Hi, everyone. It's great to be here. Thanks for having me. I don't have any financial relationships to disclose, and goals for this presentation will be to review options for pharmacologic anticoagulation, evaluate reversal options for this anticoagulation, and interpret primary literature and guideline recommendations for anticoagulation reversal. So I have been tasked with talking about this in 15 minutes. So bear with me. I will try to highlight some of the highlights in terms of reversal. So as you know, there are a number of anticoagulants that we have available to us. And I think that there are a lot of nuances that we need to consider regarding each of these agents when we are thinking about appropriate reversal strategies, if needed, for one of these agents. Dr. Miller just highlighted the coagulation cascade. But this is something that you also need to consider when you're talking about reversal of anticoagulants. It's important to understand where in the coagulation cascade they exert their effects. With many of our anticoagulants impacting factors 2, 7, 9, and 10, 10A, and thrombin, it's important for us to understand where in the coagulation cascade they exert their effects so we can select the most appropriate agent for reversal. Additionally, anticoagulant pharmacokinetics and pharmacodynamics are also going to play an important role when you're thinking about anticoagulant reversal. These agents each have their own specific nuances to consider. And also, when we think about critically ill patients who often have end-stage liver disease or renal dysfunction or acute kidney injury or acute liver dysfunction, these are also going to impact the duration of action of these medications and significantly prolong the duration of anticoagulation that maybe we were not previously expecting from these agents. Unfractionated heparin, for example, has an immediate onset. But in the context of higher doses and renal dysfunction, it can have a much longer half-life than we would previously expect. We also have limited data for factor 10A inhibitors in critically ill patients. And in these patients with either acute kidney injury or acute liver injury, their effects, again, may be prolonged in this setting. When we think about the need for reversal, not all bleeding actually requires reversal. Sometimes bleeding can just be managed by cessation of one of these agents. In terms of needing for anticoagulation reversal, major bleeding is often defined as bleeding that results in hemodynamic compromise or bleeding to a critical anatomical site, a drop in hemoglobin greater than or equal to 2, or need for greater than 2 units of blood or massive transfusion. Not only is it important to think about the reversal of anticoagulation, but we also need to think about what happens after the bleeding has resolved and we have reversed the anticoagulation, as there is a risk ranging from 7% to 12% of thrombotic events following the reversal of anticoagulation. So we also need to think about having a plan for how and when we resume anticoagulation if it's appropriate. Dr. Miller also highlighted a number of tests that are going to be very important for us to monitor and evaluate when we think about the degree of anticoagulation that patients may be experiencing. There are a number of standard lab assays that we can send off, for example, on fractionated heparin with APTT and anti-10A monitoring. But also that becomes a challenge for some of our other agents. Like for example, our factor 10A inhibitors can also impact APTT and anti-10A tests. There's also commercial assays that are available for these agents, but they may not have a turnaround time that's going to be clinically relevant for us to assess in the setting of an acute bleed. So we need to use the testing that we have available to us at this time to try to make the best understanding of how anticoagulated these patients may be, and that's going to be also interviewing the patient if we can to understand the timing of their last dose, and then assessing things that I talked about in terms of PK and PD. Are there any issues that would potentially prolong the duration of action of these agents? As I mentioned before, we are going to think about where in the coagulation cascade these agents exert their effects, and that's going to be where we target our anti-reversal agents. So in terms of thinking about are we targeting factors 2, 7, 9, and 10, thinking about neutralization of the anticoagulant effects, and adding agents that will compete for binding sites for the anticoagulants that we've administered. In terms of reversal agents, protamine is our oldest medication on this list. It is a medication that will neutralize both heparin and, to some degree, low molecular weight heparin. Vitamin K is going to increase liver synthesis of factors 2, 7, 9, and 10. We also have four-factor PCC, which includes factors 2, 7, 9, and 10. This is different from a three-factor PCC, which does not include factor 7. There is also activated PCC, which contains activated factor 7, which in this country is known as FIBA. There's also recombinant factor 7, which is NOVO7, which does have a limited role for anticoagulation reversal. Idarosuzumab is actually a specific medication that is a monoclonal antibody that binds to free dabigatran, as well as to a bound dabigatran. And then finally, we have andexanet-alpha, which competes for binding sites of R-factor 10 inhibitors. All of these medications also are going to have an increased risk for hypersensitivity and thromboembolic events, which I'll talk about more specifically in a few slides. So I'll highlight warfarin first. This is one of the agents that we do have some of the most data for in terms of anticoagulation reversal strategies. The first study that I wanted to highlight compared four-factor PCC versus FFP. So in this multicenter open-label non-inferiority study, they included non-surgical patients who had acute major bleeding with an INR greater than or equal to 2. Patients had to receive 5 to 10 milligrams of vitamin K. And then they either received four-factor PCC at 25 to 50 units per kilo or FFP at 10 to 15 cc's per kilo. And the dosing was dependent on the baseline INR at presentation. In terms of effective hemostasis, four-factor PCC patients had 72.4% versus patients who received FFP at 65.4%. Four-factor PCC also resulted in more rapid INR reversal with no differences in adverse effects. There is a 2022 meta-analysis that also pooled smaller studies that looked at the same study question comparing four-factor PCC and FFP. And they found, again, that four-factor PCC resulted in faster INR reversal and more rapid cessation of bleeding. In terms of the comparison of three-factor PCC and four-factor PCC, I'll highlight a systematic review and meta-analysis, which included 11 studies and over 1,100 patients. As I mentioned, they compared three-factor PCC and four-factor PCC in which four-factor PCC more favorably normalized INR compared to three-factor PCC with no difference in thromboembolism or mortality. And then finally, I will highlight a study that is looking at four-factor PCC, which was compared to activated PCC, which, again, in this country is FEBA. It's actually more challenging to find studies that look at FEBA for warfarin reversal as it's generally not used in this case given the increased risk or theoretical increased risk of thromboembolic events with an activated PCC compared to an unactivated PCC. And also in the setting of warfarin reversal, there's no need for the factor inhibitor bypass part of FEBA. This study is actually the largest study that I could find comparing these agents. And they included patients who had acute major bleeding with an INR greater than 1.5. They compared four-factor PCC 25 to 50 units per kilo, again, based on baseline INR, or compared to FEBA 500 to 1,000 units. In terms of achievable of INR less than 1.5, the four-factor PCC resulted in significant normalization of INR with fewer repeat doses. And there was no difference in thromboembolism or mortality when comparing these two agents. So I think the takeaway from these studies is if four-factor PCC is available to you for warfarin reversal, that is probably the primary agent that should be used for reversal of warfarin based on the available literature that we have at this point. In terms of Idarosuzumab, the REVERSE-AD trial is the landmark study that looked at this agent in this setting. This was a multi-center, prospective, open-label study that included 503 patients who either had uncontrolled bleeding or they needed reversal of dabigatran for an urgent procedure. Patients received two doses of 2.5 grams of Idarosuzumab for a total dose of 5 grams. And this study looked at the primary efficacy endpoint of median max reversal, which they measured from the end of the first Idarosuzumab infusion to four hours after the end of the second Idarosuzumab infusion. And this resulted in 100% reversal of dabigatran. The median time to bleeding cessation was 2.5 hours. And only nine patients received a repeat 5-gram dose of Idarosuzumab. There were 6.8% of patients who experienced a thrombotic event in the 90-day follow-up period, as well as 18.8% mortality. Based on this data and the unique mechanism of Idarosuzumab, if this is available at your institution, it should be the preferred agent for reversal of dabigatran. The next drug that I wanted to highlight for reversal is Andexanet Alpha, the landmark study that has looked at Andexanet Alpha for reversal of factor Xa inhibitors is the INEXA-4 trial. So this was a multicenter prospective single-group cohort. And they looked at patients with acute major bleeding who had received a factor Xa inhibitor and were within 18 hours of the last administration of this medication. They had two dosing strategies. They either used a low-dose strategy, which was a 400-milligram loading dose followed by 480-milligram infusion over two hours, or an 800-milligram loading dose followed by 960 milligrams over two hours. And this, again, was dependent on the agent that they received, the time since last administration, and the type of bleeding that they were presenting with. In this study, the median anti-10A activity decrease was greater than 90% for most agents. And 81% of patients had good or excellent hemostatic efficacy. 10% of patients experienced a thrombotic event, with unfortunately, the majority of these adverse events being stroke, MI, and other cardiovascular adverse effects. And 14% of patients experienced mortality, again, was primarily of cardiovascular causes. I think because of this data and some of the safety concerns, as well as some of the cost associated with indexa, there has been slower pickup of some centers to have this agent on formulary. Currently, in June of 2023, there was a post-marketing indexa study that was published that was hoping to answer some of these questions that I think some centers have had in terms of adding indexa to formulary. This was a multi-center prospective randomized controlled study that only looked at patients with acute intracranial hemorrhage. Again, they used the same dosing strategy as the indexa-4 study and compared this to usual care. And the preliminary results have demonstrated that the study was actually stopped early due to superior hemostatic efficacy compared to usual care. So I think many of us are anxiously awaiting the full publication of these results so that we can accurately and more deeply evaluate the efficacy and safety endpoints of this medication, particularly in the setting of ICH. In the event that you don't have indexa available or you have it restricted for certain indications, there is data for PCCs for DOAC reversal. And I'll highlight a few of these studies. So in a meta-analysis of patients with major bleeding, this included 10 studies in 340 patients. They specifically evaluated patients who received four-factor PCCs. And in this study, 69% of patients had effective management of major bleeding, which again is less than that 80% that was seen in the indexa-4 trial. However, they only saw a 4% thromboembolism rate, which is, again, compared to the 10% that was seen in the indexa-4 trial. And all-cause mortality was 16%. Since the publication of this meta-analysis, the largest multicenter retrospective observational cohort looking at PCCs in the setting of acute intracranial hemorrhage was published. This study included 663 patients who either received a PIXABAN or RIVAROXABAN. And they looked at four-factor PCC as well as FEBA. The median four-factor PCC dose was 43.8 units per kilo. And the median FEBA dose was 26.7 units per kilo. In this study, 82% of patients experienced good or excellent hemostasis. With those patients receiving FEBA having even higher rates of hemostasis than that reported in the indexa-4 trial. In this study, again, the thromboembolic rates were less than that in the indexa-4 trial at 3.8%, and 19% of patients experienced in-hospital mortality. I think these studies highlight that PCCs are an option if needed for DOAC reversal and if indexa is not available. In terms of guideline recommendations, there are a number of societal guidelines that have evaluated the literature to date looking at reversal of anticoagulants. The number of these societies include the Society of Hematology, CHEST, the Neurocritical Care Society, and a number of international societies. There is a lot of discrepancy between the guidelines, with many of them having different interpretation of the literature and obviously thinking about the specific patient populations that they include in their society guidelines. I tried to summarize some of the guideline recommendations in this study or in this table for warfarin specifically. So I would say for the most part, most guidelines agree that vitamin K should be administered to patients in need of warfarin reversal. And four-factor PCCs are preferred if available, specifically over three-factor PCCs. And NOVO7 and FEBA should be avoided for the reversal of warfarin. In terms of DOACs, the majority of guidelines recommend and dexamethylalpha or idaresuzumab if they're available for specific reversal of those factor 10A inhibitors and dabigatran. If those agents are not available, the guidelines become a lot more gray. I would say that most guidelines recommend a PCC. But in terms of which PCC you recommend or use after that, the guidelines separate quite a bit in terms of which PCC they recommend, four-factor PCC or FEBA. And there's definitely an unclear role for FFP for reversal of DOACs. The other discrepancy amongst all of the guidelines are the dosing that I know that this time is not quite long enough to even get into that controversy in terms of weight-based dosing of PCCs versus fixed doses of PCCs. So I think this leaves many of us with creating our own institutional guidelines with many discrepancies in the literature and a lot of discrepancy amongst the guideline recommendations from different societies. And so we have to create a lot of our own institutional guidelines based on what we have on formulary. We often have to carry a lot of different reversal agents on formulary depending on what type of patient population we take care of and the acuity of our hospital. So wouldn't it be great if we just had one agent that could do it all? And so in the pipeline is this agent called seroparentatag. And this agent has been suggested as being able to reverse both heparin, low molecular weight heparins and DOACs. This is a medication that reverses medications through hydrogen binding and proton-proton binding, and could potentially change the game in terms of what agents we have to carry on formulary, how many agents we have to carry on formulary to potentially reverse bleeding in patients in need of reversal. So I know I went through a lot in a short amount of time, but I think the key takeaways are that anticoagulation PK and PD should be considered when evaluating reversal options. There's data evaluating reversal options, but it's limited. And I think that we need to critically evaluate the literature that is available and think about how that applies to our patient populations. Novel reversal agents may help standardize anticoagulation reversal strategies, however, in the future. Thank you. Thank you. Applause.

anticoagulation reversal

coagulation cascade

reversal agents

DOAC guidelines

seroparentatag