Hello, everyone. Welcome to Congress 2023. During this session, we'll talk about updates on management of acute ischemic stroke. My name is Thalia Froke. I'm the NeuroICU Clinical Pharmacist Specialist at Johns Hopkins Hospital. I have no financial conflicts of interest to disclose. Today, I'll talk about evidence for utilization of tenecteplase in acute ischemic stroke. I'll also discuss the literature regarding safety and efficacy of dual antiplatelet therapy or DAPT in ischemic stroke. And finally, I'll talk about IV antiplatelet use in this setting. In acute ischemic stroke, cerebral blood flow is reduced, and this can ultimately lead to tissue damage. Predictors of poor outcome include advanced age, comorbidities, and bigger size of infarct. 30-day mortality has been reported to be up to 20% in some countries. As you can see on this slide, there is different ideologies for acute ischemic stroke. Some are cardiombolic. Some are small vessel disease, intracranial atherosclerosis, and so on. This is important because pattern of stroke recurrence really varies by stroke subtype. The rate of recurrence is the highest for large artery atherosclerosis, but then long-term risk is steadily high in patients with cardiombolic stroke with higher mortality rates. This is a busy slide, but this is just a reminder to everyone for how to think about these patients. Timeline for giving thrombolytics, timeline for taking patients for thrombectomy, and then indications and contraindications for giving IV alteplase. As we all know, bleeding is a big contraindication. We commonly take people to head CT just to rule out ICH, and obviously other types of bleed with specific timeframes are indicated in the contraindication column, and the use of anticoagulants are also listed with specifics about the INR for patients who are on Warfarin and also the timeframe for DOACs, which is typically a 48-hour mark is what we consider a recent use and inappropriate or contraindication for giving alteplase unless they have renal impairment, and then that should be also taken into account. A lot of providers and practitioners are very comfortable and familiar with IV alteplase. This is the only FDA-approved thrombolytic for acute ischemic stroke. It has the level A recommendation from the American Heart Association Acute Ischemic Stroke Guidelines. Tenexteplase, on the other hand, it's the first-line thrombolytic for MI. Early data in stroke patients with large vessel occlusion showed better perfusion. Some dose-finding studies were done, and it looks like 0.25 mg per kick with a max dose of 25 mg is really the optimal dose in the setting of acute ischemic stroke. It is given as an IV bolus only, which we'll talk about, and because of how fast it can be given and no need for a continuous infusion, it is less resource-intensive, and it may be also associated with cost-saving. Just to quickly go over some of the differences between these two thrombolytic agents, maybe the most important highlights from this slide is that tenexteplase is more fibrin-specific compared to alteplase, and that means that it may be better tolerated, especially as far as bleeding risk goes. And also, as we talked about already, tenexteplase has a longer half-life, so unlike alteplase where you need to give a bolus dose, which is that 10%, and the 90% has to go as an infusion over 60 minutes, tenexteplase is just the one dose, one bolus that we're giving over 5 seconds. One of the early studies was published in 2018 that looked at tenexteplase versus alteplase in patients within 4.5 hours of onset of symptoms, and they all had to go for thrombectomy. The reperfusion of greater than 50% was seen in 22% of tenexteplase patients versus 10% of alteplase patients, and that was statistically significant. And then, when they looked at MRS scores and functional outcomes, it seemed like tenexteplase had better results and was associated with better outcomes. More recently, in 2022, the ACT trial was published. This was a multi-center, open-label, randomized, controlled trial looking at ischemic stroke patients within 4.5 hours of symptoms, and up to 32% had thrombectomy. They reported similar functional outcomes as well as similar mortality and bleeding rates. Now, focusing on oral antiplatelet agents in acute phase of ischemic stroke, in very large randomized controlled trials, aspirin has shown to reduce death and disability at six months versus a placebo. As far as dual antiplatelet therapy goes, there's conflicting results, and we'll talk about that shortly. And this chart kind of talks about what agents are reversible and what agents are irreversible, and that's important to note just because for irreversible agents, such as aspirin, the platelet will be inhibited for the life of platelet, regardless of what the half-life of the drug is. This table summarizes some of the landmark trials that looked at DAPT and acute ischemic stroke. Just a few highlights, not to talk about every trial and all the details, but I think it's important to talk about CHANCE and how CHANCE was done in TIN minor stroke and DAPT was started within 24 hours of onset of stroke, and they did find reduction in recurrence of ischemic stroke when they looked at DAPT versus monotherapy. This was only done in Chinese patients, so not very generalizable to other patients. The other study was the POINT trial that also started these patients on DAPT very early on within 12 hours, and they found a reduction in stroke and vascular death. And finally, I wanted to highlight what happened in COMPRESS. COMPRESS was also doing the same thing, kind of looking at ischemic stroke and giving DAPT early on within the first 48 hours, but they didn't find a difference. This could be possibly because, first of all, when they gave people clopidogrel, they did not load patients, and then second of all, up to 75% of patients who got started on DAPT received it within the 24 to 48-hour mark, as opposed to that 12 to 24-hour mark, which is what CHANCE and POINT did. So starting it early in patients with minor stroke and TIA may be really the key here, and making sure that we're loading them with the right doses is also another very big factor and important factor to take away. Moving on to IV antiplatelets, as you can see, our focus here will be on Kangrelor, which is a P2Y12 inhibitor agent in IV formulation, and then Eptafibatide, which is a GP2B3A inhibitor in IV formulation as well, and we'll talk about the utility of these agents in neurointerventional procedures. Neuroendovascular procedures are becoming more and more used in neurocritical care patients. Not only higher rates of reperfusion are reported with these interventions, but also better functional outcomes are listed in the literature. IV antiplatelets could be very helpful in this setting due to their quick onset of action and also short half-life, and we'll talk about these agents and how to utilize them safely in this setting. This chart does a good job of comparing Kangrelor and Eptafibatide side by side. A few important takeaways from this chart is that, as you can see, Kangrelor has a quicker onset of action as opposed to Eptafibatide. The dosing is also listed there, and we'll talk about that. For Kangrelor, as far as clearance goes, it is independent of kidney function, but Eptafibatide requires dose adjustment in patients with current clearance of less than 50 ml per minute. We typically talk about reducing the dose by 50%, so halving the dose. As you can see, neither of the agents have any prodrugs. The half-life of Kangrelor is about anywhere from 3 to 5 minutes. For Eptafibatide, it could be up to 2 hours. And as far as time to platelet recovery, after discontinuing these agents for Kangrelor, it's about an hour. For Eptafibatide, it could be 2 to 4 hours. This table reviews some of the relevant literature for Kangrelor use in this setting and Eptafibatide use in this setting. The first two studies, retrospective, both of them pretty small and of less than 50, variable doses of Kangrelor. The first study used a very fixed dose, which we have seen in other studies as well. The second study looked at Kangrelor with the plan to titrate per RU, or platelet reactivity unit. Both of these studies had pretty reasonable outcomes. The first one, almost half of patients left the hospital with independence, mortality rate was less than 5%. The second study, they did a good job of reporting how they adjusted the dose, so it's a very helpful document for people who are trying to utilize PRU and have that available for dosing titration. And then two patients had occlusions and no hemorrhagic complications. The last one, they look at Eptafibatide, and again, another retrospective study in acute ischemic stroke. More than half of patients actually left the hospital with pretty good functional outcomes and independence. Rate of bleeding and thrombosis were similar. Here's a sample Eptafibatide protocol. I really like this protocol because it kind of helps you through the steps, and if your patient has received Alteplase versus no Alteplase, as you can see, if they are given Alteplase, the loading dose of Eptafibatide is lower than if they did not receive Alteplase. As you can also see, as we talked about, Eptafibatide has renal clearance, so if the renal function is less than 50, there should be dose adjustment in the infusion rate versus if it's over 50. And also, as far as, okay, when your patient gets the IV Eptafibatide, how do you transition them to oral agents when they are stable? Because whatever agent, oral agent, you give, there is some time to get to the peak antiplatelet activity. Commonly, what's going to happen is that in these patients, let's use Ticagrelor as an example, and especially that we have that as part of our protocol here. You overlap the infusion and the oral agent, in this case, Aspirin and Ticagrelor load for two hours. So you load your patient with Aspirin and Ticagrelor, keep that infusion for two hours, and then you stop the infusion and you start your maintenance dosing of Aspirin and Ticagrelor at a usual frequency. So Aspirin will start 24 hours after that loading dose, and Ticagrelor will start 12 hours after that loading dose. This is a sample Cangular protocol. Again, I think one of the questions that usually comes up is that, was the patient on Aspirin and an oral P2Y12 inhibitor before? If yes, that's a little bit more complicated. The oral P2Y12 inhibitor, such as Ticagrelor or Clopidogrel, they need to be stopped two to three days before basically you start this infusion of Cangular. So you start your maintenance dose, and again, as we talked about this, the maintenance dose could be very variable. If you're using your PRU as your goal of 50 to 150, as you can see, there's instructions for how to titrate that regimen, that infusion, which is great. And then if you have to transition them to oral, again, if they've been on Aspirin all along, that's great and no problem. But if this is a new start, you start Ticagrelor and Aspirin loading doses in overlap with Cangular for one to two hours. And then you stop the infusion, and then you start your Ticagrelor and Aspirin at a usual frequency. Again, your Aspirin will start 24 hours after a load, and your Ticagrelor will start 12 hours after a load. So in summary, tenecteplase appears to be an effective thermolytic agent in patients with large vessel occlusion. Rule of DAPT in acute ischemic stroke remains controversial, but short-term use within 24 hours of onset of stroke in patients with TI or minor stroke may be reasonable. And IV antipyloid agents are valuable options in high-risk patients who are undergoing endovascular procedures where rapid onset of action is desired. Thank you so much for joining me today, and hope you had a great SCCM experience.

acute ischemic stroke

tenecteplase

alteplase

dual antiplatelet therapy

IV antiplatelets