We're going to be talking about anticoagulation reversal for life-threatening bleeding. This is a case-based presentation. And this is for the critical care setting. I'm Dr. Gregory Piazza. I'm one of the vascular medicine cardiologists from Brigham and Women's Hospital. And I work closely with our team that helps to manage anticoagulation reversal for anticoagulant-associated bleeding. I'm joined by terrific colleagues today, Dr. Tony Gutierrez from Duke, and John Finikos from Brigham and Women's Hospital. And we're going to be talking about the approach to anticoagulation reversal for life-threatening bleeding. We'll start with warfarin. Then we'll move to the direct oral anticoagulants. We'll talk about methods in the hospital setting for creating strategies and approaches to standardize the care of patients that are bleeding. So what we're going to do over the next hour and a half or so is identify patient groups at risk for experiencing emergent or life-threatening bleeding as a result of anticoagulation. We're going to assess the risk of emergent or life-threatening bleeding in patients who require anticoagulants and talk about current recommendations for managing bleeding complications. We'll spend quite a bit of time on the novel pharmacology and clinical utility of specific anticoagulants and the utility of specific anticoagulation reversal agents, antidotes, so to speak. And then we'll develop treatment strategies and institution-specific approaches for incorporating the clinical evidence for recently improved anticoagulation reversal therapies and to really promote consistent delivery of high-level care without overusing these expensive reversal drugs. So we're going to start with a couple of questions, OK? And the first is to kind of get a gauge of what all of you do in your daily lives. So what is your profession? Are you a physician, one, a physician assistant, two, three, a nurse practitioner or RN, four, a pharmacist, or five, other? And I think you can go ahead and log in your votes. All right, so good mix, a lot of physicians and a lot of pharmacists, excellent. What is your practice setting? Is it academic, a community hospital or inpatient setting, managed care, private practice, long-term care, or other? Go ahead and log in your votes. All right, and let's see. OK, great, so again, a lot of academic medical center providers and a lot of community hospital providers. What does your institution currently have in place to support your management of major bleeding in patients receiving direct oral anticoagulants? One, an algorithm or a protocol. Two, a gatekeeper type specialist, a hematologist, cardiologist, neurologist that's available for consultation and support in real time. Three, we have both available. Or four, we have none of the available. Go ahead and log in your votes. Some of you are enjoying the fresh beats that they're kicking out. Let's see what we got here. All right, good mix. So many of our centers here have the availability of both of these types of services. That's great, and 16% don't have these available. We'll talk about how to institute these types of strategies and services. All right, and we're going to do, actually, Tony, do you want to do these? Sure. So I'm going to welcome up Tony Gutierrez. He's an interventional cardiologist from Duke who has a lot of experience managing bleeds from an interventional standpoint. Tony. Unfortunately, I'm causing those bleeds a lot of times. Thank you so much for showing up at this very early morning. These are pre-tests, so we will go ahead. And number one, which of the following is the greatest risk factor for warfarin-associated intracranial bleeding? Is it one, concomitant antiplatelet agents, two, advanced age, three, Caucasian race, or four, poorly controlled hypertension? And we will be going through these throughout the talk. Good, good mix. Second one, in the setting of intracranial hemorrhage and an INR of seven, which of the following is the most appropriate next step in acute management of bleeding while on warfarin? Number one, do you hold warfarin? Number two, hold warfarin and give IV, vitamin K, and FFP. Three, hold warfarin and give four-factor PCC. Four, hold warfarin and give IV, vitamin K, and four-factor PCC. All right, a small area of improvement there. And here's another patient case. The patient presents to ER after experiencing a large volume of blood stools the night before. History of hypertension, diabetes, AF. Patients on river rock span, 20 milligrams daily. In the ED, he's tachycardic, relatively hypotensive to 90 over 44. Creates 28% with a BUN of 76 and a creatinine of 1.9. ECG demonstrated AFib with RVR at a rate of 128. Which of the following is the most appropriate next step for this patient? Hold RIVA and administer IV, vitamin K, and PCC. Hold RIVA and check an anti-10A level to see if the patient still is anticoagulated before considering reversal. Hold RIVA and give IV, adexanate alpha. Or four, hold RIVA roxaban indefinitely because the risk of bleeding is too high. I'm really digging the tunes this morning. Let's see. All right. Nice little spread there. Next question. What is an appropriate laboratory assay to assess a patient's level of anticoagulation on a PIXA band? A, dilute thrombin time. B, activate partial thromboplastin time. C, INR. D, chromogenic anti-factor 10A assay calibrated to low molecular weight heparin. All right. Lastly, a patient presents to the ER with life-threatening bleeding. The patient took a PIXA band five milligrams greater than eight hours ago. Anti-factor 10A levels were found to be 2.31. What is the most appropriate next step? One, since the last PIXA band dose was over eight hours ago, low dose of adexanate alpha is appropriate. Two, idariocizumab should be administered over adexanate alpha. C, since the last PIXA band dose was five milligrams, high dose of adexanate alpha would be appropriate. D, since the anti-factor 10A level is elevated, high dose of adexanate alpha is appropriate. All right. Next question. Which of the following would not be considered when developing a bleeding management protocol? A, the frequency of life-threatening bleeding seen at the institution, low versus high. B, the least expensive drug should be given the highest consideration. C, assessment and availability of experts that can provide support in an emergency setting. D, the time period where the protocol, guideline, and or policy should be reviewed so that it is up to date. All right. Okay. So I will be talking to you about the unmet patient needs in emergent or life-threatening bleeding. I'll review clinical characteristics and management recommendations. Here is case one. A 76-year-old Caucasian female presents to the ER complaining of the worst headache of her life. The headache has been worsening over the last 24 hours. She has progressively felt more nauseous and is now having emesis. The patient has a history of well-controlled hypertension, diabetes, CAD, atrial fibrillation, and chronic kidney disease. Her morning medications include full-dose aspirin and Warfarin. She noted occasional episodes of dark, starry stools last night. Or last month, excuse me. On intake, when the patient was sitting, her heart rate was 95 beats per minute. BP was 105 over 70. When she stands, it increases to 135 beats per minute. BP decreases to 80 over 40. Textbook. Her CRIT was 21%. BUN 45, creatinine 2.5. ECG shows AF with a rate of 90 beats a minute and inferior Q waves. What is the patient's has-bled bleeding score? Is it one, zero, low risk? Two, one, moderate risk. Three, two, moderate risk. Is it four, greater than or equal to three, high risk? All right, so 60% of you got it correct. The answer is four. Let's go on to the next one. What is the patient's greatest risk factor for Warfarin associated intracranial bleeding? Is it one, concomitant antiplatelet agents? Two, advanced age. Three, race. Four, poorly controlled hypertension. All right, a little bit of spread. The answer is actually two, advanced age. And we're going to go ahead and discuss that just in a little bit. In a setting of ICH and an INR of seven, which of the following is the most appropriate next step in management? Do you, one, hold Warfarin? Two, hold Warfarin and give IV vitamin K and FFP? Do you hold Warfarin and give four-factor PCC? Or do you hold Warfarin and give IV vitamin K and four-factor PCC? All right, most of you got it correct. Nearly 80%, but we will go ahead and discuss this a little further in the slides coming up. Which of the following would not need to be considered when developing a bleeding management protocol? The frequency of life-threatening bleeding seen at an institution, low versus high? B, the least expensive drug should be given the highest consideration? C, current knowledge of the team regarding anticoagulation reversal strategies. Do they need education? Four, the decision about a certain circumstances allow deviation from the protocol? And to what extent? All right, good job. We will be again discussing these a little further, giving you the answers and why. So I'm going to start off by discussing assessing risk factors for anticoagulant-associated bleeding. The first one we will be discussing is Warfarin. So here on this slide, we have emergency hospitalizations for adverse drug events in older US patients from 2007 to 2009. On the y-axis, you have the number of hospitalizations per 10,000 outpatient medication visits. On the x-axis, you have the medication classes. The take-home point from this slide is that four drug classes are implicated in 67% of hospitalizations in this population. This study was published in the New England Journal of Medicine so it has somewhat of a good reputation, 2011. I am a cardiologist, so we like to split up the data in different ways. This is the same study, different way of showing the data. On the left, we have the medications. In the middle column, we have annual hospitalizations. Look at the number, N, nearly 100,000. And on the right, we have the proportion of ER visits resulting in hospitalization. What you can see is that Warfarin leads the pack with 33,000 admissions, 33%. And it is number three in terms of hospital ER visits leading to hospitalizations. It is behind digoxin and oral hypoglycemic agents. So what are the disadvantages of Warfarin? It has a delayed onset and offset, variable dose response. It has a very narrow therapeutic window. There are a lot of drug-drug, drug-food interactions, inconvenient monitoring. And I would argue that the one thing Warfarin excels at is making people bleed. It has a very high bleeding rate. So because of this high bleeding rate, multiple risk scores to identify modifiable predictors of bleeding have been developed. In atrial fibrillation, by far the most popular one has been the has-bled bleeding score. And here's a simple mnemonic. H is for hypertension, greater than 160, you get one point. Abnormal renal or hepatic function, one to two. Stroke is one. Bleeding history or anemia, again, one. Labal INR, target therapeutic range is less than 60%. That is the definition. Elderly, greater than 75 years of age. Please remember 75, that is a magic number that you'll be hearing throughout the talk. Drugs, antiplatelet NSAIDs, and alcohol. So if you have a high risk, you will have a score of greater than or equal to three. Moderate is one to two. And low risk is zero. So for some reason, my slide is not going forward. So the most feared complication in Warfarin use, at least Warfarin bleeding, is Warfarin-associated intracranial bleeding. So what are the risk factors for it? These are the main ones we think about. You have concomitant antiplatelet agents, two-fold increased risk. Race and ethnicity, it's four-fold if you're Asian, two if you're black or Hispanic. Poor hypertension control is two-fold increase. Advanced age is two to three. And at the very last, on the right-hand column, we have cerebral amyloid angiopathy, which will obviously be a little rare. So if we're gonna talk about Warfarin, we have to talk about polypharmacy and bleeding. Warfarin tends to be a promiscuous drug. And there's a lot of medications out there that can potentiate its effect. The ones that come to mind are antibiotics, things like fluconazole, metronidazole. Cardiovascular drugs, if you think about it, we give Warfarin for patients with atrial fibrillation. So many of them will be on amiodarone. That is a potentiator. There's also other medications that patients are on on a routine basis, things like cimetidine and omeprazole. The reason we care about that is if you have a patient on Warfarin and at least one potentiator, their odds ratio of major bleeding increases to 3.4. Another medication that's commonly used, you can remember it's D for the has blood bleeding score, is aspirin. And if you see, if a patient's on Warfarin and aspirin, their odds ratio goes up to 4.5. Below, what you can see is there's data from a study in the UK General Practice Research Database of 4,000 patients. And here they found that 58% of patients were taking at least one Warfarin potentiator. So it is a very common practice going on right now. So, and when it comes to these potentiators, there's obviously short and long-term interactions. The most common short-term, or if you think about it, makes sense, antibiotics, patients get sick, and NSAIDs, some patients do have aches every now and then. But then there's also a group that has the osteoarthritis, and they have just been used to taking NSAIDs pretty much every day. And I would argue that NSAIDs and antiplatelet agents are two of the long-term medications that patients are often on the most. One that's easy modifiable is the antiplatelet. As a cardiologist, you know it's one that we are guilty of prescribing. So why do we care? We've already talked about that intracranial hemorrhage is probably the most feared complication with any anticoagulant-associated bleeding. But why is it so much more important with warfarin? On the left, what we have here on this figure, you can show that the proportion of intracranial hemorrhage attributed to warfarin from 2005 to 2008. The take-home point here is that you can see that there's a steady rise in this incident. But really, what you want to take home is this figure on the right. On the y-axis, we have mortality, and we have mortality in warfarin-associated versus non-warfarin-associated intracranial hemorrhage. And what you can see for each year, that when warfarin is involved, the mortality rate is 10 to 15% higher compared to those that were not on warfarin. So when patients have an intracranial hemorrhage, and if they are on warfarin, they tend to do a lot worse. They tend to not survive. So here, this study is only 41 patients, but this is a good example of showing that when patients come in on INR for intracranial hemorrhage, look at the spread of their INR values, right? Some of them are in the therapeutic range, if you think about it. Warfarin, normally it's two to three, or three to four if they have a mechanical valve. But you can see some patients came in with seven, eight, or 11. So the spread is very large. However, what you really want to take home is that, think about it, the majority of our therapeutic ranges are in the two to three. So about half to 60% of these patients were within the target therapeutic range, and they suffered an intracranial hemorrhage. So what are markers of poor prognosis for intracranial hemorrhage? The first is failure to lower the INR rapidly, a large volume of blood, intraventricular extension, midline shift, and severe neurologic deficits. All of them pretty straightforward. This would be a good time to start talking about NOACs. And here, we're going to talk about the advantage of NOACs, specifically in atrial fibrillation, to reduce major bleeding. On the top, we have the odds ratio for secondary efficacy and safety outcomes. Anything to the left favors NOACs. To the right favors warfarin. On the bottom, odd ratio for major bleeding. Now, these are all the major NOAC trials for atrial fibrillation. We have RELY, Dabigatran, ROCKET, RIVAROXABAN, ARISTOTLE, APIXABAN, ENGAGE, and ADOXABAN. And what you can see, where NOACs really made their claim to fame is a decrease in the safety outcome of the efficacy of hemorrhagic stroke, you can see, decrease in 51%, and in the safety endpoint of intracranial hemorrhage, 0.48, decrease in 52%. Now, when you combine these, the odds ratio for bleeding, remember, everything to the left favors NOAC, what you can see is a 14% risk reduction. This is a very famous study published by our good doctor Christian T. Ruff. It's in Lancet in 2014. This is another very similar meta-analysis, except in this one, there's a lot of smaller studies included. And what you can see, again, everything to the left in the forest plot favors NOACs, to the right favors VKAs. And what you can see, we have a very similar number for major bleeding, a reduction of 14%. So what are the risk factors for NOAC-associated bleeding? The first one, advanced age. Remember the magic number of 75. Of note, there are some subgroup analysis in Rely, Rocket, and Aristotle that have not conclusively shown an increased risk in bleeding risk. However, despite that, dose reductions are recommended in the advanced elderly. We also have renal dysfunction. Patients with at least moderate, severe, moderate renal dysfunction have increased risk of bleeding with NOACs. Dose reductions have been recommended for those in moderate renal dysfunction. And lastly, concurrent use of antiplatelet drugs. In Rely, aspirin was increased, the risk of intracranial hemorrhage of 1.6. So let's dive in a little further into age and major bleeding. Here, we're looking at the VTE trials. We have all the major VTE trials listed here in the study group. Remember, the subgroup here, we're looking at age of 75 or greater, magic number, those versus less than 75. At the top, in the top table, we have the effective age on major bleeding for vitamin K antagonists. And what you can see, there's an increase in odds of bleeding of 3.33. Now, age, increased age, being greater than or equal to 75 years of age, also affects NOACs. But this effect is slightly less. You can see here, it's only 2.37. So what is it about the elderly that they have issues with drug metabolism? Is it their attitude? Is it the way they smell? It's really just four things. You have decreased hepatic first pass metabolism, right? There's due to decreased increased liver mass and perfusion, which causes an increase in bioavailability of some of the drugs. You have changes in body composition, loss of fat. That personally, that is something I am looking forward to. You have increases in volume and distribution for lipophilic drugs, and a decrease in volume and distribution for water-soluble drugs. Then you also have impaired SIP-mediated phase one reactions. And then also you have decreased renal excretion which increases the bioavailability of some drugs. So focus number one and number four, increase the bioavailability of the NOACs. So let's focus on renal function and major bleeding. Again, what you have here, we're looking at the VTE. Here are our major trials. On the top table, we have major bleeding for VKA. And what you can see is that the renal function here, the magic number is 50. So renal dysfunction is defined as less than or equal to 50, creatinine clearance, versus those greater than 50. Risk ratio is 2.83. And if you look at below here, we have major bleeding with NOACs and renal function. Again, less than or equal to 50, creatinine clearance versus greater. Here, you can see this is what flip-flop, what we saw for age. Renal function affects those NOACs a little more because you can see the increased risk ratio of 3.64 compared to the VKA of 2.8. So let's get to probably one of the main reasons, now that I've bored you with all this data, why you are here. So managing anticoagulation-associated bleeding. So what are the techniques for warfarin reversal? Well, the first is vitamin K. Out of all the options listed here, it's the least expensive. Reversal takes about 12 to 24 hours, and it provides sustained reversal. Next, we have FFP, fresh frozen plasma. It can take several hours to administer. What you also have to remember is that it requires a large amount of volume, two liters. So if you think about it, you've got to be concerned if a patient has active heart failure or a depressed ejection fraction. Next is PCC. There's two types, remember. Four-factor, PCC, and three-factor, which lacks factor VIIa. And the benefits of this is the low volume, fast infusion, but it becomes to get a little more pricey. Then we have recombinant factor VII, very short-acting, VIIa, very short-acting. However, it can be associated with an increased risk of thromboembolic complications such as MI or VTE. These are all things to consider. So what about a comparison between two therapies? Here we have four-factor PCC versus FFP. This is a retrospective cohort analysis published in CIRC in 2013. Small number of patients, only 300, but what you can see here is for the any adverse event, those for FFP were about 20, whereas for Octoplex, four-factor PCC was 10. So number of events cut by half. What I also want to point your attention to is down here to the important secondary outcomes. Time to INR reversal for FFP, 11.8 hours, compared to that of Octoplex, 5.7. Also, mean units of packed red blood cells, transfused, 3.2 versus 1.4. Those are a lot of units, and that's blood that is no longer in the intravascular space. So after they went ahead and did a multivariable regression analysis to obtain the adjusted relative risk of serious adverse events, what you can see FFP versus four-factor PCC increased relative risk of 1.87. So let's talk about the guidelines on anticoagulant reversal with warfarin. Here are the recommendations. All hospitals managing patients on warfarin should stock licensed four-factor PCC. Emergency anticoagulation reversal in patients with major bleeding should be with 25 to 50 units per kilogram of four-factor PCC and five milligrams of IV vitamin K. Recombinant factor 7A is not recommended for emergency anticoagulation reversal. And fresh frozen plasma produces suboptimal anticoagulation reversal and should only be used if PCC is not available. So let's walk through a scenario. Warfarin reversal, somebody's having a major hemorrhage. Step one, you want to establish sustained warfarin reversal. So you want to give vitamin K five to 10 milligrams. It's a slow IV infusion. Step two, you want to do something for the immediate scenario. You want to go ahead and give four-factor PCC 25 to 50 units per kilogram. If the three-factor PCC is available, you also want to give two units of FFP. Also, this situation is very similar to giving Narcan to somebody with an overdose. If somebody overdoses and you give them Narcan, you don't just walk out the room. You actually watch the patient and see if they need more doses. It's the same scenario here. You want to check the INR at 30 minutes and you want to check it every four to six hours for the first 24 hours, because you might have to redose. So it's very important that all of you come out with at least some, there are some nuances regarding the pharmacology of NOACs. Here we have all the five major players, mechanism, action. Really what you need to know, Dabigatran is a direct thrombin inhibitor. And you guys should have, they're going to have the slides, right? So you guys will be able to get all of this. So you don't need to focus on, you know, too much of the details right now. Everything that has an X in its name is a factor XA inhibitor. Dabigatran clearance, 80% is renal. The rest vary from 10% to possibly 50%. Peak action time, they're all between one to four hours. What you want to remember, dosing. Dabigatran is twice a day. Apixaban is twice daily. The rest are once daily. So because direct inhibitors of coagulation, such as NOACs, offer an opportunity to develop specific antidotes. There are three, well actually two, a third is on the way. Boyner-Ingelheim has Idaricizumab. It's only for Dabigatran and it is FDA approved. Next we have Portola Pharmaceuticals, a dexanet alpha. It does the factor XA inhibitors, also low molecular weight heparin, Fondoparanox. It is FDA approved. And we have Perisphere. This takes all comers, but it is currently in phase two. So these are names to keep in the back of your mind, especially these two agents. Now, as far as nonspecific reversal techniques for NOACs, the first one, Dabigatran, where 80% of it is cleared through the renal system. This is a common board question. It was on my boards. You want to remember that you can do dialysis for it. The rest, the factor XA inhibitors, you can use four-factor PCC or a PCC. Here is an example. How effective is PCC for the reversal or rivarboxaban, a factor XA inhibitor? What you can see here is at baseline, the PT is approximately 12 seconds. After taking riva, 20 milligrams BID for two and a half days goes up to around 15 to 16. After PCC is given, you can see within 15 minutes, it's already back to baseline. So it is pretty effective. So what are the pathways for NOAC reversal? So if you have a severe or life-threatening bleeding event, you have to figure out first, are they on dabigatran or direct factor XA inhibitors? If they're on dabigatran and they've ingested within the last two hours, you can go ahead and give charcoal. And remember, hemodialysis, it'd be important to call nephrology. You can also give idariosuzumab, 2.5 grams times two. For direct factor XA inhibitors, we have a dexanethalpha to bolus plus an infusion. So this is a very busy slide. Conventional coagulation testing for NOAC-associated bleeding. There's three clinical pearls I want you to walk away with here. Thrombin time can be checked to assess the presence of dabigatran. It'll be increased. Anti-10A levels will detect the presence of direct factor XA inhibitors. However, neither will quantify the degree of the anti-coagulation effect. All they will tell you is that the drug is on board and it is doing something. So here are my take-home points. You want to understand the nuances of various anti-coagulant and risk factors for bleeding because it helps identify at-risk patients. PCC provides a safer and reliable option for warfarin reversal in patients with major bleeding. NOAC reversal agents offer specific management of bleeding in severe and life-threatening cases. Excellent. Thank you, Tony. That was a great first step into anticoagulation reversal. Now we're going to talk about the latest advances in anticoagulation reversal, in particular these antidotes for reversal. Here's a case for us, a 72-year-old male presented to the ER this morning after noting bright red blood per rectum since the prior evening. He experienced large-volume bloody stools throughout the night. The patient has a history of hypertension, diabetes, and atrial fibrillation. His evening medications included Rivaroxban 20 milligrams daily. In the emergency department, the patient was tachycardic and relatively hypotensive to 92 over 44. His hematocrit was down to 28% with a BUN of 76 and a creatinine of 1.9. His ECG demonstrated atrial fibrillation with a rapid ventricular rate of about 128 beats per minute. So which of the following is the most appropriate next step in acute management? A, hold Rivaroxban and administer IV vitamin K and prothrombin complex concentrate. B, hold Rivaroxban and check an anti-10A level to see if the patient is still anticoagulated before considering reversal. C, hold Rivaroxban and give IV and dexaneth alpha. Or D, hold Rivaroxban indefinitely because the risk of bleeding is too high. Go ahead and log in your notes. All right, let's see. So most of you picked the correct answer, which is C, hold Rivaroxban and give IV and dexaneth alpha. That's the preferred reversal agent. Just quickly go through the other choices. Vitamin K doesn't have a role in reversal of the direct oral anticoagulants, in particular Rivaroxban. One of the things you'll see that's a consistent message from the guidelines about anticoagulation reversal is that you're not supposed to wait for anti-10A levels or dilute thrombin times to make a decision about whether you're going to give a reversal agent or not. And then one of the other themes that we're going to talk about is the need to restart anticoagulation as soon as it's safe for our patients who have strong indications. So rarely are we ever going to decide that the patient's never a candidate for anticoagulation going further. So what I want to start with first is the 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients with Oral Anticoagulation. These guidelines ask us to ask the following question. Does one of the following factors apply? Is there bleeding at a critical site? Is there hemodynamic instability? Is there clinically overt bleeding with a hemoglobin decrease of at least two grams per deciliter, or did the patient require administration of at least two units of packed red blood cells? If the answer is no, then the bleeding is considered non-major. And then we have to ask ourselves, does the bleed require hospitalization, surgical intervention, or transfusion? If the answer is no, then we can continue the oral anticoagulant. We can initiate appropriate local measures to control the bleeding and then reassess. If the answer is yes, that the patient requires hospitalization, requires an intervention to stop the bleeding, or needs transfusions, we're going to stop the oral anticoagulant. We're going to initiate appropriate measures to control bleeding. If the answer to the initial question is, does one of the following factors apply, either bleeding at a critical site, hemodynamic instability, or clinically overt bleeding requiring administration of packed red blood cells, or a hemoglobin decrease of at least two, then that's major bleeding. And we treat that in a more acute way. We ask ourselves, is the bleeding at a critical site or life-threatening? If the answer is no, we're going to stop oral anticoagulation. We're going to take our initial measures to try to control the bleeding locally. If that works, great. Then we are going to continue doing that. If not, then we have to consider reversal agents. If the bleed is at a critical site or it's life-threatening, then we're going to stop oral anticoagulation. And we're going to use our local measures to try to control the bleeding. And we're going to give a reversal agent to stabilize the patient. So that brings us to our next important question, which is, which oral anticoagulant is the patient taking? If it's warfarin, as we talked about, we're going to give four-factor PCC preferentially with vitamin K. If it's a direct thrombin inhibitor, although we can dialyze now with the availability of iterocizumab, we're going to usually use that acute reversal agent. We can, as Tony mentioned, use activated charcoal if the ingestion was relatively recent. For our factor Xa inhibitors, that's apixaban, adoxaban, rivaroxaban, and to some extent atrixaban. We can consider four-factor PCC based on animal studies and healthy human studies. But now with the availability of andexanet-alpha, which we'll talk a little bit more about, that's usually preferred. So let's talk about iterocizumab. This is a fascinating molecule for anticoagulant reversal in the setting of dabigatran. So what iterocizumab is is a fully humanized monoclonal antibody fragment. So it has the binding site that dabigatran looks for in thrombin as a direct thrombin inhibitor. But it doesn't have any of the catalytic or enzymatic activity that's necessary to act like thrombin. So essentially what it does is bind to the dabigatran with high affinity, because it has that binding site that so closely mimics thrombin, but it doesn't have any of the function of thrombin. So you really can't make patients prothrombotic. Essentially you're just holding onto the dabigatran, taking it out of the equation, and returning anticoagulation to normal. It doesn't have any known off-target effects. It doesn't seem to work well for reversing the heparins or other anticoagulants. It's specific for dabigatran. It's given IV, and it has an immediate onset of action. It has a relatively short half-life. So it may need to be redosed in patients that have taken a significant amount of dabigatran. And luckily, it doesn't seem to have any of the procoagulant effects that we saw with some of the other reversal agents like PCC or recombinant factor VII. We're not actually giving more clotting factors. We're binding up the dabigatran. So iterosizumab was studied in the REVERSE-AD trial. This was a multicenter, prospective, open-label, single-arm, phase III study. It divided patients into two groups, patients that had uncontrolled bleeding and patients who required an urgent invasive procedure. So groups A and groups B. They were given iterosizumab, 5 grams, as 2.5-gram IV boluses given twice, separated by up to 15 minutes. The primary endpoint was reversal, as measured by the dilute thrombin time and the echerin clotting time. And then secondary endpoints were clinically-determined hemostasis within 24 hours, and then a number of other safety endpoints, including thrombotic events. For the primary results, median maximal reversal was achieved within four hours, as measured by the dilute thrombin time and echerin clotting time in 100% of the study subjects. There were similar results obtained with activated partial thromboplastin time and thrombin time, although we don't use those coagulation tests regularly. And the dilute thrombin time normalized at a high level in the group A patients, the ones that were bleeding, and the group B patients, the ones who were going for an invasive procedure. And here we can see that. So group A, bleeding patients. Group B, procedure patients. We see that the dilute thrombin time is prolonged in patients who've been receiving dabigatran. With administration of iteracizumab, we see that the dilute thrombin time returns to baseline levels and stays down, protecting the patient from bleeding in the setting of uncontrolled bleed. And then also for procedure patients, we see the same trend. With regards to the achievement of clinical hemostasis, they divided patients up into two major categories, non-intracranial hemorrhage patients, the vast majority of which were GI bleeds, and then intracranial hemorrhage. And there was a high level of reported hemostasis in both groups. With regard to safety, one of the primary interests with any reversal agent is whether, by giving it, you'll correct coagulation but overshoot and lead to prothrombotic states where patients might develop an MI, a stroke, a DVT, or a pulmonary embolism. That really wasn't seen specifically in reverse AD. They did note some thromboembolic events. But we have to remember that in this patient population, every single patient had a clear indication for being on anticoagulation. And now we're off anticoagulation. So there's a certain risk of developing a stroke and atrial fibrillation, of developing a PE or DVT after venous thromboembolism when you have to interrupt your anticoagulation. And in this case, because it was a major bleed, patients may have had to hold their anticoagulation for quite some time. And in that setting, you can see thrombotic events. Looking at case series and unselected patient studies, it does seem to be a relatively easy reversal agent to use. You have to know. Your pharmacy has to be up on how to provide it. And you need to know the system for ordering it and getting it to the floor quickly. We have to remember that one size may not fit all. Patients that maybe have taken an overdose of dabigatran may need multiple doses of iteracizumab. Or someone who took a dose somewhat remotely may not need as much iteracizumab. Renal function, as we saw, renal function impacts the bioavailability of dabigatran. And so in patients with impaired renal function, there may be a prolonged effect of dabigatran. We may have to redose the iteracizumab. For factor Xa reversal, before we had indexonate alpha, there was quite a bit of research done in using four-factor PCC. This was largely done in animal models, things like rat tail bleeding models or rabbit kidney injury models or healthy human volunteers. Doesn't really seem to work particularly well for dabigatran. For the factor Xa inhibitors, there have been studies that show you can, with prothrombin complex concentrate, reverse the impact of these direct oral anticoagulants on clotting tests. And you can return hemostasis to normal in animal models. But that's really the vast majority of the data we have for this. There's another type of prothrombin complex concentrate called FIBA. It's an activated PCC. We use it very rarely. I'm not going to spend too much time on it. Its clinical experience is limited. It's largely been studied in animals and healthy humans. Let's talk about indexonate alpha, because that's the recommended reversal agent for the factor Xa agents. Much like iteracizumab, this is a bioengineered molecule that is designed to look like an endogenous molecule, factor X, but it doesn't have any of the intrinsic catalytic activity that factor X has. So it has a binding site for the factor Xa inhibitors, just like factor X, but it doesn't have any of the enzymatic activity. So you give this. It binds to the direct anti-Xa inhibitor, and it takes that out of the equation, allowing the prothrombinase complex to return to normal functioning and returns coagulation to normal. But it doesn't appear to increase patients into a pro-coagulant state. This was studied in two main clinical programs. The first program was ANEXA-A, which stands for apixaban, and ANEXA-R, which stands for rivaroxaban. This was a phase III trial in healthy volunteers. And then there was ANEXA-4, which was the multicenter, single-arm, open-label trial for patients that were actually bleeding. For ANEXA-A and ANEXA-R, it was really to look at the efficacy of this reversal agent for returning the anti-factor Xa activity to normal in healthy elderly volunteers. ANEXA-4 was the major study in bleeding patients. And there they looked at the impact on anti-Xa level, but also on hemostasis. So looking at the healthy volunteer study, ANEXA-A focused on apixaban, and ANEXA-R focused on rivaroxaban. Immediately, you're going to notice that the two drugs require different doses of andexanet-alpha. So for apixaban, the dose is usually 400 milligrams as an IV bolus in Part 1. In Part 2, it was 400 milligrams IV bolus, then 4 milligrams per minute as a continuous effusion for two hours. This was compared with placebo. For ANEXA-R, you required a higher dose of andexanet-alpha. It was 800 milligrams IV bolus for Part 1. In Part 2, it was 800 milligrams IV bolus, then 8 milligrams per minute for a continuous infusion of two hours versus placebo. So that's an important distinction in reversal of the direct Xa inhibitors. So here we can see for ANEXA-A, we're looking at anti-factor Xa activity. We see that it's increased after administration of apixaban. After administration of andexanet-alpha as a bolus plus infusion, we see that the anti-factor Xa activity returns to baseline levels, essentially depressed. But once the reversal agent wears off, there's a rebound anticoagulant effect that is something to bear in mind. This is where patients might have an increased risk of bleeding and where they may need to be re-dosed. For the rivaroxaban arm of the study, we see the same thing. That anti-Xa level is prolonged. We administer the andexanet-alpha. It comes down to baseline levels. Again, we see that same rebound effect. In this study, there weren't any thromboembolic events. One thing they did notice was an increase in D-dimer, the significance of which wasn't necessarily clear. Another concern was whether patients could develop neutralizing antibodies to the recombinant factor X. That didn't seem to happen. There were some infusion-related reactions during that study. Anexa-4, the clinical-based study, this were patients who were bleeding. I should note, in contrast to reverse AD, where they had patients who were going for an urgent procedure, anexa-4 did not include that patient population. It was only bleeding patients. It was multicenter, prospective, open label. There was a single study group, bleeding patients who were given the andexanet-alpha. They had to have received a dose of factor X inhibitor within 18 hours. And there were some exclusion criteria that included planned surgery within 12 hours. Here we can see the construct of the study. So patients were screened. They had to have active bleeding meeting the inclusion criteria. The last dose of factor XA inhibitor has to be within 18 hours. And they were treated with the IV bolus of andexanet-alpha and then a two-hour infusion. After the end of the infusion, there was assessment for both changes in the measurement of anticoagulation, the anti-XA level, but also a measure of clinical hemostatic efficacy through 12 hours. Here we can see how they graded hemostasis. It was excellent, good, or poor. And they divided that into visible or intracerebral hemorrhage. So in patients with acute major bleeding who had a dose within 18 hours of apixaban, adoxaban, rivaroxaban, or inoxaparin, I will tell you that most patients were either on apixaban or rivaroxaban. There were very few patients on anything else. Andexanet-alpha was given as an IV bolus and then a two-hour infusion. Look at the difference in dosing, though. This is one of the nuances that makes andexanet-alpha challenging to use. So for patients with apixaban or who are greater than seven hours from the last rivaroxaban dose, it's 400 milligrams followed by an infusion of 4 milligrams per minute for a total of 480 milligrams. For patients on inoxaparin, adoxaban, or less than seven hours from the last rivaroxaban dose, it's a bolus of 800 milligrams and then infusion of 960 milligrams at 8 milligrams per minute. So really being cognizant of the different dosing for the different anticoagulants makes this somewhat challenging to use clinically. You can see the baseline characteristics. Very representative of an anticoagulated population. Lots of AFib, lots of heart failure. Here we can see that for the apixaban patients, anti-factor 10A level comes down to baseline and then starts to rise again after the end of the infusion. But while the drug's being administered, there's very good reversal of that anti-10A effect. Same thing for rivaroxaban. With regards to hemostatic efficacy, we can see that regardless of whether the site of bleeding was GI, intracranial, or otherwise, most patients received excellent or good hemostasis after administration of the reversal drug. Nuance to the study, they looked at whether reversal of the anti-10A level correlated with control of the bleed. And it's just interesting to note that for all patients, reversing the anti-10A level didn't necessarily strongly correlate with how good control you got of the clinical bleed, with the exception of intracranial hemorrhage, where achieving a reduction in that anti-10A level portended a very good prognosis for getting control of the clinical bleed. Here we can see the safety results. There were some thromboembolic events. Most of these are related to the fact that you had a patient with a clear indication for anticoagulation who came in with a bleed, was going to be off of anticoagulation for potentially months. And in that setting, there was an increased risk of prothrombotic events. If you look at the 2019 AHA, ACC, and Heart Rhythm Society-focused update, we see that a class 1 indication is given for iterocizumab for reversal of dabigatran-associated bleeding or patients who have to go for an urgent procedure. And dexanet-alpha is given a slightly less strong recommendation, a 2A indication for reversal of rivaroxaban and apixaban for patients with life-threatening bleeding. We don't have good data on patients going for procedures, so they couldn't give a strong recommendation for that. And we didn't have, in Anexa 4, many patients who were receiving drugs other than apixaban and rivaroxaban. So there weren't enough data to really make a strong recommendation there. If you want to read more about how we handle anticoagulant reversal, the ASH guidelines from 2018 are lengthy but helpful, and you can read those, the citations down there. They talk about two main approaches to managing bleeding on 10A inhibitors. Four-factor PCC, they still, in contrast to the AHA-ACC guidelines, keep that available for centers who may not have andexanet-alpha. And then they allow you to use andexanet-alpha if you have that. They cite some of the limitations of the current data that we have that four-factor PCC and coagulation factor 10A haven't been directly compared, and studies of both approaches have lacked a comparator group. You'll never be able to do a randomized controlled trial of bleeding patients. So we understand that limitation, but it's unlikely to be fixed. So in patients who receive anticoagulation therapy for VTE and survive a major bleeding episode, there was a strong recommendation from the ASH panel that we need to make every effort possible to resume oral anticoagulation with 90 days rather than leaving it off. Because as I mentioned, these patients have a clear indication to be anticoagulated. And many of these patients have sources of bleeds that can be mitigated and should go back on their anticoagulant. We can see here that mortality is actually higher if you don't restart anticoagulation in these patients. And that's probably due to the fact, at least in the VTE world, that they're at increased risk for recurrent pulmonary embolism. And so now we're going to invite up John Finikos. John Finikos is the director of our pharmacy at Brigham and Women's Hospital. He's an incredible resource and has really, in conjunction with some of the members of our hematology group and our anticoagulation management team, the heavy burden of making sure that these drugs get used appropriately, that could be used as a matter of convenience, which they're an expensive set of drugs. So John sometimes has to say no. And he's got the arrows in his back to show for it. Thank you, Greg. And good morning to everybody. Thank you for waking up and coming here at an ungodly hour of the morning. So what Greg asked me to do and what Tony asked me to do is just to talk a little bit about taking all of this information and somehow winding it into a routine practice or a routine standard. So let's start with a case. This is one of our patients, a 73-year-old male who presents to our emergency room after a fall. He has a history of atrial fibrillation. And he has been taking Apiximan regularly. This is the sequence of events. So he reports to us at about 1.30 in the afternoon. He had a fall and a head strike at an early hour of the morning around 9 o'clock. He subsequently became unresponsive at around 11. He was transferred to our hospital for neurosurgical evaluation. And when his family brought him to us, they said that he had taken all of his medications, including his Apiximan, the night before. A CT scan was performed. You can see that he had a subdural hematoma with a midline shift. You can see all his past medical history, his medications that I think for the most part are non-contributory. And then this sequence of events occurs in terms of how to manage this patient. The first discussion is with one of our emergency room residents who decided that he thought a four-factor prothrombin complex concentrate in 1,500 units would be appropriate for this gentleman. That's a dose that we've typically used for our warfarinized patients that have suffered a bleeding event. We've used a fixed dose in reversal of the NOACs that's a little bit higher at 2,000 units. Again, this element of confusion. Our neurosurgeons arrive and they think this patient is a surgical candidate and intervene. And they suggest maybe an dexanet would be a more appropriate option. And then of course the sequence with time being consumed with looking for an OR room that's available to do this man's procedure. So I think what this presents to you is a case of an elderly man that is now suffering with a major bleeding event and the hectic sequence of events that follow right afterwards. So we've talked about what is an appropriate laboratory assay to assess this patient's level of anticoagulation. So if you pull out your clickers, is it a dilute thrombin time? Would it be an activated partial thromboplastin time? An international normalized ratio or a chromogenic anti-factor 10A assay? If you pull out your clickers, our pulling is open. The Hughes Corporation. I think we've talked a little bit about this and I think Tony alluded to it that you use the tests that are available and for the anti-10A inhibitors, obviously a chromogenic anti-factor 10A assay is appropriate. And that's what we did here. Greg talked about not wasting time in terms of decision making. I know in different laboratories and different hospitals, the time to respond to a laboratory test may be short in some facilities, longer than others and not available in even other instances. We got this test back relatively quickly and you can see that it was elevated with a 2.31 units per milliliter value. So clearly, his anticoagulant activity was still on board. So what is the most appropriate next step for this patient? Since the last dose of apixaban was the night before and clearly over 8 hours ago, is low-dose and dexamethasone appropriate? Should you give iodine racizumab over and dexamethasone? Since the last apixaban dose was 5 milligrams, a high dose would be appropriate. Or since the factor 10A level is elevated, a high dose of antexanet is appropriate. You can see the doses. So what would be the appropriate dose? So our polling is open. Oh, I guess I have to do it. I think I have to click for the music, sorry. And so here's our results. And I think we had this on the front end early. And indeed, if his dose had been taken, and I think what we want to do is follow the package insert, the recommendations that came out of the Annexa IV trial. And clearly, if this patient's dose was over 8 hours ago, the low dose of antexanet is appropriate. But we've had a number of cases now where patients who are unsure of when they have taken their last dose, their family has been unsure. We've had patients who have come in and doubled their dose of apixaban or rivaroxaban. And so while I know the guidelines suggest to you that you should delay or not delay and wait for a laboratory test, I think the laboratory test may be helpful in terms of giving you direction in terms of an appropriate dose. So what we did here is we actually gave the low dose as a treatment strategy. And then we made the decision that an OR room was available to take the patient to. Now, our neurosurgeon came to us and wanted to be assured that the anticoagulation had been reversed and asked for a repeat anti-factor Xa test. So what is an appropriate response? Do you tell the surgeon that the test would be flawed and that the clinical anti-Xa assays would be falsely elevated when and dexanet is present? The test would be flawed and the anti-Xa assays would be falsely lowered or reduced when and dexanet is present? Or the test would be helpful in qualitatively determining whether anticoagulant activity is present or absent? Would the test be helpful in that quantitatively an anti-Xa level less than 0.5 would indicate surgery would be safe to proceed? So a complicated question. The surgeon asks you for a follow-up test to measure anticoagulant activity. And so a third say the test would be helpful in qualitatively determining whether the anticoagulant activity is present or absent. I'm going to tell you that the correct answer is that your assay would be falsely elevated. We'll come back to that in a minute. So why are protocols and guidelines important? Well, the Joint Commission is on to us. They have had national patient safety goals and metrics surrounding Warfarin for a number of years. And in July of last year, they provided a series of Sentinel alerts to us. I've printed out, they have a one-page handout that you can print and post across your hospital. You see it to the right, Sentinel event alert number 61 out of the five, I'm sorry, out of the ten recommendations that they have to ensure safety surrounding direct oral anticoagulants. Five of those recommendations are related to bleeding management. So I'd urge you to go, for those of you that are involved in the joint commission surveys, our last survey was in January about a year ago, but one of our sister hospitals had an inspection in this past fall, and the surveys are already asking to see if you have the standards met in terms of oral anticoagulation. And so I think the most important one for the discussions this morning is that they are expecting that you have a protocol, and your protocol is based on evidence-based practice guidelines for the reversal of anticoagulation and the management of bleeding. They go through the details of telling you why bleeding is important to manage and why you should have a plan in place, and that also that the reversal agents are relatively new and that people are not managing them as well as you would expect. And so I think our uptake of reversal agents has been relatively slow, and the joint commission is trying to foster better practices surrounding these drugs. We wrote an article, Maureen Smyth and I and several other pharmacists, about four years ago to essentially create a checklist, if you will, in terms of crafting a protocol for your institution. You can get this document that will identify all the stakeholders you need to work with across your system, what are the standards or current practices and guidelines that you can check in on. And obviously, the main risks associated with reversal agents surrounds the cost and making sure that you select the right patients. You can see on the right all the different things that you have to consider. And I think these are the checklists, if you will, of making a sound protocol for your own institution. When you look across institutions, I think what you'll find in place in many instances is a mishmash of either protocols or guidelines that have been taken from publications or taken from other hospitals and put together. I think you should put some serious consideration into this. We talked early on, I had a question early on about having a structure. We have provided a structure at our hospital that mimics the antimicrobial stewardship program. If you look across the country, there are a number of hospitals that have done this. There are a number of publications. I can point to our work. I can point to the work of Allison Burnett down in New Mexico. But the point is, is you can embed the institution's expertise, whether it be a cardiologist, a vascular medicine specialist, or a hematologist, to work alongside with the individuals that are going to be making the selection and the recommendations for dosing on reversal agents. So at our hospital, not only do we have Greg involved, but we also have a hematologist and a pharmacist that is dedicated to watching every single patient that comes through our emergency room or another portal that is now prescribed either a blood cloning factor, like Kcentra, or a reversal agent like Iduricizumab or Indexanet. In terms of the different recommendations that are out there, I know both Tony and Greg talked about the different laboratory tests that you can use. And obviously, either thrombin time or dilute thrombin time is the appropriate test for dabigatran and an anti-factor 10A assay for our anti-10A inhibitors. The guidelines, like I said, have suggested that rather than waiting for a laboratory test, the most appropriate strategy is to ask the patient or their family member when they took their last dose and to use that as the rubric for your dosing of reversal agents. Now, I mentioned in our study or in our case that our neurosurgeon asked for a repeat anti-10A assay. And if you look at the Annexa IV trials, what you will find is that Portola, the sponsor of the trial, used a different assay than is what is commercially available. And what is depicted in this slide is we use a Stago assay at our hospital. There are two subjects here that received a Pixaban before the Indexanet dose. You can see their concentration of the Pixaban that is present in a direct calibrated measurement. You can see that post-Indexanet administration, the anti-10A value actually rises. So when you take a sample of blood and it sits in a test tube, the Indexanet dissociates. And now, all of a sudden, you have an elevation. So performing an anti-10A test in most hospitals after Indexanet administration is going to provide you with a falsely elevated value. And it won't provide much information to your clinicians. So that was the point of our case earlier. I don't think many patients know that. There are a number of different recommendations that are out there. I would urge you that the most current guideline on reversal of anticoagulants emanated out of the American College of Emergency Room Physicians. It was published in November. And that article is now available online. And they do. They don't waver in their recommendations. They do make the recommendations of using a reversal agent. So I think that's important in terms of recommendations. And Greg touched upon the ASH guidelines. I think the critical issue is surrounding the resumption of anticoagulation after bleeding. In the CHESS guideline, the recommendations are not specified. In the ASH guideline, they recommend resumption of oral anticoagulant within 90 days. If you look at the ACC expert opinion, there are recommendations there. And in high-risk patients, you may want to consider using a low dose, a prophylactic dose of anticoagulation if there is concerns with high risk of bleeding. And in their document, they recommend waiting at least a month before you restart any patients on anticoagulant therapy that has suffered an intracranial hemorrhage. So I think the important elements of this are is that there are a number of different recommendations. They're not all based on great data. And so I think within your own organization, you need to consider resumption of therapy. And the best choice may be tailoring an approach that is specific for the individual patient and their characteristics. I would be remiss in telling you that we are in the infancy of using these drugs. We reported our early experience after 150 days in the literature. We're now almost two years out and we've got close to 75 patients that we've treated now. The vast majority of patients in our hospital have been with intracranial hemorrhage and atrial fibrillation. They tend to be elderly patients. And the patients, for the most part, have done quite well in terms of their management. But we consider this to be no different than treating patients with thrombolytic therapy. We measure the time that they arrive in our door, the time that the order is presented to us, and the time the drug is actually administered. And we hoover around 39 to 42 minutes in terms of order to drug delivery at bedside. So my point here is there is an opportunity for quality improvement as we go ahead and treat these patients on a routine basis. And I think you can get better in terms of your patient selection. We have our clinicians in a room that retrospectively review what we've done. And in some instances, I'll be quite frank, the recommendations to give a reversal agent is not supported. And we've made changes in terms of our routine management. Which of the following would not need to be considered when developing a major bleeding management protocol? The frequency of life-threatening bleeding seen at the institution, considering the least expensive drug rather than the highest, the assessment and availability of experts that can provide support, and the time period where the protocol guideline and policy should be reviewed so that it's up to date. So I think, obviously, I think this is an area where we need to follow patients. This is a great project to show to the Joint Commission. The velocity of these patients that are being reversed is not every day. We see about one patient every other week or every 10 days. So I think there's an opportunity to look and see how you're doing. I think there's an opportunity to garner people and get their expert opinion. I'll tell you, I think you need to, we established a protocol when these drugs were available. We continue to make changes in our protocol. We know there's no data in the clinical trials supporting using Andexanet for patients who need surgical intervention. But we have crafted that and included it in our guidelines. And I think that's important. The drug expense is never going to go away. And I can tell you that, you know, there is an NTAP designation that follows with the drug that tries to compensate you for the drug administration. And when we've looked, there are lots, a number of articles out there. I think you need to go beyond just looking at the cost of the drug. You need to look at what you're being reimbursed for for each encounter. And I think for the most part, you're going to find if you use the NTAP correctly, you will actually break even. So in terms of guidelines and stewardship programs, obviously, who are the patients? What agents do you need to carry? Where are you going to keep them, whether they're in the emergency room or in your pharmacy? Do you give them IV push? Do you give them by infusion? Is it limited to life-threatening bleeding? Does it include patients going to the OR? How are you going to manage abnormal coagulation tests? And what is the response to those tests? I think we've learned a lot about that. I talked about surgery, the labs that you need to check on, and when anticoagulation should be restarted. And I think if you put together a team, all of these things will come out. So clearly, there is the event itself in terms of risk and benefit, assisting with the drug selection, the appropriate reversal agent. We've actually contributed to a number of registries, and not surprisingly, as one of the questions showed earlier, we see vitamin K given frequently for direct oral anticoagulants. We've seen reversal agents being given to the wrong patients, idarocizumab for factor Xa inhibitors and dexanet for direct thrombin inhibitors. So there is, in the eyes of the Joint Commission and what we've seen from registry information, opportunity for improvement. So interpretation of lab values and obviously monitoring the patient's response. Once the bleeding is resolved, you should be an advocate for resuming anticoagulation And as I mentioned before, if there is a risk of bleeding, the opportunity to give a lower dose of anticoagulant therapy, a VTE prophylaxis dose, may be appropriate. And then finally, if you can identify the causes of that event, the opportunity of eliminating or removing those offending factors may be important. And that's things like drug interactions, clearly following patients in terms of organ dysfunction and eliminating unnecessary medications. I have to mention the drug preparation. We typically give our cloning factors by IV push. We give idarocizumab by IV push. But in dexanet, it requires drug preparation. There's some thought process in here about who's going to do that prep, whether you give the bolus and infusion as a single bag or whether you separate them. It takes time in terms of the drug preparation. There is always leftover drug from the infusion dose. You can actually bill for that. So that's an important part of capturing your costs correctly. And then I mentioned that we've had problems with the programming of the pump. And we've got a guideline now that we instruct nurses to make sure we don't do any dilution. We just give concentrated drug in an infusion bag. It's important to make sure that you get the full dose and make sure that you flush the line so that full dose is given. For the blood cloning factors, I've put a little graphic in here to remind you that for the complex concentrates, we're dosing on the factor IX component. And that when you look at the different vials, even though there is a label of what's in the vials, it is different from batch to batch. And that has created some confusion for the nurses as well. So I think we've given a lot of information today. First of all, thank you for taking time out of your conference to attend at this early hour. I know you heard a lot about warfarin-related bleeding, the risks, and the interventions. You've heard a lot about DOAC-related bleeding, the risks, and the interventions that are available. Again, there is opportunity to use a specific reversal agent now. We also have the so-called prothrombin complex concentrates that are available as well. I think there is an opportunity for you, whether you're a physician or pharmacist, a nurse or a nurse practitioner, a physician assistant, to help in terms of organizing the administration of these agents at your hospital for these patients that need them. And thank you very much for your time. Thank you. We have about 10 minutes, I think, for questions and answers. Greg Piazza had a run to the airport. He is meeting a group of Israeli physicians for another meeting later this afternoon. So he sends his thank yous for attending and hopes to be here again in the future. So questions from our audience, if you have cards to fill out, please bring them forward. We'll take any questions. I see someone at the podium fire away. Yes. Great talk and thank you for that. But basically it's like preaching to the choir and it blows my mind away why there's so much resistance and why the drug and the company as a whole is doing so poorly as far as this launch because it seems like the holy grail when it comes to reversing factor X inhibitors. Also I'm from California and you can't prescribe a narcotic without giving them a prescription for Narcam. So should there be a practice pattern where anybody who's on a factor X inhibitor has probably like a buy-in or some kind of insurance buy-in for a factor X referential agent so that the emergency rooms don't hesitate administering this medication? So you want to give your experience and then I'll mention. So I think the latter point is an excellent point that there should be, you know, something tied in that they don't have to worry about the cost, but you said, I believe you mentioned that if they use it appropriately, you usually break out even, is that correct? So when we've looked, and this is the problem, when you introduce, briefly, when you introduce new drugs, there are no codes for them. So you typically provide some sort of miscellaneous code and you take a financial bath. There is now a C code, which is, again, temporary, but it provides you with reimbursement. So there are two things that are important. One, if you are a HRSA hospital, you can buy and index in it at a 340B price. And then two, the ANTAP designation will provide you with financial relief in a way that at least in the last few patients we've looked at, we seem to either break even or make a few dollars in terms of the management. So what I tell my brethren in the world of pharmacy, you can't just worry about cost. You have to look at the whole picture. And part of this involves working with your IT people to make sure the codes are right, and then your finance people to make sure that you're actually being paid correctly. And we found in both instances, neither was being done right, and I think we've fixed that. So the picture is a little bit better. And I agree. I think you make an excellent point that insurance companies, we have to do something, at least as providers, to go ahead and push so that patients have that opportunity. I fortunately, about half the time I work, I'm at the VA. So there's not really an issue. But it's really hard. As a provider, you want to make sure your patients have everything they need. You want to do the best for the patient. But I think that's something that we should probably push. I don't know how that can happen in California, but I'd be happy to be part of any push or any movement to help patients. I think we were in an exophoresite. We've been part of numerous registries, Rivecto, Soar, et cetera. So I think there's a little bit more structure around it, and there's a lot more activity discussing it. So we're a boring group around the holidays. Next question. Yeah, if you could clarify something for me or refresh my memory. As I remember from one of the New England Journal articles, there was, as you showed us, chemical reversal and hemostasis. But if I recall, the clinical outcomes, control versus Zandexin, were not particularly different. Is that memory correct? I don't recall which journal you were talking about, but I believe that was a slide, Greg had a slide that showed that I think the only one was for intracranial hemorrhage that it correlated for any other types of bleeding. At least the reversal was not associated with an actual improvement in the outcome. But I believe the intracranial hemorrhage was the trend was, no, and that actually is positive, at least for intracranial hemorrhage was, and that is, yes, that is a New England Journal. Is this the one you're talking about, 2009? Yeah, I think so. And as you suggested, the chemical changes were there. But as I remember, maybe it was from this graph, the outcomes were not particularly disparate. No, no. And this would be there's a benefit, but the outcome with that of the AUC of .64, it wasn't, the outcomes were particularly that much significant, at least the number-wise, right? Is that correct? Yeah. Yes, I think you make an excellent point for that. And then the other thought was, as I recall, the high dose is around $50,000, regardless of what reimbursement one will get. And in addition to the idea that there's oftentimes some left over, isn't the shelf life for relatively short? It is. So the likelihood you're going to see, you mean, if you have some left, you save it for a family member or something? Even in the unreconstituted agent, isn't that also relatively short? It is. I mean, I'm sure the company's not going to tell us it's going to last for six months. So my answer is, yes, once you've reconstituted it, if you don't use it, you're going to throw it away. And in talking with at least one other relatively major institution, they've had it on their formulary for a year, but haven't used it yet, major metropolitan center. And so that's sunk costs for them. So I can answer that, too. And again, I'm not a PTOA person. So you can actually, for the pharmacy folks out there, you can get the drug on consignment. So that means you don't pay for the drug. You have it in stock. When you use it, you pay for it. And that's been the model we've used for blood clotting factors. So we bought indexing it up front. We put it on consignment. There was some RFID tags that didn't work for us. So we've gone back to purchasing it direct. What I will tell you is, is if you don't use the drug, the company will take it back and reissue a new supply. If you actually don't use a dose, and we've had that happen, and you save the vials and the bag, the company will give you return or replacement supplies for those drugs as well. And I believe all of these same things hold true for Praxepine with Idurocizumab. So my point here is, is some of the obstacles that people may point to in terms of the supply chain, I think if you work with your local distributor or your sales reps, you should be able to overcome whatever the problems are. Thank you. We've had the same experience. So these are actually pretty good at dealing with it. Hi. A great series of lectures. I really enjoyed it. Thank you for presenting all of that. My question concerns, I work at a hospital where we don't have access to the index in an alpha. So in terms of using the four-factor prothrombin concentrate to reverse 10A inhibitors, is giving one dose enough? Since the four-factor is factors 2, 7, 9, and 10, there is some 10, but I don't know how much 10 is in that. So do we just give one dose of the PCC or two doses, or does it depend upon how many units of factor 10 is in each dose, or should we be dosing by the number of units of factor 10? So at least my experience is that we go ahead and give it, but then you still want to check. And if you're still having issues with bleeding, you might have to give it again. But for us, it's been pretty rare. So just one dose was sufficient in your experience? In my experience, but we haven't had, it's been pretty rare for us. One dose has been pretty much sufficient. Thank you. I'm going to say, I think it depends on the patient. We've had patients who are treated with four-factor complex and then transferred into us, and we've given more prothrombin complex concentrate. So we typically look for, if we can, if an anti-10AA level is rising, if the transferring hospital has done an imaging study and the hematoma is expanding, we have a low threshold to repeat the dose or to give a reversal agent. So I've seen both. I think the challenges are, as I know a number of my colleagues around the country have been trying to use a fixed dose of prothrombin complex concentrate, a fixed dose of fiber, and have had some success with it. I think the challenges are, is these drugs, the cloning factors were all approved for hemophilia patients, which is really a different use in a different population. And so I think there'll be more information coming out. I think the tough part is it's in small populations, 80 patients, 60 patients, 100 patients, and not in a structured way that you can, in a fixed population that you can apply all the information to the different types of patients you may see. I think that's the challenge. Another question. Good morning. Brittany from Orlando, Florida. Just a comment about developing protocols. When we were developing ours for anticoag reversal, we focused a lot on how the medications are displayed in our computerized order entry system. These names, you know, we all refer to them as Kcentra and Dexa, but they have very strange names and Factor 10A, Z, HZO, and a lot of our providers don't, and a lot of our pharmacists don't know what those are and how to find them in the system. So when you're developing your protocols, I would pay close attention to your synonyms. As pharmacists, we're trained not to use brand names because it's, you know, considered bad. But a lot of our physicians and pharmacists refer to these by their brand names. So being able to link them in the system and make them available in a very face-up way was something that we found very important when developing our protocols, both on paper and in the computerized system. Can I ask you which system you use? We actually work for the VA, so we use our homegrown system, which is even more complex in its capacity. It is complex, but actually when you want to do something, if you know the right people, it's very easy to set up. So yeah, that is one of the benefits of, even though people will say CPRS is a little old, but it's actually when you want to implement, we can get it done in like weeks and tailor it. We have a lot of customization capability, which is nice, but face-up value is important when you're talking about the way our systems display for our providers. And that might be a little hard to do something like Epic. Thank you guys for the talk. I appreciate it. Hi. Thank you. Just a quick question. The graphs from the Anexa studies, it looked like, and I know it was the other assay that they were using, but it looked like the factor, excuse me, 10A activity level returned to elevated after two to three hours, four hours. So I'm wondering if that is specific to that assay, if that is something that we need to address. For example, in the case you presented, presumably that patient would be in the operating room at that time. Do they re-dose it or why the two-hour infusion if after that they're going to rebound? And if you have any comments. I haven't really had that experience. I don't know what it is at Brigham, but if you have to re-dose. We have re-dosed. We've re-dosed. Yeah, we have. So I think we've had a couple of patients that have gone to surgery and the procedure has gone beyond and we've re-dosed. So I think that's a challenge unique to the individual. So again, I'm back to individual cases here that it makes sense. We've done the same with idarocizumab where we've had patients on dabigatran and over time after 24 hours, their dabigatran signs of anticoagulation have returned and we've re-dosed that. So I think there's more to learn in terms of when to re-dose. I'll also tell you that if you do give andexanet and you plan to take a patient to the OR that requires anticoagulation, that if you give heparin, that the monitoring of heparin will be deranged because andexanet will have an influence on heparin itself and its anti-TENA activity. And we've had one case of that. So I think this is the reason for these meetings is that you learn more about how to manage these patients and who are the ones that may need a second dose is not only appropriate but necessary. So I don't have an answer as to who the patient is in the selection process, but I think that remains the next hurdle to overcome. Certainly those surgical patients have been a challenge. Okay. But the good news is just by keeping it aware, it'll probably be up to you, say it's a patient that is in surgery and to let them know beforehand, say after what, two, three hours, you start seeing an increase in bleeding, say it's intracranial or something like that, you might want to consider. But it's important just to be aware. The surgeons might not be aware. They might just think, oh, medication, it's been given, we're in the clear. But you might want to just let them know beforehand, say if you start seeing an increase of bleeding, you might want to reconsider the re-dosing. Yeah. I imagine it gets complicated and there are many people involved. And so how that message gets communicated or to the anesthesiologist, the anesthesiologist is probably the one who's going to be ministering and it just gets complicated. Which goes back to protocols, which I think we're all learning. I know we've got a guideline now for patients, I hate to use the term guideline. We have directions on what to do and typically the recommendations to the anesthesiologist is to use bivalverudin as an anticoagulant because that has a different mechanism. Any other questions? One more. The reversal agent. So can you mix and match? I'm not sure. I've not experienced that. Have you? So we have. We've had patients, again, that have been treated in the field with a prothrombin complex concentrate and then come to us. And we've go ahead and given a reversal agent. So my answer is yes. And no increase in embolic events right now? No. Okay, perfect. Another question. One last question. I understood that it's not useful to trend the anti-factor 10A level if you're giving the andexanate alpha. Is it useful in the four-factor PCC group? My answer is yes. Yeah. Okay. And how do you decide between the low-dose or the high-dose andexa? How do you decide which one? So the dose, you can go to the andexa website. And you'll see the dose is dependent on the agent, okay? So if you give rivaroxaban more than 10 milligrams, it's typically a high-dose. If you give apixaban 5 milligrams or more, it's typically a high-dose. So it's not dependent on the level of the factor 10? No, it is not. Got it. It's dependent on the dose and the time. Okay. And those are the two components. And if you don't know either, then the recommendations are to give a high-dose. Got it. Okay. Last, any other last questions? Again, thank you very much. I think Tony will be around for questions if you have any. Thank you for coming. Thank you.

anticoagulation reversal

warfarin

direct oral anticoagulants

bleeding complications

standardize care

at-risk patient groups

reversal agents

evidence-based approaches

Andexanet-alpha

factor Xa inhibitors

Anexa-4 study

hemostasis

multidisciplinary approach

Hematology

Pharmacology

Anticoagulation

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