Great, hi everybody. I'm very happy to be here with you all today to discuss a few additional publications in neuroscience pharmacology from 2023. I have no relevant financial disclosures. In patients with acute ischemic stroke, the risk for both recurrent ischemic stroke as well as intracranial hemorrhage is the highest in the first few days after the index stroke. In patients with concomitant atrial fibrillation, clinicians must often determine the optimal time to initiate anticoagulation in such a way that balances the risks of both recurrent ischemic events as well as intracranial bleeding. It is in this setting that the authors of the ELON study set out to estimate the risks and the benefits of early versus later anticoagulation initiation with the use of direct oral anticoagulants or DOACs using imaging-based selection criteria in patients with acute ischemic stroke and atrial fibrillation. Patients were included if they had an acute ischemic stroke and atrial fibrillation, which could have been previously known or diagnosed during the hospitalization. The use of IV thrombolysis or endovascular thrombectomy was permitted as appropriate. Patients were excluded if they received therapeutic anticoagulation at stroke onset, if they had a parenchymal hematoma within the infarcted tissue or an intracranial hemorrhage remote from the infarct. Patients with serious bleeding in the previous six months or those that were at high risk for bleeding were also excluded. The timeframe that anticoagulation was initiated within the early or later treatment group was dependent upon the stroke type. Minor strokes were defined as infarcts less than 1.5 centimeters. Moderate strokes were infarcts within the distribution of a cortical superficial branch of the middle, anterior or posterior cerebral artery. And major strokes were larger infarcts in the MCA, ACA or PCA or brainstem or cerebellar lesions. Patients that were randomized to the early group began their DOAC therapy within 48 hours of a minor or moderate stroke and on day six or seven for a major stroke. The corresponding timeframe for patients randomized to the later group were day three or four, six or seven or 12 through 14 for minor, moderate or major strokes respectively. 2013 patients were included in the study and the groups were well balanced at baseline with respect to age, CHADS-VASc score, level of pre-stroke disability on the modified Rankin scale and NIH stroke scale score. Additionally, there weren't any significant differences between groups with respect to stroke type or the use of reperfusion therapy. The primary outcome of the ELAN study was a composite at 30 days of major extracranial bleeding, symptomatic intracranial hemorrhage, recurrent ischemic stroke, systemic embolism and death from a vascular cause. This primary composite outcome occurred in 2.9% of patients in the early treatment group and 4.1% in the later treatment group and was not statistically significantly different. Each of the components of the primary composite outcome are also shown in the figure and there weren't any statistically significant differences for any of these secondary outcomes. Recurrent ischemic strokes did account for more than half of the primary outcome events. The authors of the study concluded that among patients with acute ischemic stroke and atrial fibrillation, there was a similar rate of the primary composite outcome between early and later DOAC initiation. And I wanted to highlight a few limitations and considerations from this study. The first is that imaging criteria rather than the NIH stroke scale score was used to distinguish stroke severity. Classification of major strokes was heterogeneous and could encompass large infarcts within the entire MCA territory all the way to brainstem or cerebellar lesions. NIH stroke scale scores at baseline were low and there was a low overall event rate. And finally, patients that were receiving therapeutic anticoagulation at baseline were excluded. So I wanted to compare the timeframe that anticoagulation was initiated in the ELAN study to what is currently recommended in guidelines. The American Heart Association and American Stroke Association suggest that it is reasonable to delay anticoagulation beyond 14 days if the risk of hemorrhagic transformation is high and state it is reasonable to begin between days two and 14 if this risk is low. The European Stroke Organization state that a formal recommendation about the optimal time to initiate anticoagulation cannot be made based on randomized data. However, the expert opinion of the authors from that guideline state that it is reasonable to initiate anticoagulation at days three or four after a mild stroke, after seven days for a moderate infarct and 14 days for a larger infarct. And you'll notice that the timeframe that's listed within this expert opinion aligns with the time period that DOACs were started in the later treatment group of the ELAN study. After the publication of these guidelines, the timing trial from 2022 also evaluated a strategy of earlier anticoagulation initiation. That trial found that early DOACs that were started within four days was non-inferior to delayed initiation at days five to 10 for their composite outcome of recurrent ischemic strokes, symptomatic intracranial hemorrhage, and all-cause mortality. So overall, the results of the ELAN study add to the current body of literature, suggesting that in select patients, early treatment initiation can be supported if this is indicated or desired. And so in any of your patients that are at a higher thrombosis risk, these may be the patients where you may want to start DOAC therapy sooner. So transitioning now from when to initiate DOAC therapy, I wanted to discuss the management of patients presenting with an acute ischemic stroke who are already on DOAC therapy at baseline. Many of these patients could be otherwise eligible for IV thrombolysis. However, guidelines list recent DOAC ingestion within the previous 48 hours as an exclusion to IV thrombolysis because of the concern for intracranial bleeding. DOAC IVT was a retrospective study that aimed to estimate this risk of symptomatic intracranial hemorrhage in patients receiving IV thrombolytic therapy in the setting of recent DOAC ingestion. Patients with acute ischemic stroke and confirmed DOAC ingestion in the previous 48 hours were included if they received IV thrombolysis with alteplase or tenecteplase at the doses listed according to guideline standards for that region. A historical control group included patients who also received IV thrombolysis, but who were not receiving therapeutic anticoagulation at baseline. Over 33,000 patients who received IV thrombolysis were included in the study. However, only 832 patients had confirmed DOAC ingestion in the previous 48 hours. Patients in the DOAC group were more likely to be of greater age at baseline, had slightly greater degrees of pre-stroke disability on the modified Rankin scale, and had higher NIH stroke scale scores, but were less likely to be on concomitant antiplatelet therapy. Dabigatran was the most commonly used DOAC followed by Rivaroxaban, then Apixaban. And patients in the DOAC arm were more likely to receive an endovascular thrombectomy and had slightly longer times from symptom onset to IV thrombolysis administration. The authors of this study wanted to evaluate not only the outcomes in the DOAC group overall, but also further subdivided based upon the selection strategy used by the provider in the decision to administer IV thrombolysis. The three selection strategies are listed on the right-hand side of the table and include patients for which DOAC levels were available before IV thrombolysis was administered, patients that received reversal of their DOAC therapy prior to thrombolysis, and in all cases, Idariocizumab was the only reversal agent given for patients who were on Dabigatran. The third group included patients that neither had a DOAC level available nor received Idariocizumab. The primary outcome of the study was the incidence of symptomatic intracranial hemorrhage at 36 hours. This occurred in 4.1% of patients in the control group and 2.5% in the overall DOAC group with an adjusted odds ratio of 0.57 favoring the DOAC arm. When we look at the three different selection strategies, there weren't any statistically significant differences for this primary outcome amongst any of the three groups. For their secondary outcome, the authors evaluated the incidence of any intracranial hemorrhage at 36 hours. This occurred in 17% of patients in the control arm and 18% in the DOAC arm and was not statistically significantly different. However, when we evaluate the three different selection strategies, patients that neither had a DOAC level nor received Idariocizumab did have a higher adjusted odds risk for any intracranial bleeding at 36 hours. And finally, for functional independence at 90 days, which is defined as a MRS score of zero to two, there weren't any statistically significant differences amongst any of the groups for that secondary outcome. The authors concluded that in patients with acute ischemic stroke who were treated with IV thrombolysis, the use of DOACs in the previous 48 hours was not associated with an increased risk of symptomatic intracranial hemorrhage, regardless of whether patients received IV thrombolysis in the setting of a DOAC level, reversal with Idariocizumab or neither. One of the limitations of this study is Idariocizumab was the only reversal agent used. So the effects of reversal with andexanate alpha or prothrombin complex concentrate is not known. Because of the retrospective nature of this study, there is a potential risk for selection bias in that patients that were administered IV thrombolysis in the setting of recent DOAC therapy may have been deemed by the providers to be at a lower risk for symptomatic intracranial hemorrhage and indeed only 20% of patients with recent DOAC ingestion who are otherwise eligible for IV thrombolysis ended up receiving alteplase or tenecteplase therapy. Patients who received alteplase at a dose of 0.6 milligrams per kilo were also included in this study and this can limit the generalizability of these results to areas of the world where that dose is not commonly used. Finally, the historical control population was non-concurrent and there is minimal data with tenecteplase from this study as it was only administered to 6% of patients in the DOAC arm. So I wanted to compare now what the guidelines recommend with respect to administering IV thrombolysis in the setting of recent DOAC ingestion. The AHA and ASA state that IV alteplase should not be given unless coagulation labs are normal or the time since last DOAC intake was greater than 48 hours. The European Stroke Organization suggest not administering IV thrombolysis if specific coagulation tests are not available. However, if these labs are available and below the thresholds that are listed, the authors still state that there's insufficient evidence to make a recommendation in this case. And additionally, there's insufficient evidence to make a recommendation for the use of Idariocizumab to reverse Dabigatran prior to IV thrombolysis. After the publication of these guidelines, there was a large registry-based study published in JAMA in 2022 that also did not find an increased risk for symptomatic intracranial hemorrhage in the setting of recent DOAC intake in the previous seven days. However, only 2% of patients in that study had confirmed DOAC intake in the previous 48 hours. And this is the time period during which IV thrombolysis is contraindicated according to guidelines. So overall, the results of the DOAC IVT trial do suggest that IV thrombolysis might be reasonable in this patient population after very careful patient selection. However, because of the retrospective nature of the study, additional data really is warranted before widespread implementation of this approach. The third study I'll be discussing focuses on the management of chronic subdural hematomas. The proposed benefit for corticosteroids for this condition stems from the inflammatory response that is seen in the subdural space as a result of the fluid collection. And this can lead to clot expansion and clinical symptoms. In the DEXA trial, dexamethasone was compared to surgical hematoma evacuation for patients with symptomatic chronic subdural hematoma. Patients with newly diagnosed symptomatic chronic subdural hematoma as detected on head CT were included. The symptoms had to be attributed to the chronic subdural hematoma and associated with a symptom severity score of one to three on the Mark-Walder grading scale. So symptoms ranged from headache only up to severe focal neurologic deficits. Patients with acute subdural hematomas were excluded as were patients who were asymptomatic or comatose. So scores of zero or four on the Mark-Walder grading scale. Patients who had contraindications to glucocorticoids were also excluded, which could include active infection or uncontrolled diabetes. Patients that were randomized to the corticosteroid arm received a 19 day tapering course of dexamethasone with an initial dose of eight milligrams PO or IV every 12 hours, which was decreased by half every three days until off. Patients that were randomized to the surgical arm received hematoma evacuation via burr hole drainage followed by the placement of a subdural drain. 252 patients were included in the study. There were some differences in baseline characteristics with patients in the dexamethasone arm having a higher score on the MRS scale, greater use of antithrombotic medications and higher scores on the Mark-Walder grading scale. Only 1% of patients in both groups presented with severe focal neurologic deficits. The incidence of bilateral chronic subdurals on head CT was approximately 30% and the average midline shift was 9.1 millimeters. The primary endpoint of the DEXA trial was the score on the modified Rankin scale at 90 days. The likelihood of a positive functional outcome was less in the dexamethasone arm with an adjusted odds ratio of 0.55. Additionally, patients in the dexamethasone group demonstrated increased hematoma thickness on repeat head CT at two weeks, greater need for additional surgery due to hematoma recurrence and a higher complication rate. Ultimately, the DEXA trial was terminated early because of the increased incidence of complications and the worst outcomes seen in the dexamethasone arm. The authors concluded that the non-inferiority of dexamethasone on functional outcomes could not be demonstrated when compared to surgical hematoma evacuation in patients with symptomatic chronic subdural hematomas. One of the limitations of the study was the open label design, which may have affected the timing and decision to perform surgery. There was a greater degree of functional impairment at baseline in patients that were randomized to the dexamethasone arm, though the authors did try to adjust for this in their statistical analysis. There was also a previous study that also evaluated dexamethasone in a similar patient population. The DEX CSDH trial, which was published in the New England Journal of Medicine in 2020, also found worse outcomes when dexamethasone was compared to placebo. However, 94% of patients in both groups in this study received surgical hematoma evacuation. So overall, the results of the DEXA trial do add to the current body of literature suggesting a lack of benefit for corticosteroids for patients with chronic subdural hematomas. And then the final study I'll be discussing briefly is RESQ-BT2, which evaluated the glycoprotein 2b3a inhibitor tyrophoban for patients with acute ischemic stroke. The premise for this trial is that there are many patients with new acute ischemic stroke who are not candidates for IV thrombolysis or endovascular thrombectomy, either because they present outside of the time window or they have some other contraindication to therapy. Or there are patients with new acute ischemic strokes who have progression of their symptoms despite reperfusion therapy, and it's thought that collectively, these patients may benefit from an alternative antithrombotic medication. Patients were included in the study if they had an acute ischemic stroke with an NIH stroke scale score of five or greater and without the presence of a large or medium-sized vessel occlusion. Additionally, patients had to either be ineligible for reperfusion therapy, they had to have progression of their stroke symptoms, or they received IV thrombolysis followed by early neurologic deterioration or a lack of neurologic improvement. Over 1,100 patients were included in the study and randomized to either tyrophoban or aspirin for up to 48 hours. After which, patients in both arms received monotherapy with aspirin 100 milligrams daily until day 90. In the tyrophoban group, initial dosing was 0.4 micrograms per kilo per minute for 30 minutes, followed by a maintenance infusion of 0.1 micrograms per kilo per minute for up to 48 hours. Overall, patients in the tyrophoban group demonstrated a higher likelihood of excellent functional outcome at 90 days defined as an MRS score of zero to one, though this did come with an increased incidence of symptomatic intracranial hemorrhage. Overall, this study does offer limited data on the safety and efficacy of tyrophoban in patients who receive IV thrombolytic therapy since alteplase was only administered to 12% of patients in this trial. Additionally, follow-up neuroimaging at 24 to 36 hours was not mandated as part of the protocol, so this does limit the ascertainment of the incidence of asymptomatic intracranial hemorrhage. And finally, I just wanted to highlight a few additional publications that are worth reading from 2023. In the TWIST trial, the safety and efficacy of tenecteplase was evaluated in patients with wake-up stroke as assessed to be a non-contrast head CT. TICH-NOAC evaluated tranexamic acid for patients with intracranial hemorrhage in the setting of DOAC therapy. And the DASH trial was the first randomized study evaluating desmopressin for patients with spontaneous intracranial hemorrhage in the setting of antiplatelet therapy. Both TICH-NOAC and DASH were phase two trials and were smaller in size, and unfortunately, neither was able to demonstrate a benefit of either medication on hematoma expansion or functional outcomes. Then finally, I just wanted to mention that in 2023, we had the release of two guidelines on the management of aneurysmal subarachnoid hemorrhage published by the American Heart and American Stroke Association, as well as the Neurocritical Care Society. And there are my references, and with that, I thank you for your time. Thank you.

neuroscience pharmacology

ischemic stroke

anticoagulation

DOAC initiation

hemorrhage management

stroke treatment