Thank you for all the introduction, and thanks for everyone being here in person. So we're going to talk about updates and management of acute ischemic stroke. Here's our bio. Nothing to disclose. Dr. Albin's bio. Nothing to disclose as well. All right. So as you can see, we have a lot to cover in 30 minutes for acute ischemic stroke. But we're going to do our best to walk you through all these updates and hopefully answer any questions that you have at the end when all the speakers are done. So without any further ado, we're going to talk about some pathophys and epidemiology of acute ischemic stroke. Nothing really new there, but we thought that it's important to talk about the basics before talking about all the details and all the updates and more exciting stuff. As you may know, in acute ischemic stroke, blood flow to the brain tissues is reduced, and that activates a whole cascade of pro-inflammatory responses that can ultimately lead to apoptosis and necrosis and tissue death. We've learned from trials that patients who are older, patients who have comorbidities such as diabetes and hypertension, and those with a bigger stroke lesion are at higher risk of worse outcomes. And it's been reported that in advanced countries, the mortality rate has been up to 20%. And as you can imagine, this rate is probably higher in countries without all the resources. Before we talk about management of acute ischemic stroke, we fall strongly to talk about some of the ideologies. Obviously, this slide is not very comprehensive, but just to give you an idea, patients can come in with strokes because of extracranial stenosis, intracranial stenosis, small vessel disease, large vessel occlusion, cardiombolic causes, or it could be cryptogenic, which simply means we don't know why they have a stroke. Not only this is important in the acute phase of managing acute ischemic stroke, this is also important when we talk about recurrence. So as you can see on the slide, patients with large artery atherosclerosis usually have the highest risk of occurrence early on, and that's why we really emphasize on prevention early on in the ICU setting even for these patients. But then when it comes to cardiombolic strokes, the mortality is higher, but it's usually a steadily higher risk long term. So these people have higher complications over time and over years. All right. We know that this is a very complicated slide, and we're not going to go over all the details here. I don't think anyone's here to listen to all these little things, but what we wanted to highlight and get out of this slide is that when you are caring for patients with acute ischemic stroke, you are going to have clinical and pharmacologic complications, and our hope is that today we can go over some of those complications and help you with your management given some of the updates that are available in the literature. There are, as you can see, indications and contraindications for a thermolytics, and we're not going to talk about that because there is not really a whole lot of updates about who can get a thermolytic agent, but what is updated is that what is the agent that we're going to use, and what's the ultimate thermolytic agent of choice as of now. We're not talking about alteplase just because I think there's been enough said about alteplase. We all know about the NINDS trial, the ECAS trial, all the good stuff, but what we're trying to talk about today is tenecteplase and how this has been maybe the major focus in the stroke community and how maybe this might be the future of acute ischemic stroke. As we all know, as of now, this agent is not FDA approved for acute ischemic stroke. It's only FDA approved for acute management of MI, and we're not going to talk about MI today. There is some, you know, hypothesis that this drug may have a lower bleeding risk, and we'll talk about that, and then there is some literature about is this even better in management of acute ischemic stroke compared to alteplase, and with that, we're going to go and talk about the evidence. So as you can imagine, I'm a pharmacist, so before I talk about clinical trials, I like to talk about drugs and put them side by side. So alteplase versus tenecteplase, why is it that we think tenecteplase may be a better option? So there are two things I wanted to highlight here, and I think it's important to think about these agents as far as pharmacokinetics and pharmacodynamics. One thing is that tenecteplase is more fibrin-specific, and what that means is that it could possibly have a lower bleeding risk, because it's just simply more specific and more targeted for fibrin activity. The second thing is that it has a longer half-life, and that's also clinically relevant because you can only give a bolus dose as opposed to a bolus and an infusion, which I'm sure you all know about alteplase and how you need to get a pump, and the 10 percent of the bolus, and the rest, it has to be a continuous infusion. So maybe after all, this is easier and more convenient for our nursing staff, our pharmacists, and for our providers to prescribe and to administer. The second part of this, I think, shorter administration time is that maybe instead of thinking about door-to-needle, we should think about door-to-thermolysis, which is, I think, very interesting and huge, because instead of delaying transfers and trying to, you know, give this alteplase for one hour, you could simply just give a bolus and transfer your patient, or this could even happen in the neuro-IR right before your patient's going for a thrombectomy. You just give a bolus, and you're done with that. But where is the evidence coming from, and why is that important? Why is it that we're talking about this? I think everyone probably knows about the early trials and how, in 2018, there was a publication in New England Journal of Medicine that they looked at tenecteplase versus alteplase in large vessel occlusions. All patients had to go for thrombectomy. And what they found was that patients who received tenecteplase had better reperfusion, and this was looked at before thrombectomy, and also patients who got tenecteplase had better MRS, which is indicating, you know, better functional outcomes. But there are some limitations to this study, and I think that's important to think about. One is that they only look at patients with large vessel occlusion that had to go for thrombectomy, and that when they really looked at patients with excellent functional outcomes, which was MRS of zero to one, there was really no difference. So the biggest, I think, question in practice was that, can we apply this study to all of our stroke patients? Because we all know that large vessel occlusion is pretty devastating and has probably one of the highest rates of disability for stroke patients. That's probably less than 20% of most of the patients that we get in practice, so can we change our practice from alteplase to tenecteplase just for this very specific subgroup of stroke patients? So our Canadian friends actually recently did a study to ACT trial that came out a few months ago. The ACT trial came out to answer this question. So this was a randomized prospective study that looked at alteplase versus tenecteplase. As you can see, this is a much bigger study. They included a much broader subgroup of stroke patients. Only one third really had to go for thrombectomy, so that was nice to see that they did include a lot of patients that didn't go for thrombectomy. And what they found was pretty comparable results that patients in both groups had similar rates of functional outcomes and also ICH risk and other side effects were pretty similar. So with that study, I think it is probably, given the ease of administration, given that it could be possibly financially more affordable and cheaper, maybe this is a reasonable approach to think about switching from alteplase to tenecteplase. And Dr. Alban will talk about some of the complications. All right. So a lot of those decisions are being made in the stroke bed with our vascular colleagues, and then the patient comes up to the ICU and sort of, what do you have to worry about as the intensivist? So we're going to go through two of the complications and sort of considerations for post-stroke patients who are in the intensive care unit. So the one thing that we can kind of take a direct control of is, what should the blood pressure goal be? From the trials, they set the upper limit of systolic blood pressure to 180, diastolic to up to 105, but is lower better, right? The idea is that with high blood pressure, you're putting that ischemic tissue at risk of a hemorrhagic reperfusion injury. So is lower better? And the answer is probably not. So the BP target, what it showed was that the invasive BP lowering was associated with a lower risk of symptomatic intracranial hemorrhage, but at the risk of minimizing the collaterals that most of our stroke patients depend on. So the outcome in terms of the modified Rankin score at 90 days was no different. So maybe we spared a couple of patients with a little bit more hemorrhage, but at the expense of taking away the collateral that some of our patients relied on. So again, I think up to 180 still should be our goal. The other much less common but much scarier complication for these patients who have received thrombolysis is intracranial hemorrhage. The rates are actually pretty low, probably around 2% to 3%, up to 9% depending on how generous you're being. The things to look for or to the patients that you really want to keep a close eye on are those with older age, hypertension, patients who come in sicker, you know, the patients that have a very high NIH stroke scale because they had a very big stroke, and then early ischemic changes before they were given their lytic treatment. Time to treatment also sort of corresponds with who is at most high risk for having a hemorrhagic conversion. So again, those aren't things that we can necessarily modify once they get to the ICU, but certainly for those patients, we can keep a closer eye on them. I think this really highlights a very interesting thing about both lytic treatment. As you remember from the slides that Solly has showed, the plasma half-life of both these drugs is really short. Four to six minutes when we're thinking about alteplase, and 18 minutes when we think about tenecteplase, right? But the pharmacodynamics is such that these treatments put your patient basically in iatrogenic DIC for up to 12 to 24 hours, and sometimes even longer. So again, even though the half-life of the drug is very short, the effect persists for up to a day. Probably the highest risk is in that first 12 hours, this was a nice study published looking at the time to the intracranial hemorrhage, but again, up to 24 hours. So for tenecteplase, was there really any big difference? And I think the answer is no. I mean, this was definitely shown to be non-inferior. It's in sort of like 2% to 3% rates of intracranial hemorrhage. I think we should think about this as about the same. So what do you do? This is one of those terrible things that you notice like, hmm, the patient looks pretty good after they got their lytic treatment, and now they look terrible. You send them for that STAT head CT, and you find this, that you have gotten an intracranial hemorrhage. So the reversal is not Kcentra or some other sort of your typical sort of reversal agent, but actually 10 units of cryoprecipitate. This should be sent the second you see or ordered for the second you see intracranial hemorrhage on the head CT. You should also, at that point, send a fibrinogen level. Again, this is iatrogenic DIC. The fibrinogen will be low and may persist being low for 24 hours. Don't wait for that level to come back before you give the cryoprecipitate. Give it, and then if it's less than 150 or 200, you can give another round of treatment. The ASA guidelines do recommend that if you have a patient who, for whatever reason, cannot get blood products, you can give TXA or Amicar in its place. I think it's also nice to give these as a temporizing medication. So for my practice, at least specifically, it takes a minute for the cryoprecipitate to come up from the blood bank, and in the meantime, it seems very reasonable to me to go ahead and give them, you know, one gram of TXA as a temporizing measure, sort of an antidote to the lytic agent we've given. All right. The other big thing that I think all intensivists should be aware of is that, you know, lytic treatment was great, but mechanical thrombectomy is just so much better. So this was from the Hermes meta-analysis, looking at sort of the early first-generation trials. So when we think about the people who achieved a really good MRS score of less than or equal to three, we basically doubled the percentage of people who were able to achieve a good outcome with mechanical thrombectomy. Now, again, not as Sally was saying, this is 20 percent of strokes that have this large vessel occlusion. So not everyone is going to qualify, but those are the patients that are going to have the highest mortality and morbidity, and so this has just been such a game-changing innovation in our field. The number needed to treat was 2.6, so again, like, there are so few things in medicine that have that robust of a treatment effect. The early treatment windows all looked at these excellently selected patients. You know, they came in. They had door-to-groin time of about six hours. They had an excellent functional baseline. The Dawn and Diffuse trials were revolutionary in that they showed that this treatment effect could still be very, very beneficial to our patients if we used a tissue selection window. So we used to kind of think about, well, if you came in within six hours, you could get this, but the paradigm shift was saying, well, it's not about the time. It's about how much tissue is left to save, and so all of these trials sort of relied on perfusion imaging to determine how much of the brain tissue had already infarcted versus how much was still left to spare. Again, these were excellently selected patients who had an anterior LVO, who had excellent functional baselines, but this was truly a paradigm shift and now has allowed us to treat so many more patients who don't come in within the first six hours. We're not going to go through all of this, but I want everyone in the room to be aware that the shift now in the stroke field is that we are trying to make this treatment more and more accessible to patients who come in that have a lower functional baseline, that have more ischemic damage already on their head CT, that don't need perfusion imaging. We're trying to get to them faster by using mobile stroke units. We're making sure that we still give them LIDIC treatment and having trials that compare the outcomes of those sort of treated with LIDIC therapy versus not treated with LIDIC therapy. And again, we're trying to get to these smaller vessel occlusions that may still have a very big functional impact. So again, the stroke literature really increases and we're trying to make this more accessible of a procedure. To talk briefly, most of the time, the problem with reocclusion actually happens in the angiosuite itself. These intracranial atherosclerotic disease and like sort of, you know, kind of gnarly plaques can give our endovascular surgeons quite a hard time to actually get the plaque open. So there's sort of this in the middle of the angiosuite reocclusion and then there's delayed reocclusion. So, you know, you're going to get sign out from the angiosuite of whether or not the vessel was reoccluding during the procedure. The people that you have to worry about are there's a low risk, but there is a risk of reocclusion. So again, that's just, you know, in the ICU, we need to keep a detailed watch on these patients because there is this sort of two to 3% risk that the vessel was open and it's gonna close back down. Those patients are usually ones that, if we go back retrospectively, we see that there was some still clot left or the M2 occlusions. I'm not really sure what to make about this platelet count being higher than 220, but that was what the data showed. So Sally is gonna talk about sort of what they're doing in the angiosuite to kind of prevent that vessel reocclusion. All right. So this is really summarizing everything that Casey talked about, how, you know, thrombectomy is effective and we're really improving our number needed to treat and all of that. But just like any intervention, it comes with a price. And what we're gonna focus on right now is the risk of reocclusion. There's obviously many reasons for why this could happen. It could be, you know, people with large arthrosclerosis or some people may require a stent or a flow diverter for further opening the vessels and things like that. So you might have used oral agents, but remember that in this setting, a lot of patients may not have enteral access or even if they have enteral access, the surgeon or the neuro IR provider may need an agent that is very quick on and is very quick off. And that's when I think these agents come into play and we're gonna focus on two of these agents. Again, me being a pharmacist, before going and talking about all these trials, I wanted to put these agents side by side. So there is some, you know, education about these agents given that we don't see them as often in practice. So this is not the most comprehensive list, but these two agents are the agents I think mostly a lot of us see more often in practice. Cangelor and Eptafibatide, as you can see, they're very different agents, do the same thing, but work differently. A few things to highlight here is that Cangelor is quicker onset and quicker offset. So that may be something that may be attractive. It also is independent of any organ clearance or metabolism, meaning if someone has a hepatic failure or a renal dysfunction, this is probably a little bit of an easier drug to use them in. Although it's super expensive, it's just something to keep in mind. Eptafibatide, on the other hand, it has a little bit slower onset of action, meaning it takes about 30 minutes for it really to start working. And then it also has a more delayed offset of action. So if you stop the agent, it takes about two to four hours until you see a full recovery of platelets. But where is the evidence, then? This is, I think, again, a very busy slide. And when I made a slide, I think the goal and the intention here is that not to walk you through all the studies and all the outcomes. I really wanted to focus on the fact that when you look at your number of patients, look at all the studies that I have, and these are the major ones that we utilize in practice. They're all below 50 patients in acute ischemic stroke, and they're all retrospective. So what that means is that a lot of the statistics are all descriptive, so this all should be taken into account when you're really utilizing it in practice. The other piece is that when you get to the protocols of these studies, everything is variable. Some people had very strict PRU, or platelet reactivity unit, to go off of, and some people just let it to the providers and said it was up to the provider to decide how they wanted to titrate the agent. So these are some of the things to think about, but what I thought may be interesting and more practical for us is to look at some of these protocols and see how they utilize these agents. The first one that you see is about IV eptifibatide. This is from a publication by Nick Panos, one of our wonderful neuro ICU firms at Rush University, and I love this protocol because not only it gives you instruction about how to use the agent, it tells you what to do if you've given alteplase first or not, and I think that's a very commonly encountered situation in practice that someone may get neurothorombolytics, then they have to go to neuro IR, they get thrombectomy, then you get a call from the neuro IR provider that, oh, this patient received alteplase, and now I have this occlusion problem, what do I do? So as you can see, the dosing is different if they receive alteplase versus not, and then the other thing to be mindful is that based on the renal function, the dosing will be different, and then the last part is that you absolutely have to be concerned about the transition, so every time you think about transitioning these people from IV to oral, there is a risk of reocclusion and the fact that you want to make sure you have enough antipolytic activity, and for that reason, you absolutely have to load these patients with the oral agents also, and we commonly talk about overlapping these patients, the IV and the oral, for up to two hours to make sure that you have consistent antipolytic activity during that transition phase. This is another example of Kangalore, I think, protocol. This is from Casey's institution, Emory. This protocol kind of shows that in their institution, they're using PRU values, and they're pretty strict about how they go about a titration. As you can see, it looks like they give a bolus, and then they check the PRU in 30 to 60 minutes, and then they also play around with the dosing and their adjustments after they see the PRU in two to four hours after those dose adjustments, so just to give you a brief description, a lower PRU value means that your platelets are super reactive, so you want to reduce your dose, and when you get to higher levels of PRU, which is usually we think about over 150 or 200, you really have to think about, okay, my patient's a huge risk of thrombo, so you have to think about increasing your dose. The 50 to 150 that you see is something that I've seen in the literature more often than not, but again, I think we still don't have a magic answer what the best target should be. So thinking a little bit more about sort of the clinical considerations after mechanical thrombectomy. So again, one of the scary, most scary occurrences is the risk of hemorrhagic perfusion injury with intracranial hemorrhage. Some of the things to consider about which patients are at higher risk, some of it you cannot control. These are our sicker patients, right? They came in with a higher stroke volume. They had poor collaterals in this, were fast progressors. They were just the patients that had a very high clinical burden with her high NIH stroke scale, and then this periprocedural hypertension. However, one thing that you can control in the intensive care unit is this blood pressure variability, and I think that is something that we can try to keep a very smooth titration down at our blood pressure goals. And so one of the questions that comes up clinically is these patients have just gotten a ton of contrast, and as we know, contrast shows up very bright on a head CT. So it's very difficult to kind of tease out how much of this is contrast versus how much of this is acute blood. So I want to draw your attention to the role of dual energy head CTs. This is based on sort of the different, various behaviors of materials when exposed to X-ray at low and high energy. So what the dual energy CT is basically doing is giving you a scan that just looks like your normal head CT, and then a second scan that has what's called an iodine subtraction. So we can see here on the scan that's far over to the right that that hyperdense material subtracts out, meaning that this is iodine that was in the stroke bed. Again, that does mean that there's some breakdown of the blood-brain barrier, that's how the iodine got there, and so this could be just ischemic tissue, but it is very helpful when you're trying to make decisions about when to start either anticoagulation or antiplatelet therapy to kind of know more definitively was that iodine or is that actual hemorrhage. The other thing that I wanted to touch on is that despite these wonderful therapies, some patients still have gigantic strokes, even the ones that go to mechanical thrombectomy. And so I think one of the things that we as intensivists really need to be mindful of is those patients with large strokes are at risk, especially if they're young, for malignant edema and herniation. And so just to kind of clue you in that these are the patients that have greater than 2 3rds territory of the MCA involved or have a non-dominant stroke scale of greater than 15, meaning usually our right MCA syndrome greater than 15, or a left MCA syndrome greater than 20 on the NIH stroke scale. That shows you that there's probably been a lot of tissue damage done, and for those young patients, particularly they're at high risk of developing what's called malignant cerebral edema. And that's important for us to keep aware of because we know that there's actually a surgical treatment that not only decreases the mortality, but decreases morbidity. And so these are just a pooled analysis of the first generations of decompressive hemicraniectomy for large malignant MCA syndromes. Again, this was in younger patients, so again, less than 60 years old. And the important fact is that they were all taken to decompressive hemicraniectomy before they had herniation, right? So these were early interventions done before there was actual signs of damage clinically. And so the important fact here is that this was not just mortality sparing, that this actually provided patients to get to a reasonable functional outcome, and like 31% of patients getting an MRS of three, which if you've had a full territory stroke, I think is a reasonable outcome. And I think this really emphasizes to me the importance of shared decision making in these patients that we have to talk about, there is a risk that you're gonna end up with a high morbidity, but our best chance of giving you a lower morbidity scale or a better functional outcome is actually to take the bone off. And so again, if you're not practicing in a center that has neurosurgical capabilities, think early about transferring them to one that does. The other thing that intensivists I really think should focus on is that we control what their blood pressure is. There is still some like nuances to this and some gestalt of just what the surgeons feel best. BP target was another study that sort of looked at where should we set the blood pressure parameters for post-mechanical thrombectomies. I think at this point, based on that trial, it's very reasonable to aim for somewhere less than 40 to 60, sort of surgeon dependent. The important thing is that lower is not better. So this was enchanted MT, it was presented at the World Stroke Conference in 2022. The trial was stopped because the patients who are in the very intensive blood pressure lowering group actually did worse. So again, our stroke patients still respond, like they need their collaterals, lower is not better. The final thing that I'm just gonna mention real quick is that our patients, like all patients who get interventions through the groin are at risk of hemorrhagic and ischemic complications. The thing that's different about our patients is that they're more altered often. And so they're not going to be able to as clearly convey to you that they're having back pain or that they're feeling something in their stomach that's cluing you into their retroperitoneal hematoma. So again, keep a higher index of suspicion, especially if you notice a high stick. This can just explain with hypotension and sort of increased alter mental status in our patient population. Ischemic complications are also something that we have to worry about. It's very important to get pulse checks in the lower extremity. This is still a low complication risk, but is more common with angioceles, which if the plug gets dislodged, you can get this sort of very impressive ischemia. So just again, taking a look at the groin when your patient comes back. All right, we're getting to the last objective of our talk today for our section at least. So let's say we did everything for our patients. You know, we gave them a thermolytic agent that we thought was the most effective. We took them to the neuro IR. We had great outcomes, but we're worried about recurrence, especially, you know, we talked about as initially we reviewed risk of recurrence. If someone has a large artery atherosclerosis, this is a huge problem. And this is not something we think about, you know, months after their acute ischemic stroke. This is something that we are really concerned about initially and within the first 12 to 24 hours. This is a little bit of, I think, background, but not really talk about aspirin much. But as you can imagine, people have tried to do different things. Recently, we look at ticagrelor versus aspirin to see if there was better outcomes. We didn't see that. So there's no difference when they looked at patients with TIA or minor stroke, high risk TIA versus minor stroke. But I think the question that at least we see a lot in practice is that, what about DAPT? Should we send our patient out to the floor with aspirin and clopidogrel versus just monotherapy? And here's the list of medication. I think most people are familiar with the oral agent. So I'm not gonna go over that very in details, but. So again, a very, I think, busy slide. And what I wanted to get at with this slide is that probably everyone shouldn't get started on DAPT, but maybe looking at these trials can help us decide which patients would benefit the most from getting started on DAPT. I think a few things to consider. Looking at guidelines, the American Heart Association Secondary Prevention Guidelines, they do talk about that if you are considering DAPT, you wanna think about patients with significant stenosis, and they talk about 70% or higher degree of stenosis. The second thing is that if you are considering DAPT, it has to happen very early on. As you can see, I have the timeframe in green for studies that showed improvement in recurrence. So it looks like even waiting for 48 hours may be too long. So you really wanna think about the first 12 to 24 hours, obviously, after your stability had CT. And then the last thing is that studies that looked at continuation for long-term actually showed consistently higher rates of bleed. So this is something that you don't want your patient to be out for months and years and all of that. This is something I think the idea is to keep it for 21 to 90 days, and that may be the most optimal, although there are new studies looking at 30 days of DAPT and the fact that more than 30 days may be when we see the actual higher rates of bleeding, and that's something to consider. With that, we're done with this section. We're open to questions at the end.

acute ischemic stroke

updates

management

tenecteplase

thrombolytic therapy

complications

antiplatelet therapy