Hi, my name is Patrick Wietoszewski and I'm a pharmacist in the cardiothoracic surgery and ECMO program at Mayo Clinic. I'll be discussing the cardiac surgery and cardiology year-in-review updates. I wanted to take a moment to thank the CPP section and the CPP Programming Committee leadership for inviting me to do this talk. It truly is an honor and privilege to speak to you all today. I have no relevant disclosures related to this presentation. Today we'll evaluate the evidence for updates in the management of critically ill cardiovascular surgery and cardiology patients. Extracorporeal membrane oxygenation, or ECMO, is a form of temporary mechanical circulatory support that is deployed in refractory cardiopulmonary failure. ECMO is a very resource-intensive intervention, and over the past several decades it has been gaining a lot of interest as a rescue option until underlying pathologies are treated or organ transplantation can occur. Plotted here in the purple bars are the cumulative number of ECMO centers worldwide. These are data from the Extracorporeal Life Support Organization. You can see, up until the late 2000s, the number was steady around 100, but appeared to take off in the 2009-2010 time period, and this is likely following the surge in ECMO use during the H1N1 influenza pandemic. These continue to rise, and in 2020, there were over 500 ECMO centers worldwide. That's an over 400% increase from the preceding 10 years. And concurrently, I've also plotted for you the orange line, which is the number of new papers indexed in PubMed that are relevant to ECMO anticoagulation, which has also seen a very similar rise over this time period. And in 2020 alone, there were over 200 new ECMO anticoagulation papers indexed in PubMed. And this increasing interest is rightfully so, as normal physiologic coagulation is disturbed in patients on ECMO. With the introduction of the ECMO circuit, the circulating blood is exposed to a large surface area of foreign, non-endothelialized surfaces, and these include the large bore cannulas, the mechanical pump, and membrane lung, or oxygenator. And what ensues is a systemic inflammatory response, activation of cytokines, and initiation of the extrinsic coagulation pathway. And if there's severe cardiac failure or ventricular standstill, there's also a risk for thrombus formation, and this is especially true if the left heart is not adequately offloaded. The mechanical pump also contributes to coagulopathy through high shear forces that facilitate uncoiling of large von Willebrand multimers, increasing their susceptibility to cleavage. These issues are all compounded by the underlying diseases and indications for going on ECMO that might also inherently have their own coagulation imbalances. And what results is a state of platelet and coagulation factor consumption, excess activation of fibrinolysis, and a progressive thrombocytopenia. Taken all together, anticoagulation during ECMO is very complex, and it requires a very fine balance to mitigate the prothrombotic potential while minimizing hemorrhagic complications. And the clinical consequences from coagulopathies are the most common adverse events that ECMO recipients experience. On the left-hand side are adverse events separated by respiratory ECMO on top and cardiac ECMO on the bottom, and these are data from the Extracorporeal Life Support Organization Registry of nearly 80,000 ECMO runs. And I've highlighted all of the complications related to thrombotic events, including pump malfunctions, oxygenator failure, and stroke, as well as bleeding complications at the site of the cannula, surgical sites, as well as pulmonary and CNS bleeding. Now all of these coagulation-related events account for the large majority of adverse events ECMO patients experience, and they are highly consequential. Shown on the right are data from Mike Mazzeffi's group in Maryland, where they found a nearly two-fold lower survival at 90 days in patients who experienced bleeding events during ECMO. If you are listening to this session live, I'd love to hear your thoughts and experiences with anticoagulation. In adults on ECMO, which of the following would you recommend for hemostatic management? Heparin infusion, bivalrutin infusion, no anticoagulation, or would you like to hear some more information to make a decision? Please feel free to enter these in the session chat box. Now historically, heparin has been monopolized as the anticoagulant of choice during ECMO, and this is largely extrapolated from its familiarity in the setting of cardiopulmonary bypass. However, heparin does depend on antithrombin to exert its pharmacologic effect. It also has the potential for immunogenic platelet sequestration and thrombus formation through heparin-induced thrombocytopenia, and it also interacts with multiple different plasma proteins, and this leads to unreliable and inconsistent dosing. Bivalrutin is a direct thrombin inhibitor and has been gaining increasing popularity as an alternative agent for anticoagulation during ECMO. Bivalrutin has a rapid onset, short half-life, a low incidence of thrombocytopenia, a pharmacologic effect that is independent of a cofactor, and it also has reversible thrombin binding, and this has been proposed to lead to less bleeding. And today we'll discuss two new papers that were published in Critical Care Medicine in the summer and fall of last year that compared heparin and bivalrutin during ECMO. Ryan Rivasecki's group at the University of Pittsburgh converted to a primary bivalrutin ECMO program back in 2017. They performed this retrospective cohort analysis of nearly 300 VV-ECMO runs before and after this conversion. Now their cohort was young with a median age of 49 years, 60% of them were male, and these were predominantly medical admissions. There were 162 patients in the heparin group and 133 patients in the bivalrutin group. And indications for ECMO are listed here, and as you would expect, they are all respiratory indications. Most of them had acute respiratory failure, and this was more common in the bivalrutin group than the heparin group, whereas pre-lung transplant was a more common indication in the heparin group as compared to the bivalrutin group. And what they found was an over three-fold higher rate of major bleeding events in the heparin group at 41% compared to just 12% in the bivalrutin group. Similarly, the incidence of circuit thrombosis was higher in the heparin group at 33% compared to just 17% in the bivalrutin group. And this also held true when they adjusted for the duration of the ECMO run in terms of circuit thrombosis per day of ECMO. Shown on the right is the adjusted Cox regression analysis they performed that included covariates for age, sex, admission type, presence of lung transplant, and exposure to anticoagulation in the first 24 hours. And in this, they found that the bivalrutin group was significantly less likely to develop a thrombosis compared to the heparin group during their entire ECMO run. And what was very interesting was the amount of transfusions these patients received. You can see here on the left-hand side that the heparin patients also received significantly more blood transfusion than the bivalrutin patients. The heparin patients received over two and a half liters of red cells, whereas the bivalrutin were just under one liter. And this was also true to a lesser extent with plasma and platelets. And although the duration of the ECMO runs were comparable, the overall lengths of stay did not differ. There was also no difference in the ECMO survival rate, but more patients in the bivalrutin group were alive at one year after ECMO separation. Now the second paper we'll review is from Troy Seelheimer's group in the Mayo ECMO program. They performed a retrospective cohort study of adult and pediatric ECMO patients receiving bivalrutin or heparin anticoagulation. They had 333 adults that were included, and most of these were over the age of 50 years. 65% of them were male, and 40% of them were on continuous renal replacement therapy. These patients were predominantly recipients of VA ECMO in the post-cardiotomy setting, and accordingly the majority of these were central ECMO. Similarly, the 89 included pediatric patients were predominantly infants, and they were also receiving VA ECMO in the post-cardiotomy setting, as well as a large amount of eCPR. A quarter of these pediatric patients were also on continuous renal replacement therapy as well. They found no differences in the primary composite endpoint of circuit intervention and oxygenator or pump changeout rates in either of the adult or pediatric groups. However, as you can see in the adult groups, the other circuit interventions that were unspecified, rates were greater in the adult heparin group compared to the adult bivalrutin group, and also the hospital mortality rate was higher in the adult heparin group than the bivalrutin group at 53% versus 38%. Pediatric patients that received bivalrutin also had less transfusion requirement in the first 24 hours of ECMO, otherwise there were no differences in transfusions amongst the groups. Shown here is the multivariable model that they fit to assess the effects of anticoagulation choice on outcomes. The lower hospital mortality rate that we just showed in the adult bivalrutin group that was found in the crude analysis was also maintained in the multivariable analysis. Otherwise, there were no other major differences that were identified between the groups. So overall, from these two new papers, it appears that bivalrutin is emerging as an alternative for primary anticoagulation management in ECMO patients. And as discussed before, there are many scenarios that bivalrutin provides a favorable pharmacologic profile compared to heparin, and this newer evidence supports less bleeding and thrombotic complications when bivalrutin is used, as well as potentially fewer transfusion requirements compared to heparin in select patients. Now in terms of some limitations, the Rivasecki paper was exclusively in VV ECMO patients with a very large predominance of lung transplant recipients. And also, the Seelhamer paper was predominantly central VA ECMO, and so the generalizability of each of these studies is quite limited to a broad population of ECMO recipients, given their narrow scope. Additionally, both centers performed a program-wide switch to bivalrutin during the study time period. And in both of these papers, the earlier half of the study was predominated by heparin recipients. Now there might be some unaccounted-for confounding that related to the evolution of ECMO care over this time period and the increase in the program's experience temporally as time went on, and these certainly could have influenced the results. Lastly, the intensity of the anticoagulation and the amount of pausing that occurred during ECMO runs, potentially for bleeding or procedures, were not reported. So the optimal timing and dosing practices of these anticoagulants still remain unclear. Once again, if you're listening to this session live, please enter your response to this question in the session chat box. A 37-year-old male with refractory hypoxemia secondary to influenza pneumonia was cannulated for VV ECMO. CT scan of the chest demonstrates bilateral pulmonary emboli. Which of the following would you recommend for hemostatic management for this patient's ECMO circuit? Heparin infusion, bivalrutin infusion, or no anticoagulation? In conclusion, hemostatic management during ECMO is very complex. It requires a fine balance of delivering anticoagulation to prevent thrombus deposition while minimizing hemorrhagic complications. There is an increasing experience and body of evidence with the use of bivalrudin as a primary anticoagulant during ECMO. Further studies are necessary to better understand the impact of bivalrudin on the totality of ECMO management and outcomes in ECMO recipients. I wanted to thank you all for your attention and attending today.

ECMO

anticoagulation

bivalirudin

pharmacologic profile

ECMO outcomes