Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Speaker 1 00:32 Welcome to HelixTalk episode 177 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is the antidote arsenal, exploring the emergency toolbox for anticoagulant reversals. So Dr. Patel, today we're talking about how we reverse our doacs and warfarin in patients that have either major bleeding or have a life threatening emergency and they need emergency surgery. Dr. Khyati Patel 00:56 Oh, this is a great topic. Dr. Kane, just me providing anticoagulation care on the outpatient side, I don't get to deal with, you know, these agents clinically as much, aside from vitamin K, but my patients always ask, like, hey, you know, if you if I do consider going on one of those new doacs, like, is there an anticoagulation agent available? So I'm excited to get into the nitty gritty of what pharmacists need to know in terms of what dosing agents are available, what's the safety, efficacy profile and things to consider? Speaker 1 01:26 Well, why don't we start with a patient case, and honestly, Dr. Patel, this is a very common patient that I see in my clinical practice in the ICU. So a 77 year old woman comes to the emergency department after a serious motor vehicle accident. She has a number of orthopedic fractures, and she's found to have a subdural hematoma, which is a form of intracranial hemorrhage. She's intubated for airway protection because she's too sleepy because of her traumatic brain injury. So neurosurgery wants to take her to the operating room for craniotomy and an evacuation of that bleed in her brain. No family is available, but we think she's taking rivaroxaban, or Xarelto, 20 milligrams once a day for a history of afib. And this is based on prescription fill history. We actually can't talk to her. We don't have family available. So really the question is going to be, how should the anticoagulant, her rivaroxaban, be reversed so that she can safely go to surgery. And even if she wasn't going to go to surgery, how could we reverse it so that the bleed in her brain doesn't get any bigger? Dr. Khyati Patel 02:28 Yeah, and I think that's a that's a great case. And kind of, you know, go starting from the very beginning. It's just talking about, why are we even talking about these reversal agents? Right? That's because we're dealing with anticoagulants, and one of the common side effect is bleeding. We have Warfarin and we have the doacs, and, you know, the doacs are kind of becoming standard of care. We Warfarin hasn't completely disappeared as we hoped with the addition of doacs in the therapy market, but doacs are definitely the standard of care. And we do see bleeding events with doacs too, and that, that's why we were talking about this reversal agents? Speaker 1 03:02 Yeah, and you know, there is some Medicare Part D data out there about more recent anticoagulant use, and I thought this number was so interesting. So 10% of all Medicare Part D patients, so we're talking primarily adults, 65 years of age and older, 10% of them actually take an anticoagulant. And currently, in the last year or two, about two thirds of those patients are taking a doac, and about a third of those patients are taking warfarin. So that is a ton of older individuals that are taking anticoagulants, that are prone to falls and things like that, that if you fall and hit your head and you're anticoagulated, you're more likely to bleed, for example, right? Dr. Khyati Patel 03:41 And based on the evidence we have so far, these guidelines are generally preferring doacs over other anticoagulants for the treatment of nonvalvular AFib and the acute DVT or PE treatment and prevention. Speaker 1 03:56 And you know, the main reason that the guidelines prefer doacs and AFib is because doacs are associated with a lower risk of stroke, and specifically it reduces the risk of hemorrhagic stroke or intracranial hemorrhage. So it is effective for ischemic stroke, but most of the benefit versus Warfarin is actually with reduction of intracranial hemorrhage and hemorrhagic stroke. Dr. Khyati Patel 04:18 So Dr. Kane, when we say there are bleeding risk what kind of percentages or incidences are we talking about here? So it Speaker 1 04:27 kind of depends on the patient population, which makes sense. So among patients that have more risk factors for bleeding, their incidence rate of bleeding is going to be higher. But if you take a typical nonvalvular AFib patient, they're typically in their like, early to mid 70s, and their risk of having a bleeding event is a major bleeding event is about 5% over a two year period. And if you contrast that with an acute DBT or PE patient population, they're a little bit younger, and they also don't take anticoagulation for as long, so their risk is about 1% over a six month time. Period. So we're looking at a couple percentage points per year, and really both groups, but it's going to definitely dependent on patient specific factors. Dr. Khyati Patel 05:09 And then, just to clarify for the audience, here, we're talking about the major bleeding events, right? So the percentage are smaller. If you look at the safety literature for these agents, you may see the the minor bleeding events also reported. But that's not where we use these reversal agents. We use them for the very serious, major bleeding events. So that's that's where the percentages are that you describe Speaker 1 05:30 exactly, and as the name suggests, major bleed is truly a major bleeding event. These patients are almost always hospitalized. Oftentimes they're receiving blood products like packed red blood cells, they might be having a surgical procedure to stop the bleeding. These patients, when they experience a major bleeding event, this is truly a major event. And of course, the risk of a minor bleeding event is much, much higher, but the severity is not going to be as as high as a major bleeding event, right? Dr. Khyati Patel 06:00 And then, aside from them being on anticoagulant, there might be some inherent bleeding risk for the patient we've all heard of HAS-BLED score, so you know that you can calculate that encounters for things such as patients liver function and renal function. What's their bleeding history? What's their age if they're on warfarin, what's the history of INR control? Meaning it's been more up and down, like labile versus being in the right range. Additionally, looking at conditions such as previous history of stroke or uncontrolled hypertension, as well as drugs or substances they might be using that can further increase the risk of bleeding, so other anticoagulants or antiplatelets, NSAIDS, alcohol, etc, and Speaker 1 06:49 just to highlight the drug interaction aspect, dual antiplatelet therapy in particular, is one that receives a lot of attention with concurrent anticoagulants. A long time ago, we did an episode on triple oral antithrombotic therapy or T.O.T.E., and once you're on three agents, an anti platelet, a second anti platelet and an anticoagulant, obviously your risk of bleeding is going to go up substantially, right? So those are kind of the obvious drug interactions, but NSAIDs may be a little bit less obvious, but then even something like SSRIs and SNRIs, those have been associated with an increased risk of bleeding when taking an anticoagulant. But I would say the that strength of association is not nearly as strong as something like dual antiplatelet therapy, right? Dr. Khyati Patel 07:32 And then, in addition to the has blade, the inherent bleeding risk, we also pay attention to the patient's previous history for fall, or tendencies to fall, and then other medication use again that falls under drug interaction, SSRIs or SNRI as well. So those all things are considered when we are looking at this bleeding events or the rates. Speaker 1 07:55 So then Dr. till obviously, the next question is, when do we decide to reverse someone's oral anticoagulant in terms of, is it any kind of bleeding? Are there certain situations that we would allow a patient to bleed but not reverse them? What are some general thoughts or guidelines in terms of when it's appropriate to reverse an oral anticoagulant? Dr. Khyati Patel 08:16 So I think one thing we established earlier that these agents are for this major life threatening bleeding, as we, as we said earlier, these are very small percentages, but that's where they're receiving this critical care in the hospital. So that's one patient scenario that fits in mind, where we can use these agents. Speaker 1 08:35 And then, of course, the other situation would be someone who's not currently bleeding, but needs to have a surgical procedure, and that surgery can't be done when the patient is anticoagulated. So an example of that could be someone who has appendicitis and they need to have their appendix removed, but they are currently anticoagulated with an oral anticoagulant. That surgeon is going to want the patient's anticoagulant to be reversed so that they can safely do that surgical procedure, and assuming that that the surgery can't be delayed in some way, but it is urgently needed now, that would be the second other common reason that will reverse an oral anticoagulant, right? Dr. Khyati Patel 09:14 And in the patient, case that you provided, Dr. Kane, it seems like our patient kind of meets both of this criteria, right? They're having the intracranial bleeding, which is life threatening, bleed, major bleed, plus they need to go under the surgery to stop the bleeding, and so they kind of check both of these boxes to qualify for a reversal agent. Yeah. Speaker 1 09:34 And I think the kind of contrast with the indications for reversal, the reason that we don't want to reverse everyone if they have a non major bleed, or if the surgery can be delayed, is there's costs and side effects associated with the reversal strategy. So we only want to reverse someone if it's absolutely necessary. And probably the the main thing to think about is all of these patients have a reason for being anticoagulated in the first place. So. If you're going to reverse your anticoagulant, the reason that they were originally taking that anticoagulant is still there. So if they have afib, the risk of stroke is going to go up. If they recently have a DVT or PE, that clot can come back, get worse, or cause problems. So in addition to the side effects and the cost, we're unmasking the anticoagulant and whatever underlying reason that they're taking it could become a problem, right? Dr. Khyati Patel 10:25 And Dr. Kane, are there any organization that kind of put out a guideline as to how we use this reversal agent? Is there any consensus to how practices occur at different hospitals? Speaker 1 10:37 Yeah, so most hospital systems, especially larger hospital network systems will have their own, like internal guideline document in terms of best practices, what reversal strategies they have for a given anti thrombotic therapy, but there are kind of national guidelines that are out there. So three that come to my mind are the American College of Emergency Physicians or ACEP. There's also an anticoagulation form guideline, and also the American College of Cardiology, or ACC they also have their own guideline. All of these are referenced in our show notes. For the most part, there's a couple of small nuances in terms of differences, but in terms of reversing oral anticoagulation, for the most part, they're all going to follow what we'll discuss in today's episode. And there's not a lot of differences, right? Dr. Khyati Patel 11:22 And so the variations will come in from the cost perspective, or the hospital P and T Committee decisions based on the evidence and the availability of the product and whatnot, exactly. Speaker 1 11:32 And you know, really, before we jump into it, because it isn't technically a reversal strategy, but a little bit all of these oral anticoagulants, if a patient just took a dose like within the last two to four hours, we can use something called activated charcoal, which is sometimes given to patients with an overdose, to prevent absorption. So it will basically bind to the oral anticoagulant and the GI tract and prevent it from being absorbed. It's fairly uncommon that we're actually able to do this clinically, because the window of time of two to four hours from ingestion is pretty short. And you think about our patient example here, we don't know when her last dose was period, let alone if it was within the last two to four hours, so she would not be indicated for but kind of worth mentioning that every once in a while, you might get lucky and be able to give activated charcoal to prevent an anticoagulant from being absorbed, right? Dr. Khyati Patel 12:21 And this is probably more pertinent to an anticoagulant that is not warfarin, because they have a shorter, you know, half life. So maybe more appropriate. But if you did that with warfarin, the previous days of Warfarin is still in the effect, so maybe not applicable there. So depends on the agent as well. Exactly. Yeah. So talking about warfarin, you know, I in my head, it's very easy to strategize, okay, Vitamin K antagonist, give them vitamin K, and it's going to reverse it, right? It should be that easy. Speaker 1 12:51 That's half the equation, and that part that most people think about. So really, we do need a two pronged approach to how we reverse warfarin. The one is what you mentioned, which is give the body a vitamin K so that the liver can make vitamin K dependent clotting factors, so the INR over a longer period of time can be normal, but in the acute setting, we need something that's going to work now, because it takes the liver a while to make those vitamin K dependent clotting factors. So our now treatment is to literally give the patient clotting factors in an IV formulation, and by doing that, it immediately drops their INR and reverses the effects of war for now. Dr. Khyati Patel 13:31 And what would be those two strategies? I think I remember fresh frozen plasma. Is that commonly used still, or do we have other alternatives? Speaker 1 13:41 You know, we used to use fresh frozen plasma almost exclusively, but in the last probably 10 years, we've used more and more what are called prothrombin complex concentrates, or PCCs. And these have a number of advantages. And basically, the guidelines recommend using PCCs at this point and not using fresh frozen plasma unless you literally can't get a PCC. And this is basically a vial that is a laugh, lies powder where it gets reconstituted and is given to the patient. The advantages are a couple. One, you don't have to thaw it. You just have to reconstitute it. Takes a couple minutes. You don't have to type and cross it. So you're not looking at the patient's blood type and making sure you give the right kind of FFP, because the PCCs don't have any blood in them, it's way less volume. So for a typical PCC dose, it's going to be maybe about 100 milliliters, or maybe a little bit less, versus when you give plasma, it's at least a liter. So if someone is sensitive to getting IV fluid, so if someone with heart failure, for example, that can cause some problems in terms of pulmonary edema, things like that. Partially, because the volume is lower, we can give the PCCs quicker. Our risk of infusion related reactions is lower than giving plasma. And then at the end of the day, a typical dose of PCC versus a typical dose of plasma, the PC. C is way more potent. We're probably giving about 25 times more clotting factors, which means that we're going to drop the INR quicker and have a more profound effect on the INR by giving a PCC. Dr. Khyati Patel 15:11 And then, from my understanding, Doctor Kane, there's different types of PCC out there, and depending on there's some other non anti coax versal uses of PCCs as well. But for the anti COAG or the warfarin reversal, what are the two main product, or two products that we go for? Yeah. Speaker 1 15:29 So there are a number of products. A lot of the other products that we don't commonly used are for hemophilia and factor deficiencies. A lot of those are what are called three factor PCCs, or three factor prothrombin complex concentrates, so we don't use those, typically for Warford reversal. There are now two FDA approved products that are four factor PCCs that contain our vitamin K dependent clotting factors of 279, and 10. The one that's been around for a while is case Central, and then a new one that was recently approved in the last couple months is a product called belfax are and it's dosed similarly to kcentra, has the same clotting factors as case Central. So it's a another one on the market that now has FDA approval. The other one that pharmacists and other healthcare providers may be exposed to is a product called FIBA, and this is an activated PCC. So it's still a four factor PCC of 279, and 10, but cladding factor seven has been activated, so it's ready to go. So that's an apcc or an activated PCC, as opposed to just a run of the mill four factor PCC, where those four cladding factors are not activated in the vial itself. Dr. Khyati Patel 16:39 And as you kind of said earlier, these are lyophilized powders, so you're going to re concentrate them. And so a typical dose would be, depending on how hard high the patient's INR is. We're going to dose anywhere between 25 to 50 units per kilo, and this is given IV as a one time dose. Speaker 1 17:01 Yep, and we're doing this because it works immediately. So as soon as that drug goes into the patient, their INR is going to lower to the point where it's almost going to be near normal at the end of the infusion. The problem, though, is that especially cladding factor seven has a really short half life, so even though we're giving the patient cladding factors, their body is, within hours, going to start degrading some of those cladding factors that we just gave them IV and their INR is going to start going up if we don't do something to help the liver make those clotting factors. Dr. Khyati Patel 17:31 And that something is where vitamin K comes in play. And so again, these factors, 279, and 10, these are vitamin K dependent clotting factors, and in order for them to be produced, your liver will need that vitamin K. And so by giving vitamin K allows liver to make these clotting factors that were inhibited by the warfarin at once. And so that's how long term we're going to make sure that the INR remains low Exactly. Speaker 1 18:02 And you know, it takes about a day, 24 hours, whether you give it orally or IV, for the vitamin K to wake up the liver enough to make those clotting factors. But that's exactly the reason why we're giving the PCCs is a short term fix, and then the vitamin K as a longer term fix. We need both of them. We will give it IV for patients that are bleeding the doses five to 10 milligrams. Just one dose is enough. Sometimes clinicians will give more than one dose, but it's really not necessary. And really, we're giving it IV to just make 100% sure that the drug gets into the blood. We don't do im or sub q, it's IV. Historically, there was a concern about anaphylactoid reactions with it, but it's extremely rare, so giving IV is fine. Dr. Khyati Patel 18:45 And then we have vitamin K available as oral formulation as well, but oral formulation is reserved for more like outpatient cases, or you're not seeing you're seeing a higher INR, but you're not seeing this major bleed event happening, but in the case of major bleed, you're going to need to give IV to make sure that it's absorbed, that we're not dealing with any bioavailability issue. You know, given as a PL agent, Speaker 1 19:13 and just to put a number to it, the chest guidelines, which are pretty outdated at this point, suggest giving oral vitamin K only if the INR is more than 10 and the patient's not bleeding clinically. Most, most healthcare providers get uncomfortable with an INR 678, and nine. So at least in my experience, I've seen clinicians giving oral vitamin K just to make the INR go down a little bit, even though it's not above 10. But technically, the guidelines say more than 10. Dr. Khyati Patel 19:42 So Dr. Kane, you know my rule of thumb, that's interesting. How you mentioned the guidelines recommends po vitamin K only if INR is above 10. And I kind of follow that if they're not bleeding hemodynamically, they're stable, they're not going to get engaged into any sharp object related activity where there is. Completing is higher, they're going to jump off the plane or something I watch and monitor, I say, Let's omit some doses of the warfarin. You know, maybe have a nice salad with high vitamin K vegetables at home. But we don't probably need a PO vitamin K, just because vitamin K hangs around for longer. So once you give that dose, and it's really you're chasing with Warfarin to bring that INR back up again. Speaker 1 20:24 Love that, and I totally agree with that point. Dr. Patel, well, you know, we've covered Warfarin reversal. We have four doacs on the market now, and the first one that came out in 2011 was the bigotran, or Pradaxa. Why don't we talk a little bit about how we reverse the bigotran? So in this case, we actually have a monoclonal antibody fragment that is called, idarucizumab, which is kind of fun to say. The brand name is Prax bind. And this is given as two, two and a half gram IV doses over about a five minute period, as either IV push or a very quick IV infusion. And this basically binds to and rapidly neutralizes Dabigatran, and it lasts for at least 24 hours in the vast majority of cases where the patient's Dabigatran just is gone when this medication is given, right? Dr. Khyati Patel 21:10 And so kind of matches the half life of perdoxa, the Dabigatran pretty well and the outcome of this particular agent were studied in a trial called reverse ad trial. Dr. Kane, can you explain, like, the trial design and what? What did we find based on the results? Speaker 1 21:28 Yeah, so really, all of the trials that we're about to talk about are open label, single arm studies, which is a huge limitation, because it's hard to compare it to anything if you only had one arm. But basically, what they looked at were patients taking Dabigatran that either had a major bleeding event or they weren't bleeding, but they needed to have emergency surgery right now. And they gave ideary system app to all of the patients, because it was a single arm study. And what they did was that the primary endpoint was how much Dabigatran was active in the blood at a four hour mark, and at four hours, basically all Dabigatran was gone, inactive, not working in these patients, so they've easily met their primary endpoint. So probably not a big deal that they didn't have a control arm. In this study, they also looked at 24 hours, and three quarters of patients still had undetectable dabigatran levels all the way up to 24 hours. So the four hour mark was the primary endpoint. But even at 24 hours, it seemed to be really effective at getting dabigatran inactive out of the blood so that it wasn't exerting its anticoagulant effect. Dr. Khyati Patel 22:31 And obviously, you know, we gotta, even though this was a single arm study, we gotta look at the safety events of what happened when they got a idarucizumab and the opposite side, as we discussed earlier, right? These patients are on anticoagulant for a reason. Maybe they have a fit. Maybe they had a high risk for VTE. And so when you remove the anticoagulant using this reversal agent, you expose them to higher risk. And so the side effects were that we noted higher events, thrombotic events, in these patients. And in some cases, because this is a, you know, a fragment of that monoclonal antibody, some hypersensitivity reactions were also noted. Speaker 1 23:14 And, you know, not all hospitals, I'd say the majority of trauma centers especially, are going to have, I daresay, some AB on their formulary and available. But all three guidelines state that if you can't get ideary systemab, which is the preferred reversal strategy, you can choose to give a PCC. The three guidelines that we mentioned differ in terms of a preference for which PCC, whether it's an activated PCC or just a four factor an activated PCC. They also no one agrees on the dosing, whether it's 25 or 50 units per kilogram, giving a fixed dose of like 2000 units period, regardless of your body weight. So there's a lot of variability, and that really comes from is this not well studied to give a PCC, but that would be the alternative option if you can't give idea system. Dr. Khyati Patel 23:59 And then if all fails, is, is there any other option for us to get rid of the anticoagulation? Speaker 1 24:07 So theoretically, you can dialyze Dabigatran. I would say this is almost never going to be done, because these patients have they're anticoagulated, so nobody's going to be excited to put in a dialysis line to be able to get the Dabigatran out of their body, and we have these other reversal therapies that are just going to be easier logistically. So yes, you could dialyze it, but no, that's not a realistic option for most Dr. Khyati Patel 24:30 patients, right? And then, not only the logistics, but also the whole process, can take a lot longer than just giving an agent that reverses it Exactly, yep. So we discussed the direct thrombin inhibitor, the dabigatran reversal agent. We do have the direct 10 a inhibitors in the market, apixaban and rivaroxaban, and we do have a reversal agent for them as well. And that agent is andexanet alfa, the brand name is Andexxa, we've got some, you know, back and forth. It was launched in the market in us, and it was withheld for a little bit, and it was relaunched. But Dr. Kane just explaining what this andexanet alfa is, and how does it work to reverse apixaban and rivaroxaban effect? Speaker 1 25:19 Yeah. So the mechanism is pretty cool. So it's basically a decoy clotting factor 10 A. So it actually doesn't have any clotting factor activity, but it looks and feels like clotting factor 10 a in the body. So when a patient is taking rivaraxaban or apixaban, those two doacs have a higher binding affinity for this decoy index in alpha, as opposed to normal human clotting factor 10 A, so the doacs will spend all their time binding to this reversal therapy, as opposed to sending the patient's blood by binding to cladding factor 10 A. So that's kind of the mechanism, and based on that mechanism, we absolutely would expect this to work for something like edoxaban, even enoxaparin, a low molecular weight heparin, because it's hopefully it will be that decoy for these other anticoagulants as well. Dr. Khyati Patel 26:15 And I imagine, just like the Praxbind, this one also is given IV for a quicker effect. What is, what is the typical dosing for andexa, yeah. Speaker 1 26:27 So the dosing is that you give an IV bolus followed by a two hour IV infusion. The dose for both the bolus and the infusion, there's kind of two strategies. One is a low dose strategy, and then the other is a high dose strategy. The strategy is going to be based on what doac they're on, specifically what dose of doac they're on, and when their last dose was, if it is a known dose. It's a little bit complicated in terms of deciding higher low dose. And then once you do that, to give a bolus followed by an infusion. So a little bit less straightforward than IDEA says, imagine, not impossible, but enough that you have to make sure that you're doing it right, because of that complexity, right. Dr. Khyati Patel 27:05 And I think the manufacturer's website kind of provide a guidance, but your, you know, internal hospital P and T committee guidelines may also have some clarification tables for how you approach the low versus high dose application for your given patient. Speaker 1 27:20 And you know, in terms of clinical data. So the original data came from two studies that were done in healthy volunteers. So this was the ANNEXA-A and the ANNEXA-R trials for apixaban and rivaroxaban. And basically, they took healthy volunteers that were not bleeding, and they had them take either rivaroxaban or apixaban, and they gave them andexanet alfa to see how effective it was at reversing the effects of those two doacs. And it worked really well during the infusion. But then what they saw was anti factor 10, a levels started to rise at about the two to four hour mark after that bolus was given. So it definitely does reverse it. But during the healthy volunteer study, the question was, does it reverse it long enough that it would have a clinical benefit for patients that were having a major bleeding event, for example? Dr. Khyati Patel 28:12 So in that case, then they performed another study, a Nexa for trial, and this was done in patients who were on any inhibitors, who had major bleeding, yeah. Speaker 1 28:25 And just like the previous trial that we talked about with idarucizumab, this was open label, single arm, so there is no comparator. They technically included an oxaparin and edoxaban, but there are so few patients in the study, it's almost not worth talking about. It was basically in apixaban and rivaroxaban study, and just like in the healthy patient study, they showed that during the infusion the anti-factor Xa activity was very well reversed, so more than 90% reversal of apixaban and rivaroxaban, but roughly about the like two, two to four hour mark after The infusion was started, the effects seem to start waning off, and we don't know if that matters, because there's no comparator arm. So it's really hard to say whether you know the bleeding was stopped enough that the four hour mark it's okay that you still have some active anticoagulant in your blood, or maybe it's not okay. We just don't know, because there's no active comparator Dr. Khyati Patel 29:20 that's very interesting. And again, kind of pitching, looking at the safety concern as well, comparing it to the efficacy it did. The study did notice 15% overall mortality rate, although there was no, you know, we don't have the comparator arm to say whether this was different or not. Thromboembolic events were also noted at 18% again, just like either boost is a map trial. If you stop anticoagulation, these patients are taking it for a reason, you're going to see higher risk of those events. And then antibodies against the index and it alpha were noted, as well as some infusion related reactions Speaker 1 29:57 kind of hot off the press the manufacturer of index. Incident, alpha did release, a press release that they have a new study called ANNEXA-i, and they published preliminary data. That's kind of an interim analysis. In this trial, they compared andexanet alfa versus quote, unquote, usual care. I don't exactly know what usual care is. It's not mentioned in the press release. The thought is it probably includes PCCs, but we don't know for sure, and they only looked at people that were taking an oral 10 a inhibitor, so primarily apixaban and riveroxaban who had an intracranial hemorrhage. So they are looking at a very specific patient population with major bleeding. But this is really one of the first trials that we've had that had an actual comparator arm. And they they stopped the trial early because of perceived efficacy benefit with andexanet alfa versus usual care. Their main primary point that they looked at was the intracranial hemorrhage not expanding. But they also saw an increased risk of thrombotic events, and they saw no difference in mortality. And I don't want to spend too much time looking at the data, because there's not much data to look at, because it's just a press release. So really, I would say many people are very interested when this gets published, to see what the results of the trial actually are, to see what is the clinical benefit of using andexanet alfa versus an alternative therapy like a PCC. Dr. Khyati Patel 31:17 And I was talking about alternative you're right if your hospital doesn't carry index on it, alpha, the guidelines do recommend using PCC as as an alternative for reversal of this anti tena inhibitors. Speaker 1 31:31 And just like with the dabigatran reversal with PCCs, the guidelines are pretty varied in terms of which PCC, how to dose it, things like that. And again, a lot of that is derived from just not a lot of comparative head to head data on dosing strategy, A versus B or a four factor, PCC versus an a PCC an activated version. We just don't have data. So at this point, it's anyone's guess in terms of what is the best PCC strategy, if you can't use index and an alpha. Dr. Khyati Patel 32:01 And I think, I guess I mentioned it earlier that, you know, and excellent. Alpha was launched with so much excitement. And then, I don't know there was some withholding of that, but overall uptake of index on it, alpha and United States market, has not been so good. Are there any reasons why we are seeing that? Dr. Kane, Speaker 1 32:20 yeah, to say it's not good is probably an understatement. So there's a 2021, publication that showed about 10% of all US hospitals carry indexed alpha and among trauma centers, where you'd really hope that it would be carried, it's a bit less than 1/3 of trauma centers. And the main reason is twofold. One, because of the trial with that rebound effect. We don't know how big of a deal that is. We know that PCCs are going to last longer than four hours. We know that with indexed alpha, there is a rebound effect that happens at that four hour mark. We just don't know if that's clinically relevant or not. It seems like not a good thing, at least, but probably the bigger reason it's not carried is because of the cost. So when it first came out, and that joking about this type of AWP, the cost of the medication, average wholesale cost, was 25 to $50,000 for a single dose, and kudos to the manufacturer, I guess, for decreasing it. Now we're at about 13 to $26,000 for a dose. And granted, yes, hospitals don't pay the AWP, so it's some number lower than that. Well, we compare that to the AWP for sizab, which is five to 6000 or PCCs that are five to 10,000 depending on your dosing strategy. This is way, way, way higher priced, especially given that we don't know how well it works because of that rebound at the four hour Dr. Khyati Patel 33:40 mark, that is a very high AWP. And again, yes, even though hospitals may not be paying that comparatively, that just sounds a lot, not more than idarucizumab, Praxbind and the other pieces. So that makes sense. Why most, you know, some of the hospitals don't carry it, or the uptake is not as great in the United States, exactly. So going back to our patient case, Dr. Kane, you know, we again, kind of reiterating, we had a 77 year old patient in a motor vehicle accident with multi system trauma who has this subdural hematoma, and we need evacuation surgery for that. And patient, based on the medication report, is on Xarelto, 20 milligrams daily for afib, it's on the health record, but we don't know if the patient's regularly taking it, or even as to what when the patient took their last dose. So based on what we discussed, and we kind of check those two boxes where, you know, patient is having life threatening bleed and they need to go under surgery, we definitely need to employ a reversal strategy here. Speaker 1 34:45 Yeah, that reversal strategy, if your hospital carries it, would be using andexanet alfa. That's what the guidelines prefer. It's the only FDA approved reversal strategy for riveroxaban. In this case, we don't know when her last dose was, so because we don't know she would receive the dose of andexanet alfa, which is that bolus, two hour infusion afterwards, and that would basically be the extent of her reversal at that point. Dr. Khyati Patel 35:09 And Could she be a candidate for PCC? Let's say if she was at a hospital where and dexon at Alpha was not on formulary, Speaker 1 35:19 she would so if we didn't have indexed alpha, the alternative would be a PCC. Most hospitals are carrying case. Central probably should get case Sentra, but there's no reason she couldn't get any of the other four factor PCCs, or a PCCs. The dosing strategy is all over the place, and this is where it's kind of whatever the hospital protocol is for reversal. It could be a fixed dose, something like 2000 units times one, or it could be a weight based dose, like 25 or 50 units per kilogram times one dose given her injury. So her brain injury is bad enough that she had to be intubated and she's going into have surgery. Whatever dosing strategy is out there, probably favoring the more aggressive side would be appropriate in terms of giving a larger dose versus a smaller dose, given where the bleed is and how severely sick the patient is because of her trauma, right? Dr. Khyati Patel 36:11 And so clinically evaluating that picture and making a decision that said that definitely makes sense. Speaker 1 36:15 Well, Dr. Patel to kind of wrap up today's episode in terms of key concepts. One big one is going to be, when do we reverse? And we only reverse for major hemorrhage or if we have to have emergency surgery that can't be delayed. Dr. Khyati Patel 36:30 And when we're talking about reversing Warfarin in such situations, we are doing that two prong approach. So we're doing a fast acting, short term solution, such as a PCC, combined with the slower acting long term solution, which is a vitamin K. In this case, it will be intravenous vitamin K. Speaker 1 36:51 And then for the big trend reversal, the preferred therapy is going to be idary systemab or Prax bind. It's a monoclonal antibody fragment that will bind to and inactivate the bigger trend. If we can't do that, the guidelines say, go ahead and use a PCC. We just don't have as much data for that. Dr. Khyati Patel 37:07 And when it comes to those oral factor Xa inhibitors like apixaban and rivaroxaban, the FDA‑approved agent for reversal is andexanet alfa (brand Andexxa), which is basically a decoy protein with higher binding affinity where the apixaban and rivaroxaban will bind. We discussed several barriers with the use of andexanet alfa and therefore low utilization in the hospital. And so if you are at a hospital where that product is unavailable, use of PCC is recommended. Speaker 1 37:38 So Dr. Patel, I think that wraps up today's episode quite nicely. We do have show notes where we have the three references to reversal guidelines for these newer anticoagulants. In particular. We also love the five star reviews and iTunes or Apple podcasts, or wherever you listen to us. If you could tell a friend to kind of spread the word of HelixTalk, that would be wonderful. We also have a mailing list, so you can get out at our website, HelixTalk.com and you'll get an email whenever these episodes go live. So with that, I'm Dr Dr. Khyati Patel 38:07 King and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 38:11 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there to Narrator - ? 38:22 suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.