Hi. Thank you for being here. We're super excited to talk about this. I'm Lauren Koffman, and I'll be presenting indexinet-alpha as the preferred agent for intracranial hemorrhage management. The only relevant disclosure I have is to let everyone know that I would never choose to argue against a pharmacist. So, the learning objectives for today's talk, we will be discussing acute reversal of factor X inhibitors after intracranial hemorrhage, highlighting the use of prothrombin complex concentrates, PCC, and indexinet-alpha. We'll be debating the evidence associated with the use of each of these agents, ILB pro and dexinet. And we will really be focusing on evaluating the use of contemporary clinical trial data to determine the optimal therapy for factor Xa-associated intracranial hemorrhage. So, briefly, just want to talk a bit about what is spontaneous intracranial hemorrhage. It accounts for a minority of strokes, only about 10 to 15 percent in the U.S. every year. However, it is disproportionately higher in lower resource populations. And it can be reported in up to 25 to 55 percent of strokes for low to middle income countries. What really differentiates it from acute ischemic stroke is that there is a significantly higher morbidity and mortality that's been reported up to 30 to 40 percent in the first 30 days. And despite advances in neurocritical care and in vascular neurology, there really hasn't been any trend towards improved outcomes. Now, when we think about intracranial hemorrhage when anticoagulated, that's an even higher morbidity and mortality. And really, a lot of that is related to the risk of hematoma expansion. You'll see that abbreviated as HE throughout my slides, because when there's hematoma expansion, it is known to contribute to a worse outcome in neurologic deterioration. Patients that are anticoagulated are three to six times higher to develop hematoma expansion. So, just to touch upon hematoma expansion. It's one of the few things that's potentially modifiable when we take care of these patients. A lot of what we talk about in terms of managing these patients when we see them acutely is blood pressure management. And part of that is in the hopes that we will reduce hematoma expansion. Those that are anticoagulated represent nearly 20 percent of intracranial hemorrhages. And as more people are on anticoagulation, the population is aging. We will likely see more of this. The spot sign is something that we use clinically to determine who might be at risk of hematoma expansion. This is just to show you picture A is a left potaminal hemorrhage. In B, you can see the black arrows pointing to that white spot. And that's what we call the spot sign. In picture C, you can see that the white arrows pointing to it. It's expanded. And that gives you a warning that this patient's at risk for hematoma expansion, therefore at risk for worse outcomes. And in picture D, that is the CT that was performed a day later, which in fact does show that the size of the hemorrhage has expanded and there is new intraventricular hemorrhage. So when we think about how we can predict ICH outcomes, I'd say the two most common scales we have are the ICH score and the FUNC scale. The ICH score does have its limitations and criticisms. However, it's still probably one of the more common scales that we use clinically. And what it does is predict 30-day mortality. All the things you see listed under it are independent risk factors for poor outcome. So you essentially get a point if you're 80 or above. If you have an infratentorial hemorrhage, that's because in the posterior fossa, it's a smaller space. So anything that's there that's not supposed to be there puts you at risk for worse outcomes because it can cause herniation and hydrocephalus. If your volume is large, defined as over 30 mLs, if there's intraventricular hemorrhage or if you have a lower GCS, all those things get you points. The FUNC score, instead of predicting mortality, predicts functional independence at 90 days. And it uses similar metrics. However, it defines them a little bit more refinely. So in terms of age, it stratifies to under 70, 70 to 79 over 80. ICH volume, however, goes further to say obviously you're at higher risk if you have a larger hemorrhage. ICH location, categorizing into deep and infratentorial. It affects your outcomes if you have pre-ICH cognitive impairment and this only uses one stratifier for GCS. What I really want to think about is put this in a clinical context for you. If I showed you this head CT, say it's an 80-year-old woman. She came in with right-sided weakness. Her GCS is 13, and she has this left basal ganglia hemorrhage. If there is no hematoma expansion, and we think about our scales, her ICH score is a 1, so that's a 13% chance of mortality. And her FUNC score says she has a 42% chance of independence at 90 days. Now if this patient develops hematoma expansion and this hemorrhage enlarges, perhaps develops intraventricular hemorrhage, and even if her GCS drops by two points, that puts her at an ICH score 4, which predicts mortality to be 97%. And the FUNC score only calculates a 13% chance of functional independence in 90 days. So, you know, small volumes can have a huge difference in terms of clinical impact. So we've talked about why it's important to identify patients that are anticoagulated because they're at risk of developing hematoma expansion. So briefly, we'll just discuss the two different direct oral anticoagulants that we'll be focusing on today, which are rivaroxaban and apixaban. They are factor Xa inhibitors. And as everyone is aware, most clinicians are now favoring this as an agent because it causes less drug-drug interactions, and it doesn't require as intense monitoring. And as we can see here, this is just showing where in terms of the coagulation cascade it's working, and it is essentially blocking the catalytic binding site on Xa to cause its effect, which is blocking Xa, factor Xa. So, and when we just talked about how these DOACs work, we're going to now think about how indexonate alpha works. So it acts as an alternative binding site for these factor Xa inhibitors. And in trials where it was studied in healthy individuals without bleeding, it showed a marked reduction in anticoagulant and anti-factor Xa activity. And it was approved by the FDA in 2018 for reversal of rivaroxaban and apixaban due to life-threatening or uncontrolled bleeding. This is just a mock-up cartoon showing how this modified decoy molecule works. And basically, it's just going to block the site so that it's going to prevent the action of the factor Xa inhibitors from working, thereby reducing the anticoagulated activity. In terms of pharmacokinetics and pharmacodynamics, it is rapid onset. It's a short half-life of about one hour. Therefore, it does require a bolus dose followed by a two-hour infusion. It comes from 100 milligram single vials. And we do have standardized dosing for how to deliver it based on the dose of the agent they're on, rivaroxaban and apixaban, and if you have a less known well. Now, what I want to focus on its importance, we talked about how it has a rapid onset and can very quickly clear your factor anti-factor Xa activity. And we know that in terms of hematoma expansion, the majority of these patients, a significant amount, the first three hours are super critical. There's a new concept that's evolving in neurocritical care called code ICH. You know, everyone knows an acute ischemic stroke, time is brain, and the same goes for intracranial hemorrhage. So if you think about a patient that develops their symptoms at home, by the time they get to the hospital, get their head CT done, you identify them as having an intracranial hemorrhage. Easily 45 minutes to an hour have already gone by. Once you dose them with indexa, if it's appropriate in this patient, within two to five minutes of that bolus, you've already reduced the anti-factor Xa level by 92 or 94 percent. So it's so important in this critical time to address that possible anticoagulated activity, because by doing so you can reduce the risk of hematoma expansion. Now I'm going to transition to presenting some of the data that we have that compares these two reversal agents. So an exa4, this is one of the major clinical trials that examined the safety and efficacy of indexanet in terms of factor Xa inhibitor related bleeding. It was a multi-center prospective open-label study in North American Europe, and they evaluated patients with major bleeding within 18 hours of receiving their factor Xa inhibitor. The main outcomes were really looking at the change in anti-factor X activity, as well as hemostatic control after 12 hours. As you can see, I put boxes around what the major indication for the DOAC was, which was atrial fibrillation in about 80% of patients, and about 64-65% of these patients did have intracranial hemorrhage. Now what you see on the left, the top is for apixaban, the bottom is for riboroxaban. These are median plotting of what is the anti-factor Xa level, and the x-axis here is going to be time. The y-axis is your anti-factor Xa activity, and you can see by that time of the end of bolus administration, there's an extremely significant reduction in anti-Xa factor activity. And when they plotted this over here, you can just say that they essentially identified that there is good or excellent hemostasis within this group. Now, we all know trial data is really picking the best patients under the best circumstances and doing it in a highly controlled setting. But what when we think, well, how does this hold up in the real world? So this is a study that compared the Annexa 4 group to what a simulated real-world group. Retrace 2 was an observational multi-center study that was done in Germany, and they used the group that was deemed usual or real-world care, which was for the majority of patients receiving PCCs. And the objective was to compare the occurrence of hematoma expansion, which was defined as a relative increase of 35% in clinical outcomes in factor Xa-related intracranial hemorrhage. What I have shown here is that there was a significant reduction in hematoma expansion in the indexinid alpha group. And while they didn't find any significant improvement in mortality or functional outcomes, I did think it was interesting. This is a Kaplan-Meier curve showing a mortality and survival probability. So x-axis is time, y is survival probability, and you can see that as you go out further in time, there is a separation of lines. And while it's not clinically significant, I think that if they were perhaps to go further beyond this 30 days, you might see if this lines would further separate and show a higher or more statistically significant chance of surviving in the indexinid group. This is just a sensitivity analysis showing that while the functional and mortality outcomes didn't have any statistically significant difference, there are, as you can see, a lot of trends towards favoring indexinid alpha. For MRS, which is the modified Rankin scale, one of the most common functional scales we use in stroke, and mortality as well. So to go a step further, we talked about comparing to a simulated real-world group. This is a propensity score overlap weighting study, which is essentially a statistically way of reporting or simulating an RCT. And what they did is they again used the Annexa-4 group to control it to a synthetic control arm. And what I want to focus here is while they didn't find any significant differences in mortality or outcomes, I'm going to come back to this number later in my slides, that the overall difference mean change in volume was 4 mLs. And that does not sound like a lot, but I'll show you later that that can have a significant effect on outcomes. We talked about some of the major clinical studies. I just wanted to summarize here. I won't go through all this, but there's been several retrospective studies that have been done that all show that there's a lower rate of in-hospital mortality and good or excellent hemostasis when using indexinid alpha for factor Xa-related intracranial hemorrhage. So finally, this trial that I know a lot of people are anxiously awaiting to see the full publication, Annexa-I. This was presented at WSO, so I have some information that was released from that, and we are all waiting for its formal publication. But Annexa-I is a randomized multi-center clinical trial that was mainly run to try and determine the efficacy and safety of indexinid alpha when compared to usual care for factor PCC. They use standard definitions. So in terms of hematoma expansion, excellent was under 20%, good was under 35% hematoma expansion without a significant change in the next stroke scale or requiring rescue therapy in under 12 hours. But like all the other trials, it's important to remember that they did not include patients with the GCS of under 7 or those that required surgical intervention. This was stopped early based on the superior hemostatic efficacy that was found. So in terms of results, this is a pretty large study when you think about all the other trials that were done. There are over 250 patients in each group, relatively similar median hematoma volumes, about 10, which, you know, in my world is a relatively small intracranial hemorrhage, and medium baseline NIH of 9 in both groups. The primary outcome was hemostatic efficacy, and you can see in the indexinid group is 64% versus the usual care, 52%. So it is reiterating what we've seen in prior studies is that it does have perhaps better hemostatic efficacy. However, there are no differences in functional outcomes, which is defined as an MRS less than or equal to 3 at 30 days or a 30-day mortality. They did postulate that it was not significantly powered to reach the secondary outcomes. The last thing I'd like to touch upon is just thinking about the financial implications. There have been a few studies that have looked at the cost-effectiveness of indexinid alpha, and I would say that this paper, which I will briefly touch upon, is different. The other papers have found that it is not cost-effective. However, they were not necessarily used using the United States third-party payer system. The major other paper that tends to be reported is based on the Canadian health care system, and it used a simplified Markov model, whereas this is a little more sophisticated in terms of using multiple different models as you progress throughout time and takes into account changes that may be occurring due to the superior hemostatic efficacy. So this is just showing phase one, which is from admission to ICU to the first 30 days, and you progress from rehab 30 to 90 days, long-term 90 to one year, and even past one year out. In terms of the economics that were used in this case, at the time the wholesale acquisition cost for indexinid was $27.50, and PCC's was $2.62, so you see that and think there's a significantly large difference. However, you have to think about if these patients have better outcomes and require less hospital care, there is going to be a reduction in the burden of our health care system, and for those that aren't working or don't see what these costs are, mechanical ventilation per day, and this is data from 2022, it was estimated to be at least $2,400, and each day in the ICU is $5,600. And what this study effectively found was that because these patients are likely projected to have longer life years with a higher quality of adjusted life years, the incremental cost-effective ratio works out to be about $35,000. For those that aren't aware of these economics, which I was not prior to putting this together, the benchmark for the U.S. health care system is about $50,000, so that if a treatment is below that, it's deemed typically acceptable. But I would have the caveat that this study was done in 2022, well published in 2022, which was before this 55% cost reduction. Therefore, I would say that it's actually truly in this today's economy less than this. And if we say it's at least 20 to 30 percent less, which is I think a conservative estimate, it puts it at an amount that we have no problem paying for a TPA and acute ischemic hemorrhage. For patients that present in three to four and a half hours after their last known well, the incremental cost-effective ratio is about $22,000, so that's just something to think about. I won't go through all these, but we've seen the guidelines that do recommend using indexed at alpha for factor X-related hemorrhage. These are the updated ICH guidelines that came out in 2022, and this is a summary of all the other national guidelines that do recommend its use as well. So in conclusion, I think if we reduce hematoma expansion, we can have better clinical outcomes, but we need longer-term follow-up. 30 days isn't enough. We know that the natural progression for recovery in intracranial hemorrhage is reported to be at least three months, sometimes often out to six months, and we need sicker patients. These studies all excluded those without both the GCS below seven, and I understand you might not want to include patients with the extremely large hematomas, because there's always the factor of withdrawing life-sustaining care. However, there are patients with inferential hemorrhages, which can be small but extremely significant, and those patients will present with a low GCS. And patients that are going to surgical management needs to be considered as well. Availability remains an issue. It's not on a significant amount of hospital formularies, and I think it's really important to think about risk stratification, so we can identify patients who are least likely to develop thrombotic events. Thank you. I'll hand over to Dr. Roney, who will present her slides.

intracranial hemorrhage

factor Xa inhibitors

indexinet-alpha

prothrombin complex concentrates

clinical trials