hopefully use smaller pumps, smaller filters to get the job done anywhere and I'm very excited about the future of the -- of this technology throughout the hospital. Thanks for listening to me today.

And thank you, Mike, for a wonderful presentation. A lot of thought-provoking considerations there and certainly, a lot of work for us to do going forward. So if I could please have the next slide. So I've prepared some closing remarks before we move into a Q&A session. But I want to thank all 3 speakers for their wonderful presentations and you'll have an opportunity to directly ask them your questions in just a couple of minutes. Next slide, please. A very quick update on the regulatory status and clinical activities that CytoSorbents is engaged in, in regards to this indication. As noted earlier, CytoSorb received CE Mark approval this year for the removal of both ticagrelor and rivaroxaban in patients undergoing cardiac surgery. As you see on the slide, you will note on the instructions for use, the inclusion of the 2 antithrombotics to the existing approved indications for removal of cytokines, bilirubin and myoglobin. In the U.S., also earlier this year, we received FDA Breakthrough Designation for the removal of ticagrelor in patients undergoing cardiac surgery and we are currently engaged with the agency in ongoing discussions to clarify the regulatory path forward. Regarding our clinical activities that are ongoing, we have 2 dedicated prospective studies on ticagrelor removal in cardiac surgery, one in the U.K., the TISORB trial that Rob has already discussed in detail. But we also have assisted trial called CYTATION in Germany. The intent of both of these trials is to generate prospective data that will further support the broad clinical use, but also inform reimbursement decisions for this indication in both countries. We are also launching the STAR registry, which stands for safe and timely antithrombotic removal, before the end of this year, with the intent of prospectively capturing real-world clinical use of CytoSorb for this application. The registry activities will start in Europe, but the plan is to expand also in the U.S. and the rest of the world. Next slide. We talked about the clinical setting where CytoSorb could be used. We also talked about the clinical efficacy and safety of the use for these patients. However, we haven't yet discussed the size of the addressable market. In this slide, you will see our exercise to identify that size for the United States, specifically related to ticagrelor removal. There are approximately, we estimated, 600,000 cardiac operations in the U.S. annually and 2/3 of them would represent the type of operations that would be candidates for CytoSorb. We specifically for this model focused on CABG, meaning coronary artery bypass grafting surgery, and aortic surgery, for a total of approximately 354,000 operations per year. We estimated that 40% of the surgeries would be either urgent or emergent, since we believe the application of CytoSorb would primarily be used in that population. And we removed the number of cases that would be considered elective. That left us with approximately 154,000 surgeries for the U.S. We then removed patients not treated with a P2Y12 inhibitor or patients receiving another type of P2Y12 inhibitor other than ticagrelor. And in the end, we ended up with still 50,000 cases, surgical cases that will be candidates for ticagrelor removal with the CytoSorb device during cardiac surgery. With an estimated unit cost of approximately $5,000, which is directly linked to the cost savings observed in the U.K. in the study that Dr. Storey presented earlier, we estimate that the market for CytoSorb removal of ticagrelor in the United States is approaching $250 million. Next slide, please. However, that's only the beginning. We believe there's sequential growth for that market and for this application. First of all, the trends, the macro trends, are in favor for a growing opportunity. We heard today the aging of the population. We also heard from Professor Storey that ticagrelor market share is increasing. We also believe that the availability of CytoSorb will truly turn ticagrelor as the only reversible anticoagulant agent, thereby increasing its advantageous position across the board and across its competitors. We, therefore, have now in this graph shown you what the addressable market would look like if we added the opportunity of removing NOACs to the opportunity of removing ticagrelor. First, keeping this opportunity within the cardiac surgical field, that would easily double the size to $500 million. But we believe if we can execute on the ideas and the suggestions that Dr. Gibson had in his recommendation of moving to a hospital-wide system that can help remove these agents from patients requiring any type of surgery, not just cardiac surgery, then we have used the model -- multiple of at least 3x, which would bring the U.S. addressable market to $1.5 billion, again, with long-term trends suggesting even greater adoptance of this product and greater size of this opportunity. Next slide. In closing, antithrombotic drug removal with CytoSorb is a novel solution to a very large unmet hospital need. Currently, there are no available therapies to prevent bleeding. Andexxa or the PhaseBio antibody to reverse ticagrelor, which is not yet approved, are intended only for use after life-threatening bleeding has occurred. CytoSorb antithrombotic removal in cardiac surgery is safe, effective, easy to implement and is expected to lead to substantial cost savings. It's one of those rare instances where new intervention not only improves clinical outcomes but reduces overall cost. That is called a dominant value proposition: already approved in the EU for cardiac surgery and has received Breakthrough Designation by the FDA for ticagrelor removal. Ongoing clinical projects to establish removal of additional NOACs and hospital-wide clinical use are in progress. And we believe that the estimation of at-risk surgery and the whole addressable market exceeds $1.5 billion a year in the U.S. alone. With that, we want to thank you for your attention. We also want to help and thank LifeSci Advisors for hosting this event. And now we would like to turn it over to our Q&A session. Tara?

[Operator Instructions]

I think we will take our first question from Joshua Jennings from Cowen.

Can you hear me?

Yes.

Thanks to all the clinicians for the outstanding download of this opportunity. I was hoping to ask Dr. Schmoeckel, first. Thanks for the update on your center at St. Georg. And just curious about you're now -- your relaying that you're using CytoSorb in, I believe, all your ticag cases now for emergent surgeries. One, do you believe your center is an outlier in Germany? Are there many other centers using CytoSorb for ticagrelor removal currently? And do you expect many more to start utilizing it in front of the study that's now slated to kick off later this year in Germany, just looking specifically at that indication?

Well, thank you for this question. Obviously, we have presented our results on a couple of conferences. And most of our colleagues in Germany are aware of the possibilities the new therapy with the CytoSorb gives us. And as far as I am aware, there are -- most of the German centers are in the process of including the CytoSorb adsorber into their regimen for the treatment of emergency and urgent CABG patients. We are starting our study as a multicenter study in autumn now. It was a little bit delayed because of the COVID crisis. Our Ethics Committee was not having these meetings, and so we couldn't get approval, but we now have approval to start off. And I am expecting that we can start off with the first 4 centers in Germany now by the end of probably, well, August, September, something like around that. So I'm pretty much sure that this sort of therapy will go into routine clinical practice, pretty sure, in the near future.

Excellent. Maybe just one follow-up for Dr. Storey. Thanks for your download as well. I was wondering maybe the CytoSorb -- CytoSorbents team could pitch in as well, if -- on part of this question. But just wanted to hear about your current utilization of CytoSorb for the ticagrelor removal indication in your center. And then also with the TISORB study restarting enrollment, the path forward there for potential increase in utilization in the U.K., whether or not there need to be a NICE recommendation or any reimbursement that's put in place in the U.K. to catalyze strong utilization?

So I mean the use in the U.K. of this system is quite limited. There needs to be an education program to disseminate the awareness of this system amongst U.K. cardiac centers. It -- you -- the availability of this device will sort of need to lead to a sort of dynamic conversation between cardiac surgeons and cardiologists in the U.K. to look at practices and to drive both the use of ticagrelor and the use of this system to remove it when patients go for surgery and to shorten length of stay. So we're at a very early stage of that process. And TISORB really is one of the ways that the knowledge and experience within centers will be increased and stimulate some of the use. I'm not sure, not being a surgeon, being an interventional cardiologist, how many cases we've used it on. In my center at the moment, it's mainly to date being used for the odd case of cytokine removal with sort of quite strong sort of anecdotal evidence for benefit in that setting. So yes, very early stage, but potential to really take off and create a synergy between ticagrelor and the system.

Yes. I think that if I could additionally comment. CytoSorb has just received EU approval for the removal of ticagrelor in January and rivaroxaban just shortly thereafter in the past few months. We have not actually been able to get out there because of COVID-19 to actively market this application. But I think that as Europe opens up with the resolution of -- hopefully, the resolution of COVID-19, we believe that there will be much greater awareness of this application for CytoSorb out there and hopefully will help to stimulate usage in these applications.

Next, we're going to go to Andrew D'Silva from B. Riley FBR.

Can you hear me now?

Yes.

Okay. Thank you very much for hosting us today. I just have 3 quick ones and they're open to all presenters. So to start, I was curious, are there situations where you would prefer to wait and see if ticagrelor or rivaroxaban naturally left the system over time? Or are you already utilizing CytoSorb as a standard at any of your centers? And the second question kind of ties into that. As you look at everything we're seeing with COVID-19, do you actually expect that would just make more sense for everyone to just implement this immediately so that patients don't have to actually wait and come back to the hospital and potentially be infected?