Thank you for the introduction, good afternoon. I know the 49ers and Cowboys are playing right now, so don't be distracted, go Cowboys. The hope is that in the next 15 minutes we'll touch on several neurocritical care topics of interest in the preceding year, with a specific focus on acute blood pressure reduction and spontaneous intracerebral hemorrhage. We'll also highlight anticoagulation for atrial fibrillation and considerations when patients experience ICH, we'll talk about antiplatelet reversal in the setting of ICH, and then also seizure monitoring and prophylaxis in the same setting. We'll also highlight everyone's favorite topic, tenecteplase, in comparison to alteplase in the setting of acute ischemic stroke, and we'll briefly talk about venous thromboembolism and prophylaxis. We also conducted a Neurocritical Care and American College of Critical Care Pharmacists practice survey and aim to assess how all of these topics are applied today in clinical practice. I have no relevant disclosures. So the question of whether intravenous tenecteplase can replace alteplase as a standard of care for the management of acute ischemic stroke has gained recent interest in the preceding year. Tenecteplase is a genetically mutated version of tissue plasminogen activator with intentional mutations at the lysine and other protein residues. These structural enhancements aim to increase the specific bind into fibrin, resistance to inactivation by plasminogen activator inhibitor, potentially increase relative plasma half-life in comparison to alteplase. Now because of these enhancements made to the systemic structure of tenecteplase, we see that it facilitates the demonstration of subbolus, which may enhance the potential for inter-campus, inter-hospital transfers. We also know that because of the FDA-specific labeling of tenecteplase, there's a potential risk of increased dose and errors if it's not labeled appropriately for the potential indication that it's been dispensed for. However, conversely, you also have a reduced potential of dose and errors because you administer it as a single bolus versus an infusion where you have for alteplase. Finally, it is more practical to administer tenecteplase in patients with infectious precautions. Conversely, because you administer tenecteplase as a single bolus, in the event that you have new information for a patient which might change the clinical course or a patient experiences an adverse drag effect of tenecteplase, it may be a little bit too late. Now despite all of these potential theoretical enhancements to tenecteplase, alteplase has yet to be relegated as the inferior agent for the management of acute ischemic stroke with respect to a thrombolytic agent. In the next subsequent minutes, we aim to highlight briefly the relevant literature that led to what we currently see in clinical literature today regarding the comparison of tenecteplase and alteplase. So initially about a decade ago, there was a Phase 2, 2, 3B study which was a dose finance study comparing 0.1, 0.25, and 0.4 milligrams per kilo of tenecteplase in comparison to a standard dose of alteplase. The 0.4 milligram per kilo dose was eliminated because of increased symptomatic ICH found in that. The 0.1 and 0.2 milligram per kilo doses were continued, although in comparison to alteplase, we did not see any differences with respect to safety or efficacy outcomes. We did, however, see a trend towards improved outcomes with a 0.1 and 0.25 milligram per kilo tenecteplase doses. So then that informed future studies for the set-in. So the first trial that we're hoping to maybe help influence what we see today in the clinical literature is a test which was in 2015. Here patients who were eligible for thrombectomy were included, and a 0.25 milligram per kilo dose of tenecteplase was used in comparison to a standard dose of alteplase. We did not see any differences with respect to the primary outcome, which was the percent of salvage penumbra or any other safety endpoints. We have another test in 2017, which again looked at the higher dose of tenecteplase in comparison to alteplase, so the 0.4 milligram per kilo dose specifically. There were no differences in functional outcome or any safety endpoints. It's important to note that the median NIHSS in our test 2017 trial was 4, which suggests that perhaps they didn't find any safety concerns because the patients were not that sick. We then look at the Xtend-IATNK series of studies, which again first looked at patients with large vessel occlusion eligible for mechanical thrombectomy. The initial Xtend-IATNK study looked at the 0.25 milligram per kilo dose. They did see an improved reperfusion in outcomes with tenecteplase in comparison to alteplase. So the authors got really excited because they saw positive results. And then they looked at 0.25 versus 0.4 milligram per kilo. And what they found was that the 0.4 milligram per kilo dose was not better and did not also present with any additional safety concerns. The NIHSS looked at in this specific study appeared to suggest that these patients were a little bit sicker than the 2017 NORTEST study that we looked at. So in the last year, we have several clinical literature publications comparing tenecteplase and alteplase. So first we have NORTEST-2 Part A, which again repeated the same considerations for the 0.4 milligram per kilo dose in comparison to a standard dose of alteplase. We did, however, see because these patients were slightly sicker than the 2017 study, the 0.4 milligram per kilo dose was actually worse than the standard dose of care, which was alteplase. And therefore, the authors concluded that the 0.4 milligram per kilo dose for tenecteplase is not the optimal dosing strategy. And then we have experience from the Canadian ACT study, which Ronna talked a little bit about, where 0.25 milligram per kilo tenecteplase was compared with a standard dose of alteplase. Again no differences with respect to the primary or safety endpoints realized. We have some experience which was unique in mobile stroke units in Melbourne. Here the authors looked at 0.25 milligram per kilo tenecteplase in comparison to a standard dose of alteplase. And in this study, they did see that when patients presented to the ED after receiving tenecteplase in the mobile stroke unit, there was a reduction in the perfusion lesion on presentation. So that was positive. And there were no worsened safety outcomes in comparison of the 0.25 milligram per kilo tenecteplase dose versus alteplase or mortality for that matter. Finally we have experience from the TWIST trial which aimed to shed light on wake-up strokes. Again, there were no differences in functional outcomes assessed. So how do we tie all of this together? In the last year towards the end of 2022, we have a publication looking at real-world data over approximately six years. There are about 30,000 patients included in over 100 sites. We see that majority of folks who were included in this assessment received alteplase and tenecteplase was only administered in less than 2% of the patients. It is important to note though, they did find an increased rate of symptomatic ICH, but there were no differences in mortality as assessed in this claims database. So putting everything together, I know it's a lot of clinical studies that we talked about. So to highlight the main points, NORC-S2 did not appear to support the 0.4 milligram per kilo dose for tenecteplase. So that was something that was important to highlight. TIST-A suggested that tenecteplase is potentially better than alteplase. We have some experience and the Canadian Study Act would suggest that there were no differences in comparison with tenecteplase and alteplase, although perhaps tenecteplase might be better. All right. You get the gist. Tenecteplase is not better than alteplase, but perhaps it may be considered based on the theoretical benefits. So in applying all of this in clinical practice, we conducted a neurocritical care practice survey. A majority of respondents have already converted tenecteplase as their preferred thermologic therapy of choice for all patients with acute ischemic stroke irrespective of type of stroke. So looking on the far right, we have the recent recommendations for the AHA and ASA guidelines, which suggest that medication titration goals should be targeted at limiting blood pressure variation and insurance within consistent control with the goal of aiming the target within our patient presentation with the benefit of reduction of hematoma expansion. These recommendations were influenced by the available literature in the Interact and ATAC studies where we know that in post-hoc analyses, there was an increased standard deviation of blood pressure variation correlated to worsened outcomes in patients assessed at 90 days. We also know that continuous association is apparent when blood pressure is achieved and lesser variability in 24 hours after ICH leads to more favorable outcomes in the set-in. To summarize, there is a lack of evidence to guide the choice of blood pressure lowering agents during the acute and hyper-acute phase in ICH. The available literature that we have to lean on includes the ATAC and Interact studies. In the ATAC we know that ibuprofen was predominantly used, however, in patients who were refractory. There was an allowance of diltiazem or rapadil if levatolol was not available. Interact included patients who received both injectable and enteral blood pressure lowering agents, and bolus versus confusions were also considered here. We also perhaps think that venous vasodilators may be harmful because of unopposed vasodilation. So applying all of this in our practice survey, how are folks thinking about targets for blood pressure? So the majority of respondents aim for 140 or lower, but we also have some significant folks who aim for a target of 160 or less. We also wanted to assess what is the ideal blood pressure lowering agent for the management of ICH. And you can see that most folks do not have clavitapine on their systems formulary, and it's reserved for patients who are refractory to injectable nicotine. Looking at antiplatelet reversal in the setting of ICH, the guidelines suggest that platelet transfusion should be considered if patients are on aspirin and emergent neurosurgery is imminent. We do not have data to lean on from previous data, including the patch which revealed increased odds of mortality and disability when platelet transfusions were used routinely in the patients who presented with ICH. We also know that desmopressin has conflict in literature and available retrospective evaluations. And also antiplatelet therapy at the time of hemorrhage we know is associated with increased odds of mortality as well. To sum up what we know with antiplatelet reversal in the setting of ICH, the effect of antiplatelet agents on the outcome of ICH is uncertain at this time. The studies related to ICH mostly have included patients who are predominantly aspirin. We also know that available literature guided in this practice generally do not provide separate results for different antiplatelet agents. And we know that they have different PK and PD considerations. Platelet transfusions, desmopressin and TXA, although shown in non-neurocritical care specific literature, perhaps might not be substantiated routinely in neurocritical care patients. So applying all of this evidence in clinical practice, we conducted this relevant survey again. As you can see in yellow, while the guidelines don't routinely recommend platelet transfusions in patients who don't have planned or resurgent interventions, the majority of respondents commutatively still undergo a practice where they give platelets or give desmopressin or a combination of the two. You can see about a quarter of the respondents only reserve administration of platelets in the setting of planned or resurgent intervention. We're going to touch briefly on seizure, prophylaxis and monitoring in the setting of ICH. There are two main studies that were published in 2022 that aim to answer this question, although the results were not really that helpful. So first is the Seville study that identified that there were no differences in seizure occurrence in patients who routinely received seizure prophylaxis in the setting of ICH. And the PEAT trial only really informed us that maybe perhaps continuous EEG monitoring might help identify the incidence of subclinical seizures. Looking on the right of your screen, you can see that in clinical practice, most folks don't routinely use seizure prophylaxis for patients who present with ICH. And then looking at VT prophylaxis in the setting of TBI, recently there was a published study that really concluded that VT prophylaxis delay was associated with an increased odds of VTE. We also know that during the first three days, each additional day of prophylaxis delay was associated with a decreased odds in repeat neurosurgery. To summarize that finding, we know that early VT prophylaxis was associated with repeat odds of neurosurgery. And then specifically when you look at the type of agent, low molecular weight heparin appears to be better in terms of comparisons with unfractionated heparin. This is consistent with what folks are doing in clinical practice. Low molecular weight heparin appears to be preferred preferentially in comparison to unfractionated heparin. And then looking at anticoagulation in the setting of atrial fibrillation and then patients presenting with ICH and what folks are doing, we have a prospective RCT of about 100 patients to help us kind of figure out what to do for patients who present with ICH and are on anticoagulants. So here they really looked at whether or not anticoagulants were resumed after ICH versus held after ICH. And what they found was that there were no differences in serious adverse events between groups. But what was interesting that they found was that there's a high annual risk of non-fatal stroke or vascular death in patients with atrial fibrillation with AC-associated ICH whether anticoagulation was resumed or not. When do folks really resume this is interesting too. This survey suggests that folks are really feeling comfortable after two weeks of patients presenting with ICH. I know I talked about a lot of things so just to summarize everything for you all, it is unclear what the ideal thrombolytic therapy in the setting of acute ischemic stroke is. We know that we want to limit blood pressure variation and also ensure smooth and consistent control in ICH. We want to reserve platelet transfusions only if patients have planned neurosurgical intervention, larger prophylaxis in ICH is probably not a good thing to do. Early VT prophylaxis in ICH leads to increased odds of repeat neurosurgery. Lobanox is better than how infractionated heparin. And finally, the annual risk of non-fatal stroke or vascular death in patients with atrial fibrillation associated ICH is a problem and that needs to be addressed in larger randomized controlled clinical trials. Thank you for your attention. You can get back to your game now.

neurocritical care

tenecteplase

alteplase

acute ischemic stroke

efficacy and safety