Great, thank you for that wonderful presentation Neha. Again, my name is Brooke Barlow, I'm a Neurocritical Care Pharmacist at Memorial Hermann Health System and I'm going to present about the antihypertensive cocktails that we may utilize in ICH management as well as coagulopathy reversal. Just my bio there. On the objectives, like I said, anti-thrombotic reversal, we'll talk about anti-platelets as well as anti-coagulants, blood pressure reduction, and then we'll briefly discuss some of the guideline recommendations with regards to seizure prophylaxis and thromboprophylaxis. So what are our goals of therapy in terms of our pharmacotherapeutic options for patients with ICH? We kind of talked about this, you know, this is time is brain and I like to think about it as the golden hour, right, for ICH. We know that hematoma expansion, they're at highest risk within generally those first two hours, but that can extend to up to 6 to 24 hours. So that acute management that we initiate for these patients is truly critical in order to improve outcomes for these patients. And when it comes to hematoma expansion, the pharmacotherapeutic options to help reduce the risk of this would be acute blood pressure control as well as coagulopathy reversal. Now importantly, we also should think about the risk of secondary brain injury. And this comes with the management of cerebral edema, seizure control, normothermia, and the maintenance of euglycemia. Now let's talk about antithrombotic reversal and we'll start with anticoagulants. So anticoagulants and associated bleeding risk. We know that DOACs overall do have a lower annual incidence of major bleeding risk compared to warfarin. However, this risk does not remain absent and we do see a risk of ICH in this patient population. And while it is 50% lower than that of warfarin, 0.1 to 0.2% is not insignificant. And more importantly, we should think about the mortality that we see in these patients that do develop anticoagulant associated ICHs. So this is looked at the in-hospital mortality for these patients. And as you can see, patients that had no anticoagulant, their mortality was approximately 23%, which increased to 33% for those patients receiving warfarin and then 26.5% for DOACs. So again, significant outcomes that we see in these patients. So optimizing some of the reversal strategies can overall help to improve outcomes. So who to reverse? I really like this pathway that was developed in the 2022 guidelines for spontaneous ICH. Now when it comes to reversal for ICH, it's pretty simple in most cases, right? If you suspect that the anticoagulant is on board, ideally those patients should be reversed. But it's also really important to consider the timing of last administration and also what agent the patient is taking, of course. Now emergent reversal, the guidelines do not recommend waiting for laboratory parameters to come back, just given the potential delay to timing of administration of your reversal agent, if you do wait for some of those laboratory tests. However, they can be considered in cases where you're really just unsure whether or not the patient is taking an anticoagulant. And maybe you don't want to give the reversal agent given the potential risks. So in those cases, it may be optional to kind of wait for those coagulation tests. Now let's talk about a bit of warfarin reversal. So this may be some standard pharmacology for some of us, but just kind of reviewing. So vitamin K is a cofactor for some of the hepatic carboxylation of our vitamin K-dependent clotting factors. And this is through the enzyme vitamin K epoxide reductase. So warfarin inhibits this enzyme and prevents the production of, again, those vitamin K-dependent clotting factors. The half-life of warfarin is almost 60 hours, and it takes time to re-synthesize these clotting factors. So when we think about reversal, in the acute phase, we can provide some of those acute factor replacements, right, with our prothrombin complex concentrates, but making sure that we also give vitamin K, in addition to that, intravenously 10 milligrams to ensure that the patient can re-synthesize new clotting factors. And this was just, I love this chart, that kind of outlines, you know, if you only give vitamin K, that's kind of the solid line on the top. You don't see that onset until approximately 12 hours, and the peak effect to INR reversal is not until 24 hours. In contrast to PCC, you can see that it has a rapid INR reduction, but we see that wearing off effect at approximately 6 to 8 hours. So when you give the combination together, which is the dotted line on the bottom, you can see you maintain stable INR control. That's within the subtherapeutic range for these patients. So there's a big controversy in terms of what dosing to utilize. When it comes to four-factor PCC for patients for warfarin reversal, the package insert provides an INR-guided dosing for PCC. However, as we talked previously, waiting for that INR to come back may delay the initiation of reversal agents. So is there a potential opportunity to give a fixed dose of PCC instead? And this would be anywhere between 1,500 to 2,000 units. That's been looked at in the literature. So I think it also depends on your hospital and your institution, but this has been looked at and this was a recent meta-analysis that was published in 2022 that evaluated fixed versus variable dosing PCC. And it really wanted to evaluate outcomes and potential costs. So they did see that overall there was a decrease in the overall PCC dosing with the fixed dosing strategy. A reduced time to administration. As we said, you can just give that flat dose and then the potential to give another additional dose if that INR does not reach less than 1.4. Then furthermore, they actually did see a decrease in mortality in those patients that had the fixed dosing of reversal. They seen similar thrombosis risk, but again, there is that important factor that patients that did have a significantly elevated INR upon presentation may warrant additional PCC dosing. So they did see that, of course, the patients with fixed dosing did require more additional doses. So it's worth that to consider as well. Dabigatran reversal, this is maintained pretty standard for quite a while, but I just did want to review it for comprehensive purposes. So Idariocizumab is a humanized monoclonal antibody and it binds both free and thrombin-bound dabigatran. The dosing for Idariocizumab is 5 grams, however, it's two different vials. They both come in 2.5 gram doses. And this agent was approved based on the reverse AD trial that evaluated Idariocizumab for dabigatran-related major bleeding. And they did see that it was 100% effective in reversing dabigatran at four hours. But it is important to note that there was some emergence of dabigatran levels that were noted at 12 and 24 hours detected by the dilute thrombin time. And so something to consider there, of course, you see redistribution from the tissues back into the plasma. So that is some potential risk of, again, re-emergence of that dilute thrombin time being elevated. So in consideration, if dabigatran is renally cleared, so if you have a patient that has renal impairment and you're concerned for those elevated levels, dabigatran is also a dialyzable DOAC, is the only dialyzable DOAC that we have that can be removed through dialysis. So this is the great debate. And I kind of want to poll the audience. Hopefully, we can get some engagement here. How many institutions are utilizing N-dexon at alpha for reversal of factor Xa inhibitors? OK, so maybe less than 10%. And the other ones are using four-factor PCC. OK, so it seems like this is the great debate. And really, I wish I had a clear answer for you. But unfortunately, I do not. There's a lot of literature out there. A lot of the studies for four-factor PCC are retrospective in nature. The N-dexon at alpha study, the Annexa 4, was a prospective study, which kind of carries a lot of the weight when you look at these meta-analyses. And so when looking at the hemostatic efficacy, overall, I could put various meta-analyses on this slide. But a lot of them show very similar efficacy, an increased rate of thrombotic events with N-dexon at alpha, and then similar incidences of all-cause mortality in these patients. This specific one was published in 2022 recently in JAMA. And it found that four-factor PCC, as we talked, was comparable in terms of hemostatic efficacy, mortality, and thrombotic events. But in some studies, we do see increased thrombosis when it comes to N-dexon at alpha use. So let's think about some practical considerations between these two agents. As we discussed, N-dexon at alpha is actually FDA-approved for the reversal of factor Xa inhibitors. And this has elevated its recommendation in the recent ICH guidelines to a 2a recommendation. In contrast, four-factor PCC was only given a 2b recommendation because there are no prospective studies that are evaluating its use. And it's not FDA-approved for the factor Xa inhibitors. When we look at the dosing strategy, the question marks on here kind of say, well, it's an unclear benefit versus potential disadvantage. Because of course, you have to think with N-dexon at alpha, you need to know the timing of the last dose, what dose that the patient took. And if it's unknown, then you give the high-dose strategy. And so when it comes to four-factor PCCs, they give a range of 25 to 50 units per kilogram. However, which do you choose? How do you kind of select 25 versus 50? Should I choose 35 or fixed dosing? So it's kind of still unknown about the optimal dosing for four-factor PCCs in these patients. However, administration, as discussed in the stroke lecture, I kind of feel like the four-factor PCC is similar to tenecteplase. You can give it as a quick infusion versus N-dexon at alpha. You have to give a bolus and then a continuous infusion. So how that could possibly delay care in some patients and that transfer to the intensive care unit. So practical considerations. From a preparation perspective, as a pharmacist, this is something important to consider. So N-dexon at alpha comes in 100 milligram or 200 milligram vials. This can be 5 to 18 vials that you may need to prepare for the low and high-dose strategy. So I work in a community hospital setting where we do not have a stat pharmacy. So it could be a potential delay in terms of preparation of this product. And I'm sure the neurosurgeons, if they're going to the OR, may not be happy with that potential delay, right? Versus four-factor PCC, our emergency medicine pharmacists can give it at bedside and really expedite the care for those patients. The duration of action for four-factor PCC is around 6 to 8 hours. In contrast, N-dexon at alpha has a relatively short half-life. And this can lead to, like, receive rebound factor 10A levels after discontinuation of this agent. And then finally, we do see an increased thrombosis risk and there's a cost associated with N-dexon at alpha. So all of those practical considerations are important to keep in mind. And then, you know, considering the Anexa I trial is probably what's going to hopefully provide us some more insight about N-dexon at alpha versus standard of care for patients with ICH. Now, just additional, I thought this study was actually very interesting. It's just a case series that evaluated patients that received four-factor PCC at either an outside facility and then transferred to this larger academic medical center and received N-dexon at alpha. Now the patients in this case series did have some sort of neurologic decompensation that led to the team wanting to give N-dexon at alpha. And in these patients, they did see that two out of the five patients did have an increased thrombosis. They had a thrombotic event, one of which was an acute ischemic stroke and the other was a DVT within two and three days after receiving N-dexon at and PCC combination. So again, we don't have good evidence that says you can redose any of these agents or that it's appropriate to give one if the other one, you know, doesn't work, quote unquote. So just important to consider, you know, when initiating some of these therapies. Now let's discuss quickly antiplatelet reversal. So unfortunately, at this time, there's no FDA-approved agent for antiplatelet reversal, either aspirin or the P2Y12 inhibitors. However, there are some drugs in the pipeline to be aware of. The duration of action, as we know, platelet inhibition can last anywhere from five to seven days after discontinuation. A common question from the neurosurgery team is, should we give platelets? However, the PATS trial, which I'm sure we're all aware of, looked at non-traumatic ICH patients on antiplatelet therapy and did see an increased risk, odds of death and dependence, an increased risk of adverse effects in patients that received platelet transfusions that were not getting a neurosurgical intervention. So currently, the guidelines say that you should not give platelets in patients that are not receiving a surgical intervention. However, you can consider them for patients that are receiving a neurosurgical intervention. At some point, ticagrelor, which was discussed in the first lecture, is a reversible inhibitor of P2Y12, and therefore, it would not be reversed with platelets. How about desmopressin? Now, this is another controversial area. Unfortunately, we do not have one clear answer quite yet. Now, DDAVP has been used for hemophilias. It works on the V2 receptor on endothelial cells to help increase von Willebrand and factor VIII expression to improve platelet aggregation. It appears to be safe in the literature, right? There's no increased risk of hyponatremia, which may be a concern from some clinicians, or increased risk of thrombosis. But at this time, there's really an unclear benefit. Now, while this one study I have on the slide was a retrospective review that looked at hematoma expansion in patients that had an ICH and received DDAVP, we did see a significant reduction. However, further studies do not show similar benefits. So it's just important to know, you know, it may be a potential option in those patients, but we really don't have a clear benefit from this agent. There is an ongoing RCT, known as the DASH trial, looking at DDAVP versus placebo and antiplatelet reversal in ICH, so something to kind of keep in mind for future studies. Now we'll kind of quickly discuss blood pressure control. So we discussed in the golden hour, blood pressure control is truly critical to reduce the risk of hematoma expansion. It should be timely, right? Initiating blood pressure control based on the newest guidelines within less than two hours of ICH onset, with a goal to target that blood pressure within less than one hour. Now treat to target, right? So our ideal goal of systolic blood pressure for these patients is 140 with a range of 130 to 150. Now notably, patients that present with a systolic blood pressure greater than 220, we don't really have a good answer for those patients quite yet, or the patients with really severe ICHs. So in those patients, you know, of course, tailoring to your patient, maybe doing CPP or transfusion guided, you know, blood pressure control. But overall, our goal tends to be 140 for these patients. And more importantly, avoiding blood pressure variability is truly key, as that smooth and controlled blood pressure management has been shown to help improve functional outcomes for these patients. Now the optimal hand-eye hypertensive in ICH, these factors, considering we want to reduce the incidence of blood pressure variability, something with rapid onset, but a short duration of action, and easy to titrate, minimal impact on cerebral hemodynamics, and limited blood pressure variability. So the optimal agents we most commonly use are calcium channel blockers, nicardipine and clavidipine, whereas IV push labetalol can be used in that acute setting of the ED while you're trying to maybe get a continuous infusion started. Hydralazine, while it is commonly put on a lot of order sets for neuropatients, unfortunately, this agent has a very variable response in terms of its blood pressure reduction and also considering the fact that it has a really long half-life and can lead to dose stacking if you give it too frequently. Esmolol, I just kind of put in here for comprehensive purposes. It does affect heart rate more than blood pressure, so not commonly used. And then just being aware that our nitrates and dilators would increase ICP, so not preferred in this patient population. So thinking about IV push versus continuous infusion, which is better, this is a single center analysis that looked at IV push labetalol versus nicardipine in patients with acute stroke, both hemorrhagic and ischemic. And they found that the nicardipine group did have a reduced blood pressure variability compared to labetalol, which kind of makes sense when we think about an IV push PRN administration versus a continuous infusion where you can really titrate and get that type of blood pressure control. Now the differences between nicardipine and clavidipine, clavidipine does have the advantages where it has a shorter half-life, so you can double that dose every 90 seconds, which may in some cases lead to improvement in blood pressure control. It is metabolized via plasma esterases, so it does not depend on hepatic or renal function if you have somebody that presents with end organ failure, compared to nicardipine, which does rely on hepatic metabolism. The cost, however, is significantly different when you look at nicardipine versus clavidipine. Clavidipine may cost anywhere up to $120 per unit versus a max of $33 for nicardipine. The risk of fluid overload with nicardipine, however, is significant to consider, especially in those patients with congestive heart failure that may present. So considerations to maybe clavidipine in those patients or max concentrating your cardein should be a consideration. Now there have been a lot of studies that have compared nicardipine versus clavidipine in ICH. This was one single-center retrospective observational cohort study that looked at non-traumatic ICH patients and compared nicardipine versus clavidipine and found that, in fact, despite the optimal pharmacokinetic parameters of clavidipine, there was really no difference in time to target blood pressure, and in fact, it was lower in patients that received nicardipine. The need for additional blood pressure agents between the both nicardipine and clavidipine was similar. However, as we predicted, there was a total increase in volume administered with the nicardipine infusion compared to clavidipine. The cost of infusion was significantly higher with clavidipine, and then there was an increased risk of rebound hypertension and bradycardia in the clavidipine group, which was an interesting finding and not something you would anticipate. But that shorter half-life and not initiating long-acting antihypertensive before discontinuing the drip could lead to a higher risk of rebound. So the key takeaway, there's currently no difference really in time to target blood pressure control. However, considerations to the cost and increased risk of adverse effects should be a consideration when looking at nicardipine versus clavidipine in these patients. Now the last two slides, just briefly touching on VTE prophylaxis. Now there is a high incidence of VTE in these patients. Despite the fact that they are having acute bleed, we do know that they actually do have a high incidence of DVTs as well as PE-related deaths. And the incidence generally occurs within the first two to seven days. Now it's important to initiate VTE prophylaxis in these patients. Of course, those that have a stable head CT. And the guidelines do recommend within 24 to 48 hours from ICH onset, as long as their CT head is stable. And this can, again, help to reduce the incidence of a VTE. Now seizure prophylaxis, this may be something that's a bit controversial after the BEACH trial was published. But in general, right now, we do not have any good evidence to suggest for prophylactic anti-seizure medications at this time. If the patient has a confirmed seizure, then of course, in those patients, anti-seizure medications should be considered. So key takeaways, there's a golden hour within ICH, right? That emergent blood pressure control and coagulopathy reversal is critical to reduce the incidence of hematoma expansion. So treat to target, again, a target INR of less than 1.4. And looking at your target blood pressure control and reversal of coagulopathy can help to improve outcomes in these patients. And of course, remaining abreast of research that's ongoing, especially that NXI trial, which hopefully will give us some more data about andexanet versus four-factor PCC. Thank you very much.

intracerebral hemorrhage

anticoagulant reversal

blood pressure control

seizure prophylaxis

thromboprophylaxis