Good morning. My name is David Zonis, and I am a professor of surgery and a surgical intensivist at the Oregon Health and Science University in Portland, Oregon. And I'm really excited this morning to be moderating this session on the anticoagulation strategies and some real interesting innovation in extracorporeal life support and in mechanical circulatory support devices. We have about two hours to talk about four really interesting topics. And so I just wanted to briefly review the objectives that we're going to be discussing this morning. The first is we're going to talk about some of the new novel anticoagulants and anticoagulation strategies that we can use in mechanical circulatory support devices such as left ventricular assist devices. We'll have what I think is going to be a really robust conversation about the use of bivalorudin as an alternative to heparin anticoagulation as an initial strategy during the use of mechanical circulatory devices such as ECMO and other devices such as LVADs and impellas. And then along that similar theme, we'll have a discussion and a great talk about the use of anticoagulation strategies when we're forced in a situation which is uncommon but does occur, which is heparin-induced thrombocytopenia. And I don't know how many of you have been in a situation where you have a patient that's already on support and then develops heparin-induced thrombocytopenia and then you're really stuck with what your options are. And so I think this will be a really informative discussion about what strategies we have to deal with this. And then finally, in the area of innovation, we're going to wrap up with a discussion about the use and the early use of extracorporeal life support therapies as early as in the emergency department for very particular situations really early in the hospital course. And so by way of that, I'd like to introduce just briefly what the four talks are going to be like over the next hour and a half to two hours. So again, the first is Zachary Smith, who is a clinical pharmacist at the Henry Ford Hospital, and he'll be discussing this particular situation of heparin-induced thrombocytopenia and what our management and options and strategies are of dealing with this in a patient who's on extracorporeal support. This will be followed by a discussion of the novel oral anticoagulants by Jessica Crow, who is a clinical pharmacist out of Johns Hopkins, and she'll be discussing the role of these novel oral anticoagulants aside from heparin specifically in mechanical circulatory devices such as LVADs. Dr. Eddie Phan, who is out of the University of Toronto, will be discussing, I'm really looking forward to this talk, on the use of bivalirudin as an alternative to traditional heparin anticoagulation strategies and what the role could be for the use of this alternative medication. And then finally, again, in the area of innovation, we have Isaac Towle, who's an intensivist and a professor of emergency medicine from University of New Mexico, who will be discussing the early role of extracorporeal support as early as in the emergency department and will be presenting some really interesting data that supports its use. Many of us know that extracorporeal support has been part of the advanced cardiac life support algorithm for several years, and I'm really looking forward to hearing more about how this actually gets implemented early in a patient's course. Without further ado, I'd like to turn it over to our first speaker. Hello, everyone. My name is Zachary Smith. I'm a clinical pharmacy specialist at Henry Ford Hospital, and today I'll be discussing hitting the road with heparin advanced percutaneous mechanical circulatory support with heparin-induced thrombocytopenia, and I have no conflicts of interest with regards to the presentation of the information today. The objectives of the presentation are to identify anticoagulation options to manage advanced percutaneous mechanical circulatory support for patients with heparin-induced thrombocytopenia. Just a brief overview of cardiogenic shock. It's associated with mortality rates of anywhere from 3 to 67 percent depending on the classification scheme as well as the severity, and we know the incidence of cardiogenic shock is the presenting diagnosis to the cardiac ICU is increasing over time. General management includes resuscitation with fluids, vasopressors, and inotropes, and then medical interventions targeting the underlying etiology of the cardiogenic shock. Ultimately, some patients will recover. Those that do not will then go to be assessed for percutaneous mechanical circulatory support, or MCS, which we'll be focusing on today. Those that are unable to be weaned from percutaneous MCS are assessed for transplant or a durable ventricular assist device and ultimately may recover from that, but we'll be focusing on this MCS population, temporary MCS population today. The percutaneous MCS devices ultimately provide cardiac support while awaiting reversal of the cardiogenic shock etiology. We know that a quarter of patients from 2005 to 2014 received one of these devices to manage their cardiogenic shock. There are several devices that are available to clinicians. I have them listed here strictly in the cardiac output or cardiac flow that's provided. We have the intra-aortic balloon pump, which provides up to one liter per minute. You have the Impala series, depending on the device, that can provide anywhere from one to five liters of support. You have the tandem heart that can provide anywhere from two and a half to four and a half liters of support. And lastly, you have venal arterial ECMO that can provide total cardiac support as well as perform gas exchange for the patient. It's important before we start talking about HIT to understand the complexities with these devices with regards to the anticoagulation that's required. So for the Impala series, we have a setup here for the two and a half cardiac power and 5.0. Ultimately, these devices are inserted percutaneously into the ephemeral artery and it's threaded up into the aortic arch and the device is ultimately placed within the left ventricle, which withdraws blood from the left ventricle and ejects it into the aortic arch using a microaxial continuous flow pump. These pumps also provide other additional hemodynamic effects listed here. The pump is ultimately managed or controlled by an external controller. You have a dextrose purge solution, the actual pump controller, as well as a pressure bag to measure the pressure within the device. The external controller administers a dextrose purge solution to maintain a target pressure within the device to prevent blood from entering that device and ultimately preventing a thrombus or device thrombus. The purge flow rate is exclusively managed by that console. Clinicians don't have control of that and it ranges from 2 to 30 mL per hour to maintain a pressure within that device of 300 to 1100 millimeters of mercury. Dextrose 5% in water is the default solution. The manufacturer recommends adding unfractionated heparin to that purge to further prevent device thrombosis and the unfractionated heparin purge concentration that's recommended by the manufacturer is 25 or 50 units per mL. You can see on the pump console the purge information is listed here in this red box. You have the purge flow rate as well as the purge pressure. Next you have the actual motor of the device. On the left side you have blood being withdrawn from the left ventricle and then ultimately being ejected into the aortic arch through this microaxial pump and you can see coming in from the right you have the purge fluid running countercurrent to that blood flow that ultimately creates that pressure barrier and prevents blood from entering that motor. Next we have the tandem heart. The tandem heart is surgically implanted by a cut down. The catheter is threaded up through the femoral vein into the inferior vena cava and placed in the left atrium via transeptal puncture. Blood is withdrawn from the left atrium that's oxygenated and then ejected into the femoral artery via a central fusional continuous flow pump. In terms of this pump it also has an external controller that administers a purge solution to prevent thrombosis within the motor housing unit. The purge solution is delivered at a fixed rate of 10 mL so this does not modify for the tandem heart and sodium chloride or normal saline is the default purge solution. The manufacturer recommends adding a fraction of heparin to the purge at a standard concentrations of 90 units per mL. Lastly we have the venal arterial ECMO. This is a femoral axis setup. Ultimately this device has a central fusional pump, membrane oxygenator, and heat exchange. This can provide total cardiac support as well as oxygenate and remove carbon dioxide from the blood. Systemic heparin targeted toward an institution-specific anticoagulation goal is recommended and that anticoagulation goals varies depending on the institution. To summarize the anticoagulation goals on the slide here you have the parameter on the left and then the various devices moving to the right. You have your goal ACT and APTT provided for the impella and tandem heart based on the manufacturer recommendations and for venal arterial ECMO there's a broad range that's reported in the literature. Ultimately that's an institution and patient-specific decision. When looking at the heparin dose provided from the purge for the impella depending on the concentration of heparin it can range anywhere from 10 to 1500 units per mL and then for the tandem heart using the manufacturer recommended purge concentration it's 900 units per mL. So you can imagine for some patients this would lead to subtherapeutic dosing, therapeutic dosing, or supratherapeutic dosing, which adds to the complexity for these devices. In terms of systemic infraction heparin in addition to the purge it is recommended for both the impella and the tandem heart to meet those anticoagulation goals and then for VA ECMO heparin is exclusively provided through the intravenous route for this device. For the impella and tandem heart this raises a complexity because you're ultimately delivering heparin from two sources one from the purge solution and then one from the systemic intravenous heparin. So it becomes a complexity issue and a patient safety issue with delivering two sources of heparin to a patient, which when we review this management and hit it adds to the complexity of managing that disease in a patient with these devices. This is an example of a heparin protocol just to illustrate some of these concepts. You have an APDT goal listed here or range listed here. You have the impella device and then the tandem heart device as an example. This impella protocol ultimately only modifies the systemic unfractionated heparin dose based on the PTT level. For the tandem heart example you can see as you are becoming sub-therapeutic to super-therapeutic adjustments are made both to the systemic unfractionated heparin dose and the purge unfractionated heparin dose. So ultimately you know these are two principles that may help guide the management when you are taking care of patients with heparin-induced thrombocytopenia when using alternate anticoagulants using these two different principles. Unfortunately these devices are not without serious adverse effects. There's neurologic, infectious, mechanical, and vascular complications. The ones we'll be focusing on today are hematologic in nature. So we have major bleeding, hemolysis, thrombocytopenia, and then what we'll be focusing on for the remaining portion of the presentation today is heparin-induced thrombocytopenia. The rate that this has occurred that's been reported in the literature is anywhere from 0.4 to 8 percent depending on the population studied and the definition utilized. The majority of the literature points that that hit rate is towards the lower end of that spectrum reported here. Before we move into management of hit within the MCS percutaneous population we first will review general management of hit with the current evidence-based guidelines. So hit is a prothrombotic reaction meted by typically IgG antibodies targeting the platelet factor 4 heparin complex. There's two diagnostic assays that are available to help guide clinicians in diagnosis. An immunoassay which measures the presence of those antibodies, typically an example would be an ELISA reporting on optical density, and then the functional assay detects antibodies capable of binding and cross-linking platelets such as a serotonin release assay. Hit diagnosis should be guided by the 4T score instead of a non-standardized approach. The 4T score is a score that ranges from 0 to 8 and has three levels of probability. The low probability score, if a patient falls within that category it's recommended to continue current management and make no orders of assays. If it's intermediate or high probability 4T score it's recommended to discontinue all heparin products and order the immunoassay. If the immunoassay is positive it's recommended to order a functional assay to confirm the diagnosis. In terms of impaired treatment of hit based on that pretest probability score, if it's low probability it's recommended to continue the unfractioned heparin therapy. If it's intermediate probability it's recommended to provide prophylaxis or treatment with an alternate anticoagulant depending on if an indication for anticoagulation is present. And then if it's high probability clinicians should switch to an alternate anticoagulant at treatment dose. Now it's important to know that most of these recommendations are for a general ICU or medical population and don't directly apply to the percutaneous MCS population, which given the complexities that we've reviewed with these devices it puts clinicians in a challenging position. So some considerations with these guideline recommendations, these for the hit assessment and diagnosis, the 4T score hasn't been fully validated in this population so there's question on whether it can be directly used for this population. Initiating an alternate anticoagulant, there's complexities in selecting the dose and the alternate anticoagulant for this population given their critical illness. There's question on whether that alternate anticoagulant should be added to the PIRG solution to mimic what's done with unfractionated heparin and then selecting anticoagulation goal. So in these patients you'll have a higher intensity goal potentially due to the diagnosis of hit than what would be called for then with the device manufacturer recommendation anticoagulation goals. Next there's monitoring the MCS device and anticoagulant, so modifying therapy based on the hit assay. Modifying the alternate anticoagulant dose becomes complex if you're providing this within the PIRG solution. It's something that may or may not be controlled by the clinician for the impala and the tandem heart respectively. Assessment of the MCS device function, so making sure there's no pump thrombosis and then bleeding and thrombosis in the patients depending on which device has been selected different bleeding rates exist for the pumps that are used. And lastly we won't really be focusing on the long-term therapy but when patients recover and these devices are removed or they're assessed for transplant or a durable ventricular assist device there's several options that are available once the the PIRG-contained temporary MCS device has been removed such as warfarin, idrect, oral anticoagulant or fondant paranox given the underlying treatment paradigm for that patient. So in terms of using the 4T score there's two studies that exist that use the 4T score. The first study found that a 4T score less than or equal to three had a 90% negative predictive value for ruling out hit and the second study showed a 4T score greater than equal to three demonstrated a receiver operating curve of around 88%. So this seems to suggest that it's reasonable to use the 4T score at least at this time to help guide decision making when assessing a patient or for if they have hit with PIRG-continuous MCS support. Next you have assessment of hit in patients using high-risk characteristics so these are expert considerations from experts within the field. So you have high-risk characteristics so persistent thrombocytopenia, secondary fall after the initial recovery of platelets, inactive thrombus on infractionated heparin, and then absence for other cause of heparin. These recommendations take into consideration some of the complexities we reviewed. So if they don't have any of these high-risk characteristics it's recommended to order the hit assay and then consider maintaining infractionated heparin if there's a low concern for which is not typically what is done with heparin-induced thrombocytopenia but given the complexity of these patients if there's a low concern it may be reasonable. If they do have these high-risk characteristics clinicians should order the hit assay and then consider switching to an alternate agent to provide anticoagulation and removing all infractionated heparin products. Ultimately once that assay comes back if it's a negative assay maintaining infractionated heparin and then assessing for other causes of thrombocytopenia and then if the assay comes back positive consider switching to an alternate anticoagulant and removing all heparin products if they haven't been already. So these two slides seem to tie together high-risk characteristics as well as utilizing our 4T score which may help guide clinicians in the empiric diagnosis as well as management of this population. Next in terms of management once the diagnosis is empirically made or it is confirmed you have several options for acute hit management. Really the only two will be focusing on today are Argatroban and bivalrubin. Bivalrubin which are drug thrombin inhibitors that are administered intravenously. Argatroban is hepatically eliminated and bivalrubin is enzymatically eliminated with some renal elimination. The gold anticoagulation levels for heparin-induced thrombocytopenia are listed here. The reason why we're focusing on these agents is their short acting as well as having a relatively decent amount of literature supporting their use in the percutaneous MCS population. One thing that clinicians need to be mindful of these two drug thrombin inhibitors is there's currently no antidote or reversal agent available. So if a clinician was in a scenario where they're managing a patient with bleeding there's not really an antidote for these agents currently. We won't really be reviewing the remaining agents because there's limited literature supporting their use within the percutaneous MCS population and the agents are really long acting so it really precludes their use in this critically ill population that their management may be fluctuating throughout the day. In terms of initial DTI dosing within the MCS population really this is a multifactorial decision that takes into consideration several parameters. First clinicians should consider the FDA dosing considerations. So for argatraban it's dose based on a liver function using the child's PEW score. We know that lower dose requirements are needed in patients with critical illness that have multi-organ failure, those with heart failure and anasarca. For bivalrudin dose adjustments are called for based on the creatinine clearance of a patient. We know if a patient's receiving continuous renal replacement therapy this may increase the bivalrudin requirements. This is really all we'll be focusing on with regards to HIT management and ECMO. This is pretty well described in the literature and I have the dosing information listed here. Argatraban doses range from very low infusion rates up to one mic per kilo per minute in the literature. The ESLO guidelines recommend starting at 0.5 to one mic per kilo per minute. For bivalrudin the dosing report in the literature is listed here as well as ESLO recommendations of 0.03 to 0.1 milligrams per kilo per hour and ultimately it's titrated to an institution specific APTT goal. For the remaining portion we'll be focusing on the percutaneous ventricular assist devices. For argatraban you have the Impala dosing range reported in the literature for the initial dosing being 0.3 to 0.7 mics per kilo per minute, so slightly lower than what's been reported by the FDA label dosing. There's a single case report of a tandem heart that was started at one mic per kilo per minute and then for bivalrudin with the Impala it pretty much reflects FDA label dosing with regards to the ranging from 0.04 to 0.12 milligrams per kilo per hour and then there's a single case report with a tandem heart using percutaneous coronary intervention dosing for bivalrudin at 1.75 milligrams per kilogram per hour. So first we'll review the Impala management. The manufacturer recommends using an alternate anticoagulant systemically and not placing an alternate anticoagulant in a device purge solution, so this is contradictory to what's done with unfractionated heparin. Investigators did a survey of high volume centers across the United States and found that 58% of centers placed direct thrombin inhibitors within their purge solution, 25% reported using a dextrose only purge solution, and then 17% of centers reported no strategy had been developed. So to review the literature that's available, there's only 21 cases, there's definitely no comparative studies between these different approaches, and in terms of the items I'd like to point out on this slide, you know, all the Impala devices have been described as using a direct thrombin inhibitor with them. Majority of these cases are HIT positive cases. The PTT goal that was reported in the literature for the target ranged from a heparin-induced thrombocytopenia specific goal to the manufacturer device anticoagulation goals. The days of direct thrombin inhibitor therapy ranged from one and a half days up to 23 days, and importantly there was no serious bleeding events and no reports of device thrombosis in these patients. So really we're limited to case reports and case series. There's no head-to-head comparisons for these different approaches, which kind of adds to the complexity, but because there's no definitive literature to guide the management of this population. So really clinicians have three approaches that can be taken for providing anticoagulation with the Impala in the setting of HIT. Discontinuing the heparin within the purge and systemic heparin. Clinicians could use a dextrose-only purge and provide systemic direct thrombin inhibitor. Really clinicians in this scenario just have to select the DTI as well as the dose they'd like to initiate. In the second scenario, the direct thrombin inhibitor can be added to the dextrose-purge solution only and not be provided through the systemic route. In this scenario, clinicians are selecting the DTI and their dose. There needs to be an assessment of the purge rate and the variation in the rate, and then select the DTI purge concentration. It's important to be mindful that with the Impala you don't really have control of that purge infusion rate, so you're not really able to have full control over the dose that's provided. So really making sure the concentration you're selecting based on the purge rate for the patient provides the anticoagulation that's needed through that DTI purge. And then the third scenario is placing the DTI within the purge and then providing an additional IV systemic DTI similar to what's done with unfractionated heparin. So in this scenario, you're selecting the DTI and a dose, assessing the purge rate and the variation in the purge rate, selecting the DTI purge concentration, identifying the purge dose, making sure it's you know anywhere from 25 to 75 percent of what you would expect a patient to require being administered through the purge as an example, and provided the remaining direct thrombin inhibitor to reach your therapeutic goal and through the intravenous route. Next clinicians have to determine what goal they'd like to target and the frequency of monitoring. So we'll focus on these latter two options for the next few slides here. So considerations for developing a DTI purge for the Impala, assessing the expected duration of the Impala support, and if clinicians decide initially not to add the DTI, it can always be added at a later time. There is serious risk of thrombus both for the patient as well as the device, and then bleeding risk needs to be considered. In terms of selecting a DTI purge concentration, Bivalrutin and Argatrabin only have compatibility for data for D5W, so that really should be the only base solution that's used currently. And then selecting a DTI purge concentration that would not exceed the systemic dose based on the purge infusion rate. So I have the different concentrations for Argatrabin and Bivalrutin listed here, and just to show it as an example, you know you want to be thinking of what is the minimum dose that would be required with the purge solution and the maximum dose that would be provided. And I've used a lower Argatrabin concentration for this example, and then a higher Bivalrutin concentration to illustrate some points. And then ultimately you want to convert that to a patient-specific dose based on their weight. So you see for Argatrabin that's a relatively low dose, and then for Bivalrutin that can be a dose that exceeds the FDA-labeled recommendations. So then kind of comparing that So then kind of comparing that what's been reported in the literature in terms of dosing requirements, you can see that Argatrabin purge in this example would likely work for most patients, and then Bivalrutin purge is probably too high of a concentration and may provide too high of a dose leading to supertherapeutic anticoagulation. So once you've selected your purge concentration, really the next steps are selecting the total dose that you would like to administer. So in this example we're using 0.5 microns per kilo per minute, and then determine the purge dose that would be administered using your concentration. In this example we're using 50 microns per minute, and you multiply that by the purge infusion rate and then divide it by 60 to convert it to microns per minute. So you get 0.12 microns per kilo per minute. Next is calculating the initial Argatrabin systemic dose. Using the formula here you have the Argatrabin total dose minus the purge dose equates to the systemic IV dose. So in this example 0.38 microns per kilo per minute, and then coming up with a monitoring plan as listed here. Next once you've initiated the therapy you want to assess your PTTs to see if the patient's at goal. First when you're assessing your Argatrabin, the total dose has to be recalculated each time you're assessing a PTT because the purge rate may fluctuate. So ultimately you'd use the steps on the previous slide to determine the purge dose, and then once you have your PTT value you would use your standardized protocol or a patient-specific protocol. If the PTT was low, as an example, you could use the formula here to calculate what adjustment needs to be made to the systemic Argatrabin. So in this example you're reducing the total dose by 20%, so the Argatrabin total dose, or I'm sorry increasing it by 20%, so you're multiplying by 120%, and then subtracting the purge dose to get your new systemic dose, and then continuing to monitor your therapy based on your institution specific monitoring parameter. Next we'll be moving to the TANFM heart. So there's two case reports using this. Really there's one with bivalrutin and Argatrabin. Really the two options that are reported in the literature is using a sodium chloride only purge and providing systemic DTI, and then adding the DTI to the purge solution, and then providing systemic DTI. The one additional consideration is that the TANFM heart has a fixed rate of 10 miles per hour, so you can use the principles provided in the last slide to come up with a management and adjustment approach for the TANFM heart management. Lastly, clinicians should consider standardization of practice within their institution. So this allows for selection of the anticoagulation options, selecting the DTI and the purge concentrations, coming up with a monitoring plan, assigning team members who are responsible for dosing and monitoring, and then educating all the team members involved in this patient's care. Lastly, to summarize, for hit assessment it seems reasonable with the literature available to use the 4T score to guide decision making in this population, and then utilize other high-risk characteristics to guide decision making. The anticoagulation approach, selecting a DTI agent and initial dose based on the organ dysfunction present in the historical literature available. Selecting for the peripheral ventricular assist devices what approach you'd like to use at your institution for an individual patient. Selecting the anticoagulation goals and then considering standardization of practice within your institution and lastly assessing the patient as well as the device, monitoring modification of anticoagulation goals based on bleeding and thrombosis that are occurring in real time, assessing the Impala purge pressures, LDH, plasma serum, plasma for hemoglobin for device thrombosis as well as platelet levels and for extracorporeal membrane oxygenation, assessing the oxygenator as well as the circuit for clotting. And that concludes my presentation. I'd like to thank you for your attention. Good morning and thank you for the opportunity to speak with you today. I'll be addressing the controversial topic of whether direct oral anticoagulants are appropriate for use in patients with left ventricular assist devices. These agents have been shown to be safe and effective in patients with atrial fibrillation and venous thromboembolism and they have a number of pharmacokinetic advantages over warfarin. We will investigate whether these benefits extend into the LVAD population which is known to have much higher risks of both bleeding and thrombosis. I have no relevant financial disclosures for this presentation. My objectives for this presentation are to describe risks of bleeding and thrombosis associated with left ventricular assist devices, to differentiate risks of bleeding and reversal strategies for direct oral anticoagulants which I will refer to as DOACs compared to vitamin K antagonists or BKAs, and lastly to evaluate literature and summarize recommendations regarding the use of DOACs in patients with LVADs. As the prevalence of heart failure rises, LVADs are increasingly implanted as destination therapy or bridge to transplant. The three devices that are currently being used in practice are the HeartMate 2, the HeartWare which is also known as the HVAD, and the HeartMate 3. The HeartMate 2 is a larger pump that uses continuous axial flow in which the rotors have the potential to cause shear stress, thrombus formation, or have mechanical failure. The HeartWare is a smaller intraparicardial pump with continuous centrifugal flow. The HeartMate 3 is also an intraparicardial pump with centrifugal flow but is fully magnetically levitated in an effort to reduce thrombus formation. It also has intrinsic pulsatility to reduce shear stress and stasis of blood. The most common types of bleeding in LVAD patients are perioperative bleeding, gastrointestinal bleeding, and intracerebral hemorrhage. Up to 30% of LVAD patients experience major bleeding beyond the initial postoperative period and they are the most common cause of hospital readmission. The causes of bleeding in LVAD patients are multifactorial. Inferred von Willebrand syndrome occurs due to high shear stress causing proteolytic cleavage of high molecular weight von Willebrand factor molecules, and platelet dysfunction can also occur with high shear stress. Patients with LVADs require lifelong anticoagulant and antiplatelet therapy, which contributes significantly to the risk of bleeding. Angiodysplasia and arterial venous malformations also occur in LVAD patients. While the precise mechanism is not clear, it's thought to be related to the continuous blood flow in LVADs. The most common types of thrombosis in LVAD patients are pump thrombosis and ischemic stroke. Exposure to foreign surfaces results in activation of the contact pathway and areas of vascular injury can also activate the tissue factor pathway of the coagulation cascade. LVADs also have regions of blood stasis, particularly with axial flow devices, which has been improved with the design of the HeartMate 3 device. Patients with LVADs may also have comorbidities such as atrial fibrillation, hypertension, and infection, which have been shown to increase the risk of thrombosis. Thrombosis occurs relatively commonly in LVAD patients and is associated with a high rate of morbidity and mortality. Pump thrombosis is defined as clot formation with any of the components of the LVAD or clots that form elsewhere and travel into the device. Pump thrombosis can lead to acute heart failure requiring pump exchange and embolic events such as ischemic stroke. An observational study of HeartMate 2 LVADs at three institutions demonstrated a drastic rise in pump thrombosis up to 8% at three months and devices implanted after 2011. While the cause of the rise in thromboembolic events is not clear and is likely multifactorial, the use of optimal anticoagulation as an attempt to minimize the risk of bleeding may have contributed. In an effort to reduce the risk of thromboembolic events, the PREVENT trial assessed adherence to a protocol using HeartMate 2 implantation techniques, postoperative bridging with unfractionated heparin, and pump speed management. They demonstrated that adherence to key recommendations reduced the incidence of pump thrombosis from approximately 9% to 2% at six months. The rate of thromboembolic events differs with each device and in the graph you can see the incidence of thrombotic events categorized by the type of LVAD on the x-axis and percentage of patients on the y-axis. Note that these are not all direct comparisons as these event rates were compiled from several publications. The Momentum 3 trial published in 2019 demonstrated that HeartMate 3 had a lower rate of pump thrombosis of 1.4% at two years, which is shown in the orange, compared to almost 14% of patients with the HeartMate 2 device, which is shown here in blue. Ischemic stroke is relatively common and similar between the HeartMate 2 and HeartWare, but was lower with the HeartMate 3 device at approximately 10% of patients at two years. Patients with LVADs require lifelong anticoagulation to prevent thrombosis and warfarin has been the mainstay of therapy. It has the advantages of extensive experience, it's easily reversible, and can be used in patients with renal dysfunction. DOACs have become favored in the treatment of atrial fibrillation and VTE due to advantages such as wide therapeutic index, monitoring is generally not required, lower risk of ICH and limited food and drug interactions. However, both warfarin and DOACs have a number of unique disadvantages. I'll focus on a few of these in more detail since they're of high importance in patients with LVADs. Maintaining INR in the therapeutic range can be challenging in patients with LVADs due to high risk of bleeding and the potential presence of right heart failure, which can increase sensitivity to BKAs. A retrospective study of patients with continuous flow LVADs demonstrated a high risk of thrombotic events at 0.4 per patient year with an INR of less than 1.5, which was also relatively high at 0.16 with an INR of 1.5 to 1.9. Another study demonstrated that the time in therapeutic range in the past two months was significantly lower in patients with pump thrombosis compared to those without pump thrombosis. It has also been reported that the average time in therapeutic range for LVAD patients is lower when compared to a general clinic population of patients who receive warfarin for other indications. One of the advantages for using DOACs for the treatment of AFib and VTE is that certain agents may be associated with a lower rate of bleeding. Of note, the data for the bigotrine use in LVADs includes both the 110 milligram BID and the 150 milligram BID doses, so it's important to consider the bleeding risk for each dose. In the RELY trial for patients with AFib, the bigotrine dose of 110 milligrams BID was non-inferior to warfarin, but since 150 milligrams BID was superior to warfarin with a similar rate of major bleeding, the 150 milligram BID dose was approved by the FDA for patients with AFib. For patients with AFib, the bigotrine 110 milligrams BID, Adoxaban, and Apixaban were all associated with a lower rate of major bleeding when compared to warfarin. All DOACs have been shown to decrease the risk of ICH compared to warfarin, which could be beneficial in the LVAD population considering the high mortality rate associated with ICH. However, while the lower dose of the bigotrine and Apixaban had similar risk of GI bleeding compared to warfarin, the FDA-approved dose of the bigotrine, rivaroxaban, and Adoxaban are all associated with a higher rate of GI bleeding. Knowing that LVAD patients have a high risk of GI bleeding, this increased risk could be problematic, especially in patients with a history of GI bleeds, but the benefit of reduced ICH may outweigh this risk in other patients. When extrapolating from the AFib and VTE populations, any of the DOACs could be considered since they have the same or lower risk of major bleeding with lower risk of ICH. However, to ensure the risk of GI bleeding is not increased, either the lower dose of the bigotrine or Apixaban would need to be considered. We'll discuss today whether these agents are effective at preventing thrombosis and bleeding in an LVAD population. One of the other considerations is the ability to urgently reverse anticoagulation in patients with major bleeding events, which are somewhat common in patients with LVADs. The bigotrine can be reversed at a cost of approximately $5,000 with the monoclonal antibody Adaricizumab, or if Adaricizumab is not available, then activated 4-factor PCC can be considered, although PCCs have a higher cost and are associated with thromboembolic events. The factor Xa inhibitors rivaroxaban, Apixaban, and Adoxaban can all be reversed with andexan and alpha. However, it is associated with the cost of $30,000 to $60,000 per dose, as well as a high rate of thromboembolic events, which is concerning given the risk of thrombosis in patients with LVADs. Lastly, warfarin can be relatively easily reversed with IV vitamin K or FFP or an activated 4-factor PCC in cases of life-threatening hemorrhage. Another consideration for use of DOACs and LVADs is whether they effectively prevent thrombosis based on the mechanism of action. DOACs directly inhibit clotting factors within the common pathway, either factor X or factor II, as shown in the red and yellow circles. In contrast, vitamin K antagonists such as warfarin inhibit factor IX within the contact pathway, factor VII within the tissue factor pathway, as well as factors X and II within the common pathway, which are shown in the four orange circles. While inhibition of a single clotting factor by DOACs has been shown to be effective in preventing thrombosis in AFib and for the treatment of VTE, there's question of whether this is adequate in patients with LVADs. In LVADs and mechanical heart valves, coagulation is primarily triggered by blood contacting artificial surfaces via the contact pathway, which generates high concentrations of thrombin. VKAs may therefore be more effective at preventing thrombosis by inhibiting multiple pathways, including the contact activation pathway. This concern was raised in the REALIGN trial, which evaluated 252 patients with mechanical heart valves, and the trial was stopped prematurely due to harm associated with dabigatran. Patients received a high dose of dabigatran of 300 mg BID in an effort to achieve adequate concentrations for thrombin inhibition in patients with mechanical heart valves. As a reminder, the FDA-approved dose for AFib is 150 mg BID. Despite the higher dose of dabigatran, it was ineffective in the prevention of thrombosis as more patients experienced valve thrombosis and stroke. Not surprisingly, this high dose was also associated with a higher risk of major bleeding. The authors hypothesized that the contact activation pathway in the coagulation cascade produces higher concentrations of thrombin than the dabigatran molecules can inhibit, whereas warfarin is able to effectively reduce thrombin generation via the contact pathway. Prior to the publication of the REALIGN trial regarding dabigatran use in mechanical heart valves, a randomized controlled trial was designed in 2010 regarding the use of dabigatran in LVADs. This trial planned to enroll 30 patients, however, it was terminated early due to safety concerns with dabigatran. They evaluated patients with the heartware LVAD implanted more than one month ago with stable renal function and no history of major thromboembolic or bleeding events. All patients received aspirin 200 mg per day and were randomized to receive either a VKA or low dose dabigatran 110 mg VID, which was further reduced to 75 mg VID in patients with creatinine clearance between 30 and 80 mL per minute. In terms of outcomes, the authors compared thromboembolic and bleeding events between groups. The median time from LVAD implantation to randomization was similar between groups and was approximately one year. The trial was terminated early after enrolling only 16 patients due to safety concerns for increased risk of thrombosis in the dabigatran group. This is notable that differences in the risk of thrombosis were apparent even in such a small sample size. As I mentioned, the dose of 110 mg VID is lower than the FDA-approved dose for AFib and VTE, although this dose was non-inferior to warfarin in patients with AFib. However, the majority of patients in this trial had the dose further reduced to 75 mg VID for creatinine clearance of 30 to 80. This is concerning since the package labeling for AFib and VTE recommends no dose reduction for creatinine clearance greater than 30, indicating that patients were likely underdosed in this trial. However, it's still questionable whether a higher dose of dabigatran would have prevented the thrombotic events that occurred as the 300 mg VID dose that was used in the realigned trial still resulted in valve thrombosis. Of note, the average INR was maintained greater than 2 in the VKA group. In terms of study endpoints, four thromboembolic events occurred in patients receiving dabigatran, which consisted of three pump thrombosis events and one TIA. Only one patient in the VKA group experienced pump thrombosis, and that patient had a history of AFib, which may increase the risk. The graph on the right shows the Kaplan-Meier analysis of event-free survival during the study period of 12 months and shortly after with dabigatran in blue and VKA in green. The median time to treatment termination was significantly shorter in patients receiving dabigatran, which was 9 months compared to 12 months. Of note, there were no episodes of bleeding reported during the study period. This trial represents the only RCT published regarding the use of DOACs and LVADs. Limitations include the suboptimal dose of dabigatran and that the trial only included 16 patients with heartworm LVADs. Therefore, the results may not be able to be extrapolated to other LVADs, which have different characteristics. In conclusion, a lower dose of dabigatran increased thromboembolic events compared to warfarin and cannot be recommended as initial therapy in patients with LVADs. While the previous RCT demonstrated harm with first-line use of a low dose dabigatran in patients with heartworm LVADs, a case series evaluated its use as second-line therapy in patients with heartbeat 2s. This case series included 7 patients who were initially anticoagulated with VKA, then experienced at least one serious thromboembolic or hemorrhagic anticoagulation-related event, and the majority had multiple reasons to be considered a VKA failure. Patients had no major contraindications to dabigatran, and all patients received aspirin 80 mg daily. Patients were switched to dabigatran 150 mg VID if they had experienced a prior thrombotic event while on warfarin or a lower dose of 110 mg VID if they had a prior bleeding event. The authors then compared the incidence of bleeding and thrombotic events that occurred more than one month postoperatively during the periods patients received VKA or dabigatran. Patients received warfarin and dabigatran for a mean duration of 2 years each during the study period. The mean time and therapeutic range during VKA treatment was 65%, which is comparable to large randomized controlled trials. Based on the small sample size, it's challenging to draw meaningful conclusions on the differences in events, but there were no significant differences in device thrombosis, stroke, or life-threatening bleeding between VKA and dabigatran use. However, there was a significant reduction in major bleeding with the use of dabigatran when compared to VKA. This case series provided insight on the use of dabigatran as second-line therapy in patients who had failed warfarin. However, it's a very small sample size of 7 HeartMate2 patients, and therefore, results cannot be extrapolated to other types of LVADs or in patients with significant renal dysfunction. In conclusion, dabigatran at a dose of 110 mg VID could potentially be considered a second-line therapy in LVAD patients who experience a bleeding event while on warfarin, as dabigatran may reduce the risk of major bleeding. While 30% of the patients in this case series had a history of thrombosis, I believe that dabigatran still cannot be recommended in patients who experience a thrombotic event while on warfarin, based on the prior RCT that showed dabigatran has an increased risk of thrombosis compared to warfarin. However, additional study using the 150 mg VID dose is warranted. While the previous data focused on the direct thrombin inhibitor dabigatran, a case series was published last year evaluating the use of factor Xa inhibitors in LVAD patients. This case series included 6 HeartWare and 1 HeartMate2 patients who failed warfarin for thrombosis, bleeding, or difficulty maintaining therapeutic INR, and the majority had multiple reasons to be considered a VKA failure. Notably, 71% of the patients had non-adherence or difficulty maintaining INR in the therapeutic range. The majority of patients remained on aspirin, and 4 were switched from warfarin to a standard dose of apixaban, and 3 patients were switched to a low dose of rivaroxaban 15 mg daily, with this dose selected due to a history of ICH. Of note, the FDA-approved dose for AFib is rivaroxaban 20 mg daily. Thromboembolic and bleeding events were then compared. The duration of follow-up with DOACs was relatively short at 7 months, while warfarin therapy was a mean duration of 2 years. Of note, the time within therapeutic range for warfarin was less than 30%, which is extremely low. Given the small number of patients, there were no significant differences between groups, but major GI bleeding occurred in one patient receiving apixaban and one patient receiving rivaroxaban. Importantly, there were no ICH or thrombotic events during the time patients received DOACs. This case series provided insight regarding the use of TIN-A inhibitors as second-line therapy in patients who failed warfarin. However, it was a very small sample size of primarily HVAD patients. Also, a lower dose of rivaroxaban was selected given the high risk of bleeding in patients with prior ICH, so the risk of the standard 20 mg dose was not assessed. Lastly, there was less than 1 year follow-up during DOAC therapy, so the long-term event rate remains unknown. In conclusion, TIN-A inhibitors could potentially be considered in LVAD patients who fail warfarin, particularly in those who are non-adherent to warfarin or extremely challenging to maintain in the therapeutic range. Additional larger studies are necessary with longer follow-up to determine the rates of thrombotic and bleeding events. There was a recent abstract published in 2020 of a larger case series with apixaban use in 47 patients with heartwares and one heartmate 3. All patients were determined to be non-adherent to warfarin therapy, defined as inability to become trained for INR self-management or three INR values requiring intervention. Patients were maintained on antiplatelet therapy and all were switched from BKA to apixaban with a mean follow-up of 1 year. In the abstract, they only comment on cerebrovascular events, which occurred in 11% of patients. Six percent experienced ischemic stroke and four percent had fatal ICH. There was no mention of pump thrombosis in the abstract, so we'll need to wait for more data from this case series when it's published. I'd like to briefly share two case reports regarding the use of apixaban in patients with LVADs. In the first case, the patient had a history of GI bleeding prior to heartmate 2 implantation and experienced six major GI bleeds within the first post-op year. The authors balanced the need for anticoagulation with the concern for life-threatening bleeding and stated in the publication, our strategy has been dictated by our position between the devil and the deep sea. They made the decision to initiate apixaban 2.5 mg BID, which was dose reduced based on age and weight consistent with the package labeling for AFib. He was maintained on this regimen for one year without aspirin with no recurrent episodes of GI bleeding or symptoms of pump thrombosis. In the last case report, which was published in 2019, a patient was on apixaban preoperatively for AFib with no history of bleeding or thrombotic events. After heartmate 3 implantation, he experienced two episodes of tamponade requiring reoperation. During this time, antithrombotic therapy was held and he developed a large aortic valve thrombus. Since he had previously tolerated apixaban, the decision was made to initiate apixaban 5 mg BID without aspirin. He experienced no new bleeding or new thrombotic complications and had resolution of the aortic valve thrombus. Based on my communication with the authors, he was then transitioned to Warfarin after three months with no bleeding or thrombotic complications to date. There are two guidelines that comment on long-term anticoagulation therapy for patients with LVADs. The 2013 ISHLT guidelines were published before all of the evidence I presented here today, and therefore they only recommend Warfarin according to device-specific recommendations with no mention of DOACs. The European Association for Cardiothoracic Surgery recently published an expert consensus position statement on the use of long-term mechanical circulatory support in 2019. They recommend the use of VKAs and provide a Class III recommendation that the use of novel oral anticoagulants is not recommended, indicating there's evidence or general agreement that treatment is not useful and, in some cases, may be harmful. To summarize what I've shared with you today, we know that LVADs are associated with a high rate of thrombotic and bleeding complications. Treating therapeutic INR in LVAD patients is challenging, and DOACs have pharmacokinetic advantages over VKAs. In patients with AFib and VTE, DOACs have been shown to reduce the risk of ICH with similar or decreased major bleeding and similar or increased risk of GI bleeding. Reversal agents are available for DOACs, but they are costly. But the question remains, which LVAD patients should receive DOACs? In my opinion, the answer is almost no one. At major centers, the use of DOACs is extremely rare, and many report not using DOACs at all, and if they do, it's in one or two patients. Current guidelines recommend VKAs and do not recommend DOACs for LVAD patients. Larger randomized controlled trials are necessary to ensure efficacy and safety. While it's less clear who we could use DOACs in, there are some reasonable criteria for which LVAD patients should not receive DOACs. First, DOACs should not be used as first-line anticoagulation, as an RCT demonstrated increased rates of thrombosis with dabigatran compared to warfarin. I recommend avoiding DOACs in patients who experienced a thrombotic event with therapeutic INR and in patients with mechanical heart valves. Again, this is based on the increased risk of device thrombosis and ischemic stroke with dabigatran in patients with LVADs and in patients with mechanical heart valves. Major GI bleeding is common in LVAD patients, and DOACs are unlikely to be a good alternative to warfarin for patients with a history of recurrent major GI bleed, given a similar or increased rate of GI bleeding with DOACs in the AFib and VTE populations. Lastly, while obesity is common in LVAD patients, the use of DOACs is not ideal in obese patients or in those with major or multiple minor drug interactions or with significant renal dysfunction. Drug levels could potentially be monitored, but there is lack of data supporting how to appropriately dose-adjust based on these levels. So if we are going to choose a DOAC, who would be the right patient? Based on the data, we could consider DOACs in patients who have persistent non-adherence to warfarin, resulting in major bleeding or thrombosis, despite repeated counseling and close monitoring. It could also be considered in patients with a history of ICH on warfarin, although much more data is needed in this population. There is the theoretical benefit as all the DOACs decrease the risk of ICH compared to warfarin in an AFib population. In choosing which DOAC to use, apixaban may be ideal given the similar rate of GI bleeding to warfarin with decreased major bleeding and decreased ICH in an AFib population. Thank you for the opportunity to speak with you today, and I'll be happy to answer any questions during the discussion panel. Hello, my name is Eddie Phan. I'm an intensivist from the University of Toronto. I want to thank the organizers for the opportunity to speak in this session today. I'm going to be speaking about anticoagulation, specifically about bivalorudin. So it's B before H, or bivalorudin before heparin. The alphabet never lies about ECMO anticoagulation. Here are my disclosures. I'm not going to be speaking about any specific products, so it should have no relevance to the talk that I'm giving today. So the issue of anticoagulation in ECMO is an important one because, like many things in critically ill patients and in medicine in general, there's always a trade-off. The use of the extracorporeal circuit leads to some challenges due to its artificial nature, and there is a balance between thrombosis of the circuit and circuit elements due to the surface that's exposed to the patient's blood and the need for anticoagulation to prevent those complications. But of course, anticoagulation itself is a double-edged sword and can lead to bleeding. And so there's a balancing act between the optimal amount of anticoagulation to prevent thrombosis, as well as the minimal amount of anticoagulation to prevent bleeding complications. And some of these are exacerbated in patients who are supported with ECMO due to the ongoing platelet dysfunction, the possibility of von Willebrand factor dysfunction, fibrinolysis, and consumption of coagulation factors. We see this as clinicians manifested clinically in these pictures that you can see here. On the left, perhaps evidence on the oxygenator of clot formation and fibrin deposition, which can often lead to circuit dysfunction and suboptimal gas exchange, and of course the dreaded complications on the right from some of the accumulated or acquired aquagulopathy that could occur during extracorporeal support, along with the need for extraneous anticoagulation that can lead to a catastrophic intracranial hemorrhage, pictured on the right. And these complications are unfortunately not as infrequent as we would like. So when we look at some recent data, looking at large cohorts of patients supported with ECMO, you could see here just an example, a snapshot from the Extracorporeal Life Support Organization report from July of 2020. Looking back at the last five years of data reported to the registry, and here you could see a mix of things, both clotting, thrombosis, things like clots, air embolism, thrombosis of the circuit, CNS infarction, limb ischemia, and bleeding from GI bleeding, surgical site bleeding, cannula site bleeding, and of course the dreaded complication of cerebral hemorrhage. You could see that some of these rates are relatively low, cerebral hemorrhage in the 3% range, but some of them relatively common, almost 10% for thrombosis or clots of circuit components. And again, it's this fine balance that as these patients accrue complications, you might imagine that this may have adverse effects both on their ICU length of stay, the development of morbidity, and importantly of mortality as a result of these complications. And so there needs to be this fine balance between the need for anticoagulation to prevent thrombotic complications, but of course not too much to avoid bleeding complications. And then when we look outside of the registry at a number of recent, just published this year, single center observational studies, you could see that again, bleeding is relatively common, nearly half of the patients have some sort of bleeding. The rates of intracranial hemorrhage can vary substantially from center to center, probably dependent a bit on differences in center practices, variations in patient populations and indications for ECMO, but anywhere from 3% to 11%, a nearly 10% rate of ischemic stroke, and a 15% rate of thromboembolism. So again, very important and relatively prevalent complications that result from extracorporeal support and the ancillary need for anticoagulation. And so there's been lots of interest in trying to better ascertain what the optimal anticoagulation strategy would be in patients supported with extracorporeal support. And up until this time, I think it is probably not a problem for this audience to understand that heparin, unfractionated heparin, has really been the most commonly used anticoagulant for patients supported with ECMO. It's well known, the mechanism of action is well known, it's easy to reverse if needed with protamine, and it's easy to monitor using things like APTT or ACT. Unfortunately, there are some disadvantages as listed here on the right. There's some nonlinear therapeutic consequences of using heparin. There's the possible development of heparin-induced thrombocytopenia, and it may have variable effects in other patients. As a result of this issue, we're looking on the left at a sort of stylized cartoon of the coagulation cascade. You could see that there's been some increasing interest in antagonizing other aspects of the coagulation cascade. Namely, today's talk is focused on the idea of rather than working indirectly on factor X through antithrombin using things like unfractionated heparin, we might consider antagonizing directly factor IIa or thrombin using these direct thrombin inhibitors. And again, today's talk is focused on the potential use of bivalorudine. Bivalorudine, like argatroban, are direct thrombin inhibitors. Some advantages here you can see on the right are they're independent of antithrombin levels. They have a good dose response. There's really no risk of heparin-induced thrombocytopenia with the use of these agents. Bivalorudine is cleared mainly renally. Argatroban is cleared mainly through the liver. But there are, again, some disadvantages. There's no clear antagonist for these agents. There's probably, in many centers, less experience with the use of these in large-scale patients. There may be a ceiling effect depending on how you monitor these agents using APTT. And certainly for argatroban, it could interfere with INR measurements. So there's, as many things, some pros and cons to these different agents for their use in patients on ECMO. And I think it's important to know, too, that as we're thinking about what data is available to support the idea of using direct thrombin inhibitors or bivalorudine rather than heparin, we also have to consider the costs. These are by no way representative across the United States or across Canada. But just some examples I could pull from literature and from our friend Google, suggesting that, again, bivalorudine, maybe not surprisingly, is somewhat quite a bit more expensive to administer than unfractionated heparin, which is really dollars for a vial or treatment course, whereas bivalorudine is in many ways very much more expensive. Now, again, this may not be a problem if the data were to suggest that bivalorudine had advantages that would lead to overall reduction in complications, perhaps the need for transfusion, the need to return to the operating room to change circuits, which all incur costs so that the overall hospitalization costs might be less with a strategy employing bivalorudine. Again, we'll have to look to the data to see if the cost effectiveness of a strategy focused on bivalorudine would be superior to that of one using heparin. And again, interestingly, at least up until recently, there probably hasn't been a lot of penetration for the use of direct thrombin inhibitors such as bivalorudine in many ECMO centers around the world. This is a nice survey done now a few years ago by Mela Bambia from Johns Hopkins, surveying international ECMO programs to look at both their anticoagulation management as well as their transfusion protocols. And what you could see is that the vast majority of centers do have a written protocol for both anticoagulation and blood product management. And what may not be surprising, again, is that nearly all programs that were surveyed and responded used unfractionated heparin, although a very small number, just under 10%, also used other agents. Most of them monitored ACT, but they used many other different methods for monitoring their anticoagulation strategy as well, including monitoring anti-10A or using physical elastic testing such as thromboelastography. And again, when you look at the data, unfortunately, despite the fact that there are many important questions to be answered about the optimal anticoagulation strategy, the state of the data is actually not as robust as we would like it. And what you could see here from this recent systematic review that's actually in press for 2021, what you could see here is looking at a few studies, and these are selected studies that are focused on using heparin at the top here. Most of them are retrospective reviews, retrospective cohort studies of a relatively small number of patients. There is this one multicenter randomized control trial, but again, of only 40 some odd patients from Italy. So the extent of the data is unfortunately a little bit less rigorous than we would like. And again, when we look down at bivalorudin, again, mostly looking at retrospective reviews, most of them from single center studies, perhaps a large study here of 153 patients, but again, very few of them having received bivalorudin. So the data that we have to make inferences about the potential benefits or harms of bivalorudin are somewhat challenging even in 2021. And again, so when we look at some of the reasons that centers may have gone to a direct thrombin inhibitor or bivalorudin strategy, a common reason is, again, the development of heparin-induced thrombocytopenia in patients with ECMO necessitating a change in anticoagulation strategy from heparin to bivalorudin. Here, what you see is, again, a number of retrospective observational studies with very few patients, a few case reports about the efficacy. And again, I apologize that this slide is difficult to read, but summarized by the authors to say that, again, the duration of bivalorudin in these situations of patients who develop HITS was about nine days. Platelet counts on admission did, sorry, platelet counts did drop from admission throughout the course of the bivalorudin use and required platelet transfusions. These patients experienced some bleeding, some thrombosis, but again, these patient level data are difficult to interpret in the absence of a comparator group. There has been a systematic review recently looking at bivalorudin as an alternative anticoagulation strategy in ECMO patients. And again, unfortunately, what this systematic review highlights really less is data to help us decide whether using bivalorudin is useful, but rather highlighting the paucity of high-quality data we have, not only about bivalorudin use in patients with ECMO, but perhaps anticoagulation choice or use in ECMO in general. Here, these authors were only able to find eight publications comprising just under 60 patients. Most of them were case reports. They'd included a mix of both adult and pediatric patients, and only a few patients, 18, were receiving heparin as a comparison. So again, the conclusions that the authors can make here are there are very few studies, lots of variability across the data that's been published, and the variability includes the use of loading doses versus not, what kind of monitoring was used, as well as the targets that the investigators were trying to achieve by using bivalorudin. And as a result, the authors were unable to make any firm inferences regarding the effect of bivalorudin as compared to heparin on adverse events or important clinical outcomes. So still many questions to be answered. We do have some studies looking more, perhaps mechanistically or physiologically, at the effects of bivalorudin-based anticoagulation as compared to heparin on the coagulation cascade. And what you could see here, again, is some important outcomes that, again, would a strategy of using direct thrombin inhibitors, how they might affect, for instance, your blood loss on the left or the need for blood product transfusion on the right. And to summarize here in this small study of just over 20 patients, what you could see is that it seemed that over the time course of the first few days, a bivalorudin strategy of patients, and again, here's a mix of adults and kids, seemed to suggest that the amount of blood loss being recorded over the first two days was less in patients with bivalorudin as compared to heparin, and that was statistically significant. And as a result of that, the concomitant need for allogenic blood product transfusion, what you can see here on the right, seemed to be less in the whole for the bivalorudin group as compared to the heparin group. And again, that was for many of these time points statistically significant, as well as for the overall study duration. Interestingly, because perhaps of these reductions in blood loss and need for blood products, again, despite the disparity in cost between dosing of heparin and bivalorudin, the overall hospitalization costs were less in the groups that were anticoagulated with bivalorudin, not statistically significant in the adults, but statistically significant in the children's group. Again, given the very small size of the study, I would say it's more hypothesis generating than high quality data suggesting the superiority of bivalorudin, but certainly leads clinicians and investigators to consider further study to understand better whether bivalorudin would be useful. Again, a retrospective review from a recent center showing a very complex bivalorudin dosing and monitoring protocol, depending on the creatinine clearance, again, because it is mainly renally cleared, and whether to use initial bolus or loading dose, as well as how to monitor and titrate anticoagulation. Here again, it's just a very small, again, representative of the data in general, 11 cases of patients on bivalorudin, the majority of these patients receiving ECMO for respiratory failure or ARDS. I think interestingly, on the lower panel or the lower table, is looking again, perhaps less on clinical endpoints, but looking at intermediate or surrogate endpoints of how bivalorudin affected APTT and how often you could get into the target range. It's interesting to note that at least with this protocol, all patients reached their PTT goal in the first 24 hours. However, nearly three quarters of patients had significant bleeding, and all of them had some clotting within the circuit despite being in the target range, but neither the bleeding nor the clotting led to any significant need to interrupt ECMO in any of these patients. Again, hypothesis generating that perhaps a bivalorudin strategy is not only feasible, but perhaps beneficial, but again, we need better data. Again, this is a small study, perhaps one of the few studies with a direct comparison of a small group of patients, 18 patients getting heparin versus bivalorudin, and looking at some outcomes. Again, here what you could see is that perhaps a shorter time to therapeutic PTT with bivalorudin, a greater amount of time within the therapeutic range with a bivalorudin strategy. They've listed a number of clinical endpoints here. Again, a small study such as this is really not powered for clinical endpoints, but interestingly, looking at complications such as thrombosis, you could see that really no significant differences in thrombosis between the heparin and bivalorudin groups, as well as in neurologic events or bleeding complications. Again, costs here in this small study were in favor of heparin, but again, cautious caution about making any firm conclusions really here demonstrating the feasibility and likely safety at least from a bleeding thrombosis point of view of bivalorudin with very little difference in complications for bleeding and thrombosis. There was, as an abstract, a single-center retrospective case control study published at the Mayo Clinic where they matched patients with bivalorudin to two patients with heparin. They also matched on age, configuration, the number of times the sternum needed to be accessed in central versus peripheral cannulation. Here they have 33 cases and 66 controls that they identified over a seven-year period, and again, similar results to the last study, similar blood loss, similar thrombotic complication rates and transfusion requirements, similar ECMO duration and hospital survival in terms of patient outcomes, but a significantly higher number of circuit interventions required in the heparin group. Again, look forward to seeing this perhaps as a full publication, as this was published in an abstract at the ATS meeting that year. Then finally, looking at perhaps one of the larger studies, looking at the impact of anticoagulation strategy here, you could see a large group of heparin patients, perhaps a smaller group of bivalorudin patients here, and again, suggesting perhaps a reduction in both the thromboembolic complication rate as well as the bleeding rate with a bivalorudin strategy as compared to a heparin strategy. The data in adults, at least for a variety of indications, suggest that perhaps there is a safety signal, perhaps easier to get patients into the target range with bivalorudin as compared to heparin. Some conflicting data about the costs, but again, we need larger trials. Our colleagues in the pediatric world seem to be moving on this a bit quicker. A number of important publications in the last year in pediatric critical care medicine, as well as Zio, looking at bivalorudin as an alternative to heparin, as a strategy for anticoagulation in pediatric patients, and hopefully they'll come up with some answers, as well as its effects on the need for red blood cell transfusion in these cases. In the pediatric world, they have at least an ongoing prospective single-center pilot, RCT, targeting 30 neonatal or pediatric patients, where they're going to randomize patients after cannulation to either unfractionated heparin or bivalorudin, and the primary outcome is the time to goal anticoagulation as well as a look at bleeding and clotting complications in these patients. At the time this abstract was published a year ago, there were nine patients that had been enrolled today, four of them on bivalorudin, so hopefully some results from this trial will be forthcoming. Importantly, if you look at clinicaltrials.gov, again, this is just one example at least of a planned randomized controlled trial in adult ECMO patients from Johns Hopkins University, hoping to enroll about 100 patients, comparing bivalorudin to heparin. The plan, as you can see, is to begin enrolling patients in 2021. I think, again, in the field, perhaps the question is less about what is the optimal choice of anticoagulant, what about just less anticoagulation, given that bleeding and particularly intracranial hemorrhage is the dangerous complication that many people are concerned about when thinking about ECMO. Again, there are more and more investigators focused on this question. This is a group led by Cecile Auberon from, at the time, in Monash University in Melbourne, in the HELP-ECMO study, where they tried to look at a lower dose heparin strategy as compared to standard dose heparin. You could see on the right the separation in PTT and anti-tanning levels from the lower dose group as compared to the standard dose group. What you could see here is that, on the left, is that they did achieve some separation in the groups in terms of monitored coagulation parameters as well as heparin dosing. Indeed, they didn't see much in the way of differences in this pilot study in terms of platelet count, hemoglobin, fibrinogen, bilirubin, this sort of thing. Again, proof of concept that at least lower dose anticoagulation could be feasible and useful in these patients, but perhaps even more profound than that would be about using no anticoagulation. Modern circuits are relatively inert. Many of them are now coded. What about using no anticoagulation? Again, if we look back at the systematic review that's coming out this year, there are a few and a growing number of case series, again, some systematic reviews of case series or retrospective studies looking at anticoagulant-free ECMO, suggesting perhaps there's no significant difference in the rate of bleeding or thrombosis or adverse events, and perhaps that might be the optimal strategy is that in these patients who are getting relatively high flow, that anticoagulation may not be required. Again, this is just one recent publication from a group in the United States looking at the feasibility of vino-vino ECMO without systemic anticoagulation, and what you can see here is that there really was no difference in clinical outcomes in this very small study, but again, also the complication rates in the anticoagulation free arm in terms of things like neurologic dysfunction, GI bleeding, and whatnot were actually quite a bit less than those that received anticoagulation. Again, a very small study, proof of concept, hypothesis generating, and one of the important things the author suggests in this study is that as long as you keep extracorporeal blood flow greater than three to three and a half liters per minute, again, this may mitigate or obviate the need for systemic anticoagulation in these patients. There's been some growing concern, perhaps, though, that using relatively high flows may lead to other sorts of complications, particularly in those receiving VV ECMO for respiratory failure, and so again, a new trade-off may be required in a situation where to mitigate bleeding complications, you may have to increase extracorporeal blood flow or keep extracorporeal blood flow high, which may in and of itself have some of its own important consequences for patients, so more study is required. I might just finish by saying that we are very interested in this question and hopefully will generate some important pilot data around the use of anticoagulation-free ECMO, and so we're currently embarked on the AFREE ECMO study, looking at anticoagulation-free ECMO for patients supported with VV ECMO for respiratory failure. One of our fantastic fellows, Damian Rotano from Switzerland, is leading this project along with a multidisciplinary group of hematologists, surgeons, and critical care physicians at our hospital, and we hopefully will have some data on this study in the near future to share with you. So to summarize, anticoagulation during ECMO, like many things in medicine, less is probably more. Unfortunately, we have very little high-quality data regarding the optimal anticoagulation strategy in adults supported with ECMO. We don't really understand what the optimal agent, dose, target, or monitoring strategy is in these patients. Most of our data, unfortunately, are from small single-center studies that are retrospective in nature and represent cohort or case series with few comparators. As a result, we're unable to make any firm inferences or conclusions about the causal effects of these different strategies or agents on adverse events or patient outcomes in these studies. Of course, the optimal agent may depend on patient characteristics and course, and fortunately, as you saw, both in the pediatric and adult world, more data is coming about by Vallerudin and other agents. And again, perhaps really moving the field forward in anticoagulation, maybe a strategy of less or no anticoagulation, which would be the future, and more data is coming for that as well. So I want to thank you very much for your attention. I'd be happy to take questions with my other co-speakers at the end of this session. Thank you very much. Hello. I hope this finds folks doing well. My name is Isaac Towle. I'm an intensivist and emergency physician at the University of New Mexico, and I'm the director of a unique unit that is designed to streamline care between the two venues, the ED and the ICU, our UNM-EDRU, Emergency Department Resuscitation Unit. And that's the locale where, back in 2017, we implemented our first design of our robust resuscitative ECMO system, and I'm appreciative and excited to share that with you all and its utility and implementation in the ED. So I have no disclosures or conflict of interest to report, and over the next little bit we are going to, number one, define what is our ECMO, resuscitative ECMO, and perhaps what makes it a unique subset of ECLS delivery. We're going to talk about delivering resuscitative ECMO within the guise of two common pathologies that are cardiac arrest, so eCPR, as well as massive pulmonary embolus, and hopefully along the way provide tips of implementation, many of which we've learned from other centers who have been doing this with some success as well, and things that we've tweaked for our unique practice setting and resources. So what is resuscitative ECMO? For a recent chapter that we offered on the topic, we defined it as the rapid implementation of mechanical cardiac pulmonary support in acutely deteriorating patients. This can be deploying VV or VA ECMO, and as you can imagine on one side of the spectrum in terms of emergencies is eCPR, ECMO-assisted cardiopulmonary resuscitation, and so these terms, resuscitative ECMO and eCPR, are oftentimes used synonymously. And, of course, as you can see in the definition, what makes this a unique subset of ECLS delivery is that you are on the clock here, and you can imagine that it's quite different than, say, the VV patient who you have been for acute respiratory failure that you've been rounding on day in and day out with armed with all the data you need, evaluating them in a serial fashion for inclusion or exclusion criteria for mechanical support. Here, this provides additional challenges because you are, in fact, on the clock where hours and sometimes minutes really makes the difference between futility versus efficacy of the ECMO intervention. So some things when you're on the clock, of course, it is fraught with uncertainty. This makes patient selection optimization much more complicated. You're missing all sorts of data. Perhaps you're missing the ability to get a good history on the patient, lab data, imaging that you'd like to be armed with, and you're certainly oftentimes missing informed discussions either with the patient, their loved ones, or their caregivers who may know them well. In addition, there are additional technical challenges of actually getting the patient on the clock and cannulating someone in an emergent setting. For one, this requires a robust system to organize your multidisciplinary and multi-professional team to the bedside, oftentimes within minutes. You can imagine that the actual cannulation procedure is more challenging. You think of a cold and clamped down cardiogenic shock patient making vascular access more challenging, or certainly I think it's more challenging to cannulate someone with ongoing CPR happening. Additionally, you may not have imaging modalities that make it a safer procedure like fluoroscopy. Depending on your resources, you may or may not have an echocardiographer available. And of course, we're talking about situations where minutes really count, right? Because with ongoing time, with an unmitigated shock state and hypoperfusion, a low flow state, so to speak, especially during that of CPR, that is tantamount to that leads to increasing organ failures, which of course is linked to increasing mortality. And we're implementing ECMO here not just to delay mortality, but to reverse it. So without question, it is important to mitigate that low flow state if you're up to that level of mechanical support as soon as possible. And a great demonstration of that can be seen in these eCPR echoclips of a recent case we had, where on the left you see really unsatisfying intermittent ROS, which was not perfusing the patient's organs. And then after deploying VA ECMO, you see now at least we have reasonable enough LV contractility that it's opening the aortic valve, hopefully providing a reasonable coronary perfusion pressure and perfusing not only the heart, but the brain and other vital organs. And of course, this was after starting high doses of inotropes and vasopressor therapies, and that was still fraught with a low flow state. And so getting this patient on within minutes was really important. And this is, of course, before we got this patient to definitive revascularization and PCI. And so this is clearly lifesaving. But it's nice to say, talk about, okay, minutes count, but what do we have as guidance for when should we really be deploying VA ECMO, say, in this eCPR situation? And how far can we extend out that window? And for that, we can look to a host of observational studies on the topic. This is the Japan experience. Again, looking at the association between CPR duration for out-of-hospital arrest patients and favorable neurologic outcomes here with cerebral performance categories of one and two. They are looking at a whole large cohort of out-of-hospital arrest patients. Importantly, they excluded all patients who could not obtain ROSC in the field, which is particularly important in Japan because they have no termination of resuscitation, so they were otherwise bringing a lot of unsalvageable patients into the hospital. So this is a more salvageable group. And you can see if they got them on to ECMO within the first few minutes, they're survivable with neurological, good neurological function was pretty good, over 20%. But of course, at the 20-minute mark, this had dropped precipitously down to less than 2% survival with favorable neurologic outcomes. And then with each minute, it gets closer and closer to zero. And you can also see that the inflection point is somewhere between the 15 and 20-minute mark. And that is consistent with other observational studies, including this one by Reynolds and team, where they also looked at the low flow time or the CPR duration and how it corresponds with outcomes. Here, they use modified Rankin scores for neurologic outcomes. And what they found was 90% of the patients who survived with favorable neurologic outcomes, they had attained ROSC at the 16-minute mark or sooner. And again, that drops precipitously less than 1%. And so overall, this is consistent with the observational literature suggesting that we can consider the patient to have failed standard ACLS delivery somewhere between the 15 and 20-minute mark. And that's when, if the patient is a candidate, we should be ready to deploy VA ECMO. Of course, the next question is, how far can we extend out this intervention and still get good neurologic recovery? We've probably seen many case reports demonstrating 60, 90 minutes and even beyond with neurologically intact survivors. But this is really the exception rather than the rule. For the masses, you can look at some guidance from this observational study published in Critical Care Medicine in 2017. Again, they're looking at minutes of low flow time as it corresponds to survival to hospital discharge with good neurologic function. And this is for an eCPR cohort of patients. Their overall in-hospital arrest survival was just under 20%. Their out-of-hospital survival was 8.5%. And you can see here the mean low flow time was about an hour, 59 minutes. And as you can see by the red line, the low flow time, as it extends, inversely correlates to the patient's survival. But perhaps more importantly, on multivariate analysis, this low flow duration was an independent predictor of the patient's mortality. And so most experts would contend that we should really shoot for getting these patients on pump, mitigating that low flow state at 60 minutes from the time of arrest. Many experts also would assert that you can perhaps extend this window out and get good outcomes if the patient has persistent signs of life at the time. So persistently reactive pupils, spontaneous respiratory effort, particularly compelling is if the patient has purposeful motor activity with ongoing CPR. And so those are criteria that we use to extend beyond the 60-minute mark. Now, I'd be remiss to leave out the one RCT that we now have available to us because up till now for eCPR, it's all been using observational data. This is the RCT recently done by the group in Minneapolis who looked at eCPR versus standard ACLS delivery in an adult cohort with refractory VF who had transport times to the emergency department under 30 minutes. And let's look at their times and their outcomes. Their mean time from 911 call to getting the patient on VA ECMO was 59 minutes. And astoundingly, their mean time from arrival to the cath lab where they were transported to getting on pump was seven minutes. And as you may know, their outcomes were superior in the eCPR group, 43%. This is out of 15 patients in each arm versus standard of care yielded a 7% survivability. And so their data safety monitoring board stopped this trial prematurely because of the superiority of the eCPR arm. Now, of course, these authors do not understate the difficulty in reproducing such outcomes in other centers and the heavy lifting that it took for them to achieve these outcomes. And so they explicitly mentioned in their manuscript, the need for a substantial systematic reorganization of the emergency response infrastructure and say centralization of care with highly trained expert teams that respond within minutes to this time sensitive emergency cannot be understated. And so if we are going to implement an eCPR delivery system in our center or improve upon your center, we should do so with the goals of being ready to safely cannulate these patients at 15 to 20 minutes when the patient's considered refractory to ACLS, getting this patient on pump within 60 minutes and establishing return of circulation mechanical that is, but probably first and foremost, it would be short-sighted to think that we're gonna achieve similar outcomes without first focusing on optimizing our ACLS delivery system. So that's both mitigating the low flow state and minimizing the time we're delivering standard ACLS, but really optimizing our compression fraction, optimizing their hemodynamics and the way the whole team approaches bringing a game ACLS to that patient. And so with this in mind, I'd like to share you some of our improvements that we've made over the last few years. And importantly, we did not reinvent the wheel. We spent considerable time consulting with other successful centers and learning from them and implementing what they've already found to be successful. We've learned a lot from say the eCPR group at Alfred Memorial Medical Center in Melbourne, Australia. We spent a lot of time learning from our ED ECMO colleagues at Sharp Memorial Hospital. And in 2017, our first step was to implement automated CPR, both in hospital and throughout our Albuquerque EMS system. This was important to us simply to eliminate what we thought was one of the greater sources of chaos at the bedside during ACLS delivery, that long train of providers switching in and out to provide CPR. And of course we wanted out of hospital arrest patients to be able to be safely transported with good CPR and progress. And so we implemented it with EMS. Number two that we implemented was intra-arrest TEE as a matter of routine, both as a diagnostic mortality to help us understand what's going on with this patient and perhaps their etiology of arrest to evaluate the efficacy of compressions and also to make for a safer cannulation if it's echo guided. We implemented a line doc. So in the first few minutes of every cardiac arrest, we have someone who is tasked with placing femoral arterial and venous access that at the very least is going to provide for a better cardiac resuscitation with feedback from arterial lines and central venous access. And if the patient ends up being an ECMO candidate, we simply have these as placeholders so we can upsize to larger cannulae. But perhaps the most important advance that we implemented was a roles-based ACLS team delivery. We have no more than eight people at bedside. These roles are probably consistent with most things out there. Someone's running a defibrillator, for example, a respiratory therapist or pharmacist, and of course a resuscitation leader. But the unique thing that we did after learning from other centers was divide the resuscitation leader role into two distinct roles, that of an ACLS captain and in our center, that's typically an experienced nurse or junior resident who is charged with running all things ACLS, particularly organizing the rhythm and pulse checks. And that cognitively unloads the resuscitation doc from being in the weeds of the minute-to-minute all-important ACLS and allows them to do a whole host of other things, which we're going to go into in a minute. And then the third unique role that we added to our team was that of a line doc, someone who comes to the game procedurally oriented, focused tunnel vision on meticulously obtaining lines in the common femoral artery and common femoral vein. They first place four French sheaths early in the resuscitation that can be used as we described. And so I hope that if you walked into any resuscitation, any cardiac arrest, whether it's in our ED or RU or elsewhere throughout our institution, that the room makeup looks like this, and you can tell who is taking on what role based on where they're standing and how the lines of communication are flowing. Like I said, we have our ACLS captain you see here at the left upper shoulder of the patient, and they are charged with organizing the rhythm and the pulse checks, minimizing CPR cessation and optimizing that compression fraction to at least 80%. That's time spent on the chest, 80% of the time, which we know is associated with improved outcomes. And now our resuscitation doc, who you see is initially at the head of the bed, but is designed to be mobile and do all sorts of things, now can truly be the team leader, the orchestrator of things with a 50,000 foot view of the team and the ongoing resuscitation. And then third, you see the line doc at the groin, they are gowned, gloved, sterilely, they've got an ultrasound at the ready, and they are meticulously placing the CFA and the CFV sheets in the first few minutes of the resuscitation. This is what the room looks like during a team pre-brief, just minutes before the cardiac arrest patient arrives, we're all prepared. And we keep talking about what is the role of the resuscitation leader? Well, again, it is no longer to organize the rhythm and pulse checks or ask for the epinephrine dosing. This is the task of the resus leaders, right hand, that all important ACLS captain, because if the resuscitation leader was doing that, then this was you, this was you in the weeds. And now that you're not in the weeds of the minute to minute ACLS, you are now free to do all other important things, like implementing other management strategies for cardiac arrest, say identifying that this patient was perhaps a hyperkalemic arrest, and then you might add some other pharmacotherapeutic interventions. You can now do things like evaluating point of care labs, providing what we refer collectively to as precision ACLS, biofeedback of entitled CO2, diastolic blood pressure, echo guidance. You can now leave the bedside actually, talk with the MS, talk with the patient's spouse, perhaps in a consult room, do a chart biopsy. All these things once thought to never be possible, you're now able to really strictly evaluate for the ECMO inclusion and exclusion criteria. And this of course, hopefully is not entirely new for most folks listening in, because really for years now, the AHA has been recommending a roles-based team approach to ACLS delivery. And while they allow for different variations of the concept depending on your practice setting and the resources you have available, the one constant should be what you see here as a team leader at the foot of the patient that is not ensconced in any one particular procedure and is truly free to be the orchestrator of the whole team during ACLS delivery. Now, we've also designed the, or we took a page from other people's books of the three-stage approach that allows us to seamlessly implement ECMO within the guise of the cardiac arrest resuscitation. Stage one is essentially bringing a game ACLS as we described, optimizing ACLS, and the two additions to stage one are, number one, now the resusc leader is free to gather the patient's data, the ECPR inclusion and exclusion criteria. And during stage one, again, we have our lined up placing common femoral artery and common femoral vein sheets in the first few minutes. Then at approximately the 15-minute mark, if we are unsatisfied with sustained sufficient ROSC and this patient in fact is a candidate, the room gets quiet. We have a quick discussion during a timeout between the resusc leader and the cannulator reviewing those criteria. And if it's a go for ECPR, for ECMO initiation, then stage two is essentially the cannulation stage. The only thing that differs in terms of ACLS delivery is there's no more rhythm and pulse checks, no more CPR cessation or identifying shockable rhythms. We've already tried this without success. And now is when we're placing the 21 to 25 French venous cannula and the 15 or 17 French arterial cannula. During stage two, we get the patient cannulated, have another brief timeout just to assure that no other important information has come to light that would otherwise guide the arrest resuscitation. And stage three is putting the patient on pump and focusing on post-arrest care. That's optimizing the patient's hemodynamics. That is focusing on optimizing cardiac pulsatility, looking at lower extremity perfusion on the side of their arterial cannula. We hand scan all of these patients as we found that we get important information to guide further management. And then it's, of course, getting the patient to the next important stage, whether that's PCI in the cath lab or the intensive care units. And with implementation of this whole strategy that we've talked about, first of all, I should say that this is completely consistent with a recent review of best practices published in 2018 by an expert consensus panel. And again, just to review some of their recommendations are getting the patient on pump at the 15 to 20 minute mark, but within a 60 minutes timeframe, using important feedback for patient selection, like assuring that their end-tidal CO2 is greater than 10 minutes, assure that the no flow state, the arrest without CPR was under five minutes, that we're minimizing the low flow state under 60, excluding those with major comorbidities, excluding asystole as the initial arrest rhythm. And of course, considering signs of life, perhaps to extend that 60 minute window. And they too, these experts really highly recommend a roles-based ACLS delivery to have the seamless implementation of resuscitative ECMA. And we're pleased to report that with implementation of all these advances, we were able to achieve results and good outcomes at least as good as that reported in the ELSO database that you see here on the left, and then on the right, with the UNM data from 2017, 18 and 19. Full disclosure on 2019, our outcomes took a real dip in large part because we didn't really adhere to our strict inclusion exclusion criteria. We got a little too bold, but hopefully we're improving upon that in 2020 and 2021. Now, importantly, around the time in 2017, that we were implementing this ECMA resuscitative strategy for a whole host of pathologies, we were seeing that our massive PE patients were yielding mixed results. And when we look back to earlier years to see how we were managing our massive PE patients, we were surprised to find that our outcomes for massive PE patients were pretty dismal. In fact, we had a mortality for these patients upwards of 80%. Now, this was around the same time that we were reading more and more case reports and small case series of places using VA ECMO earlier to treat massive PE patients and having some success. And so we decided to implement such a strategy as well. I'm happy to report you can now look at some of the data that I'm gonna talk to you about. It's in press in the Journal of Vascular Surgery. This is our observational cohort of massive PE patients with an ECMO first approach. So in 2017 through 2019, we put 17 massive pulmonary embolus patients on VA ECMO. 10 were in the peri-arrest setting, some with intermittent ROSC. And these were overall a very sick cohort of patients with a mean lactate near nine and a mean pH of 7.1. And we were excited that we were really able to flip the script here. And our overall survivor using an early ECMO approach was 76%. And so we flipped the script between from a mortality of 80% to a survival, mostly as you can see neurologically intact of nearly 80%. And consistent with some of the other reports out there, these were relatively brief ECMO runs with a mean ECMO run of three and a half days and a spread of two to nine days. And again, consistent with some of these other reports, overwhelmingly all these patients needed was heparinization and perhaps the coagulopathy conferred to them by the ECMO circuit for just a few days. We did, like other centers, have a small number of patients. We had three patients who required additional catheter directed thrombolysis and retrieval. And so this was a real game changer for us that led to us implementing a strategy for early ECMO, just like early ECMO for failed ACLS patients. So we designed a system that allowed for early ECMO team consultation. And so now it's really one-stop shopping at UNM where all in-hospital arrests, out-of-hospital arrests, massive PE patients and even sub-massive PE patients generates an emergent page in consultation to the ECMO attending, who is also our CT vascular ICU attending. These are either EM intensivists, IM intensivists, or surgeon intensivists. There's a small group of seven of us to maintain consistency. And when we get to the patient's bedside, assuming the patient's a candidate, we really target early sheath placement and getting massive PE patients onto ECMO early. We also put the sheaths into sub-massive PE patients. And if they have, especially if they have worrisome echo findings like impending core pulmonary with RV strain and septal shift, the idea is here is we really want to get to these patients and capture them prior to any loss of spontaneous circulation. In fact, in our cohort of 17 patients, the seven that were able to cannulate before any arrest all had 100% survival, did really well. And really that leads us to try to, when at all possible to do an awake cannulation, avoid induction agents, avoid the addition of positive pressure, which we really know can push over these patients whose RV failure is kind of teetering on the precipice. And so seven, again, seven of those 17 patients were cannulated awake and remained awake through their very smooth ECMO course. Of course, all of these patients are getting heparinized. We also don't want to hamstring our providers in the ED or elsewhere in our institution if they're concerned about providing thrombolysis as the standard of care. So if the ECMO team is at the ready, we ask them to wait so we can implement an ECMO first approach. But if they feel that this patient should be thrombolyzed, we give them the green light to give TPA. And we've had a good and safe experience cannulating our patients without increased bleeding complications or increased blood products use despite cannulating them after heparinization and thrombolysis. And so in summary, regarding resuscitative ECMO, we talked about eCPR timing, both guided by the literature and expert consensus to assume that ACLS is really in a failed state at the 15 to 20 minute mark, getting these patients on within a 60 minute window, perhaps considering signs of life to extend that window. I can't emphasize enough the importance of really focusing your system on optimizing ACLS delivery that is paramount if you wanna get neurologically intact survivors like other high performing centers are reporting. And while we are still waiting for an RCT to decipher whether an early ECMO approach is superior to thrombolysis, we would advocate based on our experience and others to consider early VA ECMO implementation for massive PE patients. And with that, I want to thank you for your attention and open it up to any questions. Thank you very much. Well, thank you. Thank you all. So far, this has been a really wonderful session and four just incredible talks. And there've been many questions that have already been answered throughout the last 90 minutes. We have several more here and I'd actually like to, just as the moderator of the session, take the liberty of asking the first question and I think we'll work backwards here. And so this is a question for Isaac and about your resuscitative ECMO program. In general, how, you know, I think a lot of centers are asking, we would love to do this. We're thinking about eCPR, we're thinking about a resuscitative program. How did you get the stakeholder buy-in and how did you actually get this through because there are so many stakeholders or it's such a complex system and just in principle, how did you do it? Great question. And actually, and I'll try to be brief because it's, as you can imagine, the topic of the whole talk on its own. I think perhaps starting by restating what I think is obvious and maybe obvious the most is this is one of the more complicated ECMO populations that have emerging eCPR or massive P patients. And so I think it behooves one to add these to an already established ECMO program where you really have already embraced the stakeholders and just general ECMO care and all that comes with it as even that is a real team sport. But then I think once you have that, if you're ready to chop off the eCPR population, you're right. You should spend considerable amounts of time sitting at the table planning with all the many stakeholders. To name a few, nursing, right? Nursing leadership. This is going to use their resources significantly, change the flow of their day. You best be sure that you have buy-in so this doesn't cause problems. All your consulting services, cardiology, for example, are you on the same page of who is going to be taken rapidly to the cath lab if you put them on ECMO? Who and if so, how are you going to address LB decompression for those who don't regain pulsatility? Surgical backup. How are you going to address vascular complications or CPR induced injuries in patients who are now on ECMO and fully anticoagulated? You have a surgical team who is willing to take these folks to the operating room. And this is all being with a questionable neurologic status. Then you have to bite off EMS in your community and all the other hospitals who are invested and engaged in caring for cardiac arrest patients. Each one of these stakeholder groups provides their own unique challenges. They come to the table with their own unique perspective and their asks, so to speak. I guess I would say briefly that really every one of these challenges are huge opportunities to step up your care and create wins for each of these stakeholder groups, whether it's cardiology and palliative care. So you try to put their shoes on, what's their perspective, do a lot of listening before you do some talking and then get everybody on the same page. And then really it's about rehearsing before you go live and thinking through all the logistics of how this is gonna happen. Great, thanks. And so to Jose Diaz Gomez's question, do you have any information you can share on early functional capacity and quality of life measures at either six months or one year out from this patient population? I'm not sure if you're talking about ECPR or PE, but I'll tell you we're currently, I don't have that data on me. We're currently accumulating that. And hopefully our returns to our post-ECMO clinic are good enough to be able to come up with some robust data that we are looking into. Okay, and a specific question here from Tara Hunt, how do you prepare your team when the arrest is coming from an inpatient and you don't have a call ahead? Well, I think you maybe addressed a little bit of this, but this one page system, how do you get everybody organized to the bedside rapidly for an immediate response to get under that time constraint that you established? So we did, interestingly, this was one of those things that we didn't anticipate. We made this robust system for calls from EMS where we had time to prepare. And of course, we then shortly realized that the majority of these are unanticipated arrests all over the hospital. And so what we did was we started training everybody, lock, stock and barrel nurses, physicians on an approach for the three first providers that stumble upon this arresting patient. Provider number one, regardless of who it is, of course, address the life threats, hands on the chest with effective compressions and call for help. The second person to that patient should again address the life threats, get pads on and address shockable rhythms, right? The third person, here's the key, the third person to that patient doesn't, should not grab the airway box. They need not get, you know, get the med kit or anything like that. That third person can now recognize life threats are being addressed. I am going to organize the roles and I'm going to any subsequent person that walks in, we're gonna figure out where those people are gonna be standing and how the lines of communication are flowing. So interestingly, we've shifted our paradigm for in-hospital arrests where the third person there really organizes this eight member team approach. And while that takes an additional 20 to 30 seconds, it really sets you up for success over the next 20, 30 minutes. All right, this is just a follow-up to Lillian Emlitt's question. And maybe this is for, well, I guess I would just open this to everyone. If we're gonna think about either anticoagulant free ECMO runs or using an alternate agent, what has been the experience? Are you okay running the flows higher? I'll tell you in our trauma patient population, we often run them anticoagulant free. Anticoagulant free, especially when they have traumatic brain injury for a few days until we get a stable scan. And then we usually wait 24 hours after a stable head CT, and then we'll start an anticoagulant in that population. We've also had a few where we've run them anticoagulant free for their entire run. And really we just run their flows a little higher. But I'm curious, especially since we can't get away from COVID and we have this concern of hypercoagulability, what's everyone's thoughts about this balance of either just going to a different anticoagulant strategy or being anticoagulant free and then running our flows higher? And maybe we'll start with Eddie. Sure, yeah. So it's a great question. I think again, an important question in the field that needs to be answered. We have the same experience, David, that you mentioned, whether it's a trauma patient or a post-lung transplant patient, post-complex thoracic surgical patient where bleeding risks are high, we run them heparin free for days until we feel that hemostasis is reasonable and the bleeding risk is low with restarting heparin. But there's great variability. I mean, I think this is what we don't know and we don't even know how high flow has to be. So in that one study I quoted, they just wanted the extracorporeal blood flow to be above three. We're not talking like five or six liters. So it just can't be very low at least in that one study. And these are questions that need to be answered. And I think, again, I feel like there are very few, at least in our experience, in these patients who are at high risk of bleeding of running them anticoagulant free for a few days. So I think really the question for the field is probably less, it is my opinion, less about what is the right anticoagulant choice rather than do we need anticoagulants at all. VA ECMO might be a bit of a different beast because obviously the risk of embolization directly into the systemic circulation is a bit different than embolizing to your lung. I mean, it's not a good situation, but the risks are a little bit different in magnitude. So, but at least in the VV world, I think this is really an important question that needs to be answered. Thanks, any other thoughts from the rest of the panel? I can just share our experience with our VV ECMO COVID patients. In the beginning, we attempted to run more of them off of systemic anticoagulation with just aggressive VTE prophylaxis. And many of them did develop thromboembolic complications. I will also say that they also had a lot of bleeding complications. And so there are many that we were forced to not use anticoagulation. So I think it's a difficult balance and we haven't come up with a great strategy. So it's really been more patient specific in terms of how we manage it. Great, Zach, I wanted to kind of return to a question that, so you're presented with a patient who now has been running with heparin and there's a high suspicion in the team that there may be HIT. And you realize that everything's heparin bonded. And now you're thinking about either it's changing your strategy or we've had some members of the team ask this question, well, can we continue to do this? Do we need to exchange our equipment? There really isn't a lot out on the market that's not heparin bonded. But what would you recommend for your anticoagulation strategy when this question comes up about they're already on support and now we've got this heparin that we can't get out of the system completely? Yeah, I think this is a very complex scenario. And I think ultimately it's a case by case decision amongst the multidisciplinary team as well as the patient's family, just clearly understanding the risks and benefits. I think the first approach for HIT is trying to remove all the heparin products in this scenario is potentially not an option due to the limited... There are other polymers that have been used, but it seems like those are currently not available. So you're in a scenario where you have heparin bound products that have to be used. So I think it's like from a multidisciplinary team deciding if there's alternatives with the mechanically support devices, can something else be used to manage this patient? Or just understanding that we might just have to provide a direct thrombin inhibitor and hope for the best in this scenario. If you're truly in a scenario where you have to maintain this circuit that has heparin. With that, unfortunately, there was a report of over 5,000 patients that assessed for the incidence of heparin-induced thrombocytopenia. It was extremely rare, less than 0.5%. So I think that's a fortunate aspect in this population that the true HIT, it seems to be extremely rare in this population than it's been reported in other cardiac surgery populations. I think some of the cases I described today, these were patients that had percutaneous VADs that ultimately got organ transplant or a durable VAD. Those teams did plasma exchange to remove the heparin antibodies. I'm not available or aware of anything like that in this type of scenario, but I think they're involving a multidisciplinary team and really understanding the risks and benefits of all these therapeutic options. Having a conversation with the patient about whatever the team feels is the best approach and making sure they're aware of the risks and the benefits. Great. We have less than a minute left here, but one last question that came up is maybe for Isaac. Do you recommend regionalization that you should bypass smaller hospitals for this select patient population to come to a resuscitative ECMO center preferentially, versus going to the local hospital and then doing an inter-facility transfer in? Yeah, no, I think, I believe, no question. If you can make that happen and work through whatever politics of your locale, it doesn't seem like a tenable situation to think you're gonna get it, keep someone an ECPR candidate if they're not transported to a hospital that isn't doing this and doing this routinely. And as an example of creating opportunities out of this, since sometimes it's jockeying, it's a bit of a turf battle, you can also open up your ECMO services and help unload all these other hospitals for people who need mechanical support and open those avenue lines of communication. Great. Thank you so much. And thanks for a really wonderful session. And I think for the questions that we may not have been able to get to, we'll try to get them all answered. And in this Q&A session that people can then return to to get their answers that they've requested. All right. Well, thank you all very much for a great session. Thank you.

anticoagulation strategies

extracorporeal life support

mechanical circulatory support devices

novel anticoagulants

LVADs

bivalirudin

heparin anticoagulation

ECMO

heparin-induced thrombocytopenia

emergency department

oral anticoagulants

cardiac arrest patients

pulmonary embolism cases

stakeholder buy-in

resuscitative ECMO programs