Good afternoon, everyone. The warriors of the conference still here. Well, I have the pleasure of now presenting the four-factor PCC as being the preferred strategy for ICH management. Disclosures here, again, these topics were pre-assigned, so it doesn't necessarily reflect our opinions. But nonetheless, I'm going to present to you what we know about PCC. So maybe you'll find at the end if it reflects my opinion or not. Well, if not, we'll chat out in the hallway. So one thing I want to level set around is that even though the title says reversal, this debate is not about two reversal agents. It's about two different types of strategy to manage ICH, one being a reversal strategy and the other being to a clotting factor replacement strategy. So with that said, I think all of us have walked around the meeting. You have probably got a mocha in the exhibit hall that told you an XII has stopped because we're saving the world. It's all over everywhere, and even when I went to upload my slides for this presentation, there was the whole here's the data, and I actually used what I pulled up there and put it in my slides. So I'm like, what am I doing? You've set me up to fail here. So what I'm going to say is that PCCs should not be superior to indexin alpha because indexin does reverse. From a pharmacologic standpoint, it should not be superior. It reverses the drug, but yet look at how many of you are sitting here, and we're still debating it. So let's go from there. My stance is that PCCs are resilient. The timeless resilience of PCCs. It has stood the test of time, debate after debate after debate, and yet we still sit here. So I'm going to take a look at this from a past, present, and future standpoint and make a few points, and then Dr. Coffman will come up and rebuttal everything I said and undo it. And then after that, we can have time to talk. So let's look at the past. Why are we here? We are here because of the increase and significant increase in utilization of DOACs. You look at the graphic that I have here, all DOACs are here on the yellow line. Warfarin is black, and you see how much it's kind of really tailed off. And then certainly, apixaban is the most common of our factor XA agents. And why do we have such uptake? Well, as Dr. Coffman already said, there is less bleeding associated with the factor XA agents. They are nice agents for us to use for our AFib patients. However, the risk of bleeding in ICH is not zero. We still have a significant amount of patients that can experience ICH from DOACs itself. And so we're left with kind of these two strategies of a reversal strategy versus a factor replacement strategy. That's why we're here. Now, I would be remiss to not include this because the best treatment and the winner of the debate is actually prevention, okay? That is the best way to treat this, is identify who's at risk, have risk mitigation strategies, and making sure we're using these agents appropriately and understanding age, creatinine clearances, drug interactions, risk of falls, all of these things that was published in this paper in 2021, and to make sure that we are mitigating the risk. And that's what I really hope you leave here today with, is a way and know that you're mitigating the risk of anybody on any of these agents. We also need to have a pharmacologic common language. I've been really big in implementation science and understanding from a pharmacologic standpoint what you expect to happen. And dexanet alpha does reverse. We saw that, and Dr. Kaufman showed us how it works eloquently, and it can cause an impact on the 10A levels because of its mechanism. And that has one of the co-primary endpoints. We focused on that surrogate endpoint of 10A levels. PCCs, on the other hand, don't do anything to the DOAC. They don't impact factor 10A levels. We never expect it to. It's not going to do anything to the DOAC itself. All it's going to do is flood the system with the clotting factors that the DOACs are inhibiting, and that's what it does. So, again, it's a different strategy. So, why are we having the debate here today? It starts with looking at the history and the approval timelines of our different anticoagulant agents. The first DOAC was dabigatran approved in 2010. It was followed very soon after that by a rivaroxaban and then a pixaban. So, rivaroxaban, our first factor 10A, was approved in 2011. And so, we went from 2011 to 2018 without a reversal strategy. We had nothing. It took a long time. Patients didn't stop having ICHs during that time period while we waited. We still had to figure out something. So, what do we do? What happens? Well, there was some preclinical data, some healthy volunteers, some anecdotal reports that suggested, well, maybe the PCCs could work. Okay? So, as we know, the PCCs indication is for warfarin, not for the DOACs. And so, we're left in this situation where the FDA approved this class of drugs. Yes, it has less bleeding than warfarin and risk of ICH, but yet it was approved without any reversal strategy at all. And that left all of us that are in this room to figure out what to do next. We had to wait until 2018 to have that reversal strategy. So, what I say that we did, we had to fly the plane while we were building it. Okay? Not an optimal strategy in any stretch of the imagination because it's certainly going to be off-label use. We don't know what we're doing. You're never going to get mass clinical trial data when you're trying to fly the plane, when you're building it. You're just doing it, and you're certainly not going to exclude patients that have a GCS less than seven. Okay? We didn't know the dose to be used. Big debate, and I'll have a slide and we'll talk about that. And then what is the meaningful outcome we're trying to achieve here? Isn't hemostatic efficacy? Is it hematoma expansion? Is it TAN-A levels? What are we trying to do? Like, there's nothing that's really there, and everybody's reporting. It's the Wild West. Everybody's reporting everything different. We'll talk about that a bit in a minute. So, a little bit about the dosing considerations. This has been a big thing related to factor PCCs. I'm not going to stand up here and say that there is good level evidence to suggest PCCs work, but we were not given the opportunity to figure that out because we were left in that time period where we had nothing. Remember, we had to build the plane while we were flying it. So, whatever we had was what we had, and we had to use it. And I've been in neurocritical care my entire career, and that's pretty much been the whole standard for neurocritical care is having really messy data that we have to figure out decisions on. So, there's not an optimal dosing strategy. There are some guidelines that do recommend the variable dosing based on the body weight. Recent literature suggests that a fixed dosing strategy might have similar effectiveness to this variable dosing strategy. And that's great because some of the advantages of the fixed dosing is a lower amount of drugs you total doses you give, cost can be lower, administration time is reduced, we know time is brain, that's critical, and reduced risk of the thromboembolic events. And in fact, the anticoagulation forum now recommends the fixed dose and not the variable dose. So, I think there's been some strong evidence that's pushing us to the fixed dose, and I think a lot of, there's been a lot of uptake with the fixed dosing. So, we may be coming to an end with that piece. So, I'm not going to put up these nice studies and graphics of these randomized control trials. There's a lot, and I can tell you when preparing for this talk, and you look at the literature that you pull, you get overwhelmed. There's stuff everywhere. There's so much information. So, I read all of this, and what did I learn? Okay. What I learned are the studies are mostly retrospective, uncontrolled, not blinded, a lot of risk of selection and measurement bias. They use different endpoints, no uniform efficacy assessment. Everything was different. Even the time that they did the follow-up CT could be different. They never report times. They don't report the ICH score or FUNC score. They don't have any of this information in there, so it makes it very hard to really understand. And then the dosing strategy was all over the place, of course, with it. However, with that said, with that, that sounds bad. I should go sit down in the front row right now and just end it, right? Because that sounds terrible. But even with that, four-factor PCCs were recommended as a reasonable option to manage these patients with factor Xa inhibitor-related bleeding. And in fact, before indexonant, it was the recommended agent, present. Here are the guidelines. Dr. Kaufman showed the guidelines, and here we have the indexonant, and here is what is related to the four-factor PC that she didn't show. And what I want to point out is, is that while you see that the class of the recommendation was 2A for indexonant versus 2B for PCCs, well, we didn't have the luxury of doing randomized control trials because we were building the plane while we were flying it, okay? However, the level of evidence is the same in this guideline. When you look at the algorithm that you see here, and based on all of this, and I said it should be pharmacologically superior, all of it should be superior, we're stopping studies early, everything should be superior. You should not have two decision points here. It should go straight to indexonant for factor Xa, but it doesn't. It goes to this decision point, is it available? Now why in the world would that be an option given everything that we have, knowing the pharmacology? So that is the big question, is it available? And in fact, it likely is not. This is a study, now granted it was published, it looked at data from 2020, but it was two years after indexonant came out. They took a look at all the Medicare-based hospitals around the country and reviewed the availability of the two reversal agents, the one for dabigatran and indexonant. And when you look at it, even though we know that the factor Xa inhibitors are 20 times more likely to be used for AFib over dabigatran, the availability of indexonant is five times less likely than it is to see the reversal agent for dabigatran. And if you look at this, this shows you the availability, the darker the color, the more availability this is for our reversal agent for dabigatran, this is indexonant. It is white out, not available. So why is that? So we have a situation where you have a true reversal agent, it's improved and endorsed, but yet not available. So what I'm going to point out and some of the things that I'm going to leave you with here is some of this relates to the lack of standardization. We don't have common data elements on any of the reports, so it's hard to make sense of any of the data. And we'll go through that a little bit. What are the clinical meaningful outcomes? Real world experience versus controlled clinical trial experience is really important to think about, and then cost and logistical issues. So we'll go through that quickly. There are a lot of meta-analyses up there, and it gets really, really confusing. And it's hard for these meta-analyses because there's so much heterogeneity in what they include because you're not using the same endpoints, you're not reporting things at the same time, the hemostatic effectiveness criteria are all different, and then you're comparing stuff that the indexonant has to clinical trial data that would be on that side, that's very controlled, that's excluding patients that have GCSs less than seven and huge ICH volumes, whereas the PCC may not have done that because it was real world, just amassing, we have to treat these patients, what do we do? But yet when you look at these studies and they're all over, there's nothing that says, like I expected it to see, is that indexa is so much better. Like, in fact, it's just really not a lot of differences that you see when you look at these meta-analyses. And why? Here's from that study all the different criteria they used to define hemostatic effectiveness. Now the most common is the International Society of Thrombosis criteria, but, you know, it's still different in every place, and then what does this mean clinically? How does it relate to clinical outcomes? So yes, we can have hemostatic effectiveness, but where it really matters is that modified Rankin score, and what does that mean, what are the patients really doing, because it's truly going to be cost effective. You have to have an impact on that, like TPA did. Now here's some of the studies that I think Dr. Kaufman talked about where we compared these real world observational simulated environments of four-factor PCC to clinical trial data from the indexa forearm, and in fact, when you look at it, the hemostatic effectiveness was superior with indexa, however, one thing that doesn't get talked about a lot is really understanding the underlying pathophysiology of the ICH, and was it traumatic in nature, non-traumatic in nature, is it single compartment, multiple compartment, because it likely will impact your outcomes, and in fact, they took a small number, not powered, of single compartment ICH and or IVH, and they really showed no difference in the hemostatic effectiveness in that group. So it raises the question that we're throwing all comers of ICH in there, but it's a very heterogeneity disease state, and we've got to get a better idea of what patients will respond and what's our patient selection criteria. We've got to get a better handle on that. And then this is the study from comparing it that she talked about to the Retrace2 database, and the usual care, while it was a lot of PCC, it wasn't all PCC, okay? So I think that's the other part you've got to look at when it says usual care. You can't assume it's all PCC, because some usual care is no treatment at all, okay? So when you look at this, yes, the hematoma expansion was higher in hospital mortality, actually didn't show a difference, even with the hematoma expansion being higher, but the other part that I want to point out that's also equally as important, we've got to identify our patients and who needs to be included, but we also have to realize, and we know this as clinicians treating ICH, it's not one single intervention that's going to make a difference on hematoma expansion, it's the bundle, right? And when you look at the Retrace2 database, they had significantly higher systolic blood pressures than the INEXA trial had. So could that have been an impact on the hematoma volume expansion? They had more patients that had IVH as well. So again, understanding the patients, knowing the risk factors, and then also making sure that we're treating glycemic control, fever controls, blood pressure control, et cetera. This is one of the largest meta-analyses, and I put it up here because it just confused me even more. I don't know if anybody's read this. I mean, are y'all confused as I am? Because from my standpoint, I'm a pharmacist. I love pharmacology. I teach pharmacology. And it should make sense to me, but this is not making sense. Like, why is this not better? And you start looking at all these studies, and it's like, okay, here's these hemostatic effectiveness. They all use different criteria. The ranges kind of overlap each other between INDEXA and four-factor PCCs. The safety, it seems to be a trend towards more thromboembolic events with INDEXA versus four-factor PCCs. But it doesn't really tell me one way or the other this is better. And again, it's because of a lot of the issues we have with the heterogeneity of the studies, what we're looking at, and the differences in some of the pathophysiology. So here's that study that I got from when I uploaded my slides. This was a little flyer that was on the website that showed me the INDEXA-I results. And what you have on here, again, it did select the patients out. So it still wasn't true real world, okay, because Dr. Kaufman did a good job pointing that out. And in fact, when you look at it, I put up here in this light blue, this was the hemostatic effectiveness of INDEXA-IV. It was 80%. And then when they went to a more real world, it went down. Now, granted, this is more all ICH, and that was all comers, but still it went down. And then usual care, again, wasn't all PCCs. It was 87% PCCs, but it included patients that got no treatment at all, largely done in Germany, not a lot of sites here in the U.S. And then when you look at, there's no difference in mortality or modified Rankin score between INDEXA and usual care. And in fact, there was a small report that came out right after INDEXA was released on the market about one investigator's experience with using INDEXA. And when they used it in the hospital, when it was first released on their formulary, they actually found that there was a 40% mortality rate when they used it in patients who weren't the ones that were going to respond well. It was like more all comers. So I think there's more to be known there, and we don't know that. There's conflicting economic data. I'm moving on, okay? I can give you a study that's going to counteract anything, okay? It's conflicting. It's not answered. Because this is not answered. We have conflicting data. It's hard. To me, this is the most important slide that I hope we leave here with, and I think that we will reach common ground on this, is that we need more consistency in reporting. This was a nice paper that was published in 2021 in Stroke that talked about we need common data elements, but baseline demographic and clinical factors that will tell us what kind of patients we're selecting, those key prognostic risk for ICH and the prognosis of it, and then the outcomes, not just hemostatic effectiveness. More of the outcomes related to functional outcomes. Time is important. Time is brain. Nobody reports time in these studies. It is all over the place. And I even encourage you at your institution, if you're doing quality improvement methods, identify the time. Everybody uses different times. It's a variable time shift. We should be good at this. We do thrombolytics in stroke. We should be really good at time and knowing what it is and knowing what the door to needle time is or last dose to needle time. The key is it has to get in the patient. I don't care how effective it might look from a pharmacologic standpoint. If you can't get it in the patient, it's not effective. And in fact, there's a big turnaround time for indexing an alpha. It can be upwards of 30 to 60 minutes. If you're trying to go through all the processes, depending on your hospital, some are better than others. And I realize that. And we can debate that too. But I do know on average, I've seen reported around 30 to 60 minutes that it takes to do the reconstitution of it and get it to the patient. So where does this leave us today? This is a slide. And I'm not going to have time. I'm going to run out of time. But this is how I teach pharmacy students to make clinical decisions as a framework of IESA, Indication, Effectiveness, Safety, and then Logistics or Patient-Related Factors. Patient-wise, we know one is off-label. One is on-label. Effectiveness, I have no clue. It's all over the place. Okay? However, I do know that the level of evidence is the same for both agents in the stroke guidelines. Safety, there's been no difference on mortality. When you look at the mortality data, it's conflicting. Some might suggest that INDEXA has more thromboembolic risk. And in fact, that was an initial concern the FDA had before they approved INDEXA was on some of those risks of the thromboembolic risk because it was quite high initially. And then the adherence, INDEXA does take time to reconstitute. The cost is higher. They actually had to add that TAC payment to even make it be in the ballpark to become close to have it where it would be anywhere related to an economic analysis to say it would work. PCCs have fast administration. The cost is much less and it's widely available. So I'm leaving you with some questions and then I'll let Dr. Kaufman come up and rebuttal what I've said. Number one, we have to know what is the clinically meaningful outcome. There have been a lot of studies that looked at hematoma expansion that looked at single interventions and while we thought it should work, they didn't really relate to the functional outcome that we wanted. So we've got to work together in a more bundled approach. We then need to figure out, you know, is surrogate endpoints the right thing? We got to be careful with that. I mean, the Annexa I, one of its endpoints was the 10A levels. Well, PCC is not going to affect that. Usual care is not going to affect that. What does that mean? And in fact, I'm not even sure in Annexa IV that the anti-10A actually had a significant impact on the hemostatic effectiveness. So what is our endpoints? Do we need surrogates? What do they look like? We have to develop all those common data elements, identify what patients and what strategies work for them. And then the quick question is, is it even going to matter? Because drug discovery and drug development is moving past the 10A agents and moving into a new target, a new target of new anticoagulants. Of course, there's the hint for a long time now of the universal inhibitor or reversal agent, excuse me. But in the grand scheme of things, when I've looked at the recommendations, if this universal strategy comes out, PCCs are still there in the mix. So prevention is the best treatment. The win of the debate is prevention. Please focus on prevention. Time is critical. Make sure you're building in time and inequality and improvement initiatives that you're doing and looking at. And we need to come to terms of what our time things are and standardize it. We have a lot of questions that remain, but we need a common language and common data elements to answer any of them in the real world. We need to think about personalized therapy and who's going to best respond. As she talked about, those with the bleeds that could benefit from this that expand may have low GCS scores, so excluding them are not the right thing to do. And then real world data is essential, but only when you have common data elements. So as I started, PCCs are resilient. They have stood the test of time. They are standing, I guess, in this debate, hopefully. But I do think the time has come for us to develop a common language, a common way to look at this, and to understand which strategy should be used for which patients and really understand that better. So with that, I thank you for your attention and time, and I'll turn it back over to Dr. Kaufman.

intracerebral hemorrhage

prothrombin complex concentrate

andexanet alpha

factor Xa inhibitors

preventative measures

individualized treatments