Stroke Alert

On Episode 19 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2022 issue of Stroke: "Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion" and "Recurrent Ischemic Stroke and Bleeding in Patients With AF Who Suffered an Acute Stroke While on Treatment With NOACs." She also interviews Dr. Alexander Nave about "Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events." Dr. Negar Asdaghi: Let's start with a few questions. 1) How much time do we actually save if we were to transfer all patients with suspected target vessel occlusion directly to the angiosuite and practically bypassing our current conventional imaging model? 2) What is the impact of an impaired metabolic state as measured by abnormal glucose and triglyceride tolerance tests on the risk of stroke recurrence in patients with ischemic stroke? 3) And finally, should we or should we not change the anticoagulant therapy of a patient with atrial fibrillation who suffered an ischemic stroke despite appropriate treatment with anticoagulation? We have the answers to these questions and much more in today's podcast because this is the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The August 2022 issue of Stroke contains a range of really stimulating articles. We have an interesting study titled "Individual and Joint Effects of Influenza-Like Illness and Vaccinations on Stroke in the Young," led by Dr. Amelia Boehme and colleagues from Columbia University, with its accompanying editorial on how influenza-like illness is associated with increased risk of stroke in the young and middle-aged population while vaccinations of any type is protective of this risk. In a different paper, as part of a population-based study out of Scotland, Dr. Rustam Al-Shahi Salman from University of Edinburgh and colleagues report on a positive association between the use of beta-blockers, especially propranolol, and a lower risk of cerebral cavernous malformation, or CCM, associated intracranial hemorrhage. This study's findings are very interesting and quite important, and I encourage you to review the growing literature to suggest how beta-blockers may, in fact, reduce the risk of CCM-related hemorrhages through their anti-angiogenic properties. Dr. Negar Asdaghi: Later in the podcast, I have the great pleasure of interviewing Dr. Alexander Nave from Charité University Hospital in Berlin to discuss the relationship between having an impaired metabolic state in the setting of acute stroke and the risk of ischemic stroke recurrence, as we'll review the long-awaited results of the Berlin "Cream&Sugar" study, a very catchy title. But first, with these two articles. Dr. Negar Asdaghi: Time to successful endovascular reperfusion is an important predictor of clinical outcomes in patients with acute ischemic stroke related to a large vessel occlusion. And for years, we've known that the faster we're able to open the affected artery, the better the ischemic stroke outcomes are. Correspondingly, systems of care have adapted to various requirements of this so-called rapid workflow to ensure that all necessary pre-reperfusion steps are completed as fast as possible, preferably most in parallel to one another. And if any steps are unnecessary, they're bypassed altogether. Dr. Negar Asdaghi: Despite all these modifications to date, time from conventional imaging to angiosuite arrival remains both the longest and the most variable interval in the intra-hospital workflow prior to endovascular therapy. So, it's not surprising that many recent studies have evaluated whether the current model of hospital arrival, then transfer to the scanner for imaging, then transfer to the angiosuite for endovascular therapy, can be replaced by a simpler model where, based on clinical assessment, a patient with high likelihood of having a target vessel occlusion can directly be transferred to the angiosuite, where fast stroke imaging, including CT, CT angiogram, and CT perfusion, are completed on the angiotable using the flat panel imaging technology. Dr. Negar Asdaghi: If the patient is then found to be eligible to receive reperfusion therapies, including intravenous thrombolytics, they can receive the treatments and then proceed to endovascular thrombectomy without any further delays. So, in this issue of the journal, in the study titled "Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion," Dr. Raul Nogueira from Department of Neurology at Emory University and colleagues performed a systematic review and meta-analysis of published articles on this topic. So, they included seven articles for this analysis after pulling over 4000 articles using the common search engines for this meta-analysis. These articles included two single-centered European randomized controlled trials, one conducted in Germany, and the other one conducted in Spain, and five observational studies for a total of 1971 patients. The primary outcome was the odds of achieving favorable neurological recovery as defined by a modified Rankin Scale of zero to two at 90 days. Dr. Negar Asdaghi: Now, a few things to note: All studies reported door-to-puncture times, but not all reported door-to-reperfusion times or rate of successful reperfusion, and we know that these metrics are important in predicting the odds of safety and efficacy outcomes of endovascular therapy. And also it's important to note that not all details of the safety and efficacy outcome measures were reported in all of those seven studies. So, with that, here are the main findings of the meta-analysis. First off, amongst patients who were directly transferred to the angiosuite across these seven studies, the overall rate of false activation was 28%, meaning that after imaging assessment, 28% of those who were directly taken to the angiotable were not found to have a target occlusion, and as such, there was no need to further proceed to endovascular thrombectomy. And this is a practical finding of this meta-analysis as we deal with resource allocation and concerns of potentially overwhelming the neurointerventional teams. Dr. Negar Asdaghi: Now, moving on to the next finding of the study, the direct angio approach significantly reduced door-to-puncture times by a median of 30 minutes, and door-to-reperfusion times, when these metrics were available, by a median of 33 minutes as compared to the conventional imaging approach. So, bypassing conventional CT does translate into faster time metrics. These were, of course, expected findings of this meta-analysis, but nonetheless, important to quantify. But these faster time metrics did not improve the endovascular procedural outcomes, meaning that the direct to angio approach did not increase the odds of achieving a TICI 2b or better reperfusion, which is how successful reperfusion is defined, or the odds of achieving full reperfusion, meaning modified TICI 2c or greater reperfusion. Dr. Negar Asdaghi: So, it's great to get to the angiosuite fast, but that does not impact the procedural outcomes of endovascular therapy. Despite the above, the faster approach resulted in a significantly better functional independence outcome as measured by mRS Scale at 90 days, again emphasizing how important time is when it comes to endovascular outcomes. Now, the authors also performed a number of subgroup analysis in this meta-analysis, which I'd like to highlight some of them. We know that the impact of time on endovascular outcomes is more robust in the early time window. So, not surprisingly, when restricting the primary outcomes to those presenting within six hours from symptom onset, the favorable effect of direct to angio approach persisted in the early time window as well. Dr. Negar Asdaghi: Another important subgroup analysis was when restricting data to those patients who were transferred from a primary hospital to an endovascularly-capable center, the direct angio method didn't really have a significant impact on improving the primary outcome. Why is that? Let me repeat. So, when they restricted the analysis to those patients who were transferred from one hospital to an endovascularly-capable center, they did not find the same significant positive impact on endovascular outcomes in the direct to angio approach. I think the way we can explain this from a pathophysiological standpoint is that transferred patients are more likely to be slow progressors and, therefore, less likely to be impacted by delays in the workflow process as compared to the fast progressors. Dr. Negar Asdaghi: Take-home message: We've got to be fast in the fast progressors, and it's safe to assume that those who are within the first six hours after presentation are more likely to be fast progressors, and these workflow modifications are, therefore, much more robust and much more impactful in patients who present early on after their symptoms onset. And finally, in terms of safety outcomes, there were no significant differences in the rate of symptomatic intracerebral hemorrhage rate or the 90-day mortality rates either for the whole study population or when the analysis was restricted to those treated in the early time window. Dr. Negar Asdaghi: So, in summary, what we learned from this large meta-analysis is that as compared to the current conventional imaging model, the direct transfer to angio model is not only plausible and unlikely to overwhelm the interventional teams, as only less than 30% of patients in a direct method were not eligible for endovascular thrombectomy, but also this method is safe and results in significant improvements in workflow time metrics and functional outcomes. So, as the saying goes, select faster, select less, and treat more will likely be the future of endovascular therapy, particularly in the early time window. Dr. Negar Asdaghi: We know that oral anticoagulants reduce the risk of ischemic events in patients with atrial fibrillation. Nonvitamin K antagonist oral anticoagulants, or NOACs, also known as direct oral anticoagulants, or DOACs, are currently the standard of care for treatment of patients with non-valvular atrial fibrillation. Now, we have to keep in mind that although NOACs reduce the risk of ischemic stroke and systemic embolism in atrial fibrillation, they don't completely abolish the risk. So, they're not curative treatments for AFib, and patients can still experience embolic events despite appropriate treatment with these agents. In a meta-analysis of randomized trials, the residual risk of ischemic events in patients treated with NOACs was estimated at 1.4% per year, but this number is a lot lower than what is reported by real-life observational studies. Dr. Negar Asdaghi: In the large multicenter RENO study, which was published in this journal in 2019, we learned that in the setting of atrial fibrillation treated with a NOAC, a number of factors, including atrial enlargement, dyslipidemia, scoring high on the CHA2DS2-VASc score, and the use of low dose of NOACs, especially off-label low dose use of these medications, are significantly associated with increased risk of recurrent ischemic events despite treatment. But there's still a number of important questions that we routinely encounter in practice, most important of which is how to manage these patients with these so-called breakthrough ischemic events moving forward? Do we switch them to a different NOAC or go back to a vitamin K antagonist? Should we add an antiplatelet treatment to the regimen? And importantly, how do we counsel these patients and their families on their future risk of recurrent ischemic or hemorrhagic events? Dr. Negar Asdaghi: So, in the current issue of the journal, the RENO investigators, led by Dr. Maurizio Paciaroni and Valeria Caso, set out to answer some of these important questions as part of the RENO-EXTEND study, which basically followed the patients in the RENO cohort for at least 12 months, evaluating them for either recurrent ischemic or hemorrhagic events, whether occurring intra or extracranially. So, a bit about this cohort. The RENO study was a multicenter observational cohort across 43 centers in Europe and the United States, including consecutive patients with atrial fibrillation who presented to the hospital with an acute ischemic stroke despite being on a NOAC therapy. Patients were enrolled in the study only if they were compliant with their NOAC treatment and they had not missed their treatment for any reasons for greater than 24 hours prior to their index event. Dr. Negar Asdaghi: The patients were followed in the cohort and the choice of whether or not to start and timing, very importantly, for resumption of anticoagulation therapies were left to the discretion of the treating physicians. For the current paper, they analyzed 1240 patients. After the index event, 39.5%, so close to 40%, had their NOACs changed to another NOAC, mostly to a different class of NOAC. 42.5% continued with the same NOAC at the same dose. 6.7% continued with the same NOAC, but the dose was increased, and a small percentage were shifted to warfarin, that was only 4.7% of the patients. And 6.6% were shifted to low molecular weight heparin or were never prescribed oral anticoagulations after that index event for a variety of reasons, such as earlier ischemic recurrence, early hemorrhagic transformation, or early death or severe index stroke. And the overall median follow up in the study was 15 months. Dr. Negar Asdaghi: So, with that, here are the main study findings. The annual rate of the primary outcome of recurrent ischemic or hemorrhagic events, again, a reminder that these could have been intra or extracranial events, was 13.4%. The majority of these events were ischemic stroke, followed by major extracranial bleeding, then intracranial bleeding and systemic embolism. We have to note that this overall primary outcome rate is a lot higher than what was observed as part of the randomized trials of NOACs, as we noted earlier, which is an important finding of these real-life studies. Now, with regards to the factors predicting the primary outcome, having a higher CHA2DS2-VASc score and persistent hypertension were both predictive of recurrent ischemic events, whether ischemic stroke or systemic embolism. Next, the predictive factors for hemorrhagic events, either intracranial or major extracranial bleeding, included age, for each year increase in age, the odds increased by 1.1; history of major bleeding in the past; and, very importantly, a scenario that not uncommonly happens in routine practice, which is the addition of antiplatelet to a NOAC after the so-called NOAC failure. Dr. Negar Asdaghi: And finally, it turns out that changing that failed NOAC to a different agent didn't really seem to make a difference at all. As we mentioned earlier, close to 40% of patients were changed from one NOAC to another agent after the index ischemic event, and when they looked at the primary outcome, there was no difference in the rate of combined ischemic and hemorrhagic events, or the ischemic events alone, or bleeding outcomes alone, amongst patients who changed their NOAC to a different agent as compared to those who did not. The authors performed a number of subanalyses to see whether a particular strategy, for example, a switch from a particular class of NOACs to another class, or change in dosage, or NOAC to warfarin change, may be more or less beneficial in reducing the primary outcome, and there was really no difference between any of these strategies with the exception of one group. Dr. Negar Asdaghi: It turns out that the cumulative risk of ischemic and hemorrhagic events were a lot higher in those 6.6% of patients in whom NOAC treatment was changed to low molecular weight heparin injection. But I think one should consider this observation as hypothesis generating. First off, it was just a very small percentage of patients in this study that actually did go through this switch. And also we should note that in practice, we reserve a switch to low molecular weight heparin injection in only special cases. Some examples would be patients in whom there's a consideration of a hypercoagulable state, whether cancer related or not. But regardless, I think what we learned from this finding is that the patients in whom low molecular weight heparin injection is considered after a NOAC or an anticoagulant failure are likely very high risk patients for recurrent thromboembolic and hemorrhagic events. Dr. Negar Asdaghi: So, in summary, we learned a number of important lessons from RENO-EXTEND study. Number one, patients with atrial fibrillation presenting with a breakthrough ischemic stroke, despite treatment with NOAC, represent a high-risk group of patients who continue to be at a substantial risk for recurrent events, mostly ischemic, but also hemorrhagic. And this substantial risk was actually over 10% in the current study. Number two, we also learned that various strategies of changing the dose or class of anticoagulants don't seem to have much, if any, benefit in reducing the recurrent event outcomes. And finally, the addition of antiplatelet to oral anticoagulant therapies in this situation is not a good idea. This strategy gets us more in trouble and can increase the risk of bleeding and confers practically no benefits. Finally, these are the types of patients in whom we may have to consider other treatment options, such as left atrial appendage closure, and I'm sure we'll hear more on this in the future. Dr. Negar Asdaghi: Having an abnormal lipid profile has long been recognized as a risk factor for development of vascular disorders, particularly leading to atherosclerosis, but this association varies for the different components of the lipid panel and is most robust for elevated low density lipoprotein cholesterol levels, or LDL, causing various vascular disorders. Amongst patients with ischemic stroke and TIA, randomized trials have also shown that lowering LDL can reduce the risk of major cardiovascular events, including the risk of ischemic stroke, but the connection between elevated triglyceride levels and the risk of recurrent ischemic stroke is less clear. Moving from lipids to sugar, the presence of uncontrolled diabetes increases the risk of stroke by two to five folds, depending on the patient population studied and coexistence of other risk factors. In contrast, impaired glucose tolerance, which is an intermediate metabolic state between normal glucose tolerance and diabetes, has also been found to be associated with an increased risk of stroke in patients with coronary artery disease, but this association is less clear amongst patients with ischemic stroke. Dr. Negar Asdaghi: In clinical practice, fasting blood glucose and lipid profiles are routinely measured post-stroke, but we put a greater emphasis on the elevated LDL and hemoglobin A1C levels, and, in general, pay less attention, if any, to other metabolic derangements, including the impaired glucose tolerance state or even abnormal triglyceride levels. So, the question is, what is the impact of these metabolic derangements on the risk of stroke recurrence amongst patients presenting with ischemic stroke? In the current issue of the journal, in the study titled "A Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events: The Berlin 'Cream&Sugar' Study," we learn about these important associations. Joining me now is the first author of this paper, Dr. Alexander Nave. Dr. Nave is a neurologist and clinician scientist at Charité University Hospital in Berlin. He leads a junior research group as part of the Center of Stroke Research in Berlin and has a special interest in stroke rehabilitation and cardioembolic risk factors of stroke. Good morning, Alex, from Miami. Good afternoon to you in Berlin. Thank you for joining us. Welcome to our podcast. Dr. Alexander Nave: Hi, thank you very much. I'm very happy to be with you. Dr. Negar Asdaghi: All right. Let's go over the background of what we knew on the association between elevated triglyceride levels and the risk of recurrent stroke. Dr. Alexander Nave: Sure. So, as you pointed out earlier, diabetes and hypercholesterolemia are well established risk factors for first and recurrent ischemic stroke. However, for triglyceride levels, this association is less well understood and somewhat inconclusive. So, prior large epidemiological studies of the healthy population from the U.S. and from Denmark have shown an independent association of triglyceride levels in the risk of vascular events, including ischemic stroke. This association was actually stronger for non-fasting triglycerides levels compared to fasting triglycerides levels. In the ischemic stroke population, however, there were only a few investigations with conflicting results. So, the SPARCL trial, for example, which was a large secondary prevention stroke trial with more than 3000 stroke patients, showed that triglyceride levels were associated with major cardiovascular events, but not with recurrent ischemic stroke. So, therefore, we designed the Berlin "Cream&Sugar" study to investigate the association of postprandial triglyceride levels following an oral triglyceride tolerance test with recurrent vascular risk. Dr. Negar Asdaghi: So, let me just summarize. From SPARCL, actually, we knew that an increased level of triglycerides were associated with increased risk of development of cardiovascular events, so things such as coronary artery events and so on, but not an increased risk of stroke. And that's where you come in with the new study, the Berlin "Cream&Sugar" study. Now, before we talk about the study, can you tell us a little bit about the tests that were done, the oral triglyceride and glucose tolerance tests? Dr. Alexander Nave: Absolutely. So, both tests eventually help us to evaluate the glucose and lipid metabolism of a patient. So, the OGTT, the oral glucose tolerance test, as most of the listeners probably know, is a test that helps us to assess the ability of the patient to metabolize glucose after receiving a drink with a standard dose of 75 grams of glucose. The blood glucose levels after one hour and two hours then help us to diagnose diabetes or pre-diabetic state of the patient. So, we're not only evaluating the fasting state, but we can also quantify the body's response to a glucose challenge. And as an equivalent, the OTTT, the oral triglyceride tolerance test, will test the ability of a patient to metabolize triglycerides after oral ingestion of a lipid challenge, which is usually a certain amount of fat. However, this test is less well studied and without any standardized diagnostic criteria so far. And in contrast to the OGTT, the OTTT has not been tested in the stroke population so far. Dr. Negar Asdaghi: So, we're not just looking at those metrics of fasting sugar or fasting lipids and triglycerides specifically, we're looking at the patient's ability to metabolize glucose or triglyceride levels. So, now, with that understanding, can you tell us a little bit about the methodology of the study? Dr. Alexander Nave: Yes, of course. So the Berlin "Cream&Sugar" study was a prospective observational study recruiting acute stroke patients between 2009 and 2017 at the Charité University Hospital in Berlin. And we included first-ever ischemic stroke patients within three days to seven days after onset of stroke, and all patients received a sequential OTTT OGTT. So, all recruited patients received fasting blood sampling in the morning before taking the OTTT with 250 cc of cream, which corresponds to 30% of fat intake. So, all patients without known diabetes mellitus additionally had the OGTT with 75 grams of glucose starting three hours after the OTTT. Dr. Alexander Nave: And all patients received consecutive blood tests at three hours, four hours, and five hours after start of the OTTT to determine the course of glucose and triglyceride levels in the blood. And after one year, we performed follow up of all patients. The primary outcome was recurrent fatal or non-fatal ischemic stroke, and secondary outcome was a composite endpoint of recurrent vascular events, including ischemic stroke, TIA, myocardial infarction, and coronary revascularization, as well as cardiovascular death. And we compared patients with high versus low fasting and nonfasting triglyceride and glucose levels, respectively, using Cox regression analysis. Dr. Negar Asdaghi: Okay. 250 cc of cream and 75 grams of sugar right after a stroke. Was it challenging to recruit patients? Dr. Alexander Nave: Yes, that was a task. And we did experience some difficulties during the course of the study. It was not easy to ask a patient to drink a glass of cream during the first week after suffering from a stroke, obviously. In fact, a substantial number of patients eventually did not participate or did not complete the OTTT. However, in our study, we showed that performing a sequential OGTT OTTT within seven days after stroke was feasible. Approximately 10% of patients reported only minor adverse events such as nausea, diarrhea, and bloating. But with regards to the study population, overall, we enrolled 755 patients, 523 have completed the challenge and entered follow up. So, considering the fact that we had some difficulties in recruitment, was not surprising that we predominantly ended up with minor ischemic stroke patients, considering that we did not include patients with dysphagia or patients that were not able to give informed consent in the early phase after stroke. The median NIHSS was one with an interquartile range of zero to three. And, as I mentioned previously, this was because patients with impaired swallowing could not be included into the study. Dr. Negar Asdaghi: Okay. So, 750 patients within a week after their stroke, majority of them, as you mentioned, had mild ischemic events, were enrolled, and then they underwent sequential OTTT and OGTT tests. And then they were followed for a year for the primary outcomes. Now I think we're ready to hear the primary results. Dr. Alexander Nave: Sure. So, overall, 54 patients, 10% of the total population, reached a study endpoint within one year follow up. 31 patients experienced recurrent ischemic stroke within one year. So, when we compared the highest quartiles of triglyceride levels to the lowest quartiles, neither fasting nor postprandial triglyceride levels were associated with recurrent stroke. Similarly, fasting triglyceride levels were not associated with major cardiovascular events one year after stroke. Surprisingly though, higher postprandial triglycerides, measured at five hours after OTTT, were significantly associated with a lower risk for recurrent vascular events. The hazard ratio was 0.42, and the confidence interval 0.18 to 0.95. So, regarding glucose levels, on the other hand, we found no associations between glucose levels and recurrent vascular risk at all. Dr. Negar Asdaghi: Interesting. So, before I ask you what your takeaway is from all of this, the first question is the 10% rate of primary outcome. Were you at all surprised by this? This seems quite high for the recurrent rate of vascular events after the first year after ischemic stroke and TIA. Dr. Alexander Nave: Well, actually, when the "Cream&Sugar" study was designed, we expected the recurrent event rate to be even higher, approximately 10% of recurrent stroke events within one year and not 10% recurrent vascular events as a composite outcome. But as we know from previous registries, such as the TIA registry, the recurrent risk of vascular events after TIA and minor stroke is much lower now. So, I think with the reported 7% of recurrent stroke events, we're actually quite in line with the reports of the TIA registry, considering the fact also that we had no TIA patients enrolled in our study and had quite a high proportion of patients with large artery atherosclerosis as well as atrial fibrillation. Dr. Negar Asdaghi: So, thank you. This is a grim reminder that ischemic stroke patients remain at high risk of having recurrent vascular events. Alex, what should be our top two takeaway messages from your study? Dr. Alexander Nave: So, first, I think a sequential OTTT OGTT probably does not contribute a lot to future vascular risk stratification in ischemic stroke patients. So, I think all patients and carers can be relieved. There's no need to implement an OTTT into routine clinical care. However, based on our results, I think further studies are necessary and needed to better understand the importance of glucose and lipid metabolism in patients after acute ischemic stroke. And eventually we might figure out some nice information how we can improve risk prediction. Dr. Negar Asdaghi: So, it's good to know that we don't have to ask patients to drink a lot of cream after stroke. Can you tell us a little bit about the future of the Berlin "Cream&Sugar" study group? What are the next steps for the authors and the study group? Dr. Alexander Nave: Absolutely. Well, since there's no urgent need to start another large study soon, I think it would be reasonable to get our data and merge it with datas from other groups who also investigated the role of an OTTT in cardiovascular risk cohorts, also to increase power and detect some other signals. And we want to have a more detailed look at the variability of triglycerides and glucose levels following sequential OTTT OGTT. So, not only go into the absolute levels that you can measure at certain time points, but also how much these parameters fluctuate over time. Dr. Negar Asdaghi: To Alexander Nave, it's been a pleasure interviewing you on the podcast today. We look forward to covering more of your work in the future. Dr. Alexander Nave: Thank you very much. It was a pleasure to talk to you. Dr. Negar Asdaghi: And this concludes our podcast for the August 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three topical reviews, from "Strategies for Maintaining Brain Health: The Role of Stroke Risk Factors Unique to Elderly Women" to "Ethical Considerations in Surgical Decompression for Stroke." These articles summarize a large body of evidence, which I encourage you to review. And before we end our August podcast, I'd like to take a moment to recognize the incredible dedication and hard work of our medical students and fellows, especially the young doctors who are just starting their training this year. Dr. Negar Asdaghi: And if you happen to be one of those young doctors who is listening to our podcast in one of those sleepless on-call nights, I want to recount the story of Dr. Carl David Anderson, who won the Nobel Prize in physics for his discovery of the first particle of antimatter known as positron on August 2, 1932. A positron is actually the identical twin of the well-known negative electron, and its discovery in the 1930s truly changed our understanding of the origin of the universe, and it's practically impacted all aspects of science, not to mention it's impacted medicine and medical imaging. But the moral of the story lies in the fact that on August 2, when Anderson announced his discovery, he was a post-doctoral fellow himself, hadn't even graduated yet. So, if you are such a trainee, I hope you know that your hard work, combined with that incredible scientific inquisition, has the potential to change our understanding of the universe. And what better way to do this? You guessed it, than staying alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 18 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2022 issue of Stroke: "Impact of Shunting Practice Patterns During Carotid Endarterectomy for Symptomatic Carotid Stenosis" and "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke." She also interviews Dr. Magdy Selim about his article "Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial." Dr. Negar Asdaghi: Let's start with some questions. 1) Is deferoxamine mesylate yet another failed agent for treatment of patients with intracerebral hemorrhage, or is deferoxamine getting us closer than ever to an approved therapy for this deadly form of stroke? 2) Are different strokes happening to different folks due to their disadvantaged socioeconomic status? 3) And finally, how does a surgeon's personal practice preference to either routinely or selectively use carotid shunting during carotid endarterectomy impact the recurrent risk of stroke or death in patients with symptomatic carotid disease? We'll tackle these questions and a lot more in today's podcast as we continue to cover the cerebrovascular world's latest and greatest because, without a doubt, this is the best in Stroke. Dr. Negar Asdaghi: Welcome back to the July issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The July 2022 issue of Stroke contains a range of really interesting papers that I'd like to highlight here. As part of our Cochrane Corner articles, giving us short summaries of the long systematic review of a given topic, we have two short articles, one on the issue of local versus general anesthesia for carotid endarterectomy, where we learn that based on the current evidence, there's no convincing difference between local versus general anesthesia in the risk of stroke and death within 30 days after the procedure. In the second Cochrane Corner article, titled "Information Provision for Stroke Survivors and Their Carers," we learn that stroke survivors and their caregivers routinely report dissatisfaction with information provided to them by their clinicians about their condition and how active approaches to information provision is superior to its passive forms in improving patients' involvement in their care, their satisfaction, and, ultimately and not surprisingly, their stroke outcome. Dr. Negar Asdaghi: As part of our original contributions in this issue of the journal, we have an important paper titled "The Risk of Early Versus Later Rebleeding From Dural AV Fistulas With Cortical Venous Drainage." We are reminded in this paper that cranial dural arteriovenous fistulas are classified based on their venous drainage into those with or those without cortical venous drainage, or CVD. Dural AV fistulas without CVD rarely cause intracranial bleeding, while those with CVD may cause hemorrhage. In this study, the authors show that the risk of rebleeding of dural AV fistulas with CVD presenting with hemorrhage is increased in the first two weeks after ICH, emphasizing the importance of early detection of these malformations by vascular imaging and early treatment of AV fistulas with cortical drainage. This paper is another analysis from the CONDOR registry. Our devoted Stroke Alert listeners recall that we covered this registry in more detail when we interviewed Dr. Amin-Hanjani last October on the outcomes of intracerebral hemorrhage patients found to have dural AV fistulas. I encourage you to review these articles in addition to listening to our podcast today. Dr. Negar Asdaghi: Later in the podcast, I have the distinct honor of interviewing Dr. Magdy Selim from Harvard Medical School on a critical analysis from i-DEF trial to examine the long-term outcome of patients with ICH who were randomized to receive deferoxamine versus placebo. As an expert in the field of intracerebral hemorrhage and a member of the recently published American Heart Association Guidelines Committee, Dr. Selim was not fazed at all about the neutral results of the trial. "The future of ICH is bright," he says, and in the interview, he tells us why. But first, with these two articles. Dr. Negar Asdaghi: Since its first reported successful surgery in 1953, carotid endarterectomy, or CEA, has become a common surgical procedure to prevent ischemic stroke in patients with carotid disease. CEA requires a temporary clamping of the carotid artery that is being worked on. During this time, the ipsilateral hemisphere is, of course, dependent on collateral flow from the posterior circulation or from the contralateral anterior circulation to maintain its perfusion pressure. Intraoperatively, various methods are used to monitor cerebral perfusion, and the risk of clamping-induced hypoperfusion is obviously variable for each patient depending on the patient's specific anatomy, their collateral status, and other risk factors. One way to protect the brain against possible clamp-induced ischemia is to do carotid shunting. The problem is that carotid shunting also comes with its own set of risks and problems. There's the risk of causing carotid dissection, embolization of pieces of the plaque during shunt insertion, or the risk of causing air embolism. Dr. Negar Asdaghi: There are also other shunt-related local complications that should be noted, such as possibility of causing injuries to the cranial nerves or development of neck hematoma related to the more extensive surgical exposure required for shunting. So, it's not surprising that the practice patterns with regards to shunting is quite variable amongst different surgeons. There are surgeons that are considered routine shunters, and those who are considered selective shunters, meaning that the shunt is inserted only in cases with a particular indication. The question is whether the surgeon's preference for shunting can impact the CEA outcomes. In the current issue of the journal, we have an interesting study led by Dr. Randall DeMartino from the Division of Vascular and Endovascular Surgery at Mayo Clinic, Rochester, where the authors look at the impact of shunting practice patterns during carotid endarterectomy on the following post-CEA outcomes: number one, in-hospital stroke and in-hospital death rates, and number two, combined stroke and death in patients with a recent symptomatic carotid disease, that is, carotid stenosis associated with a history of either ipsilateral stroke or TIA within the past 14 days of endarterectomy. Dr. Negar Asdaghi: So, the data for the study came from the ongoing Vascular Quality Initiative database, which comprises a network of more than 600 North American academic and community hospitals, and collects data on 12 different vascular procedures, one of which is CEA. The study included over 13,000 carotid endarterectomies performed from 2010 to 2019 for symptomatic carotid patients. This number came after they applied their exclusion criteria to all CEAs performed in the database during this timeframe, importantly excluding any asymptomatic carotid surgeries or those in whom surgery was performed after the two-week mark post qualifying TIA or stroke. Now, before we go over the results, let's go over some definitions used in the study. They had to classify surgeons to be able to do the study into two categories of routine versus selective shunters. So, what they did was to analyze all consecutive CEAs, whether they were done on symptomatic or asymptomatic carotids, in this database, aggregated at the surgeon level. Surgeons routinely shunting in over 95% of their procedures were gauged as routine shunters. Otherwise, they were classified as selective shunters. Dr. Negar Asdaghi: Now, coming to each case included in this study, each surgical case was, in turn, classified into four categories based on whether or not a shunt was actually used for that particular case: category one, no shunt used; category two, shunt used as a routine procedure; number three, shunt used for a preoperative, mostly anatomical indication; number four, shunt was used for an intraoperative indication, which, as we mentioned before, these are mostly intraoperative hemodynamic compromised situations. And here are the results: In total, 3,186 of surgeries, that is 24% of surgeries, were performed by routine shunters versus 76% by selective shunters. So, most surgeons were selective shunters in this study. The demographic of patients operated by the routine versus selective shunters were more or less similar with regards to the age of the patients, most of their vascular risk factors, and the degree of ipsilateral or contralateral carotid stenosis or occlusion, with a few notable exceptions, in that patients undergoing surgery by routine shunters were more likely White, more likely to have had a prior CABG, more likely to undergo the operation while taking a P2Y12 inhibitor antiplatelet agent, and these patients were more likely to have had a TIA rather than a stroke as their qualifying event, which probably explains why they were more likely to be operated on within 48 hours of symptom onset as well. So, the authors accounted for these differences when they did their multivariate analysis. Dr. Negar Asdaghi: The other thing to note was that overall, routine shunters used a shunt in 98.1% of their cases, whereas selective shunters used them in 46% of their cases. Now, in terms of their study outcomes, the shunting practice pattern did not impact the primary outcomes of in-hospital stroke or death, or a combination of these two outcomes, or even the odds of development of cranial nerve injuries or hemorrhage in the adjusted model, which is really good news here. But interestingly, in the final adjusted model, whether or not an actual shunt was placed during surgery did significantly increase the risk of postoperative stroke, with the odds ratio of 1.29, an effect that was entirely driven by the use of shunt by a surgeon classified as a selective shunter in this study. Dr. Negar Asdaghi: So, in simple terms, if a shunt was placed during CEA, it did increase the risk of stroke only if that surgeon was a selective shunter. Another interesting association was that amongst selective shunters, placing a shunt for a patient with a very recent ischemic event, that is, TIA or stroke within the past 48 hours prior to surgery, and placing a shunt for an intraoperative indication, meaning shunt placement was not pre-surgically planned, also significantly increased the risk of postoperative stroke. So, what we learned from the study is that, though a surgeon's shunting practice pattern did not have an impact on the overall postoperative risk of stroke or death, the placement of a shunt did indeed increase the risk of postoperative stroke only if it was placed by a surgeon who is a selective shunter, especially for an intraoperative indication in a patient with a recent ischemic event. Dr. Negar Asdaghi: So, shunts can be tricky, especially if they're done by a surgeon who doesn't place them routinely. So, my take-home message is that ultimately, like every other procedure in medicine, clinical outcomes are as much operator dependent as they are patient dependent, and for every procedure, it's fair to say that practice makes perfect. Dr. Negar Asdaghi: It is now more than 25 years since intravenous thrombolytic therapy has been approved for treatment of patients with acute ischemic stroke and more than seven years since randomized control trials demonstrated the efficacy of mechanical thrombectomy to improve clinical outcome in ischemic stroke patients with large vessel occlusions. To date, reperfusion therapies are the only available acute treatments for select patients with ischemic stroke. What do we mean by "select"? "Select" meaning that not all patients will benefit from these therapies, making it absolutely necessary for clinicians to be up to date with various indications and contraindications to use these therapies. Needless to say that the criteria for reperfusion therapies do not and should not consider the socioeconomic status of patients, but sadly, socioeconomic inequalities seem to impact the use of reperfusion therapies. Dr. Negar Asdaghi: In this issue of the journal, in the study titled "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke," Dr. Øgendahl Buus from Aarhus University Hospital in Denmark and colleagues studied the impact of the socioeconomic status of stroke patients on the odds of receiving reperfusion therapies in the large nationwide Danish Stroke Registry, or DSR. Now a bit about the registry: DSR contains prospectively collected nationwide data on all stroke patients admitted to Danish hospitals. It's interesting to note that in Denmark, stroke patients are exclusively admitted to public hospitals, and all departments treating stroke patients are obligated to report data to DSR. Now, for this study, they included over 63,000 stroke patients from 2013 to 2018. After excluding hemorrhagic stroke, TIAs, and other exclusion criteria of the study, they arrived at their sample size of 37,187 patients that were included in this study. Dr. Negar Asdaghi: Now, a few definitions. The socioeconomic status of each patient was determined based on three parameters. Parameter number one, their educational level. It was categorized into three levels of low, medium, or high levels of education. Category number two, income level. This was calculated based on the average family equivalent disposable income, or FED income, during five years prior to stroke onset, again classified into three categories of high, medium, or low income. And the third factor was the employment status of the patient during the calendar year prior to the stroke onset, also categorized into three categories of employed, unemployed, and retired. And, of course, the authors used various definitions to be able to fit special situations into these categories. For instance, a person who is temporarily unemployed due to illness or other special situation was still categorized under the employed category. So, that gave them, in total, nine groups to analyze across these three categories. Dr. Negar Asdaghi: And here are their findings. The median age of total stroke patients in the cohort was 73.2 years, 44.1% were women, 41% categorized under low educational level, 68% retired, and 33.3% had low income levels. Not surprisingly, patients and hospital characteristics varied tremendously across these nine groups of education, employment, and income, and a univariate analysis in general, low socioeconomic status was associated with more severe strokes, living alone, living at an assisted living residency, having had prior stroke, high comorbidity index score, hypertension, and late hospital arrival. So, they accounted for these differences in their multivariate analysis. Dr. Negar Asdaghi: Now, overall, the treatment rates of IV thrombolysis was 17.6%, which is actually considered a very high percentage as compared to other registry-based studies, but the percentage of IV thrombolytic use dramatically varied based on the different socioeconomic designation. So, let's look at this. In the univariate analysis, for education, intravenous thrombolysis rates were 19.3% among patients with high educational level compared to 16.2% among patients with low educational level. Let's look at income. For income, IV thrombolytic treatment rates reach 20.7% for high-income patients compared to 14.8% for low-income patients. For employment status, thrombolytic rates were 23.7% among employed patients compared to 15.7% for unemployed patients. In their fully adjusted models, unemployed patients were less likely to receive IV lytics as compared to their employed counterparts. Dr. Negar Asdaghi: Now, for thrombectomy, socioeconomic gradients were also noted for these three categories. For education, thrombectomy rates were 4.5% among patients with high education level compared to 3.6% among patients with low educational level. For income, treatment rates were 3.2% among low-income patients compared to 4.7% among high-income patients. But arguably, the most robust differences were noted again across the category of employment. Employed patients were nearly twice more likely to receive thrombectomy as compared to unemployed patients, rates being 5.1% versus 2.8%, respectively. Now, when they adjusted their analysis to only those patients presenting within the reperfusion time windows in the fully adjusted models, unemployment and low income remain significant negative predictors of receiving both of these reperfusion therapies. So, what we learned from this study is that stroke patients who were unemployed, earned a relatively low income, or had fewer years of formal education were less likely to receive life-saving reperfusion therapies despite potentially being eligible for these treatments. Dr. Negar Asdaghi: Now, let's take a moment to really understand that data presented here are in the context of a tax-funded, universal healthcare offered across Denmark, where we can at least make the assumption that financial constraints potentially preventing access to therapies are likely minimized. There are many countries around the globe where patients or family members have to pay for these therapies before even receiving them. So, these findings from the current study from Denmark are alarming in that they point to possibly more robust inequalities across the globe in other healthcare systems. Dr. Negar Asdaghi: Intracerebral hemorrhage, or ICH, is an aggressive form of stroke, typically carrying a higher morbidity and mortality than its ischemic counterpart. Yet much of the research in the field of intracerebral hemorrhage has followed the ischemic stroke footsteps, including defining the optimal primary outcome for the randomized trials of ICH. For ischemic stroke, the 90-day functional outcome, as measured by the modified Rankin Scale, is commonly used as a primary outcome in clinical trials. There are many reasons for this selection, including the ease of use and the fact that the majority of functional recovery post-ischemic stroke occurs during the first 90-day time period. But time to maximum recovery and, importantly, the trajectory of recovery may be different in hemorrhagic as compared to ischemic stroke. Defining the long-term outcomes and longitudinal trajectory of recovery in ICH is, therefore, important to better understand its prognosis and, of course, selecting the appropriate primary outcome measure for future randomized trials of ICH. Dr. Negar Asdaghi: In the recent years, the safety and efficacy of various agents to improve ICH outcomes have been tested. Deferoxamine mesylate, an iron-chelating agent, is one such agent that was recently studied as part of the i-DEF multicenter randomized trial, and the main results of the study were published in Lancet Neurology in 2019. In the current issue of the journal, in the study titled "Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage," we learn about the results of a post hoc analysis of i-DEF that looks at the trajectory of functional outcome in patients enrolled in the trial with a special attention on their continued recovery after the 90-day post-ICH mark. Dr. Negar Asdaghi: Joining me now is the senior author of this paper, Dr. Magdy Selim, who's also one of the primary investigators of i-DEF trial. Dr. Selim is a Professor of Neurology at Harvard Medical School and Chief of Stroke Division at Beth Israel Deaconess Medical Center in Boston. He's a world renowned researcher in the field of cerebrovascular disorders with special focus on treatment of patients with intracerebral hemorrhage. Dr. Selim has led and currently leads multiple National Institutes of Health-funded clinical trials of intracerebral hemorrhage, including the ongoing SATURN trial. I'm delighted to welcome him to our podcast today. Good afternoon, Magdy. Thank you for joining us today. Dr. Magdy Selim: Thank you, Dr. Asdaghi. It's really my pleasure to be here with you, and I'm certainly honored to do this today. Dr. Negar Asdaghi: That's great. Thank you. So, let's start with some background on deferoxamine and the literature supporting the use of deferoxamine before i-DEF. Dr. Magdy Selim: So, as you mentioned, deferoxamine is an iron chelator; it binds to iron and removes excess iron from the body. The unique thing about it is that it has other neuroprotective properties, which are good for hemorrhagic stroke and ischemic stroke. It also has anti-inflammatory and anti-apoptotic effects. It even lowers the blood pressure, which we know sometimes is helpful in intracerebral hemorrhage. The rationale behind this or why this would be effective really comes from animal studies. After you have a hemorrhage, there is hemolysis of the red blood cells, there is a release of hemoglobin degradation products, in particular, iron, and the accumulation of iron in the hematoma and the surrounding tissue triggers a cascade of molecular and cellular events that lead to what we call secondary injury, characterized by inflammation, hydroxyl radical formation, and cell death. And many animal studies, animal models of intracerebral hemorrhage, whether in pigs or in rats, young or aged rats, have shown that treatment with deferoxamine can reduce iron in the brain after intracerebral hemorrhage and also results in improved performance on behavioral tests. And that was the reason why we moved into clinical testing. Dr. Negar Asdaghi: So, a lot of encouraging data before the trial. Can we hear a little bit about the trial, its design, and inclusion criteria, please? Dr. Magdy Selim: Sure. So i-DEF was a phase 2 study, and actually it started as Hi-DEF, which was high dose deferoxamine, and then became i-DEF, which intermediate dose deferoxamine. So, it's a randomized, double blind, placebo control trial. We used something called futility design, which is actually sort of new in the stroke field. And we had 294 patients who had supratentorial hemorrhage that were randomized within 24 hours to either get placebo or deferoxamine. And deferoxamine initially was given at 62 mg per day for three days, but then we ran into some safety issues with this high dose, and that's why we lowered it to 32, and that became the intermediate dose, or the i-DEF. So, the only kind of thing unique about inclusion/exclusion criteria was that there was an age cutoff, patients had to be 80 or younger. They needed to have some deficit on the exam, so their NIH Stroke Scale had to be 6 or greater, and their GCS had to be greater than 6, and their modified Rankin before the onset of the hemorrhage had to be less than 1. Dr. Negar Asdaghi: And so, what were the primary and secondary outcomes in i-DEF? Dr. Magdy Selim: The primary outcome was twofold actually. One of them was safety. One of the issues we ran into with the high dose is that the drug is associated with increased risk for adult respiratory distress syndrome, ARDS. So, we wanted to make sure that this lower dose was safe, and it does not increase the instance of ARDS. The second thing was, as I said, we used something called the futility design, and we wanted to compare the outcome of patients treated with deferoxamine versus placebo to determine whether it's futile to move to a large phase 3 trial or not. And what we were looking at is a difference in outcome and modified Rankin 0 to 2 at 90 days, and the difference would be at least 12% in favor of deferoxamine in order for us to move forward. You asked about the secondary outcomes as well? Dr. Negar Asdaghi: Yes. Dr. Magdy Selim: So, actually, the secondary outcomes, they're relevant because they're relevant to the study that we just published. So, the secondary outcomes was also to look at modified Rankin 0 to 3, instead of 0 to 2, at 90 days and the difference between the two treatment groups. We wanted to look at the ordinal distribution of the Rankin at the same time point. And we also wanted to look at all the outcomes at six months, 180 days. And that came a little bit later in the course of the study because there was some evidence emerging at that time that maybe assessment of outcome later in intracerebral hemorrhage would be more accurate than assessing it early on. Dr. Negar Asdaghi: So, I want to come back to the secondary outcome, of course, that's sort of the topic of your current paper in this issue of the journal, but can you just briefly tell us, please, the primary outcome and the sort of results of what was published in 2019 with i-DEF before we move on to the current paper? Dr. Magdy Selim: Yeah. So, as I said, the primary outcome was the difference in the proportion of patients that achieved modified Rankin 0 to 2 at 90 days, and what we wanted to see is a difference of around 12%. Unfortunately, the primary outcome was neutral, we did not see that. But what we saw actually, almost all the secondary outcomes were positive, except for the primary outcome. So, when we looked at the secondary outcome using modified Rankin 0 to 3, instead of 0 to 2, the difference was 12.1%. When we looked at the difference in the modified Rankin 0 to 2 at six months, the difference was 15.6% in favor of deferoxamine, but these were secondary outcomes and not the primary outcomes. Dr. Negar Asdaghi: So, the trial is almost positive. It just depends on how you define the primary outcome, which is really a nice segue to your current study. In the current study, you looked at this secondary outcome in a longitudinal way and looked at the mRS of 0 to 2 at six months from ICH. Can you please tell us about this current paper? Dr. Magdy Selim: Yeah. So, one of the things that we did with i-DEF is that we were checking the modified Rankin at different time points for all the patients. So, we had it after one week, after one month, after two months, after three months, and after six months. And what we wanted really was a couple of things, just in patients with intracerebral hemorrhage without any treatment, what's the natural course of recovery? And the interesting thing we found out is that patients actually continue to improve over time, and that's what you expect, but what we didn't expect is that they even continue to improve after 90 days. Dr. Magdy Selim: We always used to think that maximum recovery is around 90 days from ischemic stroke literature, but we saw a lot of patients getting better after 90 days. And this turns out to be also the case with deferoxamine, but the interesting thing is that the percentage of patients that had a good outcome, modified Rankin 0 to 2, was higher with deferoxamine at day seven, at day 30, at day 60, not at 90 days, but again at six months. So, actually, it was higher at all time points except our primary endpoint. Dr. Negar Asdaghi: So, Magdy, you've already answered my next question, which is exactly what you alluded to, deferoxamine seemed to have improved the outcomes at all of those time points, except for the 90 day, which was the primary outcome of your trial. Why do you think the magic was lost at 90 days? Dr. Magdy Selim: This is really the million-dollar question. I think we obviously struggled over this. And we went back, we thought maybe there was misrating of the modified Rankin in some of the patients. We tried to correct for this. The difference was bigger, but still not significant. So, we don't really have a good reason to tell you why, at this particular time point, we didn't see the difference except bad luck, I think. But I mean, there are reasons, I think, the question that people actually ask me is the opposite, is why do you think a drug that you give for three days early on is going to make a difference after six months? And I think there are biological reasons to explain this. Dr. Magdy Selim: So, what happened is that those hemorrhage patients have a lot of other problems. They have increased ICP, they have hydrocephalus, they have intraventricular hemorrhage, and actually iron has been implicated in the development of hydrocephalus in chronic white matter injury. So, my explanation is that you start early on with the treatment, it does help, but it takes a while for it to kick in and for this kind of medical complication to resolve until actually you see the true effect of the drug. And maybe that's why you see the unmasking at the end between the two groups. Dr. Negar Asdaghi: Yeah, I think I want to recap this for our listeners. Very important to, again, think about those things that some of the acute therapies that we offer the patients may not have a measurable improvement outcome difference early on, certainly with intravenous thrombolysis, we saw that, whereas we saw measurable outcome difference at 90 days, or maybe in this case at six months, but not quite early on. So, it doesn't mean that they don't work. We just are unable to measure that difference and improvement early on. So, what do you think the future holds for deferoxamine? Are we going to see another trial? Dr. Magdy Selim: Well, I certainly hope so. We're working on some few ideas for that. A lot of people think that maybe we should just do the same thing, but look at six months as the primary outcome. But I think we're actually, that's probably not our primary thinking at this point in time. So, we have published other papers, other analysis, to show that the effect of deferoxamine actually relates to the volume of the hemorrhage. So, if the hemorrhage is very small, there is very minimal benefit. If the hemorrhage is very large, also there is very minimal benefit. And that's really to get kind of the big bang for your buck. You really want people who have mild-to-moderate size hemorrhages. So, we're thinking of a couple of ways to go about deferoxamine with this, whether alone or in combination with other interventions. So, hopefully, we'll have some stuff to share with you in the coming few years, two or three. Dr. Negar Asdaghi: We'll definitely look forward to reading about those or being involved in the trials as a site, but there's a great way of just actually talking about my next question. It's just completely different than the current paper. I wanted to digress a bit and talk about the recently published intracerebral hemorrhage guidelines, which just published a few months ago. You were part of the guidelines committee. Can you give us a little bit of your point of view of what are the top two most important updates from the guidelines in ICH treatment? Dr. Magdy Selim: Actually, the guidelines, for the first time this year, in the first page, they have the top 10 take-home messages or top 10 new ones. So, in my opinion, the most important ones, we usually tell you what to do, but here we tell you what not to do because we think it's not good for the patients. So, for example, using steroids just as a prophylactic therapy is actually not recommended. The same thing, we see a lot of people put patients with hemorrhage on hypertonic saline, hyperosmolar therapy, just prophylactically. I don't think there's any benefit that this helps as well, and the same thing for antiepileptic drugs. So, that was one important point. The second one was blood pressure lowering, and there is emphasis now that whatever you use to lower the blood pressure, you want to make sure that the blood pressure variability is very minimal and that there is a smooth kind of control over blood pressure that has been shown to be actually important in terms of help. I'm going to make them three, not two, because I think the third one is important. Dr. Negar Asdaghi: Okay. I'll give you one more then. Dr. Magdy Selim: Which is the first time we include this in the guideline, and with emphasis on the role of the home caregiver for hemorrhage patients and the psychological support, the education that they need, and the training that they need to actually care for these patients and how to improve their quality of life. So, I think that's an important aspect that we didn't touch upon before, and obviously very important. Dr. Negar Asdaghi: Very important points. Let me just review them again for our listeners. So, don't do steroids, hypertonics, and preemptive antiepileptic therapies. They don't work. The second point that you raise is reduction of blood pressure, important to keep that in mind, but paying attention to blood pressure variability. And the third one, the importance of social aspect of care of patients with intracerebral hemorrhage. That's great for us. Let me just end with one last question. Magdy, thank you so much for all of this wonderful take-home messages from the current study from i-DEF and also the guidelines. There's been a lot of excitement in the field of ischemic stroke with the success of reperfusion therapies, and yet not much for intracerebral hemorrhage. What is your hope in terms of future therapies for ICH? Dr. Magdy Selim: So, I happen to be one of the people who is very optimistic about the future of ICH. I think it's just a matter of time. But I think we need to make some changes. We need to really treat ICH as an emergency, so time is really important. And I think right now, you see a hemorrhage patient, they just put them on the side because they think that there's nothing to do. But the way I see the future evolving, and probably the breaking point to be, is that we can diagnose ICH in the field. You immediately lower the blood pressure, reverse coagulopathy if you can, and even kind of use hemostatic agents, if the FASTEST trial shows evidence to support that, and then you take them to the hospital where there might be some role for hematoma reduction using minimally invasive therapy and some other treatments like deferoxamine, or there are a lot of other agents to target the secondary injury at the same time. So, I think it's going to be a combination of things, and they need to happen in tandem and continuously, but we need to start quickly on these patients. Dr. Negar Asdaghi: Dr. Magdy Selim, it's been a pleasure interviewing you on the podcast. We look forward to having you back and covering more of your work. Thank you for joining us. Dr. Magdy Selim: Thank you very much for having me. Dr. Negar Asdaghi: And this concludes our podcast for the July 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including a series of Focus Updates on the very topic of, you guessed it, intracerebral hemorrhage. These updates are great complements to the newly published American Heart Association guidelines for the management of patients with spontaneous intracerebral hemorrhage in May 2022. Dr. Negar Asdaghi: And with this, we end our July podcast and draw inspiration from one particular July story, which unfolded on July 20. In 1969, on this day, Commander Neil Armstrong and lunar module pilot Buzz Aldrin landed on the moon, and Armstrong became the first person to walk on the moon. The crew of Apollo 11 changed the course of history, landing humanity on another celestial body for the first time and later safely returning everyone back to earth. Armstrong, an experienced naval aviator, a test pilot, a decorated veteran, astronaut, and university professor, passed away in 2012 from complications of coronary artery disease, reminding us that every step we take in understanding, diagnosing, and treating vascular disorders is truly part of that giant leap to save the mankind. And what better way to do this than to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 18 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2022 issue of Stroke: "Impact of Shunting Practice Patterns During Carotid Endarterectomy for Symptomatic Carotid Stenosis" and "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke." She also interviews Dr. Magdy Selim about his article "Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial." Dr. Negar Asdaghi: Let's start with some questions. 1) Is deferoxamine mesylate yet another failed agent for treatment of patients with intracerebral hemorrhage, or is deferoxamine getting us closer than ever to an approved therapy for this deadly form of stroke? 2) Are different strokes happening to different folks due to their disadvantaged socioeconomic status? 3) And finally, how does a surgeon's personal practice preference to either routinely or selectively use carotid shunting during carotid endarterectomy impact the recurrent risk of stroke or death in patients with symptomatic carotid disease? We'll tackle these questions and a lot more in today's podcast as we continue to cover the cerebrovascular world's latest and greatest because, without a doubt, this is the best in Stroke. Dr. Negar Asdaghi: Welcome back to the July issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The July 2022 issue of Stroke contains a range of really interesting papers that I'd like to highlight here. As part of our Cochrane Corner articles, giving us short summaries of the long systematic review of a given topic, we have two short articles, one on the issue of local versus general anesthesia for carotid endarterectomy, where we learn that based on the current evidence, there's no convincing difference between local versus general anesthesia in the risk of stroke and death within 30 days after the procedure. In the second Cochrane Corner article, titled "Information Provision for Stroke Survivors and Their Carers," we learn that stroke survivors and their caregivers routinely report dissatisfaction with information provided to them by their clinicians about their condition and how active approaches to information provision is superior to its passive forms in improving patients' involvement in their care, their satisfaction, and, ultimately and not surprisingly, their stroke outcome. Dr. Negar Asdaghi: As part of our original contributions in this issue of the journal, we have an important paper titled "The Risk of Early Versus Later Rebleeding From Dural AV Fistulas With Cortical Venous Drainage." We are reminded in this paper that cranial dural arteriovenous fistulas are classified based on their venous drainage into those with or those without cortical venous drainage, or CVD. Dural AV fistulas without CVD rarely cause intracranial bleeding, while those with CVD may cause hemorrhage. In this study, the authors show that the risk of rebleeding of dural AV fistulas with CVD presenting with hemorrhage is increased in the first two weeks after ICH, emphasizing the importance of early detection of these malformations by vascular imaging and early treatment of AV fistulas with cortical drainage. This paper is another analysis from the CONDOR registry. Our devoted Stroke Alert listeners recall that we covered this registry in more detail when we interviewed Dr. Amin-Hanjani last October on the outcomes of intracerebral hemorrhage patients found to have dural AV fistulas. I encourage you to review these articles in addition to listening to our podcast today. Dr. Negar Asdaghi: Later in the podcast, I have the distinct honor of interviewing Dr. Magdy Selim from Harvard Medical School on a critical analysis from i-DEF trial to examine the long-term outcome of patients with ICH who were randomized to receive deferoxamine versus placebo. As an expert in the field of intracerebral hemorrhage and a member of the recently published American Heart Association Guidelines Committee, Dr. Selim was not fazed at all about the neutral results of the trial. "The future of ICH is bright," he says, and in the interview, he tells us why. But first, with these two articles. Dr. Negar Asdaghi: Since its first reported successful surgery in 1953, carotid endarterectomy, or CEA, has become a common surgical procedure to prevent ischemic stroke in patients with carotid disease. CEA requires a temporary clamping of the carotid artery that is being worked on. During this time, the ipsilateral hemisphere is, of course, dependent on collateral flow from the posterior circulation or from the contralateral anterior circulation to maintain its perfusion pressure. Intraoperatively, various methods are used to monitor cerebral perfusion, and the risk of clamping-induced hypoperfusion is obviously variable for each patient depending on the patient's specific anatomy, their collateral status, and other risk factors. One way to protect the brain against possible clamp-induced ischemia is to do carotid shunting. The problem is that carotid shunting also comes with its own set of risks and problems. There's the risk of causing carotid dissection, embolization of pieces of the plaque during shunt insertion, or the risk of causing air embolism. Dr. Negar Asdaghi: There are also other shunt-related local complications that should be noted, such as possibility of causing injuries to the cranial nerves or development of neck hematoma related to the more extensive surgical exposure required for shunting. So, it's not surprising that the practice patterns with regards to shunting is quite variable amongst different surgeons. There are surgeons that are considered routine shunters, and those who are considered selective shunters, meaning that the shunt is inserted only in cases with a particular indication. The question is whether the surgeon's preference for shunting can impact the CEA outcomes. In the current issue of the journal, we have an interesting study led by Dr. Randall DeMartino from the Division of Vascular and Endovascular Surgery at Mayo Clinic, Rochester, where the authors look at the impact of shunting practice patterns during carotid endarterectomy on the following post-CEA outcomes: number one, in-hospital stroke and in-hospital death rates, and number two, combined stroke and death in patients with a recent symptomatic carotid disease, that is, carotid stenosis associated with a history of either ipsilateral stroke or TIA within the past 14 days of endarterectomy. Dr. Negar Asdaghi: So, the data for the study came from the ongoing Vascular Quality Initiative database, which comprises a network of more than 600 North American academic and community hospitals, and collects data on 12 different vascular procedures, one of which is CEA. The study included over 13,000 carotid endarterectomies performed from 2010 to 2019 for symptomatic carotid patients. This number came after they applied their exclusion criteria to all CEAs performed in the database during this timeframe, importantly excluding any asymptomatic carotid surgeries or those in whom surgery was performed after the two-week mark post qualifying TIA or stroke. Now, before we go over the results, let's go over some definitions used in the study. They had to classify surgeons to be able to do the study into two categories of routine versus selective shunters. So, what they did was to analyze all consecutive CEAs, whether they were done on symptomatic or asymptomatic carotids, in this database, aggregated at the surgeon level. Surgeons routinely shunting in over 95% of their procedures were gauged as routine shunters. Otherwise, they were classified as selective shunters. Dr. Negar Asdaghi: Now, coming to each case included in this study, each surgical case was, in turn, classified into four categories based on whether or not a shunt was actually used for that particular case: category one, no shunt used; category two, shunt used as a routine procedure; number three, shunt used for a preoperative, mostly anatomical indication; number four, shunt was used for an intraoperative indication, which, as we mentioned before, these are mostly intraoperative hemodynamic compromised situations. And here are the results: In total, 3,186 of surgeries, that is 24% of surgeries, were performed by routine shunters versus 76% by selective shunters. So, most surgeons were selective shunters in this study. The demographic of patients operated by the routine versus selective shunters were more or less similar with regards to the age of the patients, most of their vascular risk factors, and the degree of ipsilateral or contralateral carotid stenosis or occlusion, with a few notable exceptions, in that patients undergoing surgery by routine shunters were more likely White, more likely to have had a prior CABG, more likely to undergo the operation while taking a P2Y12 inhibitor antiplatelet agent, and these patients were more likely to have had a TIA rather than a stroke as their qualifying event, which probably explains why they were more likely to be operated on within 48 hours of symptom onset as well. So, the authors accounted for these differences when they did their multivariate analysis. Dr. Negar Asdaghi: The other thing to note was that overall, routine shunters used a shunt in 98.1% of their cases, whereas selective shunters used them in 46% of their cases. Now, in terms of their study outcomes, the shunting practice pattern did not impact the primary outcomes of in-hospital stroke or death, or a combination of these two outcomes, or even the odds of development of cranial nerve injuries or hemorrhage in the adjusted model, which is really good news here. But interestingly, in the final adjusted model, whether or not an actual shunt was placed during surgery did significantly increase the risk of postoperative stroke, with the odds ratio of 1.29, an effect that was entirely driven by the use of shunt by a surgeon classified as a selective shunter in this study. Dr. Negar Asdaghi: So, in simple terms, if a shunt was placed during CEA, it did increase the risk of stroke only if that surgeon was a selective shunter. Another interesting association was that amongst selective shunters, placing a shunt for a patient with a very recent ischemic event, that is, TIA or stroke within the past 48 hours prior to surgery, and placing a shunt for an intraoperative indication, meaning shunt placement was not pre-surgically planned, also significantly increased the risk of postoperative stroke. So, what we learned from the study is that, though a surgeon's shunting practice pattern did not have an impact on the overall postoperative risk of stroke or death, the placement of a shunt did indeed increase the risk of postoperative stroke only if it was placed by a surgeon who is a selective shunter, especially for an intraoperative indication in a patient with a recent ischemic event. Dr. Negar Asdaghi: So, shunts can be tricky, especially if they're done by a surgeon who doesn't place them routinely. So, my take-home message is that ultimately, like every other procedure in medicine, clinical outcomes are as much operator dependent as they are patient dependent, and for every procedure, it's fair to say that practice makes perfect. Dr. Negar Asdaghi: It is now more than 25 years since intravenous thrombolytic therapy has been approved for treatment of patients with acute ischemic stroke and more than seven years since randomized control trials demonstrated the efficacy of mechanical thrombectomy to improve clinical outcome in ischemic stroke patients with large vessel occlusions. To date, reperfusion therapies are the only available acute treatments for select patients with ischemic stroke. What do we mean by "select"? "Select" meaning that not all patients will benefit from these therapies, making it absolutely necessary for clinicians to be up to date with various indications and contraindications to use these therapies. Needless to say that the criteria for reperfusion therapies do not and should not consider the socioeconomic status of patients, but sadly, socioeconomic inequalities seem to impact the use of reperfusion therapies. Dr. Negar Asdaghi: In this issue of the journal, in the study titled "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke," Dr. Øgendahl Buus from Aarhus University Hospital in Denmark and colleagues studied the impact of the socioeconomic status of stroke patients on the odds of receiving reperfusion therapies in the large nationwide Danish Stroke Registry, or DSR. Now a bit about the registry: DSR contains prospectively collected nationwide data on all stroke patients admitted to Danish hospitals. It's interesting to note that in Denmark, stroke patients are exclusively admitted to public hospitals, and all departments treating stroke patients are obligated to report data to DSR. Now, for this study, they included over 63,000 stroke patients from 2013 to 2018. After excluding hemorrhagic stroke, TIAs, and other exclusion criteria of the study, they arrived at their sample size of 37,187 patients that were included in this study. Dr. Negar Asdaghi: Now, a few definitions. The socioeconomic status of each patient was determined based on three parameters. Parameter number one, their educational level. It was categorized into three levels of low, medium, or high levels of education. Category number two, income level. This was calculated based on the average family equivalent disposable income, or FED income, during five years prior to stroke onset, again classified into three categories of high, medium, or low income. And the third factor was the employment status of the patient during the calendar year prior to the stroke onset, also categorized into three categories of employed, unemployed, and retired. And, of course, the authors used various definitions to be able to fit special situations into these categories. For instance, a person who is temporarily unemployed due to illness or other special situation was still categorized under the employed category. So, that gave them, in total, nine groups to analyze across these three categories. Dr. Negar Asdaghi: And here are their findings. The median age of total stroke patients in the cohort was 73.2 years, 44.1% were women, 41% categorized under low educational level, 68% retired, and 33.3% had low income levels. Not surprisingly, patients and hospital characteristics varied tremendously across these nine groups of education, employment, and income, and a univariate analysis in general, low socioeconomic status was associated with more severe strokes, living alone, living at an assisted living residency, having had prior stroke, high comorbidity index score, hypertension, and late hospital arrival. So, they accounted for these differences in their multivariate analysis. Dr. Negar Asdaghi: Now, overall, the treatment rates of IV thrombolysis was 17.6%, which is actually considered a very high percentage as compared to other registry-based studies, but the percentage of IV thrombolytic use dramatically varied based on the different socioeconomic designation. So, let's look at this. In the univariate analysis, for education, intravenous thrombolysis rates were 19.3% among patients with high educational level compared to 16.2% among patients with low educational level. Let's look at income. For income, IV thrombolytic treatment rates reach 20.7% for high-income patients compared to 14.8% for low-income patients. For employment status, thrombolytic rates were 23.7% among employed patients compared to 15.7% for unemployed patients. In their fully adjusted models, unemployed patients were less likely to receive IV lytics as compared to their employed counterparts. Dr. Negar Asdaghi: Now, for thrombectomy, socioeconomic gradients were also noted for these three categories. For education, thrombectomy rates were 4.5% among patients with high education level compared to 3.6% among patients with low educational level. For income, treatment rates were 3.2% among low-income patients compared to 4.7% among high-income patients. But arguably, the most robust differences were noted again across the category of employment. Employed patients were nearly twice more likely to receive thrombectomy as compared to unemployed patients, rates being 5.1% versus 2.8%, respectively. Now, when they adjusted their analysis to only those patients presenting within the reperfusion time windows in the fully adjusted models, unemployment and low income remain significant negative predictors of receiving both of these reperfusion therapies. So, what we learned from this study is that stroke patients who were unemployed, earned a relatively low income, or had fewer years of formal education were less likely to receive life-saving reperfusion therapies despite potentially being eligible for these treatments. Dr. Negar Asdaghi: Now, let's take a moment to really understand that data presented here are in the context of a tax-funded, universal healthcare offered across Denmark, where we can at least make the assumption that financial constraints potentially preventing access to therapies are likely minimized. There are many countries around the globe where patients or family members have to pay for these therapies before even receiving them. So, these findings from the current study from Denmark are alarming in that they point to possibly more robust inequalities across the globe in other healthcare systems. Dr. Negar Asdaghi: Intracerebral hemorrhage, or ICH, is an aggressive form of stroke, typically carrying a higher morbidity and mortality than its ischemic counterpart. Yet much of the research in the field of intracerebral hemorrhage has followed the ischemic stroke footsteps, including defining the optimal primary outcome for the randomized trials of ICH. For ischemic stroke, the 90-day functional outcome, as measured by the modified Rankin Scale, is commonly used as a primary outcome in clinical trials. There are many reasons for this selection, including the ease of use and the fact that the majority of functional recovery post-ischemic stroke occurs during the first 90-day time period. But time to maximum recovery and, importantly, the trajectory of recovery may be different in hemorrhagic as compared to ischemic stroke. Defining the long-term outcomes and longitudinal trajectory of recovery in ICH is, therefore, important to better understand its prognosis and, of course, selecting the appropriate primary outcome measure for future randomized trials of ICH. Dr. Negar Asdaghi: In the recent years, the safety and efficacy of various agents to improve ICH outcomes have been tested. Deferoxamine mesylate, an iron-chelating agent, is one such agent that was recently studied as part of the i-DEF multicenter randomized trial, and the main results of the study were published in Lancet Neurology in 2019. In the current issue of the journal, in the study titled "Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage," we learn about the results of a post hoc analysis of i-DEF that looks at the trajectory of functional outcome in patients enrolled in the trial with a special attention on their continued recovery after the 90-day post-ICH mark. Dr. Negar Asdaghi: Joining me now is the senior author of this paper, Dr. Magdy Selim, who's also one of the primary investigators of i-DEF trial. Dr. Selim is a Professor of Neurology at Harvard Medical School and Chief of Stroke Division at Beth Israel Deaconess Medical Center in Boston. He's a world renowned researcher in the field of cerebrovascular disorders with special focus on treatment of patients with intracerebral hemorrhage. Dr. Selim has led and currently leads multiple National Institutes of Health-funded clinical trials of intracerebral hemorrhage, including the ongoing SATURN trial. I'm delighted to welcome him to our podcast today. Good afternoon, Magdy. Thank you for joining us today. Dr. Magdy Selim: Thank you, Dr. Asdaghi. It's really my pleasure to be here with you, and I'm certainly honored to do this today. Dr. Negar Asdaghi: That's great. Thank you. So, let's start with some background on deferoxamine and the literature supporting the use of deferoxamine before i-DEF. Dr. Magdy Selim: So, as you mentioned, deferoxamine is an iron chelator; it binds to iron and removes excess iron from the body. The unique thing about it is that it has other neuroprotective properties, which are good for hemorrhagic stroke and ischemic stroke. It also has anti-inflammatory and anti-apoptotic effects. It even lowers the blood pressure, which we know sometimes is helpful in intracerebral hemorrhage. The rationale behind this or why this would be effective really comes from animal studies. After you have a hemorrhage, there is hemolysis of the red blood cells, there is a release of hemoglobin degradation products, in particular, iron, and the accumulation of iron in the hematoma and the surrounding tissue triggers a cascade of molecular and cellular events that lead to what we call secondary injury, characterized by inflammation, hydroxyl radical formation, and cell death. And many animal studies, animal models of intracerebral hemorrhage, whether in pigs or in rats, young or aged rats, have shown that treatment with deferoxamine can reduce iron in the brain after intracerebral hemorrhage and also results in improved performance on behavioral tests. And that was the reason why we moved into clinical testing. Dr. Negar Asdaghi: So, a lot of encouraging data before the trial. Can we hear a little bit about the trial, its design, and inclusion criteria, please? Dr. Magdy Selim: Sure. So i-DEF was a phase 2 study, and actually it started as Hi-DEF, which was high dose deferoxamine, and then became i-DEF, which intermediate dose deferoxamine. So, it's a randomized, double blind, placebo control trial. We used something called futility design, which is actually sort of new in the stroke field. And we had 294 patients who had supratentorial hemorrhage that were randomized within 24 hours to either get placebo or deferoxamine. And deferoxamine initially was given at 62 mg per day for three days, but then we ran into some safety issues with this high dose, and that's why we lowered it to 32, and that became the intermediate dose, or the i-DEF. So, the only kind of thing unique about inclusion/exclusion criteria was that there was an age cutoff, patients had to be 80 or younger. They needed to have some deficit on the exam, so their NIH Stroke Scale had to be 6 or greater, and their GCS had to be greater than 6, and their modified Rankin before the onset of the hemorrhage had to be less than 1. Dr. Negar Asdaghi: And so, what were the primary and secondary outcomes in i-DEF? Dr. Magdy Selim: The primary outcome was twofold actually. One of them was safety. One of the issues we ran into with the high dose is that the drug is associated with increased risk for adult respiratory distress syndrome, ARDS. So, we wanted to make sure that this lower dose was safe, and it does not increase the instance of ARDS. The second thing was, as I said, we used something called the futility design, and we wanted to compare the outcome of patients treated with deferoxamine versus placebo to determine whether it's futile to move to a large phase 3 trial or not. And what we were looking at is a difference in outcome and modified Rankin 0 to 2 at 90 days, and the difference would be at least 12% in favor of deferoxamine in order for us to move forward. You asked about the secondary outcomes as well? Dr. Negar Asdaghi: Yes. Dr. Magdy Selim: So, actually, the secondary outcomes, they're relevant because they're relevant to the study that we just published. So, the secondary outcomes was also to look at modified Rankin 0 to 3, instead of 0 to 2, at 90 days and the difference between the two treatment groups. We wanted to look at the ordinal distribution of the Rankin at the same time point. And we also wanted to look at all the outcomes at six months, 180 days. And that came a little bit later in the course of the study because there was some evidence emerging at that time that maybe assessment of outcome later in intracerebral hemorrhage would be more accurate than assessing it early on. Dr. Negar Asdaghi: So, I want to come back to the secondary outcome, of course, that's sort of the topic of your current paper in this issue of the journal, but can you just briefly tell us, please, the primary outcome and the sort of results of what was published in 2019 with i-DEF before we move on to the current paper? Dr. Magdy Selim: Yeah. So, as I said, the primary outcome was the difference in the proportion of patients that achieved modified Rankin 0 to 2 at 90 days, and what we wanted to see is a difference of around 12%. Unfortunately, the primary outcome was neutral, we did not see that. But what we saw actually, almost all the secondary outcomes were positive, except for the primary outcome. So, when we looked at the secondary outcome using modified Rankin 0 to 3, instead of 0 to 2, the difference was 12.1%. When we looked at the difference in the modified Rankin 0 to 2 at six months, the difference was 15.6% in favor of deferoxamine, but these were secondary outcomes and not the primary outcomes. Dr. Negar Asdaghi: So, the trial is almost positive. It just depends on how you define the primary outcome, which is really a nice segue to your current study. In the current study, you looked at this secondary outcome in a longitudinal way and looked at the mRS of 0 to 2 at six months from ICH. Can you please tell us about this current paper? Dr. Magdy Selim: Yeah. So, one of the things that we did with i-DEF is that we were checking the modified Rankin at different time points for all the patients. So, we had it after one week, after one month, after two months, after three months, and after six months. And what we wanted really was a couple of things, just in patients with intracerebral hemorrhage without any treatment, what's the natural course of recovery? And the interesting thing we found out is that patients actually continue to improve over time, and that's what you expect, but what we didn't expect is that they even continue to improve after 90 days. Dr. Magdy Selim: We always used to think that maximum recovery is around 90 days from ischemic stroke literature, but we saw a lot of patients getting better after 90 days. And this turns out to be also the case with deferoxamine, but the interesting thing is that the percentage of patients that had a good outcome, modified Rankin 0 to 2, was higher with deferoxamine at day seven, at day 30, at day 60, not at 90 days, but again at six months. So, actually, it was higher at all time points except our primary endpoint. Dr. Negar Asdaghi: So, Magdy, you've already answered my next question, which is exactly what you alluded to, deferoxamine seemed to have improved the outcomes at all of those time points, except for the 90 day, which was the primary outcome of your trial. Why do you think the magic was lost at 90 days? Dr. Magdy Selim: This is really the million-dollar question. I think we obviously struggled over this. And we went back, we thought maybe there was misrating of the modified Rankin in some of the patients. We tried to correct for this. The difference was bigger, but still not significant. So, we don't really have a good reason to tell you why, at this particular time point, we didn't see the difference except bad luck, I think. But I mean, there are reasons, I think, the question that people actually ask me is the opposite, is why do you think a drug that you give for three days early on is going to make a difference after six months? And I think there are biological reasons to explain this. Dr. Magdy Selim: So, what happened is that those hemorrhage patients have a lot of other problems. They have increased ICP, they have hydrocephalus, they have intraventricular hemorrhage, and actually iron has been implicated in the development of hydrocephalus in chronic white matter injury. So, my explanation is that you start early on with the treatment, it does help, but it takes a while for it to kick in and for this kind of medical complication to resolve until actually you see the true effect of the drug. And maybe that's why you see the unmasking at the end between the two groups. Dr. Negar Asdaghi: Yeah, I think I want to recap this for our listeners. Very important to, again, think about those things that some of the acute therapies that we offer the patients may not have a measurable improvement outcome difference early on, certainly with intravenous thrombolysis, we saw that, whereas we saw measurable outcome difference at 90 days, or maybe in this case at six months, but not quite early on. So, it doesn't mean that they don't work. We just are unable to measure that difference and improvement early on. So, what do you think the future holds for deferoxamine? Are we going to see another trial? Dr. Magdy Selim: Well, I certainly hope so. We're working on some few ideas for that. A lot of people think that maybe we should just do the same thing, but look at six months as the primary outcome. But I think we're actually, that's probably not our primary thinking at this point in time. So, we have published other papers, other analysis, to show that the effect of deferoxamine actually relates to the volume of the hemorrhage. So, if the hemorrhage is very small, there is very minimal benefit. If the hemorrhage is very large, also there is very minimal benefit. And that's really to get kind of the big bang for your buck. You really want people who have mild-to-moderate size hemorrhages. So, we're thinking of a couple of ways to go about deferoxamine with this, whether alone or in combination with other interventions. So, hopefully, we'll have some stuff to share with you in the coming few years, two or three. Dr. Negar Asdaghi: We'll definitely look forward to reading about those or being involved in the trials as a site, but there's a great way of just actually talking about my next question. It's just completely different than the current paper. I wanted to digress a bit and talk about the recently published intracerebral hemorrhage guidelines, which just published a few months ago. You were part of the guidelines committee. Can you give us a little bit of your point of view of what are the top two most important updates from the guidelines in ICH treatment? Dr. Magdy Selim: Actually, the guidelines, for the first time this year, in the first page, they have the top 10 take-home messages or top 10 new ones. So, in my opinion, the most important ones, we usually tell you what to do, but here we tell you what not to do because we think it's not good for the patients. So, for example, using steroids just as a prophylactic therapy is actually not recommended. The same thing, we see a lot of people put patients with hemorrhage on hypertonic saline, hyperosmolar therapy, just prophylactically. I don't think there's any benefit that this helps as well, and the same thing for antiepileptic drugs. So, that was one important point. The second one was blood pressure lowering, and there is emphasis now that whatever you use to lower the blood pressure, you want to make sure that the blood pressure variability is very minimal and that there is a smooth kind of control over blood pressure that has been shown to be actually important in terms of help. I'm going to make them three, not two, because I think the third one is important. Dr. Negar Asdaghi: Okay. I'll give you one more then. Dr. Magdy Selim: Which is the first time we include this in the guideline, and with emphasis on the role of the home caregiver for hemorrhage patients and the psychological support, the education that they need, and the training that they need to actually care for these patients and how to improve their quality of life. So, I think that's an important aspect that we didn't touch upon before, and obviously very important. Dr. Negar Asdaghi: Very important points. Let me just review them again for our listeners. So, don't do steroids, hypertonics, and preemptive antiepileptic therapies. They don't work. The second point that you raise is reduction of blood pressure, important to keep that in mind, but paying attention to blood pressure variability. And the third one, the importance of social aspect of care of patients with intracerebral hemorrhage. That's great for us. Let me just end with one last question. Magdy, thank you so much for all of this wonderful take-home messages from the current study from i-DEF and also the guidelines. There's been a lot of excitement in the field of ischemic stroke with the success of reperfusion therapies, and yet not much for intracerebral hemorrhage. What is your hope in terms of future therapies for ICH? Dr. Magdy Selim: So, I happen to be one of the people who is very optimistic about the future of ICH. I think it's just a matter of time. But I think we need to make some changes. We need to really treat ICH as an emergency, so time is really important. And I think right now, you see a hemorrhage patient, they just put them on the side because they think that there's nothing to do. But the way I see the future evolving, and probably the breaking point to be, is that we can diagnose ICH in the field. You immediately lower the blood pressure, reverse coagulopathy if you can, and even kind of use hemostatic agents, if the FASTEST trial shows evidence to support that, and then you take them to the hospital where there might be some role for hematoma reduction using minimally invasive therapy and some other treatments like deferoxamine, or there are a lot of other agents to target the secondary injury at the same time. So, I think it's going to be a combination of things, and they need to happen in tandem and continuously, but we need to start quickly on these patients. Dr. Negar Asdaghi: Dr. Magdy Selim, it's been a pleasure interviewing you on the podcast. We look forward to having you back and covering more of your work. Thank you for joining us. Dr. Magdy Selim: Thank you very much for having me. Dr. Negar Asdaghi: And this concludes our podcast for the July 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including a series of Focus Updates on the very topic of, you guessed it, intracerebral hemorrhage. These updates are great complements to the newly published American Heart Association guidelines for the management of patients with spontaneous intracerebral hemorrhage in May 2022. Dr. Negar Asdaghi: And with this, we end our July podcast and draw inspiration from one particular July story, which unfolded on July 20. In 1969, on this day, Commander Neil Armstrong and lunar module pilot Buzz Aldrin landed on the moon, and Armstrong became the first person to walk on the moon. The crew of Apollo 11 changed the course of history, landing humanity on another celestial body for the first time and later safely returning everyone back to earth. Armstrong, an experienced naval aviator, a test pilot, a decorated veteran, astronaut, and university professor, passed away in 2012 from complications of coronary artery disease, reminding us that every step we take in understanding, diagnosing, and treating vascular disorders is truly part of that giant leap to save the mankind. And what better way to do this than to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 17 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2022 issue of Stroke: "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage" and "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns." She also interviews Dr. Bruce Campbell on his article "Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy." Dr. Negar Asdaghi: Let's start with some questions. 1) Is vitamin D that golden key to recovery from intracerebral hemorrhage? 2) Endovascular therapies seem to have prevailed where thrombolytics have failed. In the era of fast and furious thrombectomy, what is the role of pre-thrombectomy thrombolysis? 3) And finally, 20 years of clinical research has failed to demonstrate the superiority of anticoagulation over antiplatelet therapies for treatment of patients in sinus rhythm with low left ventricular ejection fraction, and yet, our practice patterns have not changed. Why do we remain resolute in prescribing anticoagulation despite the lack of evidence? We're back here to tackle the toughest questions with our Stroke Alert Podcast because this is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to another extremely motivating Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The June 2022 issue of Stroke contains a number of interesting articles. As part of our Advances in Stroke, we have two articles, one on the topic of cost-effectiveness of stroke care to inform health policy and the second on the current state and the future of emerging stroke therapies. As part of our Original Contributions category, we have an interesting study by Dr. [Ben] Assayag and colleagues from the Department of Neurology at Tel Aviv Sourasky Medical Center, where we learned that just over 10% of patients with TIA and stroke developed post-traumatic stress disorder, or PTSD. Higher presenting stroke severity, preexisting white matter disease, and having anxious coping styles are risk factors for development of post-stroke PTSD. Dr. Negar Asdaghi: In another Original Contribution, by Dr. Daehoon Kim and colleagues from Yonsei University College of Medicine in Seoul, South Korea, we read with interest on the topic of whether or not we should be anticoagulating frail patients with atrial fibrillation. In this large population-based cohort, which included patients with atrial fibrillation older than 65 years of age with frailty as defined by a score of equal or greater than five on Hospital Frailty Risk Score, we learned that despite their frailty, patients with atrial fibrillation still significantly benefit from oral anticoagulation therapy. In this study, those treated with anticoagulation had lower net adverse clinical events as compared to those untreated. We also learned that direct oral anticoagulants provided lower incidence of stroke, bleeding, and mortality over Coumadin. This paper really provided practical information on treatment of frail patients with atrial fibrillation. So, I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Bruce Campbell from University of Melbourne in Australia on an especially timely topic, that is the role of intravenous thrombolytics prior to endovascular therapy. Dr. Campbell is a leading authority on the topic, and his interview does not disappoint. But first, with these two articles. Dr. Negar Asdaghi: In the setting of intracerebral hemorrhage, or ICH, aside from the primary brain insult that occurs at the time of hemorrhage, secondary brain injuries continue for days and sometimes to months mostly due to the pathological response of the brain to byproducts of hematoma lysis or RBC degradation products. Today, the majority of spontaneous ICH cases are not surgically evacuated, so we rely on the body's own ability to clear blood for hematoma clearance, and obviously the faster the clearance, the better the outcome. Erythrophagocytosis by monocyte-derived macrophages contributes to hematoma clearance and ultimately to the functional recovery from ICH. So, it's conceivable that therapeutic approaches to enhance the endogenous erythrophagocytosis can potentially improve ICH outcomes. Vitamin D has been known to have variety of functions within the central nervous system, and it turns out that it may also be one such therapeutic option to improve the much needed erythrophagocytosis in intracerebral hemorrhage. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage," a group of researchers led by Dr. Jiaxin Liu from the Department of Surgery at Queen Mary Hospital at the University of Hong Kong studied the effects of oral vitamin D administered two hours after the induction of hematoma in a rodent model of ICH using direct collagenase injection into the striatum of the mouse. Eighty-nine young mice and 78 middle-aged mice were included in the study and randomly divided into three groups. Group one were sham-operated mice; group two, ICH mice treated with vehicle, which was corn oil; and group three, vitamin D-treated ICH mice. In the third group, 1000 international unit per kg of vitamin D diluted in corn oil was administered orally using a pipette two hours after the induction of ICH to mice, and then daily afterwards. And here are their top three findings of this study. Dr. Negar Asdaghi: Number one, vitamin D-treated mice did better than vehicle on two neurobehavioral tests that were completed in the study. On the cylinder test, treatment with vitamin D significantly alleviated the asymmetric usage of four limbs at day seven, and vitamin D elongated the duration that the mice could run on the accelerated rod at day 10 on the rotarod test. Dr. Negar Asdaghi: Number two, in terms of hematoma resolution and perihematoma edema, it's an issue that we deal with, with ICH, they used MRI imaging for edema measurement on T2-weighted images, and then sacrificed the mice and used digital quantification of hematoma volume with fresh brain specimens. And they found that treatment with vitamin D significantly alleviated both the ICH-associated brain swelling on MR and resulted in significant reduction in hematoma volume on the fresh brain specimens when compared with the vehicle-treated group at day three and day five. Dr. Negar Asdaghi: And finally, their third main finding is in terms of erythrophagocytosis. So, the pathway that is mediated by the monocyte-derived macrophages is an endogenous pathway, that is, PPAR-γ (which stands for peroxisome proliferator-activated receptor γ) and its downstream scavenger receptor CD36 mediated. This pathway is essential for directing the endogenous erythrophagocytosis. Using flow cytometry, they found that vitamin D-treated mice had more mature macrophages expressing the scavenger receptor CD36, which was not expressed by the undifferentiated monocytes. Dr. Negar Asdaghi: Western blot analysis confirmed that vitamin D treatment increased the tissue levels of CD36 and the upstream PPAR-γ levels in the brain at day five after collagenase model. Locally, vitamin D-enriched phagocytes that were positive for PPAR-γ and CD36 in the perihematoma regions. So, in summary, vitamin D increased the number of mature macrophages rather than undifferentiated monocytes in the perihematoma region and accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. So, bottom line is that in vitamin D, we have a simple, accessible, and well-tolerated agent to improve both the ICH outcomes and enhance hematoma resolution, but this we all observed in rodents. So, we stay tuned with interest to find out whether the same success will be seen in humans treated with vitamin D after intracerebral hemorrhage. Dr. Negar Asdaghi: Patients with depressed left ventricular ejection fraction, or low EF, are at risk of development of ischemic stroke even if they remain in sinus rhythm. The optimal antithrombotic treatment for these patients is still unknown. Over the past two decades, we have a number of randomized trials studying the efficacy of oral anticoagulation, predominantly Coumadin, over aspirin therapy in prevention of all forms of stroke, that is ischemic and hemorrhagic, and death in patients with a low EF in sinus rhythm. Dr. Negar Asdaghi: The meta-analysis of WASH, HELAS, WATCH, and WARCEF trials showed that treatment of low ejection fraction patients in sinus rhythm with Coumadin does reduce the subsequent risk of stroke, but it comes at the cost of a higher major bleeding risk in this population. The COMMANDER HF clinical trial published in New England Journal of Medicine in October 2018 studied whether low-dose rivaroxaban at 2.5 milligram BID was superior to placebo in patients with recent worsening of chronic heart failure, reduced ejection fraction, coronary artery disease, but no atrial fibrillation, and very similar to its prior counterparts, it did not show that rivaroxaban was associated with a lower rate of combined death, myocardial infarction, or stroke as compared to placebo. But very similar to prior studies, it also showed that rivaroxaban-treated patients had a lower risk of subsequent ischemic stroke. This poses a conundrum for stroke neurologists treating patients with this condition, especially after they present with an embolic-appearing stroke. So, the question is, how often do we encounter this situation, and what do we do in routine practice? We know that when there is equipoise, there's practice variation. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm," Dr. Richa Sharma from the Department of Neurology at Yale School of Medicine and colleagues examined the prevalence of heart failure with sinus rhythm among hospitalized patients with acute ischemic stroke and the physician's practice patterns with regard to the choice of antithrombotics in this population. Dr. Negar Asdaghi: So, let's look at their study. The study was comprised of five separate study cohorts of hospitalized acute ischemic stroke patients in the Greater Cincinnati Northern Kentucky Stroke Study for the year 2005, 2010, and 2015, and then four additional academic hospital-based cohorts in the United States during different timeframes. These were the Massachusetts General Hospital from 2002 to 2016, Rhode Island Hospital from 2016 to 2018, Yale-New Haven Hospital 2015 to 2017, and Cornell Acute Stroke Academic Registry from 2011 to 2018. All of these cohorts combined contributed to the 19,155 total number of patients in this study, which included over 14,000 patients that had documented left ventricular ejection fraction. Amongst those, 1,426 had a depressed EF and were included in this study. The investigator obviously excluded those with documented atrial fibrillation and flutter. And so the sample size for this analysis was 805 patients. And here are their main results. Dr. Negar Asdaghi: The overall prevalence of this condition, that is low ejection fraction and sinus rhythm, among hospitalized acute ischemic stroke patients was 5%. It varied slightly between the different cohorts in this study from 4 to 6%. In terms of the antithrombotic treatment patterns, this information was available in close to 500 patients in the cohort. Overall, 59% of patients were discharged on an antiplatelet treatment alone, and 41% on anticoagulation. But these percentages significantly varied between the different institutions and was as low as 22% in one of the cohorts and as high as 45% in another cohort. Dr. Negar Asdaghi: So, what were the factors that were associated with the use of anticoagulation at discharge? They found that the absolute percentage of left ventricular ejection fraction and the presenting NIH Stroke Scales were associated with anticoagulation use. That is, the lower the percentage of EF and the higher the presenting NIH Stroke Scale, the more likely physicians were to discharge the patients on an anticoagulation in univariate analysis, but in multivariate analysis, only the study site and presenting NIH Stroke Scale over eight were independently associated with anticoagulation use. Dr. Negar Asdaghi: Now, interestingly, 2002 to 2018, which was their overall study period, was a time during which some of the largest and neutral randomized trials on the topic of anticoagulation versus antiplatelet were published, including the WATCH and the WARCEF trial. But the authors found no temporal variation in anticoagulation practice patterns before and after the publication of the results of these trials. So, it appears that we didn't change our minds. So, overall, we have some important takeaway messages from this study. We learned that 5% of hospitalized acute ischemic stroke patients have low left ventricular ejection fraction and remain in sinus rhythm without atrial fibrillation. Today, over 40% of patients with this condition are anticoagulated at discharge despite the results of the randomized trials, but the practice is widely variable among different institutions, and a higher presenting NIH Stroke Scale is a significant predictor of anticoagulation use at discharge in this population. Dr. Negar Asdaghi: Almost 20 years after the approval of intravenous thrombolysis for treatment of patients with acute ischemic stroke, endovascular therapy was approved for treatment of select ischemic stroke patients with a large vessel occlusion. The two treatments are, therefore, entangled, as one was the standard of care while the second one was being tested. Therefore, all endovascularly treated patients enrolled in randomized trials would've received intravenous thrombolysis if eligible. Now, with the overwhelming success of endovascular therapy in achieving reperfusion in areas where IV thrombolysis has drastically failed, there're still critical questions regarding the added value of IV thrombolysis to endovascularly treated patients. The critical question remains as to whether eligible ischemic stroke patients who have immediate access to endovascular thrombectomy should receive prior IV thrombolysis, or should we skip the thrombolysis step altogether and just move to the angio suite as fast as possible. And there are, of course, arguments for and against each approach. Dr. Negar Asdaghi: In this issue of the journal, in an invited topical review titled "The Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy," we learn about these arguments as the authors go through a comprehensive review of the current literature on this issue. I'm joined today by the first author of this review, Dr. Bruce Campbell, to discuss this paper. Dr. Campbell absolutely needs no introduction to our Stroke listeners. He's a professor of neurology and head of neurology and stroke at Royal Melbourne Hospital, University of Melbourne, in Australia. He's a pioneer in the field of acute stroke therapies and acute neuroimaging. He has served as the lead investigator of multiple landmark randomized trials, including EXTEND-IA and EXTEND-IA TNK, and holds multiple leadership roles. He's the clinical director of the Stroke Foundation and co-chairs the Australian Stroke Guidelines Working Party and the coordinator of the National Brain School Training Program for Neurologists in Training. And, of course, last but not least, he's my friend. So, I'm delighted to welcome him to our podcast today. Top of the morning to you, Bruce, 6:00 a.m. in Melbourne. That's quite some dedication. Thank you for being here. Dr. Bruce Campbell: It's great to be with you. Thanks for the invitation. Dr. Negar Asdaghi: Congrats on the paper, really exciting topic. So, let's just start with this question as part of a case. We have a patient with an M1 occlusion, a large clinical syndrome presenting two hours out from their symptom onset, and we are at a hospital where the angio suite is ready. What are some of the benefits of basically spending time in giving IV thrombolytics first rather than quickly going to the angio suite? Dr. Bruce Campbell: I think a key element of this case is that the patient has presented directly to a hospital with immediate access to thrombectomy. Thrombolytic used in drip-and-ship transfer patients really isn't controversial, and the recent randomized trials excluded them. So, the debate's all about this context of bridging thrombolytics in patients presenting directly to a comprehensive stroke center. And you mentioned spending time giving lytics, but in fact, if you do things in parallel, that shouldn't be the case. It shouldn't delay thrombectomy if you go and give thrombolysis. Dr. Bruce Campbell: So, the general principle is that getting the artery open faster by any means is better, and IV thrombolytic certainly has the potential to open the artery before thrombectomy in a proportion of patients, perhaps not that many, but it may also facilitate the thrombectomy. So, in the randomized trials, reperfusion after the thrombectomy was significantly better when patients had had bridging thrombolytic despite a low rate of pre-endovascular reperfusion. Other reasons for giving the lytics are the potential safety net it provides if the thrombectomy procedure is unexpectedly delayed or fails to get the artery open, and there's also this potential for lytics to dissolve distal embolic fragments and perhaps improve microvascular reperfusion. Dr. Negar Asdaghi: So, great. So, let me summarize for our listeners what you mentioned. First off, so these are arguments in favor of giving lytics. As you mentioned, we're not really wasting time. These processes occur in parallel, so it's not like we're wasting time in giving a therapy that is potentially not as efficacious as thrombectomy is. And number two, we have improved the possibility of early reperfusion, perhaps, with the lytics. And if there are some fragments or distal clots that thrombectomy wouldn't have reached, then the lytics would. And then also there is also the chance that the thrombectomy might have failed in difficult access, and so on and so forth, and at least the patient has some chance of revascularization with the lytics. So, if these are the arguments for giving lytics, what are the arguments against giving lytics in this scenario? Dr. Bruce Campbell: The main argument is the potential to reduce both the intracerebral and systemic hemorrhagic complications. There's also potential cost saving by skipping thrombolytics. That's probably more relevant in low-resource settings, particularly when relatives may have to pay for the thrombolytic before treatment is initiated, and that can be burdensome and also potentially delay the thrombectomy. There's a theoretical concern about thrombus fragmentation with lytics and potential migration of the clot out of reach of the thrombectomy or to new territories. But final reperfusion, as I mentioned, was, on average, better with the patient having a lytic on board in the randomized trials. Dr. Negar Asdaghi: Perfect. And I want to highlight this issue of thrombus fragmentation because I think our readers will read more and more about this idea of, as you mentioned, fragmentation will potentially make an accessible clot for thrombectomy inaccessible. But I see that later in our questions, we're going to address that as part of the findings of randomized trials as well. So, these are some of the arguments for and against. And before we go to the randomized trials, I'd like to get an overview of what we knew as part of observational studies and non-randomized studies prior to more recent randomized trials on this topic. Dr. Bruce Campbell: There've been a couple of nice systematic reviews and meta-analyses of the observational data, and notably in most of these studies, the direct thrombectomy patients had contraindications to lytics, and that introduces confounding factors that are difficult to adjust for. For what that's worth, the functional independence, mortality outcomes were better in the bridging patients. Hemorrhage rates weren't always higher with the lytic, and one study by Jonathan Coutinho in JAMA Neurology for the SWIFT and STAR studies showed the opposite despite them having really careful adjustment for all the confounders they could think of. And the meta-analysis by Eva Mistry in Stroke did not detect a difference in symptomatic ICH between the direct and bridging strategies. One thing that should be less affected by the patient characteristics would be the technical efficacy outcomes, and it was interesting that in the observational data, the patients who'd had bridging lytic had higher mTICI 2b-3 rates and also fewer device passes. Dr. Negar Asdaghi: Okay. And now we do have further information with all of these new randomized trials. So, why don't we start with some of the earlier studies, the three, SKIP, DEVT, and DIRECT-MT, and start with those studies first before we move to some more recent European trials. Dr. Bruce Campbell: SKIP was performed in Japan, and it used the lower 0.6 milligram per kilogram dose of alteplase that's standard there, and DEVT and DIRECT-MT were performed in China. All three of them showed numerically similar functional outcomes with slight trends favoring direct thrombectomy. SKIP had a smaller sample size and did not meet its non-inferiority criteria, and the other two trials did meet their specified non-inferiority margin, but it could be argued those margins were overly generous. If you think about non-inferiority trials, we generally try to set a margin for non-inferiority such as lower 95% confidence interval for the trial intervention would sacrifice up to 50% of the reference treatment effect. And it's difficult to estimate the effect of alteplase in this specific population. But if you think of the Emberson meta-analysis of alteplase, overall zero to three hours alteplase versus placebo has a 10% effect size and mRS 0-1, three to four and a half hours of 5% effect size. And we regard that as clinically important. So, half of 5%, 2.5%, is a lot tighter margin than any of the direct randomized trials employed. Dr. Negar Asdaghi: So, Bruce, let me recap what you just mentioned. Two out of the three earlier trials seem to suggest that perhaps skipping IV therapy is the way to go rather than bridging as these two trials met the non-inferiority criteria if we believe that non-inferiority margins you mentioned. And now we have a couple of more trials, more recent trials. Can you tell us about these trials please? Dr. Bruce Campbell: MR CLEAN-NO IV in a European population did not demonstrate non-inferiority, and the point estimate slightly favored bridging. Interestingly, in that trial, the symptomatic intracerebral hemorrhage risk, which was one of the main drivers for trying this strategy, was 5.9% in the direct and 5.3 in the bridging group. So, there's no hint of benefit from dropping the lytic on that metric. SWIFT-DIRECT was more selective in only enrolling internal carotid and M1 occlusions, which had a lower chance of early recanalization with lytic. But the protocol also specified giving the full dose of lytic. In the other trials, it seems the alteplase infusion was often stopped once the patient was in the angio suite, so the full dose may not have been delivered. And despite very low pre-endovascular recanalization in that selected group in SWIFT-DIRECT, the end of procedure reperfusion was significantly better in the bridging group, which is a consistent finding across the trials and suggests that the lytic may improve the thrombectomy outcome. Dr. Bruce Campbell: DIRECT-SAFE, the final of those trials, was interesting in that the patients were enrolled roughly 50:50 from Australia, New Zealand, versus Asia. And in contrast to the original three randomized trials in Asian patients, DIRECT-SAFE found a significant benefit of bridging lytic in Asian patients. So, it'd be very interesting to see the results of the IRIS individual patient data meta-analysis, but we may not find a difference in Asian versus Caucasian patients despite those initial trials and despite substantial differences in the prevalence of intracranial atherosclerosis, which has often been proposed as something that would increase the risk of having bridging thrombolytic on board. Dr. Bruce Campbell: The original study level estimate of symptomatic hemorrhage had a borderline significant 1.8% absolute reduction in the direct group. Whether those data were not all core lab adjudicated and the final analysis may show a smaller difference than that. Notably, given that trend with symptomatic intracerebral hemorrhage, mortality did not differ significantly, and, in fact, the trend favored bridging patients. So, the symptomatic hemorrhage slight trend into increase did not translate into any hint of increased mortality. Dr. Negar Asdaghi: So, Bruce, a lot of information, and I need a recap for me. So, let me try to recap some of the things you said, and please jump in. So, so far, the newer data really basically don't show us any convincing evidence that skipping is the way to go, and direct endovascular we really don't have data in favor of going directly to the angio suite. And the jury is still out regarding an increase in the symptomatic intracerebral hemorrhage rate amongst those that actually are pre-treated with IV therapy. Is that correct? Dr. Bruce Campbell: That's correct. So, none of the three recent trials met their non-inferiority margins. And again, we had this issue of relatively generous non-inferiority margins, and the symptomatic hemorrhage, it would make sense that there's a small difference, but it's not really been borne out in the data to be statistically significant at this stage. And again, this individual patient data meta-analysis is keenly awaited to get the most accurate estimate on that. Dr. Negar Asdaghi: So, while we wait that, I'm going to digress a little bit and ask you a question that's not addressed in the paper that you have in this issue of the journal, and that's the CHOICE trial. So, by now, we have the results of CHOICE trial. Do you mind first give us a brief overview of what CHOICE was and how you feel that the results of CHOICE would affect this field of direct versus bridging in general? Dr. Bruce Campbell: CHOICE is a very interesting study in that it tested giving the intra-arterial lytic at the end of a thrombectomy procedure that had achieved an mTICI 2b or better, which is what we traditionally regarded as angiographic success. The idea was to improve microvascular flow, and that may be the case. The trial was terminated early due to logistic reasons and showed a very large effect size that requires replication. The subgroup analyses are interesting in that the benefits seem to mostly accrue in patients who'd not already had intravenous lytic. Dr. Bruce Campbell: So, perhaps giving the IV lytic before thrombectomy can still benefit patients after the thrombectomy, as well as achieving early recanalization in a proportion of patients and perhaps facilitating the thrombectomy. The other issue to address with the DIRECT trials is that with the exception of a few patients in DIRECT-SAFE, the comparator was alteplase and not tenecteplase. And we have data from EXTEND-IA TNK that tenecteplase bridging is not just non-inferior, but superior to alteplase bridging. There's an ongoing Brazilian trial of exactly that, tenecteplase versus the direct approach, which will be very interesting. Dr. Negar Asdaghi: So, great, Bruce. I just want to repeat this segment again for our listeners. So, CHOICE is a very interesting study, looked at giving intraarterial alteplase to patients after endovascular therapy was completed and after they'd already achieved the complete and successful revascularization, and the trial was terminated early because of logistic reasons. So, we have to keep in mind, this was a smaller study, early termination, but the effect size was pretty large in favor of giving lytics. Dr. Negar Asdaghi: So, what you mentioned is interesting, and I think that it's really worth paying attention to, that the majority of the benefits seem to have occurred from intraarterial thrombolytics in patients that have not been given intravenous lytics prior to endovascular therapy. So, in other words, you need some sort of lytics either before or after the endovascular thrombectomy to achieve that ultimate improved outcome. So, moving forward now from the randomized trials that we have on bridging versus direct thrombectomy, you have mentioned in the paper some interesting subgroups that may benefit or not benefit as much from bridging versus direct thrombectomy. Do you want to elaborate a little more about those subgroup analyses? Dr. Bruce Campbell: The idea of precision selection or individualized treatment is being talked about a lot given there didn't seem to be much overall difference between strategies in the randomized trials, but it's important to note that the randomized trial actually disadvantages the bridging group by delaying lytic until the patient was firstly confirmed eligible for thrombectomy and then consented and randomized. Putting that aside, if we could identify a subgroup who clearly benefit from skipping lytic and, importantly, identify them without delaying lytic for those who likely benefit, that's clearly attractive. Dr. Bruce Campbell: Currently, I'd say we have not identified that kind of subgroup, and the planned IRIS individual patient data meta-analysis will be critical for that. Patients with a large ischemic core are one potential group where there's a high risk of bleeding hypothesized. To date, there is no definitive data to indicate the risk is lower with the direct approach. Patients who need stents certainly may benefit from not having a lytic on board because they often need adjuvant antithrombotics that could increase the bleeding risk. But the question there is whether we can confidently identify those patients before the procedure, and I think that's unclear at this stage. Patients with really large clot burdens and proximal occlusions have sometimes been said not to benefit from IV lytic based on the low rates of pre-endovascular reperfusion, but the randomized trials really hinted other benefits like this potential facilitative thrombectomy. So, that hypothesis may be insecure as well. Dr. Negar Asdaghi: And how about age? Have you come across and has there been any signal towards an impact or interaction between age and benefit from pre-endovascular thrombectomy and thrombolytics? Dr. Bruce Campbell: It's an interesting question because age has not generally been a treatment effect modifier in previous stroke studies with thrombolytics and thrombectomy, and the individual direct thrombectomy trials that have reported subgroups haven't shown any convincing heterogeneity by age. There's certainly no indication that older patients are at risk from bridging in what I've seen so far. Dr. Negar Asdaghi: So, this question comes up in clinical practice all the time, that a person's older, perhaps more atrophy, more vascular risk factors and white matter disease, and they're more prone, so to speak, of having a symptomatic intracerebral hemorrhage. So, what you're saying is, from the data we have, there's really no signal in favor of withholding pre-thrombectomy lytics in this population. So, it's important to know this. Bruce, what should be our final takeaway message from this study? Dr. Bruce Campbell: I tend to agree with the recent European Stroke Organization and ESMINT guideline that for now, patients should receive lytic as early as possible and in parallel with the decision to perform thrombectomy such that neither treatment delays the other. I think if we can identify a subgroup that benefits from direct thrombectomy, and that's confirmed in the individual patient data and meta-analysis, and we can identify them without disadvantaging the majority of patients, and also that the ongoing improvements in IV lytic strategies don't render the existing trial data obsolete, then we may, in future, skip lytic for some patients, but we are not there yet. Dr. Negar Asdaghi: So, that's amazing, Bruce. We look forward to reviewing the paper and individual data meta-analysis and interviewing you, hopefully at a better hour your time, on that. Thank you very much for joining us on the podcast today. Dr. Bruce Campbell: Thanks again for the invitation. It's been great talking to you. Dr. Negar Asdaghi: Thank you. Dr. Negar Asdaghi: And this concludes our podcast for the June 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three very interesting images that are presented as part of a new article type, Stroke Images, and a special report in Comments and Opinions section on "Bias in Stroke Evaluation: Rethinking the Cookie Theft Picture." June is the month of Pride, and in spirit of equality, we hope to do our part to reduce all biases in stroke processes of care, diagnosis, and outcomes as we continue to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 17 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2022 issue of Stroke: "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage" and "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns." She also interviews Dr. Bruce Campbell on his article "Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy." Dr. Negar Asdaghi: Let's start with some questions. 1) Is vitamin D that golden key to recovery from intracerebral hemorrhage? 2) Endovascular therapies seem to have prevailed where thrombolytics have failed. In the era of fast and furious thrombectomy, what is the role of pre-thrombectomy thrombolysis? 3) And finally, 20 years of clinical research has failed to demonstrate the superiority of anticoagulation over antiplatelet therapies for treatment of patients in sinus rhythm with low left ventricular ejection fraction, and yet, our practice patterns have not changed. Why do we remain resolute in prescribing anticoagulation despite the lack of evidence? We're back here to tackle the toughest questions with our Stroke Alert Podcast because this is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to another extremely motivating Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The June 2022 issue of Stroke contains a number of interesting articles. As part of our Advances in Stroke, we have two articles, one on the topic of cost-effectiveness of stroke care to inform health policy and the second on the current state and the future of emerging stroke therapies. As part of our Original Contributions category, we have an interesting study by Dr. [Ben] Assayag and colleagues from the Department of Neurology at Tel Aviv Sourasky Medical Center, where we learned that just over 10% of patients with TIA and stroke developed post-traumatic stress disorder, or PTSD. Higher presenting stroke severity, preexisting white matter disease, and having anxious coping styles are risk factors for development of post-stroke PTSD. Dr. Negar Asdaghi: In another Original Contribution, by Dr. Daehoon Kim and colleagues from Yonsei University College of Medicine in Seoul, South Korea, we read with interest on the topic of whether or not we should be anticoagulating frail patients with atrial fibrillation. In this large population-based cohort, which included patients with atrial fibrillation older than 65 years of age with frailty as defined by a score of equal or greater than five on Hospital Frailty Risk Score, we learned that despite their frailty, patients with atrial fibrillation still significantly benefit from oral anticoagulation therapy. In this study, those treated with anticoagulation had lower net adverse clinical events as compared to those untreated. We also learned that direct oral anticoagulants provided lower incidence of stroke, bleeding, and mortality over Coumadin. This paper really provided practical information on treatment of frail patients with atrial fibrillation. So, I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Bruce Campbell from University of Melbourne in Australia on an especially timely topic, that is the role of intravenous thrombolytics prior to endovascular therapy. Dr. Campbell is a leading authority on the topic, and his interview does not disappoint. But first, with these two articles. Dr. Negar Asdaghi: In the setting of intracerebral hemorrhage, or ICH, aside from the primary brain insult that occurs at the time of hemorrhage, secondary brain injuries continue for days and sometimes to months mostly due to the pathological response of the brain to byproducts of hematoma lysis or RBC degradation products. Today, the majority of spontaneous ICH cases are not surgically evacuated, so we rely on the body's own ability to clear blood for hematoma clearance, and obviously the faster the clearance, the better the outcome. Erythrophagocytosis by monocyte-derived macrophages contributes to hematoma clearance and ultimately to the functional recovery from ICH. So, it's conceivable that therapeutic approaches to enhance the endogenous erythrophagocytosis can potentially improve ICH outcomes. Vitamin D has been known to have variety of functions within the central nervous system, and it turns out that it may also be one such therapeutic option to improve the much needed erythrophagocytosis in intracerebral hemorrhage. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage," a group of researchers led by Dr. Jiaxin Liu from the Department of Surgery at Queen Mary Hospital at the University of Hong Kong studied the effects of oral vitamin D administered two hours after the induction of hematoma in a rodent model of ICH using direct collagenase injection into the striatum of the mouse. Eighty-nine young mice and 78 middle-aged mice were included in the study and randomly divided into three groups. Group one were sham-operated mice; group two, ICH mice treated with vehicle, which was corn oil; and group three, vitamin D-treated ICH mice. In the third group, 1000 international unit per kg of vitamin D diluted in corn oil was administered orally using a pipette two hours after the induction of ICH to mice, and then daily afterwards. And here are their top three findings of this study. Dr. Negar Asdaghi: Number one, vitamin D-treated mice did better than vehicle on two neurobehavioral tests that were completed in the study. On the cylinder test, treatment with vitamin D significantly alleviated the asymmetric usage of four limbs at day seven, and vitamin D elongated the duration that the mice could run on the accelerated rod at day 10 on the rotarod test. Dr. Negar Asdaghi: Number two, in terms of hematoma resolution and perihematoma edema, it's an issue that we deal with, with ICH, they used MRI imaging for edema measurement on T2-weighted images, and then sacrificed the mice and used digital quantification of hematoma volume with fresh brain specimens. And they found that treatment with vitamin D significantly alleviated both the ICH-associated brain swelling on MR and resulted in significant reduction in hematoma volume on the fresh brain specimens when compared with the vehicle-treated group at day three and day five. Dr. Negar Asdaghi: And finally, their third main finding is in terms of erythrophagocytosis. So, the pathway that is mediated by the monocyte-derived macrophages is an endogenous pathway, that is, PPAR-γ (which stands for peroxisome proliferator-activated receptor γ) and its downstream scavenger receptor CD36 mediated. This pathway is essential for directing the endogenous erythrophagocytosis. Using flow cytometry, they found that vitamin D-treated mice had more mature macrophages expressing the scavenger receptor CD36, which was not expressed by the undifferentiated monocytes. Dr. Negar Asdaghi: Western blot analysis confirmed that vitamin D treatment increased the tissue levels of CD36 and the upstream PPAR-γ levels in the brain at day five after collagenase model. Locally, vitamin D-enriched phagocytes that were positive for PPAR-γ and CD36 in the perihematoma regions. So, in summary, vitamin D increased the number of mature macrophages rather than undifferentiated monocytes in the perihematoma region and accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. So, bottom line is that in vitamin D, we have a simple, accessible, and well-tolerated agent to improve both the ICH outcomes and enhance hematoma resolution, but this we all observed in rodents. So, we stay tuned with interest to find out whether the same success will be seen in humans treated with vitamin D after intracerebral hemorrhage. Dr. Negar Asdaghi: Patients with depressed left ventricular ejection fraction, or low EF, are at risk of development of ischemic stroke even if they remain in sinus rhythm. The optimal antithrombotic treatment for these patients is still unknown. Over the past two decades, we have a number of randomized trials studying the efficacy of oral anticoagulation, predominantly Coumadin, over aspirin therapy in prevention of all forms of stroke, that is ischemic and hemorrhagic, and death in patients with a low EF in sinus rhythm. Dr. Negar Asdaghi: The meta-analysis of WASH, HELAS, WATCH, and WARCEF trials showed that treatment of low ejection fraction patients in sinus rhythm with Coumadin does reduce the subsequent risk of stroke, but it comes at the cost of a higher major bleeding risk in this population. The COMMANDER HF clinical trial published in New England Journal of Medicine in October 2018 studied whether low-dose rivaroxaban at 2.5 milligram BID was superior to placebo in patients with recent worsening of chronic heart failure, reduced ejection fraction, coronary artery disease, but no atrial fibrillation, and very similar to its prior counterparts, it did not show that rivaroxaban was associated with a lower rate of combined death, myocardial infarction, or stroke as compared to placebo. But very similar to prior studies, it also showed that rivaroxaban-treated patients had a lower risk of subsequent ischemic stroke. This poses a conundrum for stroke neurologists treating patients with this condition, especially after they present with an embolic-appearing stroke. So, the question is, how often do we encounter this situation, and what do we do in routine practice? We know that when there is equipoise, there's practice variation. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm," Dr. Richa Sharma from the Department of Neurology at Yale School of Medicine and colleagues examined the prevalence of heart failure with sinus rhythm among hospitalized patients with acute ischemic stroke and the physician's practice patterns with regard to the choice of antithrombotics in this population. Dr. Negar Asdaghi: So, let's look at their study. The study was comprised of five separate study cohorts of hospitalized acute ischemic stroke patients in the Greater Cincinnati Northern Kentucky Stroke Study for the year 2005, 2010, and 2015, and then four additional academic hospital-based cohorts in the United States during different timeframes. These were the Massachusetts General Hospital from 2002 to 2016, Rhode Island Hospital from 2016 to 2018, Yale-New Haven Hospital 2015 to 2017, and Cornell Acute Stroke Academic Registry from 2011 to 2018. All of these cohorts combined contributed to the 19,155 total number of patients in this study, which included over 14,000 patients that had documented left ventricular ejection fraction. Amongst those, 1,426 had a depressed EF and were included in this study. The investigator obviously excluded those with documented atrial fibrillation and flutter. And so the sample size for this analysis was 805 patients. And here are their main results. Dr. Negar Asdaghi: The overall prevalence of this condition, that is low ejection fraction and sinus rhythm, among hospitalized acute ischemic stroke patients was 5%. It varied slightly between the different cohorts in this study from 4 to 6%. In terms of the antithrombotic treatment patterns, this information was available in close to 500 patients in the cohort. Overall, 59% of patients were discharged on an antiplatelet treatment alone, and 41% on anticoagulation. But these percentages significantly varied between the different institutions and was as low as 22% in one of the cohorts and as high as 45% in another cohort. Dr. Negar Asdaghi: So, what were the factors that were associated with the use of anticoagulation at discharge? They found that the absolute percentage of left ventricular ejection fraction and the presenting NIH Stroke Scales were associated with anticoagulation use. That is, the lower the percentage of EF and the higher the presenting NIH Stroke Scale, the more likely physicians were to discharge the patients on an anticoagulation in univariate analysis, but in multivariate analysis, only the study site and presenting NIH Stroke Scale over eight were independently associated with anticoagulation use. Dr. Negar Asdaghi: Now, interestingly, 2002 to 2018, which was their overall study period, was a time during which some of the largest and neutral randomized trials on the topic of anticoagulation versus antiplatelet were published, including the WATCH and the WARCEF trial. But the authors found no temporal variation in anticoagulation practice patterns before and after the publication of the results of these trials. So, it appears that we didn't change our minds. So, overall, we have some important takeaway messages from this study. We learned that 5% of hospitalized acute ischemic stroke patients have low left ventricular ejection fraction and remain in sinus rhythm without atrial fibrillation. Today, over 40% of patients with this condition are anticoagulated at discharge despite the results of the randomized trials, but the practice is widely variable among different institutions, and a higher presenting NIH Stroke Scale is a significant predictor of anticoagulation use at discharge in this population. Dr. Negar Asdaghi: Almost 20 years after the approval of intravenous thrombolysis for treatment of patients with acute ischemic stroke, endovascular therapy was approved for treatment of select ischemic stroke patients with a large vessel occlusion. The two treatments are, therefore, entangled, as one was the standard of care while the second one was being tested. Therefore, all endovascularly treated patients enrolled in randomized trials would've received intravenous thrombolysis if eligible. Now, with the overwhelming success of endovascular therapy in achieving reperfusion in areas where IV thrombolysis has drastically failed, there're still critical questions regarding the added value of IV thrombolysis to endovascularly treated patients. The critical question remains as to whether eligible ischemic stroke patients who have immediate access to endovascular thrombectomy should receive prior IV thrombolysis, or should we skip the thrombolysis step altogether and just move to the angio suite as fast as possible. And there are, of course, arguments for and against each approach. Dr. Negar Asdaghi: In this issue of the journal, in an invited topical review titled "The Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy," we learn about these arguments as the authors go through a comprehensive review of the current literature on this issue. I'm joined today by the first author of this review, Dr. Bruce Campbell, to discuss this paper. Dr. Campbell absolutely needs no introduction to our Stroke listeners. He's a professor of neurology and head of neurology and stroke at Royal Melbourne Hospital, University of Melbourne, in Australia. He's a pioneer in the field of acute stroke therapies and acute neuroimaging. He has served as the lead investigator of multiple landmark randomized trials, including EXTEND-IA and EXTEND-IA TNK, and holds multiple leadership roles. He's the clinical director of the Stroke Foundation and co-chairs the Australian Stroke Guidelines Working Party and the coordinator of the National Brain School Training Program for Neurologists in Training. And, of course, last but not least, he's my friend. So, I'm delighted to welcome him to our podcast today. Top of the morning to you, Bruce, 6:00 a.m. in Melbourne. That's quite some dedication. Thank you for being here. Dr. Bruce Campbell: It's great to be with you. Thanks for the invitation. Dr. Negar Asdaghi: Congrats on the paper, really exciting topic. So, let's just start with this question as part of a case. We have a patient with an M1 occlusion, a large clinical syndrome presenting two hours out from their symptom onset, and we are at a hospital where the angio suite is ready. What are some of the benefits of basically spending time in giving IV thrombolytics first rather than quickly going to the angio suite? Dr. Bruce Campbell: I think a key element of this case is that the patient has presented directly to a hospital with immediate access to thrombectomy. Thrombolytic used in drip-and-ship transfer patients really isn't controversial, and the recent randomized trials excluded them. So, the debate's all about this context of bridging thrombolytics in patients presenting directly to a comprehensive stroke center. And you mentioned spending time giving lytics, but in fact, if you do things in parallel, that shouldn't be the case. It shouldn't delay thrombectomy if you go and give thrombolysis. Dr. Bruce Campbell: So, the general principle is that getting the artery open faster by any means is better, and IV thrombolytic certainly has the potential to open the artery before thrombectomy in a proportion of patients, perhaps not that many, but it may also facilitate the thrombectomy. So, in the randomized trials, reperfusion after the thrombectomy was significantly better when patients had had bridging thrombolytic despite a low rate of pre-endovascular reperfusion. Other reasons for giving the lytics are the potential safety net it provides if the thrombectomy procedure is unexpectedly delayed or fails to get the artery open, and there's also this potential for lytics to dissolve distal embolic fragments and perhaps improve microvascular reperfusion. Dr. Negar Asdaghi: So, great. So, let me summarize for our listeners what you mentioned. First off, so these are arguments in favor of giving lytics. As you mentioned, we're not really wasting time. These processes occur in parallel, so it's not like we're wasting time in giving a therapy that is potentially not as efficacious as thrombectomy is. And number two, we have improved the possibility of early reperfusion, perhaps, with the lytics. And if there are some fragments or distal clots that thrombectomy wouldn't have reached, then the lytics would. And then also there is also the chance that the thrombectomy might have failed in difficult access, and so on and so forth, and at least the patient has some chance of revascularization with the lytics. So, if these are the arguments for giving lytics, what are the arguments against giving lytics in this scenario? Dr. Bruce Campbell: The main argument is the potential to reduce both the intracerebral and systemic hemorrhagic complications. There's also potential cost saving by skipping thrombolytics. That's probably more relevant in low-resource settings, particularly when relatives may have to pay for the thrombolytic before treatment is initiated, and that can be burdensome and also potentially delay the thrombectomy. There's a theoretical concern about thrombus fragmentation with lytics and potential migration of the clot out of reach of the thrombectomy or to new territories. But final reperfusion, as I mentioned, was, on average, better with the patient having a lytic on board in the randomized trials. Dr. Negar Asdaghi: Perfect. And I want to highlight this issue of thrombus fragmentation because I think our readers will read more and more about this idea of, as you mentioned, fragmentation will potentially make an accessible clot for thrombectomy inaccessible. But I see that later in our questions, we're going to address that as part of the findings of randomized trials as well. So, these are some of the arguments for and against. And before we go to the randomized trials, I'd like to get an overview of what we knew as part of observational studies and non-randomized studies prior to more recent randomized trials on this topic. Dr. Bruce Campbell: There've been a couple of nice systematic reviews and meta-analyses of the observational data, and notably in most of these studies, the direct thrombectomy patients had contraindications to lytics, and that introduces confounding factors that are difficult to adjust for. For what that's worth, the functional independence, mortality outcomes were better in the bridging patients. Hemorrhage rates weren't always higher with the lytic, and one study by Jonathan Coutinho in JAMA Neurology for the SWIFT and STAR studies showed the opposite despite them having really careful adjustment for all the confounders they could think of. And the meta-analysis by Eva Mistry in Stroke did not detect a difference in symptomatic ICH between the direct and bridging strategies. One thing that should be less affected by the patient characteristics would be the technical efficacy outcomes, and it was interesting that in the observational data, the patients who'd had bridging lytic had higher mTICI 2b-3 rates and also fewer device passes. Dr. Negar Asdaghi: Okay. And now we do have further information with all of these new randomized trials. So, why don't we start with some of the earlier studies, the three, SKIP, DEVT, and DIRECT-MT, and start with those studies first before we move to some more recent European trials. Dr. Bruce Campbell: SKIP was performed in Japan, and it used the lower 0.6 milligram per kilogram dose of alteplase that's standard there, and DEVT and DIRECT-MT were performed in China. All three of them showed numerically similar functional outcomes with slight trends favoring direct thrombectomy. SKIP had a smaller sample size and did not meet its non-inferiority criteria, and the other two trials did meet their specified non-inferiority margin, but it could be argued those margins were overly generous. If you think about non-inferiority trials, we generally try to set a margin for non-inferiority such as lower 95% confidence interval for the trial intervention would sacrifice up to 50% of the reference treatment effect. And it's difficult to estimate the effect of alteplase in this specific population. But if you think of the Emberson meta-analysis of alteplase, overall zero to three hours alteplase versus placebo has a 10% effect size and mRS 0-1, three to four and a half hours of 5% effect size. And we regard that as clinically important. So, half of 5%, 2.5%, is a lot tighter margin than any of the direct randomized trials employed. Dr. Negar Asdaghi: So, Bruce, let me recap what you just mentioned. Two out of the three earlier trials seem to suggest that perhaps skipping IV therapy is the way to go rather than bridging as these two trials met the non-inferiority criteria if we believe that non-inferiority margins you mentioned. And now we have a couple of more trials, more recent trials. Can you tell us about these trials please? Dr. Bruce Campbell: MR CLEAN-NO IV in a European population did not demonstrate non-inferiority, and the point estimate slightly favored bridging. Interestingly, in that trial, the symptomatic intracerebral hemorrhage risk, which was one of the main drivers for trying this strategy, was 5.9% in the direct and 5.3 in the bridging group. So, there's no hint of benefit from dropping the lytic on that metric. SWIFT-DIRECT was more selective in only enrolling internal carotid and M1 occlusions, which had a lower chance of early recanalization with lytic. But the protocol also specified giving the full dose of lytic. In the other trials, it seems the alteplase infusion was often stopped once the patient was in the angio suite, so the full dose may not have been delivered. And despite very low pre-endovascular recanalization in that selected group in SWIFT-DIRECT, the end of procedure reperfusion was significantly better in the bridging group, which is a consistent finding across the trials and suggests that the lytic may improve the thrombectomy outcome. Dr. Bruce Campbell: DIRECT-SAFE, the final of those trials, was interesting in that the patients were enrolled roughly 50:50 from Australia, New Zealand, versus Asia. And in contrast to the original three randomized trials in Asian patients, DIRECT-SAFE found a significant benefit of bridging lytic in Asian patients. So, it'd be very interesting to see the results of the IRIS individual patient data meta-analysis, but we may not find a difference in Asian versus Caucasian patients despite those initial trials and despite substantial differences in the prevalence of intracranial atherosclerosis, which has often been proposed as something that would increase the risk of having bridging thrombolytic on board. Dr. Bruce Campbell: The original study level estimate of symptomatic hemorrhage had a borderline significant 1.8% absolute reduction in the direct group. Whether those data were not all core lab adjudicated and the final analysis may show a smaller difference than that. Notably, given that trend with symptomatic intracerebral hemorrhage, mortality did not differ significantly, and, in fact, the trend favored bridging patients. So, the symptomatic hemorrhage slight trend into increase did not translate into any hint of increased mortality. Dr. Negar Asdaghi: So, Bruce, a lot of information, and I need a recap for me. So, let me try to recap some of the things you said, and please jump in. So, so far, the newer data really basically don't show us any convincing evidence that skipping is the way to go, and direct endovascular we really don't have data in favor of going directly to the angio suite. And the jury is still out regarding an increase in the symptomatic intracerebral hemorrhage rate amongst those that actually are pre-treated with IV therapy. Is that correct? Dr. Bruce Campbell: That's correct. So, none of the three recent trials met their non-inferiority margins. And again, we had this issue of relatively generous non-inferiority margins, and the symptomatic hemorrhage, it would make sense that there's a small difference, but it's not really been borne out in the data to be statistically significant at this stage. And again, this individual patient data meta-analysis is keenly awaited to get the most accurate estimate on that. Dr. Negar Asdaghi: So, while we wait that, I'm going to digress a little bit and ask you a question that's not addressed in the paper that you have in this issue of the journal, and that's the CHOICE trial. So, by now, we have the results of CHOICE trial. Do you mind first give us a brief overview of what CHOICE was and how you feel that the results of CHOICE would affect this field of direct versus bridging in general? Dr. Bruce Campbell: CHOICE is a very interesting study in that it tested giving the intra-arterial lytic at the end of a thrombectomy procedure that had achieved an mTICI 2b or better, which is what we traditionally regarded as angiographic success. The idea was to improve microvascular flow, and that may be the case. The trial was terminated early due to logistic reasons and showed a very large effect size that requires replication. The subgroup analyses are interesting in that the benefits seem to mostly accrue in patients who'd not already had intravenous lytic. Dr. Bruce Campbell: So, perhaps giving the IV lytic before thrombectomy can still benefit patients after the thrombectomy, as well as achieving early recanalization in a proportion of patients and perhaps facilitating the thrombectomy. The other issue to address with the DIRECT trials is that with the exception of a few patients in DIRECT-SAFE, the comparator was alteplase and not tenecteplase. And we have data from EXTEND-IA TNK that tenecteplase bridging is not just non-inferior, but superior to alteplase bridging. There's an ongoing Brazilian trial of exactly that, tenecteplase versus the direct approach, which will be very interesting. Dr. Negar Asdaghi: So, great, Bruce. I just want to repeat this segment again for our listeners. So, CHOICE is a very interesting study, looked at giving intraarterial alteplase to patients after endovascular therapy was completed and after they'd already achieved the complete and successful revascularization, and the trial was terminated early because of logistic reasons. So, we have to keep in mind, this was a smaller study, early termination, but the effect size was pretty large in favor of giving lytics. Dr. Negar Asdaghi: So, what you mentioned is interesting, and I think that it's really worth paying attention to, that the majority of the benefits seem to have occurred from intraarterial thrombolytics in patients that have not been given intravenous lytics prior to endovascular therapy. So, in other words, you need some sort of lytics either before or after the endovascular thrombectomy to achieve that ultimate improved outcome. So, moving forward now from the randomized trials that we have on bridging versus direct thrombectomy, you have mentioned in the paper some interesting subgroups that may benefit or not benefit as much from bridging versus direct thrombectomy. Do you want to elaborate a little more about those subgroup analyses? Dr. Bruce Campbell: The idea of precision selection or individualized treatment is being talked about a lot given there didn't seem to be much overall difference between strategies in the randomized trials, but it's important to note that the randomized trial actually disadvantages the bridging group by delaying lytic until the patient was firstly confirmed eligible for thrombectomy and then consented and randomized. Putting that aside, if we could identify a subgroup who clearly benefit from skipping lytic and, importantly, identify them without delaying lytic for those who likely benefit, that's clearly attractive. Dr. Bruce Campbell: Currently, I'd say we have not identified that kind of subgroup, and the planned IRIS individual patient data meta-analysis will be critical for that. Patients with a large ischemic core are one potential group where there's a high risk of bleeding hypothesized. To date, there is no definitive data to indicate the risk is lower with the direct approach. Patients who need stents certainly may benefit from not having a lytic on board because they often need adjuvant antithrombotics that could increase the bleeding risk. But the question there is whether we can confidently identify those patients before the procedure, and I think that's unclear at this stage. Patients with really large clot burdens and proximal occlusions have sometimes been said not to benefit from IV lytic based on the low rates of pre-endovascular reperfusion, but the randomized trials really hinted other benefits like this potential facilitative thrombectomy. So, that hypothesis may be insecure as well. Dr. Negar Asdaghi: And how about age? Have you come across and has there been any signal towards an impact or interaction between age and benefit from pre-endovascular thrombectomy and thrombolytics? Dr. Bruce Campbell: It's an interesting question because age has not generally been a treatment effect modifier in previous stroke studies with thrombolytics and thrombectomy, and the individual direct thrombectomy trials that have reported subgroups haven't shown any convincing heterogeneity by age. There's certainly no indication that older patients are at risk from bridging in what I've seen so far. Dr. Negar Asdaghi: So, this question comes up in clinical practice all the time, that a person's older, perhaps more atrophy, more vascular risk factors and white matter disease, and they're more prone, so to speak, of having a symptomatic intracerebral hemorrhage. So, what you're saying is, from the data we have, there's really no signal in favor of withholding pre-thrombectomy lytics in this population. So, it's important to know this. Bruce, what should be our final takeaway message from this study? Dr. Bruce Campbell: I tend to agree with the recent European Stroke Organization and ESMINT guideline that for now, patients should receive lytic as early as possible and in parallel with the decision to perform thrombectomy such that neither treatment delays the other. I think if we can identify a subgroup that benefits from direct thrombectomy, and that's confirmed in the individual patient data and meta-analysis, and we can identify them without disadvantaging the majority of patients, and also that the ongoing improvements in IV lytic strategies don't render the existing trial data obsolete, then we may, in future, skip lytic for some patients, but we are not there yet. Dr. Negar Asdaghi: So, that's amazing, Bruce. We look forward to reviewing the paper and individual data meta-analysis and interviewing you, hopefully at a better hour your time, on that. Thank you very much for joining us on the podcast today. Dr. Bruce Campbell: Thanks again for the invitation. It's been great talking to you. Dr. Negar Asdaghi: Thank you. Dr. Negar Asdaghi: And this concludes our podcast for the June 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three very interesting images that are presented as part of a new article type, Stroke Images, and a special report in Comments and Opinions section on "Bias in Stroke Evaluation: Rethinking the Cookie Theft Picture." June is the month of Pride, and in spirit of equality, we hope to do our part to reduce all biases in stroke processes of care, diagnosis, and outcomes as we continue to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 16 of the Stroke Alert Podcast, Dr. Negar Asdaghi highlights two articles from the May issue of Stroke: "Number of Affected Relatives, Age, Smoking, and Hypertension Prediction Score for Intracranial Aneurysms in Persons With a Family History for Subarachnoid Hemorrhage" and "Endovascular Treatment for Acute Ischemic Stroke With or Without General Anesthesia." She also interviews Dr. Patrick Lyden on "The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results." Dr. Negar Asdaghi: Let's start with some questions. 1) How is it that stroke can be cured in rodents but not in humans? 2) Are we wasting time or gaining time with general anesthesia before endovascular thrombectomy? 3) My father had an aneurysmal subarachnoid hemorrhage, Doctor. What is my risk of having an aneurysm, and how often should we check for one? We're back here with the Stroke Alert Podcast to tackle the toughest questions in the field because this is the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to the May 2022 issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the May 2022 issue of Stroke, we have a number of papers that I'd like to highlight. We have seven articles as part of our Focused Update on the topic of neuroimmunology and stroke, organized by our own Stroke editors, Drs. Johannes Boltze and Miguel Perez-Pinzon. We also have an interesting study by Dr. David Saadoun and colleagues from Sorbonne University in Paris, where we learn that in patients with Takayasu disease, how the delay in diagnosis, as defined by the time from symptom onset to the diagnosis being over one year, was significantly associated with development of ischemic cerebrovascular events. In the Comments and Opinions section, we have an interesting study by Dr. Goldenberg and colleagues from University of Toronto on the benefits of GLP-1 receptor agonists for stroke reduction in type 2 diabetes and why should stroke neurologists be familiar with this new class of diabetic medication. Dr. Negar Asdaghi: Later, in the interview section of the podcast, I have the great honor of interviewing Dr. Patrick Lyden, one of the founding fathers of thrombolytic therapy in stroke, as he walks us through the Stroke Preclinical Assessment Network and what his hopes are for the future of stroke therapy. I also ask him for some advice, and he did tell us about the view from the top, as he truly stands on the shoulder of giants. But first with these two articles. Dr. Negar Asdaghi: In a landmark population-based study out of Sweden that was published in Brain in 2008, we learned that the odds of development of aneurysmal subarachnoid hemorrhage for individuals with one first-degree relative with a prior history of aneurysmal subarachnoid hemorrhage was 2.15. For individuals with two affected first-degree relatives, the odds ratio was 51. So, it's not surprising that a great deal of anxiety is caused within a family when a relative has an aneurysmal subarachnoid hemorrhage, especially if that family member was young or another member of the family had the same condition before. This scenario is commonly followed by a number of inevitable questions: Should all family members of the affected individual be screened for presence of an intracranial aneurysm? If yes, how often should vascular imaging be performed, and should other aneurysmal risk factors, such as age, sex, smoking, and hypertension, be also considered in the screening decision-making? In this issue of the journal, as part of a derivation-validation study, a group of investigators, led by Dr. Charlotte Zuurbier from University Medical Center at Utrecht Brain Center in the Netherlands, studied the ability of a simple scoring system that was developed in their derivation cohort to predict the presence of an intracranial aneurysm on vascular imaging. Dr. Negar Asdaghi: They then tested the scoring model in their validation cohort. So, for their development cohort, they used data on 660 persons who were screened at the University Medical Center for presence of an intracranial aneurysm because they had two or more affected first-degree relatives with a prior history of aneurysmal subarachnoid hemorrhage. The median age of participants at the time of first screening was 40, and 59% were female. Dr. Negar Asdaghi: So, in this cohort, the investigators simply looked at factors that were independently associated with finding an aneurysm on vascular screening by their multivariate analysis. And they identified the following factors; the first factor was the number of affected relatives. Now, a reminder that all of these people in the cohort had at least two first-degree relatives with an aneurysmal subarachnoid hemorrhage. And they found that amongst these people, those that had three or more family members with aneurysmal subarachnoid hemorrhage were significantly more likely to have a positive screening test for intracranial aneurysm. The next factor was older age — the older that relative, the more likely their screening imaging was positive for an aneurysm — and the other independent factors were smoking and hypertension. So they created the NASH acronym; N for number of relatives, A for age, S for smoking, and H for hypertension. When assigning points for each of these factors, the NASH scoring system had a C statistics of 0.68 in predicting whether or not someone would have a positive test, which is an intracranial aneurysm. Dr. Negar Asdaghi: And now a reminder for our listeners that C statistics gives us the probability that a person with a certain condition, in this case, a certain NASH score, will have the outcome of interest, in this case, an aneurysm found by vascular imaging. In general, for C statistics, the closer we get to 1, the more robust is our predictive model. Values over 0.7 indicate that we have a good model, but values over 0.8 indicate a very strong model. So the NASH score, at 0.68, has a reasonably good capability in predicting who will or will not have an intracranial aneurysm if we complete the vascular imaging. But it's not a very strong model, and this should be kept in mind. Let's look at some of their numbers. In their development cohort, the probability of finding an intracranial aneurysm for a person who scored low on NASH, that is a young person who never smoked and is not hypertensive, was only 5%, whereas the probability of finding an intracranial aneurysm in a person who scored high on NASH, that is an older person in their 60s or 70s, with three or more affected relatives, who is hypertensive and a smoker, was 36%. Dr. Negar Asdaghi: So, then they tested this NASH score in their external validation cohort and found that the likelihood of identifying an aneurysm increased as expected along the range of predicted probabilities of NASH. That is, the higher the score, the more likely to find an aneurysm on screening with vascular imaging. And the C statistics in the validation cohort was slightly lower than the C statistics in the derivation cohort. So, the important lesson we learned from this study is that the risk of having an intracranial aneurysm in a person who has a first-degree family member with a prior history of aneurysmal subarachnoid hemorrhage is substantially different depending on their NASH score, and this should be taken into consideration when deciding on screening and counseling various family members of the affected patient or prioritizing who should be screened first in routine practice. Dr. Negar Asdaghi: The ideal anesthetic management during endovascular therapy is still unknown. A number of studies have compared the different anesthetic options available during thrombectomy, which include general anesthesia, or GA, conscious sedation, use of local anesthesia, and no sedation at all. The main argument for doing endovascular therapy under general anesthesia is that although this procedure will take some precious pre-thrombectomy time, it does result in strict immobility. And that is really ideal in the sense that it improves catheter navigation and interpretation of angiography, in addition to obviously providing a secure airway and, of course, avoiding the need to have to do an emergency intubation in case of procedural complications. The argument against general anesthesia is not only the issue of time but also the risk of hypotension and hemodynamic compromise, especially during induction, and the loss of very valuable neurological examination in a completely sedated patient during the procedure. Dr. Negar Asdaghi: The question is, does general anesthesia improve or worsen neurological and functional outcomes post-thrombectomy? Several smaller randomized trials have looked at this very question, mainly comparing GA to all other forms of sedation during thrombectomy, but they have yielded inconsistent findings regarding the three-month functional outcome. Dr. Negar Asdaghi: Some of them showed that patients under GA ended up doing better. Some showed no difference in the overall outcomes. But overall, their pooled analysis suggested that GA might be superior to the competing counterpart, which is the conscious sedation, and associated with better functional outcome. But these centers had highly specialized anesthesia teams, and it's possible that their findings may not be generalizable to routine practice. So, in this issue of the journal, using the Swiss Stroke Registry, Dr. Benjamin Wagner from the Department of Neurology at the University Hospital in Basel and colleagues report on the outcomes of endovascularly treated patients in the Swiss Stroke Registry receiving thrombectomy for an anterior circulation stroke with or without general anesthesia. The primary outcome was disability on the modified Rankin Scale after three months. For this study, they excluded one out of the nine centers in the registry that had lots of missing data on their three-month follow-up. Dr. Negar Asdaghi: And so, from 2014 to 2017, 1,284 patients across eight stroke centers in the registry were included in this study. Sixty-six percent received thrombectomy under general anesthesia. On baseline comparison, the patients in the GA group were older, had a higher NIH Stroke Scale on admission, had worse preclinical functional status, and more likely to have presented with multi-territorial ischemic stroke. So, many reasons as to why people who underwent general anesthesia would have a worse clinical outcome in this study. So, now let's look at their primary outcome. In the unadjusted model, the three-month modified Rankin Scale was significantly worse in the GA group as compared to the non-GA group, which is obviously expected given the differences in their baseline characteristics. Dr. Negar Asdaghi: But what was surprising was that the odds of having a higher mRS score was significantly greater still in the adjusted models. They also did propensity score matching analysis, and they found that the NIH Stroke Scale after 24 hours, and the odds of dependency and death and mortality were all higher in the adjusted model in the GA group. They also looked at a number of secondary outcomes and found that door-to-puncture time was longer in the GA group. Dr. Negar Asdaghi: And also these patients were more likely to be transferred to ICU after treatment as compared to the non-GA treated counterparts. The authors point out that these real-world data are in keeping with the findings from the HERMES meta-analysis, which included over 1,700 endovascularly treated patients, and two previously published large registry data, one from Italy, which included over 4,000 endovascularly treated patients, and one from Germany, including 5,808 patients, all of them showing a worse functional outcome in endovascular therapy if the treatment was performed under general anesthesia, as compared to all other forms of sedation or no sedation at all. Again, these findings are in contrast with the reassuring results of the randomized trials on this topic, specifically in contrast to the AnStroke, SIESTA, and GOLIATH randomized trials, which compare GA to conscious sedation, showing either neutral or positive results in favor of general anesthesia pre-thrombectomy. Dr. Negar Asdaghi: So, in summary, what we learned from this real-world, observational study is that general anesthesia was associated with worse functional outcome post-endovascular thrombectomy, independent of other confounders, which means that the jury is still out on the ideal form of anesthesia for an individual patient prior to endovascular therapy, and we definitely need larger, multicenter studies on this topic. Dr. Negar Asdaghi: There are over a thousand experimental treatments that have shown benefit in prevention of neurological disability in animal models of ischemic stroke but have failed to show the same efficacy in human randomized trials. In fact, to date, reperfusion therapies, either in the form of intravenous lytic therapies or endovascular treatments, are the only successful treatments available to improve clinical outcomes in patients who suffer from ischemic stroke, and stroke remains a leading cause of death and disability worldwide. How come stroke can be cured in rodents but not in humans? Are neuroprotective therapies, or as more correctly referred to, the cerebroprotective therapies, the epitome of bench-to-bedside translational research failure? And if this is true, what are the key contributors to the scientific conundrum, and how can this be averted in the future? This is the question that a remarkable group of neuroscientists, led by Dr. Patrick Lyden from University of Southern California, are hoping to answer. Dr. Negar Asdaghi: In this issue of the journal, these investigators describe the rationale, design, feasibility, and stage 1 results of their multicenter SPAN collaboration, which stands for the Stroke Preclinical Assessment Network. I'm joined today by Professor Lyden himself to discuss this collaboration. Now, Professor Lyden absolutely needs no introduction to our stroke community, but as always, introductions are nice. So, here we go. Dr. Lyden is a Professor of Physiology, Neuroscience, and Neurology at Zilkha Neurogenetic Institute, Keck School of Medicine, at USC. He has truly been a leader in the field of preclinical and clinical vascular research with over 30 years of experience in conducting studies and randomized trials, including conducting the pivotal NINDS clinical trial that led to the approval of the first treatment for acute ischemic stroke in 1996. Throughout his exemplary career, he has accumulated many accolades and is the recipient of multiple awards and honors, including the prestigious 2019 American Stroke Association William Feinberg Award for Excellence in Clinical Stroke. Good morning, Pat, it's truly an honor to welcome you to our podcast today. Dr. Patrick Lyden: Thanks, I'm glad to be here. Dr. Negar Asdaghi: Well, in the era of successful reperfusion therapies, it seems that the new generation of stroke neurologists and interventionalists have their eyes, so to speak, on the clock and are interested in opening the blood vessels and opening them fast. In the age of reperfusion treatments, why do we still need to talk about the role of cerebroprotective treatments? Dr. Patrick Lyden: Well, not to sound too glib about it, but not everybody gets better after a thrombectomy. So, thrombectomy is good, it's more effective than anything else that we've tried before, but there are a remaining number of patients with a residual disability. Not only that, and from a more scientific standpoint, thrombectomy offers us the opportunity now to combine cerebroprotective therapy with known reperfusion. Remember, before, we didn't know when the artery had opened, but now we do an embolectomy, we know there's reperfusion. It gives us the opportunity to know that we're combining our treatment with reperfusion. Dr. Negar Asdaghi: So, in the paper, you discussed how hundreds of treatments have been studied and shown efficacy in reducing neurological disability in animal models of stroke, and yet failed in human studies. In your opinion, what were the top two most disappointing studies in terms of clinical failure despite pre-clinical encouraging data? Dr. Patrick Lyden: Well, the first one I mentioned was personal because it was the first one that I led, and it was a molecule called clomethiazole that I had helped establish the rationale for in my very first grant. So, it was the first trial I led, it was multinational, and, of course, I firmly believed we were going to hit a home run, and we failed. But to the field, the real watershed moment in neuroprotective therapy was the so-called SAINT II Trial. SAINT II was a study of a drug called NXY-059, and it was the first drug that purportedly had satisfied all of the so-called STAIR criteria. The STAIR criteria came out of a roundtable between academics and industry on how to best qualify drugs preclinically before going to human trials. And the idea was, if you were a 10 out of 10 on the STAIR criteria, then you should win when you come to human clinical trials. And the SAINT II Trial, which I was a co-leader, a co-investigator, on, also failed. Dr. Patrick Lyden: And so many, many, many drugs had failed by that point. Tens of millions, if not a hundred million dollars, had been spent by industry, and SAINT II really caused the field to stop. Industry stopped investing in stroke; academic investment in stroke dried up. NIH funding became more difficult to get after SAINT II, and that really was sort of the really historical low moment in the development of treatment for stroke. Dr. Negar Asdaghi: I was a resident when SAINT II came out, and I remember that somber feeling. Dr. Patrick Lyden: It was a sad day. Dr. Negar Asdaghi: Yeah. So, in the paper, you outline a number of potential causes as to why this translational failure may have occurred. But you highlighted the absence of preclinical scientific rigor as the most responsible source. And you already alluded to this a little bit. Can you please tell us a bit more? Dr. Patrick Lyden: Absolutely. And first, of course, we have to say that the ideal clinical trial design is not available. We really don't know the absolute best way to test the drugs in human clinical trials. But leave that for another day. Dr. Patrick Lyden: On the preclinical side, what can we say we're doing wrong? We're not sure, but one thing that has been highlighted over and over is that we don't approach preclinical characterization with as much rigor as we should. What do I mean by that? Animal models recapitulate for us some of the biology of a stroke, but not all. For example, many, many times we test a drug in a young model, an animal that's quite young, corresponding to a late teenager in human terms. Well, that's ridiculous. Stroke occurs in elderly people, and so on. So, the NIH called in a landmark conference for additional rigor, enhanced rigor. And I should mention the STAIR criteria were a first attempt at this. STAIR put out guidelines that said animals should be elderly, the animals should be randomized, et cetera, et cetera. And so that didn't happen. Although the STAIR criteria were out there, very few laboratories really committed to full rigor. And so the NIH funded the Stroke Preclinical Assessment Network, SPAN, to implement every aspect that we could think of that would add the best possible scientific design, the utmost rigor. So, we implemented true blinded assessment, true randomization, complete case ascertainment where we follow every single subject in the study and account for dropouts and subjects that don't complete the treatment, and, most importantly, a proper statistical design with adequate power and very large numbers. And the hypothesis that we're testing is that additional rigor in SPAN will lead to a better positive predictive value when we think about drugs that should go forward for testing in human stroke trials. Dr. Negar Asdaghi: So, I think you already answered my next question, which was basically, why do you think SPAN is going to achieve what all others have failed to achieve? But I wanted to simplify and repeat what you mentioned. So, in simple terms, what SPAN is trying to do is to bring all preclinical research to a level of scientific rigor that was not necessarily present and make it a multicenter effort. And can you a little bit tell us about the different stages, again, of SPAN? Dr. Patrick Lyden: Well, I'm not arguing that all preclinical research needs to be done following a SPAN type of model. Where SPAN fits in is at the end of a development project. So, if you want to characterize the cellular and molecular mechanisms, you don't need to do all of this rigor that we're doing. Just study the drug in the lab and do the mechanistic studies that need to be done. If you want to do dose finding, it doesn't need to be done this way. But at the end of that, OK, first we establish the mechanism, that's the first stage. Then we establish the toxicity. Then we establish target engagement. At the end, we are looking for some evidence that the drug will have a beneficial effect on outcomes. And in previous animal models, the only outcome, generally, the most common outcome that was studied, was size of the stroke. But in humans, the FDA does not recognize stroke size as a valid outcome. Dr. Patrick Lyden: We look at function, most often measured with the Rankin score and the NIH Stroke Scale. So, we had to create a functional outcome, and then we had to study it at multiple laboratories to make sure we could replicate the effect across multiple sites. And we chose what's called a multi-arm, multi-stage (MAMS) statistical design. All the drugs start out in the experiment at the end of the first interim analysis, which is 25% of the sample size. We cull any compounds or treatments that appear futile are removed. Any that appear effective move on. At the end of the second stage, there's more culling. There's a total of four stages, and we're about to enter stage four, by the way. That's starting next week. And in stage four, there will be, at most, two, maybe only one treatment that has appeared non-futile and possibly effective for final characterization. Dr. Negar Asdaghi: So, really interesting. I just want to highlight two important comments that you mentioned for our listeners again. So this is multi-layer, as you mentioned, multi-arm, multi-stages. It's sort of filter by filter, just ensuring that what we're seeing, the efficacy we're seeing in preclinical studies, will potentially be replicated in clinical studies. And what you mentioned that's very important is outcomes that classically is measured in animal models are infarct volume that are obviously very important but not necessarily may translate to exactly what we look at in clinical studies, which is functional outcomes, modified Rankin score and NIH Stroke Scale. So, with that, I want to then come back to the treatments that are actually being studied as part of SPAN. You have six very different agents as part of SPAN, from tocilizumab to uric acid. Why do you think these therapies will work? Dr. Patrick Lyden: Well, my job as the PI of the coordinating center is to remain completely agnostic to the treatments. So, everybody's equal, and they all come in on an equal playing field. We actually have a mechanical treatment called remote ischemic conditioning, as well, and then five drugs. And these were selected through a peer review process at NIH. And then we were informed at the coordinating center what drugs we would be studying. Five drugs and one treatment. And then, of course, the challenge to us was to somehow create a blinded, randomized situation. Now, this turned out to be a fascinating, it's more mechanical, but how do you blind when some of the drugs are given orally, some are given intraperitoneally, some are given intravenously, some are given once, some are given multiple times? So, we had to work with the manufacturers and inventors of these drugs and figure out a way to package them, and in the paper, actually, there's a photograph in the appendix that shows we had to find these bottles that were amber-colored and how to load them and lyophilize the drug. Dr. Patrick Lyden: And it's actually pretty fascinating how we were able to get all of these different, wildly different therapies, as you say, into a paradigm where they could be tested one against another in a truly blinded, truly randomized way. Dr. Negar Asdaghi: Do you think you can go on record and say which one is your favorite? Dr. Patrick Lyden: My favorite drug's not even in SPAN. I am truly agnostic because where my heart is, is with a drug that I've been studying in my laboratory completely separately and not part of SPAN. Dr. Negar Asdaghi: All right, so we don't have a favorite. So, in a recent review article in Stroke, you commented on treatments used by ancient Persians, Greeks, and Romans to remedy the brain affected by stroke and how the future generation of physicians will look back at our current practices of stroke with the same, how you said, awe and bemusement we hold for Galen, Aristotle, and Avicenna. How do you think stroke will be treated in the year 2222? Dr. Patrick Lyden: Well, first of all, and to be serious for just one moment, 200 years from now, I worry more about the climate than about medicine. And I really believe our biggest efforts need to be spent on saving the planet. But assuming we make it that long, obviously diagnostic methods will be completely different. Using ionizing radiation to scan the body will be laughed at by physicians in the future. There'll be detection technologies that aren't even on our radar yet today. And then treatments will be cellular focused and regionally focused. We give a drug through a vein and it circulates throughout the entire body, and I'm sure physicians in the future will find a way to somehow get treatment into the part of the body that's injured, not the whole body. And then, who knows? All we can say is they will laugh at us in the same way that we laugh at Theodoric the Barber of York. Dr. Negar Asdaghi: Let's move on from the future to the past. You're arguably one of the founding fathers of reperfusion therapies. You were instrumental in getting intravenous lytic therapy approved in 1996. It literally took the field 20 years for the next treatment to be approved, that's endovascular treatment. If you could go back in time and give your young self an advice on the subject of research, of course, design and execution, what advice would you give yourself? Dr. Patrick Lyden: Don't listen to old guys. We got a lot of advice from gray-bearded folks back when we were putting together the tPA trial, and fortunately we ignored some very bad advice and did what we imagined was the right thing to do as young, headstrong up-and-comers do. The other thing is, we really believed that by publishing our science very objectively, without editorial comment, we would be listened to. And that was dead wrong. So, the data was printed in the New England Journal in a very neutral tone, and we felt people would read that data and they would start using tPA the day after the publication. And, as you say, it took 20 years for tPA to really gain widespread acceptance, thrombolytic therapy. Today, people view it as standard, but it wasn't that way at the beginning. And I would say to myself and my colleagues at that time, "Don't be afraid to promote a positive result." Yes, it has to be done with the utmost rigor, but once you have a positive result, there will be plenty of people around pretending they know more than you and telling the world why you are wrong. And it's very important to stand up for your science and stand up for your results and say, no, no, no, no, that interpretation is wrong. The data says what we said it says, and this is an effective treatment and should be used, as an example. Dr. Negar Asdaghi: What a great advice. Just be bold and say it loud and stand up for your science. Pat, it's been a pleasure interviewing you and having you on the podcast. We really look forward to watching your research. Bring, let me say it again, 2222 closer to now. Dr. Patrick Lyden: Thank you. Glad to be here. Dr. Negar Asdaghi: Thank you. Dr. Negar Asdaghi: And this concludes our podcast for the May 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including two articles on quality improvement in stroke and neurohospitalist—inpatient teleneurology, which comes as part of our Advances in Stroke series prepared by our section editors. And as we close our podcast today, let's take a moment and ask ourselves the same question that I asked Dr. Lyden earlier. What is the next frontier in stroke treatment? Past reperfusion therapies, we have to find ways to preserve the neurons and not just the neurons, all components of the brain. So, is the future of stroke therapy cerebroprotection? Ever since the dawn of history, humanity has lived alongside of death with the conscious apprehension that as we age, we lose the very gift of life. But unlike our ancestors, the search for immortality isn't the quest to find a fountain of youth anymore. We learned that death is inevitable, but with medicine, we can reduce illness and suffering to prolong a life worth living, one with a healthy brain. And today we're closer than ever to this modern immortality with cerebroprotection in stroke, as we stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 16 of the Stroke Alert Podcast, Dr. Negar Asdaghi highlights two articles from the May issue of Stroke: "Number of Affected Relatives, Age, Smoking, and Hypertension Prediction Score for Intracranial Aneurysms in Persons With a Family History for Subarachnoid Hemorrhage" and "Endovascular Treatment for Acute Ischemic Stroke With or Without General Anesthesia." She also interviews Dr. Patrick Lyden on "The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results." Dr. Negar Asdaghi: Let's start with some questions. 1) How is it that stroke can be cured in rodents but not in humans? 2) Are we wasting time or gaining time with general anesthesia before endovascular thrombectomy? 3) My father had an aneurysmal subarachnoid hemorrhage, Doctor. What is my risk of having an aneurysm, and how often should we check for one? We're back here with the Stroke Alert Podcast to tackle the toughest questions in the field because this is the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to the May 2022 issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the May 2022 issue of Stroke, we have a number of papers that I'd like to highlight. We have seven articles as part of our Focused Update on the topic of neuroimmunology and stroke, organized by our own Stroke editors, Drs. Johannes Boltze and Miguel Perez-Pinzon. We also have an interesting study by Dr. David Saadoun and colleagues from Sorbonne University in Paris, where we learn that in patients with Takayasu disease, how the delay in diagnosis, as defined by the time from symptom onset to the diagnosis being over one year, was significantly associated with development of ischemic cerebrovascular events. In the Comments and Opinions section, we have an interesting study by Dr. Goldenberg and colleagues from University of Toronto on the benefits of GLP-1 receptor agonists for stroke reduction in type 2 diabetes and why should stroke neurologists be familiar with this new class of diabetic medication. Dr. Negar Asdaghi: Later, in the interview section of the podcast, I have the great honor of interviewing Dr. Patrick Lyden, one of the founding fathers of thrombolytic therapy in stroke, as he walks us through the Stroke Preclinical Assessment Network and what his hopes are for the future of stroke therapy. I also ask him for some advice, and he did tell us about the view from the top, as he truly stands on the shoulder of giants. But first with these two articles. Dr. Negar Asdaghi: In a landmark population-based study out of Sweden that was published in Brain in 2008, we learned that the odds of development of aneurysmal subarachnoid hemorrhage for individuals with one first-degree relative with a prior history of aneurysmal subarachnoid hemorrhage was 2.15. For individuals with two affected first-degree relatives, the odds ratio was 51. So, it's not surprising that a great deal of anxiety is caused within a family when a relative has an aneurysmal subarachnoid hemorrhage, especially if that family member was young or another member of the family had the same condition before. This scenario is commonly followed by a number of inevitable questions: Should all family members of the affected individual be screened for presence of an intracranial aneurysm? If yes, how often should vascular imaging be performed, and should other aneurysmal risk factors, such as age, sex, smoking, and hypertension, be also considered in the screening decision-making? In this issue of the journal, as part of a derivation-validation study, a group of investigators, led by Dr. Charlotte Zuurbier from University Medical Center at Utrecht Brain Center in the Netherlands, studied the ability of a simple scoring system that was developed in their derivation cohort to predict the presence of an intracranial aneurysm on vascular imaging. Dr. Negar Asdaghi: They then tested the scoring model in their validation cohort. So, for their development cohort, they used data on 660 persons who were screened at the University Medical Center for presence of an intracranial aneurysm because they had two or more affected first-degree relatives with a prior history of aneurysmal subarachnoid hemorrhage. The median age of participants at the time of first screening was 40, and 59% were female. Dr. Negar Asdaghi: So, in this cohort, the investigators simply looked at factors that were independently associated with finding an aneurysm on vascular screening by their multivariate analysis. And they identified the following factors; the first factor was the number of affected relatives. Now, a reminder that all of these people in the cohort had at least two first-degree relatives with an aneurysmal subarachnoid hemorrhage. And they found that amongst these people, those that had three or more family members with aneurysmal subarachnoid hemorrhage were significantly more likely to have a positive screening test for intracranial aneurysm. The next factor was older age — the older that relative, the more likely their screening imaging was positive for an aneurysm — and the other independent factors were smoking and hypertension. So they created the NASH acronym; N for number of relatives, A for age, S for smoking, and H for hypertension. When assigning points for each of these factors, the NASH scoring system had a C statistics of 0.68 in predicting whether or not someone would have a positive test, which is an intracranial aneurysm. Dr. Negar Asdaghi: And now a reminder for our listeners that C statistics gives us the probability that a person with a certain condition, in this case, a certain NASH score, will have the outcome of interest, in this case, an aneurysm found by vascular imaging. In general, for C statistics, the closer we get to 1, the more robust is our predictive model. Values over 0.7 indicate that we have a good model, but values over 0.8 indicate a very strong model. So the NASH score, at 0.68, has a reasonably good capability in predicting who will or will not have an intracranial aneurysm if we complete the vascular imaging. But it's not a very strong model, and this should be kept in mind. Let's look at some of their numbers. In their development cohort, the probability of finding an intracranial aneurysm for a person who scored low on NASH, that is a young person who never smoked and is not hypertensive, was only 5%, whereas the probability of finding an intracranial aneurysm in a person who scored high on NASH, that is an older person in their 60s or 70s, with three or more affected relatives, who is hypertensive and a smoker, was 36%. Dr. Negar Asdaghi: So, then they tested this NASH score in their external validation cohort and found that the likelihood of identifying an aneurysm increased as expected along the range of predicted probabilities of NASH. That is, the higher the score, the more likely to find an aneurysm on screening with vascular imaging. And the C statistics in the validation cohort was slightly lower than the C statistics in the derivation cohort. So, the important lesson we learned from this study is that the risk of having an intracranial aneurysm in a person who has a first-degree family member with a prior history of aneurysmal subarachnoid hemorrhage is substantially different depending on their NASH score, and this should be taken into consideration when deciding on screening and counseling various family members of the affected patient or prioritizing who should be screened first in routine practice. Dr. Negar Asdaghi: The ideal anesthetic management during endovascular therapy is still unknown. A number of studies have compared the different anesthetic options available during thrombectomy, which include general anesthesia, or GA, conscious sedation, use of local anesthesia, and no sedation at all. The main argument for doing endovascular therapy under general anesthesia is that although this procedure will take some precious pre-thrombectomy time, it does result in strict immobility. And that is really ideal in the sense that it improves catheter navigation and interpretation of angiography, in addition to obviously providing a secure airway and, of course, avoiding the need to have to do an emergency intubation in case of procedural complications. The argument against general anesthesia is not only the issue of time but also the risk of hypotension and hemodynamic compromise, especially during induction, and the loss of very valuable neurological examination in a completely sedated patient during the procedure. Dr. Negar Asdaghi: The question is, does general anesthesia improve or worsen neurological and functional outcomes post-thrombectomy? Several smaller randomized trials have looked at this very question, mainly comparing GA to all other forms of sedation during thrombectomy, but they have yielded inconsistent findings regarding the three-month functional outcome. Dr. Negar Asdaghi: Some of them showed that patients under GA ended up doing better. Some showed no difference in the overall outcomes. But overall, their pooled analysis suggested that GA might be superior to the competing counterpart, which is the conscious sedation, and associated with better functional outcome. But these centers had highly specialized anesthesia teams, and it's possible that their findings may not be generalizable to routine practice. So, in this issue of the journal, using the Swiss Stroke Registry, Dr. Benjamin Wagner from the Department of Neurology at the University Hospital in Basel and colleagues report on the outcomes of endovascularly treated patients in the Swiss Stroke Registry receiving thrombectomy for an anterior circulation stroke with or without general anesthesia. The primary outcome was disability on the modified Rankin Scale after three months. For this study, they excluded one out of the nine centers in the registry that had lots of missing data on their three-month follow-up. Dr. Negar Asdaghi: And so, from 2014 to 2017, 1,284 patients across eight stroke centers in the registry were included in this study. Sixty-six percent received thrombectomy under general anesthesia. On baseline comparison, the patients in the GA group were older, had a higher NIH Stroke Scale on admission, had worse preclinical functional status, and more likely to have presented with multi-territorial ischemic stroke. So, many reasons as to why people who underwent general anesthesia would have a worse clinical outcome in this study. So, now let's look at their primary outcome. In the unadjusted model, the three-month modified Rankin Scale was significantly worse in the GA group as compared to the non-GA group, which is obviously expected given the differences in their baseline characteristics. Dr. Negar Asdaghi: But what was surprising was that the odds of having a higher mRS score was significantly greater still in the adjusted models. They also did propensity score matching analysis, and they found that the NIH Stroke Scale after 24 hours, and the odds of dependency and death and mortality were all higher in the adjusted model in the GA group. They also looked at a number of secondary outcomes and found that door-to-puncture time was longer in the GA group. Dr. Negar Asdaghi: And also these patients were more likely to be transferred to ICU after treatment as compared to the non-GA treated counterparts. The authors point out that these real-world data are in keeping with the findings from the HERMES meta-analysis, which included over 1,700 endovascularly treated patients, and two previously published large registry data, one from Italy, which included over 4,000 endovascularly treated patients, and one from Germany, including 5,808 patients, all of them showing a worse functional outcome in endovascular therapy if the treatment was performed under general anesthesia, as compared to all other forms of sedation or no sedation at all. Again, these findings are in contrast with the reassuring results of the randomized trials on this topic, specifically in contrast to the AnStroke, SIESTA, and GOLIATH randomized trials, which compare GA to conscious sedation, showing either neutral or positive results in favor of general anesthesia pre-thrombectomy. Dr. Negar Asdaghi: So, in summary, what we learned from this real-world, observational study is that general anesthesia was associated with worse functional outcome post-endovascular thrombectomy, independent of other confounders, which means that the jury is still out on the ideal form of anesthesia for an individual patient prior to endovascular therapy, and we definitely need larger, multicenter studies on this topic. Dr. Negar Asdaghi: There are over a thousand experimental treatments that have shown benefit in prevention of neurological disability in animal models of ischemic stroke but have failed to show the same efficacy in human randomized trials. In fact, to date, reperfusion therapies, either in the form of intravenous lytic therapies or endovascular treatments, are the only successful treatments available to improve clinical outcomes in patients who suffer from ischemic stroke, and stroke remains a leading cause of death and disability worldwide. How come stroke can be cured in rodents but not in humans? Are neuroprotective therapies, or as more correctly referred to, the cerebroprotective therapies, the epitome of bench-to-bedside translational research failure? And if this is true, what are the key contributors to the scientific conundrum, and how can this be averted in the future? This is the question that a remarkable group of neuroscientists, led by Dr. Patrick Lyden from University of Southern California, are hoping to answer. Dr. Negar Asdaghi: In this issue of the journal, these investigators describe the rationale, design, feasibility, and stage 1 results of their multicenter SPAN collaboration, which stands for the Stroke Preclinical Assessment Network. I'm joined today by Professor Lyden himself to discuss this collaboration. Now, Professor Lyden absolutely needs no introduction to our stroke community, but as always, introductions are nice. So, here we go. Dr. Lyden is a Professor of Physiology, Neuroscience, and Neurology at Zilkha Neurogenetic Institute, Keck School of Medicine, at USC. He has truly been a leader in the field of preclinical and clinical vascular research with over 30 years of experience in conducting studies and randomized trials, including conducting the pivotal NINDS clinical trial that led to the approval of the first treatment for acute ischemic stroke in 1996. Throughout his exemplary career, he has accumulated many accolades and is the recipient of multiple awards and honors, including the prestigious 2019 American Stroke Association William Feinberg Award for Excellence in Clinical Stroke. Good morning, Pat, it's truly an honor to welcome you to our podcast today. Dr. Patrick Lyden: Thanks, I'm glad to be here. Dr. Negar Asdaghi: Well, in the era of successful reperfusion therapies, it seems that the new generation of stroke neurologists and interventionalists have their eyes, so to speak, on the clock and are interested in opening the blood vessels and opening them fast. In the age of reperfusion treatments, why do we still need to talk about the role of cerebroprotective treatments? Dr. Patrick Lyden: Well, not to sound too glib about it, but not everybody gets better after a thrombectomy. So, thrombectomy is good, it's more effective than anything else that we've tried before, but there are a remaining number of patients with a residual disability. Not only that, and from a more scientific standpoint, thrombectomy offers us the opportunity now to combine cerebroprotective therapy with known reperfusion. Remember, before, we didn't know when the artery had opened, but now we do an embolectomy, we know there's reperfusion. It gives us the opportunity to know that we're combining our treatment with reperfusion. Dr. Negar Asdaghi: So, in the paper, you discussed how hundreds of treatments have been studied and shown efficacy in reducing neurological disability in animal models of stroke, and yet failed in human studies. In your opinion, what were the top two most disappointing studies in terms of clinical failure despite pre-clinical encouraging data? Dr. Patrick Lyden: Well, the first one I mentioned was personal because it was the first one that I led, and it was a molecule called clomethiazole that I had helped establish the rationale for in my very first grant. So, it was the first trial I led, it was multinational, and, of course, I firmly believed we were going to hit a home run, and we failed. But to the field, the real watershed moment in neuroprotective therapy was the so-called SAINT II Trial. SAINT II was a study of a drug called NXY-059, and it was the first drug that purportedly had satisfied all of the so-called STAIR criteria. The STAIR criteria came out of a roundtable between academics and industry on how to best qualify drugs preclinically before going to human trials. And the idea was, if you were a 10 out of 10 on the STAIR criteria, then you should win when you come to human clinical trials. And the SAINT II Trial, which I was a co-leader, a co-investigator, on, also failed. Dr. Patrick Lyden: And so many, many, many drugs had failed by that point. Tens of millions, if not a hundred million dollars, had been spent by industry, and SAINT II really caused the field to stop. Industry stopped investing in stroke; academic investment in stroke dried up. NIH funding became more difficult to get after SAINT II, and that really was sort of the really historical low moment in the development of treatment for stroke. Dr. Negar Asdaghi: I was a resident when SAINT II came out, and I remember that somber feeling. Dr. Patrick Lyden: It was a sad day. Dr. Negar Asdaghi: Yeah. So, in the paper, you outline a number of potential causes as to why this translational failure may have occurred. But you highlighted the absence of preclinical scientific rigor as the most responsible source. And you already alluded to this a little bit. Can you please tell us a bit more? Dr. Patrick Lyden: Absolutely. And first, of course, we have to say that the ideal clinical trial design is not available. We really don't know the absolute best way to test the drugs in human clinical trials. But leave that for another day. Dr. Patrick Lyden: On the preclinical side, what can we say we're doing wrong? We're not sure, but one thing that has been highlighted over and over is that we don't approach preclinical characterization with as much rigor as we should. What do I mean by that? Animal models recapitulate for us some of the biology of a stroke, but not all. For example, many, many times we test a drug in a young model, an animal that's quite young, corresponding to a late teenager in human terms. Well, that's ridiculous. Stroke occurs in elderly people, and so on. So, the NIH called in a landmark conference for additional rigor, enhanced rigor. And I should mention the STAIR criteria were a first attempt at this. STAIR put out guidelines that said animals should be elderly, the animals should be randomized, et cetera, et cetera. And so that didn't happen. Although the STAIR criteria were out there, very few laboratories really committed to full rigor. And so the NIH funded the Stroke Preclinical Assessment Network, SPAN, to implement every aspect that we could think of that would add the best possible scientific design, the utmost rigor. So, we implemented true blinded assessment, true randomization, complete case ascertainment where we follow every single subject in the study and account for dropouts and subjects that don't complete the treatment, and, most importantly, a proper statistical design with adequate power and very large numbers. And the hypothesis that we're testing is that additional rigor in SPAN will lead to a better positive predictive value when we think about drugs that should go forward for testing in human stroke trials. Dr. Negar Asdaghi: So, I think you already answered my next question, which was basically, why do you think SPAN is going to achieve what all others have failed to achieve? But I wanted to simplify and repeat what you mentioned. So, in simple terms, what SPAN is trying to do is to bring all preclinical research to a level of scientific rigor that was not necessarily present and make it a multicenter effort. And can you a little bit tell us about the different stages, again, of SPAN? Dr. Patrick Lyden: Well, I'm not arguing that all preclinical research needs to be done following a SPAN type of model. Where SPAN fits in is at the end of a development project. So, if you want to characterize the cellular and molecular mechanisms, you don't need to do all of this rigor that we're doing. Just study the drug in the lab and do the mechanistic studies that need to be done. If you want to do dose finding, it doesn't need to be done this way. But at the end of that, OK, first we establish the mechanism, that's the first stage. Then we establish the toxicity. Then we establish target engagement. At the end, we are looking for some evidence that the drug will have a beneficial effect on outcomes. And in previous animal models, the only outcome, generally, the most common outcome that was studied, was size of the stroke. But in humans, the FDA does not recognize stroke size as a valid outcome. Dr. Patrick Lyden: We look at function, most often measured with the Rankin score and the NIH Stroke Scale. So, we had to create a functional outcome, and then we had to study it at multiple laboratories to make sure we could replicate the effect across multiple sites. And we chose what's called a multi-arm, multi-stage (MAMS) statistical design. All the drugs start out in the experiment at the end of the first interim analysis, which is 25% of the sample size. We cull any compounds or treatments that appear futile are removed. Any that appear effective move on. At the end of the second stage, there's more culling. There's a total of four stages, and we're about to enter stage four, by the way. That's starting next week. And in stage four, there will be, at most, two, maybe only one treatment that has appeared non-futile and possibly effective for final characterization. Dr. Negar Asdaghi: So, really interesting. I just want to highlight two important comments that you mentioned for our listeners again. So this is multi-layer, as you mentioned, multi-arm, multi-stages. It's sort of filter by filter, just ensuring that what we're seeing, the efficacy we're seeing in preclinical studies, will potentially be replicated in clinical studies. And what you mentioned that's very important is outcomes that classically is measured in animal models are infarct volume that are obviously very important but not necessarily may translate to exactly what we look at in clinical studies, which is functional outcomes, modified Rankin score and NIH Stroke Scale. So, with that, I want to then come back to the treatments that are actually being studied as part of SPAN. You have six very different agents as part of SPAN, from tocilizumab to uric acid. Why do you think these therapies will work? Dr. Patrick Lyden: Well, my job as the PI of the coordinating center is to remain completely agnostic to the treatments. So, everybody's equal, and they all come in on an equal playing field. We actually have a mechanical treatment called remote ischemic conditioning, as well, and then five drugs. And these were selected through a peer review process at NIH. And then we were informed at the coordinating center what drugs we would be studying. Five drugs and one treatment. And then, of course, the challenge to us was to somehow create a blinded, randomized situation. Now, this turned out to be a fascinating, it's more mechanical, but how do you blind when some of the drugs are given orally, some are given intraperitoneally, some are given intravenously, some are given once, some are given multiple times? So, we had to work with the manufacturers and inventors of these drugs and figure out a way to package them, and in the paper, actually, there's a photograph in the appendix that shows we had to find these bottles that were amber-colored and how to load them and lyophilize the drug. Dr. Patrick Lyden: And it's actually pretty fascinating how we were able to get all of these different, wildly different therapies, as you say, into a paradigm where they could be tested one against another in a truly blinded, truly randomized way. Dr. Negar Asdaghi: Do you think you can go on record and say which one is your favorite? Dr. Patrick Lyden: My favorite drug's not even in SPAN. I am truly agnostic because where my heart is, is with a drug that I've been studying in my laboratory completely separately and not part of SPAN. Dr. Negar Asdaghi: All right, so we don't have a favorite. So, in a recent review article in Stroke, you commented on treatments used by ancient Persians, Greeks, and Romans to remedy the brain affected by stroke and how the future generation of physicians will look back at our current practices of stroke with the same, how you said, awe and bemusement we hold for Galen, Aristotle, and Avicenna. How do you think stroke will be treated in the year 2222? Dr. Patrick Lyden: Well, first of all, and to be serious for just one moment, 200 years from now, I worry more about the climate than about medicine. And I really believe our biggest efforts need to be spent on saving the planet. But assuming we make it that long, obviously diagnostic methods will be completely different. Using ionizing radiation to scan the body will be laughed at by physicians in the future. There'll be detection technologies that aren't even on our radar yet today. And then treatments will be cellular focused and regionally focused. We give a drug through a vein and it circulates throughout the entire body, and I'm sure physicians in the future will find a way to somehow get treatment into the part of the body that's injured, not the whole body. And then, who knows? All we can say is they will laugh at us in the same way that we laugh at Theodoric the Barber of York. Dr. Negar Asdaghi: Let's move on from the future to the past. You're arguably one of the founding fathers of reperfusion therapies. You were instrumental in getting intravenous lytic therapy approved in 1996. It literally took the field 20 years for the next treatment to be approved, that's endovascular treatment. If you could go back in time and give your young self an advice on the subject of research, of course, design and execution, what advice would you give yourself? Dr. Patrick Lyden: Don't listen to old guys. We got a lot of advice from gray-bearded folks back when we were putting together the tPA trial, and fortunately we ignored some very bad advice and did what we imagined was the right thing to do as young, headstrong up-and-comers do. The other thing is, we really believed that by publishing our science very objectively, without editorial comment, we would be listened to. And that was dead wrong. So, the data was printed in the New England Journal in a very neutral tone, and we felt people would read that data and they would start using tPA the day after the publication. And, as you say, it took 20 years for tPA to really gain widespread acceptance, thrombolytic therapy. Today, people view it as standard, but it wasn't that way at the beginning. And I would say to myself and my colleagues at that time, "Don't be afraid to promote a positive result." Yes, it has to be done with the utmost rigor, but once you have a positive result, there will be plenty of people around pretending they know more than you and telling the world why you are wrong. And it's very important to stand up for your science and stand up for your results and say, no, no, no, no, that interpretation is wrong. The data says what we said it says, and this is an effective treatment and should be used, as an example. Dr. Negar Asdaghi: What a great advice. Just be bold and say it loud and stand up for your science. Pat, it's been a pleasure interviewing you and having you on the podcast. We really look forward to watching your research. Bring, let me say it again, 2222 closer to now. Dr. Patrick Lyden: Thank you. Glad to be here. Dr. Negar Asdaghi: Thank you. Dr. Negar Asdaghi: And this concludes our podcast for the May 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including two articles on quality improvement in stroke and neurohospitalist—inpatient teleneurology, which comes as part of our Advances in Stroke series prepared by our section editors. And as we close our podcast today, let's take a moment and ask ourselves the same question that I asked Dr. Lyden earlier. What is the next frontier in stroke treatment? Past reperfusion therapies, we have to find ways to preserve the neurons and not just the neurons, all components of the brain. So, is the future of stroke therapy cerebroprotection? Ever since the dawn of history, humanity has lived alongside of death with the conscious apprehension that as we age, we lose the very gift of life. But unlike our ancestors, the search for immortality isn't the quest to find a fountain of youth anymore. We learned that death is inevitable, but with medicine, we can reduce illness and suffering to prolong a life worth living, one with a healthy brain. And today we're closer than ever to this modern immortality with cerebroprotection in stroke, as we stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 15 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the April 2022 issue of Stroke: "Kawasaki Disease May Increase the Risk of Subsequent Cerebrovascular Disease" and "Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage." She also interviews Dr. François Gros-Louis about his article "Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function." Dr. Negar Asdaghi: 1) How would you counsel the parent of a child who has just recovered from Kawasaki disease on their child's future risk of having a stroke? 2) Should we or should we not treat stress hyperglycemia in the setting of acute intracerebral hemorrhage? 3) What is the CRISPR-Cas9 gene editing technology? And why, if you haven't heard of it already, you most definitely should be listening to this podcast? We're back here with the April issue of the Stroke Alert Podcast, and this is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to another extremely informative Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine, and your host for the monthly Stroke Alert Podcast. The April 2022 issue of Stroke contains a range of really exciting papers and topics. In the paper titled "Vascular Response to Spreading Depolarization Predicts Stroke Outcome," we have a really interesting in vivo mouse model of ischemic stroke, looking at the spreading patterns of cortical depolarization and the subsequent vascular response to this by way of hyperemia. The researchers from Zurich University, led by Dr. Binder and colleagues, walk us through how the patterns of hyperemia can actually predict the severity of subsequent ischemic injury. Dr. Negar Asdaghi: In a separate paper in this issue of the journal, we're reminded of how the classic NIH Stroke Scale can underestimate the severity of neurological symptoms and outcomes in patients with posterior circulation infarcts. In the paper led by Dr. Alemseged and colleagues, the investigators from the Royal Melbourne Hospital in Australia evaluate the prognostic accuracy of the Posterior NIH Stroke Scale, which is the modified version of the classic NIH Stroke Scale, in predicting the outcomes of patients with posterior circulation infarcts. Dr. Negar Asdaghi: I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. François Gros-Louis from Laval University in Quebec to discuss the latest in gene editing technology and how this technology has helped his team unravel the biological function of RNF213 susceptibility gene in Moyamoya disease. But first with these two articles. Dr. Negar Asdaghi: Kawasaki disease, which was first described in 1976, is an acute febrile illness predominantly affecting children younger than five years of age. In addition to fever, other clinical signs of the disease include rash, bilateral conjunctival injection, cervical lymphadenopathy, swelling of the hands and feet, and irritation and inflammation of the mouth, lips, and throat. Now, for those of us like me who are adult neurologists, here is a quick review of the pathophysiology of Kawasaki disease. Dr. Negar Asdaghi: This is a medium vessel vasculopathy, most significantly affecting the coronary arteries, a vasculopathy that is characterized by three linked pathological processes, necrotizing arteritis, subacute to chronic vasculitis, and luminal myofibroblastic proliferation. So, simply put, these processes can lead to stenotic lesions in various vascular beds, which are affected by this disease. Dr. Negar Asdaghi: And as we mentioned earlier, the most recognized vascular blood vessels affected by Kawasaki disease are the coronary arteries, which can lead to myocardial ischemia, infarction, and sudden death in these cases. However, involvement of other vascular beds, including cerebral vessels, are also increasingly reported as part of Kawasaki disease. Dr. Negar Asdaghi: So, in the current issue of the journal, Dr. Chien-Heng Lin from the Division of Pediatric Pulmonology at China Medical University Children's Hospital in Taiwan and colleagues studied the subsequent risk of cerebrovascular events in patients with Kawasaki disease. Using the National Health Insurance Research Database of Taiwan, they collected data on 8467 children with Kawasaki disease from 2000 to 2012. And for each child with Kawasaki, data was also collected on four randomly selected non-Kawasaki disease children who were matched with the Kawasaki cohort for sex, urbanization level of residence, and parental occupation. Dr. Negar Asdaghi: So, that gave them a sample size of over 33,000 children for their non-Kawasaki cohort. And then they compared the risk of subsequent stroke in children between the two cohorts. The study period for any given patient would end when the said patient was either diagnosed with a cerebrovascular disease or withdrew from the research database. Dr. Negar Asdaghi: So, in terms of their demographics, 61% of patients in the Kawasaki group were boys; 88% of the Kawasaki cohort were younger than five years of age. So, here are the findings. Number one, the incident rate of subsequent cerebrovascular disease was 14.7 per hundred thousand person years in the Kawasaki cohort versus only 4.6 per hundred thousand person years in the non-Kawasaki cohort. That's greater than a threefold higher incidence rate of cerebrovascular disorders for children who had Kawasaki disease before. Dr. Negar Asdaghi: This finding was independent of other potential confounders, which they adjusted for in their multivariate analysis. Now, the length of follow up was a median of 9.8 years for the entire cohort. And on the issue of time, they found two important associations. The first finding was that when the follow-up time was stratified by five-year periods, Kawasaki disease cohort patients showed a significantly higher risk of developing a stroke within the first five years after being diagnosed. Dr. Negar Asdaghi: And the second important association was that when they looked at the age at the time of diagnosis of Kawasaki, children who were younger than five years at the time of diagnosis were at a significantly higher risk of having a future stroke as compared to those who were older than five at the time of diagnosis. Dr. Negar Asdaghi: So, simply put, the risk of subsequent stroke was higher in children who acquired the disease at a younger age, and that risk was higher in the first few years after the diagnosis of Kawasaki disease. The authors discuss a number of putative mechanisms to link Kawasaki with stroke. The most important being a cardiac source of embolism that we already alluded to, but other etiologies, including medium vessel cerebral vasculitis, or hypercoagulability in the setting of increased systemic inflammation, and even Kawasaki disease-associated aneurysmal rupture to cause hemorrhagic forms of stroke, are discussed in the paper and should be considered in the correct setting in children with a prior history of this disease. Dr. Negar Asdaghi: So, what we learned from this large population-based pediatric study is that Kawasaki disease does indeed increase the risk of subsequent cerebrovascular disorders, and its influence is stronger in children who are diagnosed with this condition under the age of five, and the time period during which the risk of stroke is the highest is within the first five years after the diagnosis. Dr. Negar Asdaghi: In the setting of spontaneous intracerebral hemorrhage, or ICH, much research has focused on the association between hypertension and blood pressure-lowering therapies and hematoma expansion and functional outcomes, but a lot less attention relatively has been given to the impact of hyperglycemia and ICH-related outcomes. Dr. Negar Asdaghi: The current guidelines state that serum glucose should be monitored and both hypo- and hyperglycemia should be avoided in the setting of ICH. The older studies have given us inconsistent results as to whether or not hyperglycemia can increase the risk of ICH-related mortality. More recent studies have suggested that perhaps persistent hyperglycemia is indeed a predictor of poor neurological outcomes in ICH, but these results come from smaller single-center studies, which require further confirmation. And this confirmation is exactly what Dr. Adnan Qureshi from Zeenat Qureshi Stroke Institute and the Department of Neurology at University of Missouri and colleagues aim to give us in their study titled "Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage." Dr. Negar Asdaghi: So, they use data from the ATACH-2 study, and a quick reminder that ATACH-2 was a multicenter randomized control trial of a thousand patients with acute spontaneous intracerebral hemorrhage enrolled within four and a half hours from symptom onset, and patients were randomized to either the intensive blood pressure control treatment arm to maintain their systolic blood pressure goal of 110 to 139 millimeter of mercury versus standard treatment arm, which was keeping their systolic blood pressure above 140, between 140 to 179 millimeter of mercury, in the first 24 hours after randomization. Dr. Negar Asdaghi: You will recall that enrollment of ATACH-2 was stopped early because of futility after pre-specified interim analysis. The main results of the trial was published in 2016 in New England Journal of Medicine, and the primary results did not show a lower rate of death or disability in patients assigned to the intensive treatment group. Dr. Negar Asdaghi: So, in the current paper, in this current issue of the journal, the authors looked at the glycemic status of the patients enrolled in the trial. As part of the trial, patients had a complete chemistry panel at baseline, 24, 48, and 72 hours from onset. So, they used the glucose measurement from this panel and defined moderate hyperglycemia as serum glucose level of over 140 and under 180 and severe hyperglycemia as serum glucose levels of equal or greater than 180. Dr. Negar Asdaghi: Now, persistent hyperglycemia was if two consecutive serum glucose levels were in the moderate or severe categories. And, very simply, they looked at the effects of hyperglycemia on ICH outcomes. And importantly, they evaluated whether hyperglycemia modified the effects of intensive blood pressure reduction on outcomes of ICH. So, of the thousand participants in ATACH-2, 11% had persistent moderate hyperglycemia, and 17% had severe persistent hyperglycemia. Those in the hyperglycemic group were more likely to be diabetic, not surprisingly, more likely to have a history of hypertension and dyslipidemia as compared to the normal glycemic patients. Dr. Negar Asdaghi: And here are the results. Number one, serious adverse events were higher in the hyperglycemic groups, whether we're talking about the moderate or the severe hyperglycemic groups. This is despite the fact that the rate of hematoma expansion and perihematomal edema was not different based on the hyperglycemic status. However, the hyperglycemic patients were more likely to have serious adverse events, which were operationally defined as complications that were not expected to have occurred from the study intervention, in this case, the intensive hypertensive therapy, and resulted in either death or prolonged hospitalization or persistent or significant disabilities. Now, serious renal adverse events, which are, of course, expected as a complication for aggressive blood pressure therapy, were also significantly higher in the hyperglycemic category. Dr. Negar Asdaghi: Now, their next important finding was that overall, both moderate and severe hyperglycemia was associated with higher odds of 90 days disability or death post-ICH adjusting for typical variables that could predict these outcomes, such as GCS score, hematoma volume, presence or absence of intraventricular hemorrhage, amongst other factors that they accounted for. Dr. Negar Asdaghi: Now, number three, this is perhaps the most important finding of the study. Among patients without a preexisting history of diabetes, both moderate and severe hyperglycemia increased the risk of death and disability at 90 days after adjusting for all the potential confounders, but hyperglycemia was not associated with these poor outcomes in those with a prior history of diabetes. I'm going to pause here to let this information sink in. Let's go over them again, stress hyperglycemia in non-diabetics was associated with poor ICH outcomes, but high sugars in diabetics did not predict the same poor outcomes. And finally, they looked at the possible interactions between the glycemic status and the ATACH-2 intervention, which as we alluded to earlier, which was intensive versus standard blood pressure therapy, and it turns out that the intensive systolic blood pressure reduction was indeed associated with a lower rate of hematoma expansion only in patients with normal glycemia, but not in those with moderate or severe hyperglycemia. Dr. Negar Asdaghi: So, this is again food for thought. Simply put, if the sugars are not well controlled, it appears that intensive blood pressure control would not lower the rate of hematoma expansion. Blood pressure lowering works when the sugar levels are controlled. So, overall, here are the two simple messages of this study. Number one, hyperglycemia in the acute setting of intracerebral hemorrhage is associated with poor outcomes or death only in those with stress hyperglycemia, meaning in those who have high sugar levels, but are not diabetic. Dr. Negar Asdaghi: Number two, there seems to be an important interaction between the acute glycemic status of the patients and how intensive blood pressure control can prevent hematoma expansion, in that intensive BP control is only effective in prevention of hematoma expansion if the sugar levels are normal. So, a lot of thought-provoking and hypothesis-generating findings, and definitely more to come on this topic. Dr. Negar Asdaghi: Moyamoya disease, or MMD, is an idiopathic disorder characterized by progressive stenosis of the supraclinoid internal carotid artery and its main branches in subsequent formation of a network of abnormal lenticulostriate collaterals. First described in Japan, the term "Moyamoya" is a Japanese expression for the puff of smoke and describes the characteristic appearance of the tangled and abnormal collateral vessels that are seen in angiography in various stages of the Moyamoya disease. Dr. Negar Asdaghi: Epidemiological studies have revealed several risk factors associated with Moyamoya disease, including Asian ethnicity, female gender, and a family history of the disorder. Given that 15% of MMD patients have a family history of this disease, it's not surprising that genetic factors are suspected to underlie its pathogenesis. Now, a polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17 has been identified as the strongest genetic susceptibility factor for Moyamoya disease specifically in the East Asian population. Dr. Negar Asdaghi: But despite the many advances in understanding the pathophysiology of MMD, as well as advances in animal models and genetic studies, to date, none of the animal models of RNF213 have quite replicated the vascular abnormalities that are typically seen in human Moyamoya disease. Dr. Negar Asdaghi: The scientists feel that this is related to how little is known about the exact biological function of RNF213 gene and the protein it encodes. So, in the current issue of the journal, in the study titled "Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function," Dr. François Gros-Louis from CHU de Québec Research Center at Laval University in Québec and colleagues aim to study the biological functions of RNF213 using a novel genome editing technology by the name of CRISPR-Cas9 technology. Dr. Negar Asdaghi: Joining me now is Dr. Gros-Louis himself to discuss the findings of this paper. Dr. Gros-Louis is a Professor of Neurosciences at the Department of Surgery at Laval University. He holds the Canada Research Chair in Brain Disease Modeling and is the Director of the Induced Pluripotent Stem Cell Platform research in Québec. Dr. Negar Asdaghi: Good morning, François. Welcome to our podcast. And thank you so much for joining us. Dr. François Gros-Louis: My pleasure. Dr. Negar Asdaghi: François, you have to promise to hold my clinician's hand through this interview as obviously these are some foreign subjects for us, but very excited to learn from your study and learn from you on the association between RNF213 and the pathophysiology of what happens in Moyamoya disease. Now, before we talk about your paper, can you please talk to us about some basic concepts? What is the RNF213 protein? Dr. François Gros-Louis: Yes. The RNF213 gene is thought to be involved in mediating protein, protein interactions. The protein also contains a domain which is associated with an ATPase activity. This gene is a susceptibility gene for Moyamoya disease, as you mentioned in the introduction, vascular disorder of intracranial arteries. It's encoded in ubiquitously expressed protein. The protein is found to be expressed throughout the cytocell with the partial association in the intracellular membrane and cytoskeleton. Its expression varies according to the tested tissue type or location or cellular types. Dr. François Gros-Louis: Although the function of RNF213 protein is unknown, studies suggest that it plays a role in the proper development of blood vessels, cell proliferation, and inflammation. Recently, RNF213 has been reported to be associated with angiogenesis. However, little is known about its endogenous function or its pathogenic role in Moyamoya disease. Our results are in line with these results and indicate that RNF213 could also be a key regulator of cerebral endothelial integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. Dr. Negar Asdaghi: So, just to continue on this, there's quite a bit of research already done on association of the RNF213 gene, that's located, as we noted earlier, on chromosome 17, and basically susceptibility of development of Moyamoya disease. Can you give our listeners a brief overview of this genetic connections and what was known from past research? Dr. François Gros-Louis: Yeah, there is a couple polymorphism describing this gene, the most frequent, the most prevalent genetic study have identified the variant R4810K, meaning for arginine is replaced by another amino acid at the position of 4810 within the protein. It's a large protein and a large gene and a susceptible gene and a risk factor for developing Moyamoya disease. Dr. François Gros-Louis: So, people bearing this variant have a higher chance to develop the disease. This is a loss of function variant, also called inactivating mutation, meaning that the mutated gene product have less or no function. So, this variant is found in heterozygous, meaning one copy, or two copy homozygous in Moyamoya disease patients. While patient bearing homozygous mutation develop a more severe disease with earlier age of onset and worse prognosis, patients bearing heterozygous mutation can also develop the disease. Dr. François Gros-Louis: So, strong evidence suggests that the carrying rate of RNF213 R4810K mutant is closely related and give a higher chance to develop the disease. Interestingly, also with colleagues, we found that there are other variants within this genes leading to what we think is a gain of function mutation have been associated also with other cerebrovascular disease, such as intracranial aneurysms. Dr. Negar Asdaghi: So, François, this is very interesting. Let me recap what you mentioned so I know that I understood it. So, this is an interesting gene, this RNF213, and basically evidence shows that mutations in the RNF213, whether it's loss of function or gain of function, both can result in variety of cerebrovascular disorders. And interestingly, the phenotype of the disease when it comes to loss of function of this gene is actually correlated with whether a person is a carrier, homozygous carrier of this gene, loss of function, or heterozygous carrier of the gene. Dr. Negar Asdaghi: So, very interesting information for clinicians who treat patients with Moyamoya disease, specifically those who have a family history of Moyamoya disease, so perhaps a higher chance of carrying a genetic susceptibility gene. Now, we want to get to the paper that you published in this issue of the journal, but I think before we talk about your paper, we also have to have a basic understanding of this CRISPR-Cas9 technology, which is the new genome editing technology that you use in your experiments. Can you please give us a little bit of an overview of this technology? Dr. François Gros-Louis: Yes. CRISPR-Cas9 gene editing is genetic engineering technique in molecular biology by which the genomes of living organisms may be modified. This technology allows genetic material to be added, removed, or altered at particular location in the genome. Several approaches to genome editing have been developed. Recent one is known as CRISPR-Cas9. So, the CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, and more accurate, and also more efficient than other existing genome editing methods. It's clearly revolutionizing the field in research. Dr. Negar Asdaghi: So, it's very exciting. It's truly a new chapter in gene targeting research and editing research. So, now we're ready to hear about your study. And I guess the first part of the study was just to look at how various cells in vitro that you used had expressed RNF213. Can you please tell us about the first part of your experiments? Dr. François Gros-Louis: Yeah. We first wanted to know where the protein is expressed or where the protein is more highly expressed. So, we found by doing immunofluorescence analysis that the RNF213, so we confirmed that it's ubiquitously expressed in the cytoplasm of different cellular types. So, we found that significant difference also in the expression of RNF213 protein levels in several endothelial cells, where we found it's been highly expressed when compared to other endothelial cells isolated from different other body location, meaning outside of the CNS. So, it's highly expressed also when compared to smooth muscle cells or fibroblasts. Dr. Negar Asdaghi: Okay. So, just again, to recap for our listeners, this is, this RNF213 protein, is ubiquitously expressed in many different cell types, but you did find a significantly higher expression rates in endothelial cells, specifically those endothelial cells that were derived from cerebrovasculature. So, that's the first exciting part of the experiments that you showed in the study. Now, using the CRISPR-Cas9 technology, you and your team were able to successfully create an in vitro RNF213 knockout model. Can you please tell us about these models and also the main findings of your study? Dr. François Gros-Louis: Yeah, so taken together, the results we presented in the article indicate that RNF213 could be a key regulator of cerebral, endothelial and tight junctions integrity whose disruption could be an early pathological mechanisms leading to Moyamoya disease. So, we established for the first time an easily reproducible and stable in vitro 3D model generated using the CRISPR-Cas9 gene editing technology. Dr. François Gros-Louis: This advanced 3D culture approach has emerged as an excellent system to recapitulate histopathological feature reminiscent to disease pathogenesis. So, 3D cell culture approach is different from standard 2D culture, where cells are cultured, monolayered into a Petri dish. And we have results showing that the 3D cell culture system better mimic the in vivo conditions in terms of cell to cell and cell to matrix interaction and lead to histopathological phenotypic feature can be observed in cell culture, in a 3D fashion. Quite interestingly, alongside of providing the first evidence for the role of RNF213, the maintenance of endothelial barrier and the potential implication of this gene in the expression of maturation of tight junctions. So, we define a novel role for PECAM-1 as well in barrier impairment as a part of the disease pathogenic mechanisms. Dr. Negar Asdaghi: Okay. And now this is really interesting. So, I wanted to, again, recap some of the important points that you raised here. First of all, your in vitro models are different than the classic in vitro models, where 2D cells were basically grown in a Petri dish. You are trying to, more and more, replicating what happens, for instance, in blood vessels, where you have endothelial cells overlying mesenchymal cells underneath them, so tunica intima and then tunica media, and so you have 3D cells, where various types of cells are overlying each other in a more in vivo representation of what happens in blood vessels, which is truly interesting. Dr. Negar Asdaghi: And what you found was, in sort of summary, was that these knockout endothelial cells ended up having abnormal tight junctions and abnormal connectivity, which basically would lead in an in vivo model to abnormal leaky blood brain barrier, if this were truly in the in vivo model. Does that summarize the findings of the paper? Dr. François Gros-Louis: Yes, perfectly. Dr. Negar Asdaghi: Perfect. And so I want to also give us a chance to talk about the important pro-inflammatory aspects of these knockout cells. You did find that a number of cytokines were expressed in excess in those RNF213 deficient cells. Can you please elaborate on those findings? Dr. François Gros-Louis: So, to further investigate whether inflammation plays an important role in RNF213-associated Moyamoya disease development, we indeed performed experiments to study pro-inflammatory cytokines and analyze the immune secretome profiles of cerebral RNF213 deficient endothelial cells. So, then the cells can secrete different cytokines or different other proteins. So, by analyzing the secretome, we found an end secretion of a few pro-inflammatory cytokines indicating that inflammation may also play a central role in the initiation of the immune response in the pathogenesis of the disease. Dr. Negar Asdaghi: So, this is exciting, François. For years, we thought about the pathophysiology of Moyamoya disease as a disorder involving large vessels. And perhaps the initial thought was that it starts with excessive proliferation of smooth muscles within the middle layer of the cerebral blood vessels, in tunica media, and then perhaps subsequently there will be other abnormalities, including the intimal hyperplasia that is classically seen in Moyamoya. Dr. Negar Asdaghi: Your study seems to propose a shift in that pathophysiological paradigm, where the problem seems to start from endothelial cells, so inside of the blood vessels and the tunica intima, and then gradually would go out to the middle layers, and, of course, proposes the hyperinflammatory state in the Moyamoya disease as well. So truly interesting. Do you think that that is the new or rather a paradigm shift for pathophysiology of MMD? Dr. François Gros-Louis: That's a great question. Our results certainly demonstrated that endothelial cells are involving in the disease pathogenesis in Moyamoya disease, but it doesn't exclude the possibility that other cell types might also be involved in the disease pathogenesis. We know, like you mentioned, that a blood vessel is formed by two different cell layers, tunica intima, media, and adventitia, containing, respectively, endothelial cells, smooth muscle cells, and fibroblasts. So which cells are to be blamed in Moyamoya disease is a question of many ongoing results studies over the years. Dr. François Gros-Louis: So, using tissue-engineered approach to reconstruct small caliber blood vessels, as we developed in my lab, in combination with patient-derived stem cells, in which adult cells isolated from a patient of any individuals can be reprogrammed into stem cells and re-differentiated into different cell types in occurrence, smooth muscle, fibroblasts, or endothelial cells. We would like to generate blood vessels in which each of the different cellular layers will harbor or not, or a combination with RNF213 mutants. So, this will hopefully help us to elucidate this question. Dr. Negar Asdaghi: That's perfect. So, François, before we end the interview, I wanted to ask two more questions. So, what should be our top two takeaway messages from your study? Dr. François Gros-Louis: We believe that the innovative transdisciplinary approach to generate, for the first time, as we describe in the article, an in vitro 3D model recapitulating important diseases features. So, this model could become a unique tool in precision medicine to study Moyamoya disease or other RNF213-associated pathologies. So, our study provides, for the first time, role of RNF213 in the maintenance of blood-brain barrier and the potential implication of RNF213 in the expression and maturation of tight junctions. Taken together, our data define a novel role for PECAM-1 in the blood-brain barrier impairment in Moyamoya disease. Dr. François Gros-Louis: So, better characterization of each, also this regulated inflammatory molecules, we found taken separately could reveal a crucial information and help elaborate a more precise approach. Hence, this pro-inflammatory signature could be used as a circulatory biomarker for the follow-up of Moyamoya disease patients and to manage an appropriate treatment, according to the pathology progression. Dr. Negar Asdaghi: François, this is great. And last, I want to digress a little bit and ask you about the future of gene editing. I think it's important to end our interview with a little bit of a discussion regarding the future of CRISPR-Cas9 technology. In subatomic quantum physics, people talk about the God particles. And I feel that the CRISPR-Cas9 technology is, in a way, like playing God, if you agree. What do you think is the future for gene editing, and how do you see that helping us in terms of treatment of genetic causes of cerebrovascular disorders? Dr. François Gros-Louis: Yes, gene editing is, like I said, revolutionizing, of course, experimental therapies for genetic disorder and generated excitement for new and improved gene therapies. We can think that it will be possible to correct any gene mutations associated with a disease to reestablish the normal or natural gene function and help treating the targeted diseases. But also, to me, the future of genome editing also resides in optimizing next generation disease models. The use of genome editing, in particular, the CRISPR-Cas9 technology, has extended to potential in generating new personalized model for a number of disorder, not only including Moyamoya disease or other cerebrovascular diseases, but also diseases like Alzheimer's, ALS, or Parkinson's disease, for which obtaining patient sample is difficult. Dr. François Gros-Louis: No one wants to give up a bit of his brain. So modeling it, this disease, in vitro will be really helpful in combination also gene editing with the stem cells, induced pluripotent stem cells technology, will allow the generation of better model to mimic human disease and reflects the genetic drivers that govern specific pathology. So, the synergy between IPS cell-based model system and gene editing will play a pivotal role in the root of precision medicine and clinical translation in the future. Dr. Negar Asdaghi: Dr. François Gros-Louis, it was a pleasure learning from you. And we look forward to the endless possibilities brought by the future of genome editing technology. Dr. François Gros-Louis: It was a pleasure discussing with you. Dr. Negar Asdaghi: Thank you for joining us. Dr. Negar Asdaghi: And this concludes our podcast for the April 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including a series of Focused Updates on the topic of blood pressure management in stroke, organized by Dr. Else Sandset. I would also like to draw your attention to two scientific statements from the American Heart Association, which appear in print in the April issue. The first one is titled "Identifying Best Practices to Improve Evaluation and Management of In-Hospital Stroke," and the second one is on the effect of marijuana use on brain health. Dr. Negar Asdaghi: And now, to end our podcast, last month, in honor of the 2022 Olympic Games, and to celebrate those with determination to survive and push despite the most difficult of circumstances, we ended our podcast with the story of a refugee Olympic athlete. Dr. Negar Asdaghi: Sadly, since our last podcast, the world has seen even darker days of war, mass immigration, displacement, and human suffering. At times like this, we're reminded that although not all of us can help everyone, but at least each of us can do something to help someone, and the comfort in knowing that what we do in the field of medicine, from daily patient care to the scientific work leading to the next medical breakthrough, every action is a step forward in reducing the suffering of another person. And what better way to do this than staying alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 14 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the March 2022 issue of Stroke: "Natural Course of Cerebral Cavernous Malformations in Children" and "Direct Oral Anticoagulants Versus Warfarin in Cerebral Venous Thrombosis (ACTION-CVT)." She also interviews Dr. Mohammad Anadani about his article "Magnitude of Blood Pressure Change After Endovascular Therapy and Outcomes." Dr. Negar Asdaghi: 1) Are direct oral anticoagulants a reasonable alternative to warfarin for treatments of patients with cerebral venous thrombosis? 2) What are the predictors of first and recurrent intracerebral hemorrhage in patients with cerebral cavernous malformation? 3) Is there an optimal blood pressure target after successful endovascular thrombectomy? We have the answers and much more in today's podcast. This is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome to another incredibly informing Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The March 2022 issue of Stroke includes a number of papers published in conjunction with their oral presentation at the International Stroke Conference in New Orleans, from contemporary trends in the nationwide incidence of primary intracerebral hemorrhage, to disparities in Internet use among U.S. stroke survivors' implication for telerehabilitation during COVID-19 and beyond. I encourage you to review these timely topics in addition to listening to our podcast today. Later, in our interview section, I discussed the optimal blood pressure goal after endovascular therapy and the results of a subgroup analysis of the BP-TARGET randomized trials with Dr. Mohammad Anadani from the Department of Neurology at Washington University in St. Louis. But first with these two articles. Dr. Negar Asdaghi: Cerebral cavernous malformations, also referred to as cavernous angiomas, cavernomas, cav mals, or CCMs, are angiographically occult, low flow, vascular lesions with no large arterial inflow or venous outflow vessels. These are clusters of dilated sinusoidal vascular channels that are aligned by a single layer of endothelium without the normal surrounding vascular smooth muscles, and they lack the normal tight junctions between their endothelial cells. Cavernomas can be found in both children and adults. So, the question is, how do these lesions present, especially in children, and what is their natural course? Now, before we answer these questions, let's review a few important points about cavernomas and what is known about these lesions in the literature. Number one, cavernomas are acquired lesions. Although initially thought to be congenital, they're now known to be acquired as comparing by many reports of patients with normal MRI findings, who later developed a CCM. Number two, they're not always benign. While most of them can have a benign course, cerebral cavernomas can be a cause for headaches, seizure disorders and intracerebral hemorrhage, which is, of course, their most feared complication. Dr. Negar Asdaghi: Number three, though CCMs are rare vascular disorders with a prevalence of 0.6% in children and young adults, about a quarter of patients with a confirmed diagnosis of cerebral cavernous malformation are under the age of 18. And number four and finally, data seem to suggest that the risk of hemorrhage is potentially higher in the pediatric population than their adult counterparts. So, determining the natural course of CCMs and predictors of intracerebral hemorrhage is important for all patients, but especially important in the pediatric population. Now, in the current issue of the journal, in the paper titled "Natural Course of Cerebral Cavernous Malformations in Children: A Five-Year Follow-Up Study," a German group of investigators led by Dr. Alejandro Santos from the Department of Neurosurgery and Spine Surgery at University Hospital in Essen and colleagues studied the clinical presentation and predictors of intracerebral hemorrhage in their pediatric population over a 17-year study period. Dr. Negar Asdaghi: So, they identified 129 patients with a diagnosis of cerebral cavernous malformation that had baseline MRI imaging completed and at least one or more follow-ups during the study period. Now, some of these patients were treated surgically and some conservatively in the study. The mean age of their study was 10, and over 50% of their study population was male. Developmental venous anomalies, or DVAs, were detected in 15% of their study population, and 20% had brain stem cavernoma localization. Now, importantly, half of these kids, so that's 55.8% of their study population, presented with an intracerebral hemorrhage, and that's how their cavernomas were diagnosed. So, what were their top three findings? Dr. Negar Asdaghi: Number one, on the comparison of conservatively treated patients to those treated surgically, which was 37% of their cohort, they found that overall these two groups had comparable clinical characteristics and demographics with regards to sex, age, multiplicity of cavernomas, brain stem location, and family history of their lesions. But not surprisingly, those who were surgically treated were more likely to have presented with an intracerebral hemorrhage and less likely to be asymptomatic, meaning that their cavernoma was not an incidental finding as compared to those who were conservatively treated. Dr. Negar Asdaghi: Number two, when they looked at predictors of presentation with intracerebral hemorrhage, they found that family history of cavernomas and brain stem cavernomas were significant predictors of presenting intracerebral hemorrhage. Number three, when they excluded those who underwent surgery, the annual risk of hemorrhage for the overall untreated participants was 4.1%. However, we should note that this rate significantly varied based on certain characteristics of the patients. The risk of hemorrhage, or rather the risk of re-hemorrhage, was double this baseline, that is 8.1%, for those cavernomas that presented with a bleed at presentation. The annual rate of hemorrhage was equally high at 7.1% for brain stem cavernomas, and then this rate gradually declined for familial form cavernomas at 6.2% annual risk of hemorrhage and multiple cavernomas at 4.8%. And it went all the way down to 0.4% annual risk of hemorrhage for asymptomatic incidentally found cerebral cavernomas. So, in the multivariate analysis, presentation with an ICH remained an independent predictor of re-hemorrhage and cavernomas with a high hazard ratio of 14. That is 14-fold higher risk of hemorrhage in cavernomas that present with a bleed as compared to those that did not. Dr. Negar Asdaghi: Now, finally, on the association between DVAs and risk of hemorrhage, this study showed a possible reduced risk of hemorrhage in cavernomas that had associated DVAs, but this was not a statistically significant association. It is important to note that this finding is in keeping with the published studies in the adult population, but in contrast to the previously published data in the pediatric population. So, this association between presence of a developmental venous anomaly and cavernomas and the risk of subsequent hemorrhage needs to be furthered studied. So, what did we learn from this study? Pediatric patients with brain stem cavernomas and familial cavernomas have a higher risk of intracerebral hemorrhage as mode of presentation. The risk of re-hemorrhage is 14 times higher in cavernomas that present with an ICH as compared to cavernomas that did not bleed. And the probability of bleed tends to increase over time. Dr. Negar Asdaghi: Cerebral venous sinus thrombosis, or CVST, refers to thrombosis in the dural venous sinuses, cortical veins, deep cerebral veins, or a combination of these venous structures. CVST is an uncommon cause of stroke accounting for overall 1% of all strokes and can cause venous ischemic infarcts or intracerebral hemorrhage and importantly has a high morbidity and mortality if unrecognized and left untreated. Anticoagulation is generally the mainstay of therapy for CVST, which needs to be initiated as soon as possible, even in the presence of hemorrhage in the brain. The data regarding the choice of anticoagulation in CVST is generally extrapolated from randomized studies completed in patients with systemic venous thromboembolism, so conditions such as pulmonary emboli or deep venous thrombosis, and indicate that direct oral anticoagulants, or DOACs, are viable alternatives to traditional warfarin therapy in this patient population. This question was specifically studied in the RESPECT-CVT trial, which was a small European randomized trial that included 120 patients with cerebral vein thrombosis, randomized to either receiving dose adjusted warfarin or dabigatran at 150 milligram BID. Dr. Negar Asdaghi: The results of the study was published in JAMA Neurology in 2019 and showed that CVST patients treated with either dabigatran or warfarin were at low risk of recurrent venous thromboembolism, and they also showed a comparable safety profile in terms of risk of hemorrhage or mortality in patients treated with DOAC as compared to warfarin. But how do DOACs perform as compared to warfarin in routine practice is unknown. So, in this issue of the journal, in the study titled, "Direct Oral Anticoagulants Versus Warfarin in Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study," the ACTION-CVT investigators, led by Dr. Shadi Yaghi from the Department of Neurology at Brown University, aimed to compare the safety profile of DOACs to that of warfarin, in a multicenter international study that included 1025 imaging-confirmed CVST patients from multiple centers in the United States, Italy, Switzerland, and New Zealand. Dr. Negar Asdaghi: They had a number of exclusion criteria for this study, excluding patients with active cancer, those with a confirmed history of antiphospholipid antibody syndrome and those who were not treated with an oral anticoagulant. And after excluding these patients, it gave them their study sample of 845 CVST patients. So, what were their main findings? Number one, in keeping with a prior literature on CVST, these patients were young, their mean age was 44, and majority of them were women, so that was 67% of their cohort. And they found that a third of these patients were actually treated with a DOAC, and, in addition, another 15% received a DOAC at some times during their treatment course. Finding number two, the most common DOAC used in this population was apixaban, that was 66% of cases treated with a direct oral anticoagulant, followed by rivaroxaban in 18% of cases, and then dabigatran used in 13.5% of DOAC-treated cases. Dr. Negar Asdaghi: Important finding number three. A total of 27 patients had recurrent CVST, which also included patients with progression of their cerebral vein thrombosis on follow-up vascular imaging, and 17 patients had recurrent venous thromboembolism, and two had both. So, during their mean follow-up of 345 days, they had the rate of 5.68 recurrent venous thrombosis per 100 patient years. These rates were not different for DOAC-treated versus warfarin-treated patients in both unadjusted and adjusted models. Now, very important finding number four. When they looked at the rate of recanalization on follow-up imaging, for those in whom this information was available, partial or complete recanalization occurred in 86% of DOAC-treated patients versus 84% of warfarin-treated patients. This was not a statistically significant difference in the unadjusted or the adjusted models. Recanalization is, of course, an important determinant of outcomes in CVST and should be noted that recanalization is, of course, an important determinant of outcomes in CVST since persistent thrombosis through chronic raised ICP can potentially lead to a variety of neurological morbidities, such as chronic headache, chronic papilledema and increased risk of development of dural AV fistulas. Dr. Negar Asdaghi: Now, finally, in terms of safety profile, they had 31 hemorrhages, 23 intracranial, majority were symptomatic and 9 extracranial hemorrhages. The hazard ratio for hemorrhage or death was similar for DOAC- and warfarin-treated patients, again in the unadjusted and adjusted models. So, bottom line, in this large international cohort of patients with CVST treated with an oral anticoagulant in routine practice, patients treated with DOACs had similar clinical and radiographic outcomes and had a similar favorable safety profile when compared to those treated with warfarin. So, we stay tuned for the results of the ongoing randomized trials on this subject. Dr. Negar Asdaghi: What is the optimal blood pressure target after endovascular therapy? This is a commonly encountered question in routine clinical practice with a not-so-straightforward and easy answer. After a successful endovascular treatment, high systolic blood pressure targets are thought to be associated with increased risk of reperfusion injury and development of intraparenchymal hemorrhage, leading to worsening of clinical outcomes. Conversely, low blood pressure targets may worsen the ischemic penumbra, especially in the setting of incomplete perfusion. The current stroke guidelines recommendations regarding blood pressure control after endovascular treatment are mostly extrapolated from the post-thrombolysis studies. The BP-TARGET trial was a recently completed randomized study in France that aimed to assess the safety and efficacy of intensive blood pressure lowering, that is systolic blood pressure of less than 130, as compared to standard of care, that is systolic blood pressure between 130 to 185, after successful endovascular therapy in acute ischemic stroke. Dr. Negar Asdaghi: This was a neutral study, and the main results of the trial was published in early 2021 in Lancet Neurology. And if you missed it, well, as always, we're here with the Stroke Alert Podcast to fill in the gaps. So, we'll review the trial results with our podcast guest today, Dr. Mohammad Anadani, from the Department of Neurology at Washington University in St. Louis, who's also the first author of a paper in the current issue of the journal titled "Magnitude of Blood Pressure Change After Endovascular Therapy and Outcomes: Insight From the Blood Pressure-TARGET Trial." This was a post hoc analysis of the BP-TARGET trial, looking at the extent of blood pressure reduction and its implications of clinical outcomes. Welcome, Mohammad, thank you for joining us on the podcast today. Dr. Mohammad Anadani: Thank you for having me. It's a pleasure to be here with you today. Dr. Negar Asdaghi: Thank you. So, blood pressure control is a really simple and yet extremely complicated topic when it comes to the collateral support before reperfusion therapies, and then, of course, the possibility of reperfusion injury post-thrombectomy in the setting of an ischemic stroke related to a large vessel occlusion. Can you please give our listeners an overview of the topic of blood pressure control in this setting? Dr. Mohammad Anadani: Yes, absolutely. I totally agree. The topic of blood pressure control after, in patients with large vessel occlusion, is very complicated. And when we talk about blood pressure control, I think we should differentiate between pre-recanalization and post-recanalization. In the pre-recanalization period, the main focus should be to maintain adequate perfusion to ischemic penumbra to prevent infarct expansion. So, there is consensus that hypotension should be avoided at all costs pre-recanalization. When it comes to the post-reperfusion, here it gets a little bit more complicated. We do have a large body of evidence, as you mentioned, for the association between high blood pressure in the post-reperfusion period and the risk of poor outcome. What we don't know yet is if active reduction of blood pressure after reperfusion is beneficial. And that's why, as you mention, the American Heart Association guidelines just recommend a systolic blood pressure less than 180, just because of the lack of data to support the benefit of blood pressure reduction. Dr. Negar Asdaghi: Perfect. So, this was definitely the topic that the BP-TARGET trial set out to investigate. What is the optimal blood pressure target after successful revascularization therapy? Can you please tell us a little bit about the trial, the design and the inclusion criteria? Dr. Mohammad Anadani: The Blood Pressure-TARGET trial, or BP-TARGET trial, aimed to assess the safety and efficacy of intensive blood pressure lowering treatment. The trial enrolled patients with anterior circulation large vessel occlusion, that is M1 or ICA occlusion, or tandem occlusion, which is both M1 and ICA occlusion. The patients who were treated with endovascular therapy and achieved successful reperfusion, and they defined successful reperfusion as modified treatment cerebral ischemia 2b to 3. And then after enrollment, the patients were randomized in one-to-one ratio into intensive blood pressure control, which is systolic blood pressure less than 130, and standard blood pressure control, which is systolic blood pressure less than 185. Now, these two cutoffs came in from some evidence that systolic blood pressure less than 130 is beneficial in these patients or this is the optimal cutoff for patients with successful reperfusion. For the standard group, the design of the trial, at the time of the design of the trial, that was the standard or recommended European guidelines, blood pressure group. And the study was conducted in France between June 2017 and September 2019. Dr. Negar Asdaghi: Thank you, Mohammad. So, I want to recap for our listeners, we're looking at a French study that was conducted in four centers, in France. And it's a very recent study, recently completed. The whole thing was completed over the past five years. So, very interesting because it's applicable to our current treatment models. And these were patients with a large vessel occlusion in the anterior circulation that had undergone thrombectomy. All have achieved a successful revascularization, as you defined, TICI 2b or C or TICI 3, and then they were randomized to either standard of care in terms of post-thrombectomy blood pressure control or the intensive group, which was under systolic blood pressure of 130. Did I recap that correctly? Dr. Mohammad Anadani: Correct. Dr. Negar Asdaghi: Perfect. So, now we're ready for the primary outcome. So, what was the primary outcome of the trial? Dr. Mohammad Anadani: The primary outcome was any radiographic intraparenchymal hemorrhage that was seen on CT within 24 hours to 36 hours after successful reperfusion. Dr. Negar Asdaghi: This is interesting, Mohammad, this is a different primary outcome than we're used to in a usual randomized trial that commonly uses a modified Rankin scale of usually at 90 days. Do you have any insight as to why a radiographic outcome was chosen for this particular study, and obviously what would be fine as part of the trial? Dr. Mohammad Anadani: Yes. So, the main reason why the study investigator chose this as a primary outcome was because really the benefit of, or at least what is thought to be the benefit from systolic blood pressure reduction, is to lower intraparenchymal hemorrhage or the risk of intraparenchymal hemorrhage. So, to assist the efficacy of this intensive blood pressure lowering, the first thing we expect to see is lower intraparenchymal hemorrhage. So, when you have your target as intraparenchymal hemorrhage, it truly requires much smaller sample size than having functional outcome as the primary outcome. Dr. Negar Asdaghi: Okay, perfect. And I think we're ready to hear the results for the main BP-TARGET trial. Dr. Mohammad Anadani: The results of the trial were disappointing for people who were interested in this topic. The primary outcome, which, again, was an intraparenchymal hemorrhage, occurred in 42% of patient intensive arm and 43% of patient the standard arm. And there was no difference in the risk of intraparenchymal hemorrhage between the two groups. Dr. Negar Asdaghi: Well, I think you can phrase it as disappointing, or more room to understand the pathophysiology and also onto bigger and better trials. And so I want to now move on the current paper in this issue of the journal, which is a post hoc analysis of the trial. Can you tell us a little more about your study? Dr. Mohammad Anadani: In our study, we wanted to study the blood pressure as dynamic target. So, we wanted to see if there is any association between blood pressure change from baseline with the functional and safety outcome after endovascular therapy. And also we wanted to understand the shape of the association. In other words, to see, is there a point after which the blood pressure reduction becomes helpful? So, to do that, we did this post hoc analysis of the BP-TARGET trial, and we only enrolled patients who had more than 50% of planned blood pressure measurements. And then we defined systolic blood pressure change as the difference in the mean achieved blood pressure in three different time points: zero to one hour, one to six hours, and six to 24 hours minus the baseline systolic blood pressure. And here we considered the end-of-procedure blood pressure as the baseline systolic blood pressure. Dr. Negar Asdaghi: All right. So, I want to recap what you mentioned before we hear what you found in the study. So, really, blood pressure, as you noted, is a dynamic factor. It's not just a target, but other words, is how fast you're reducing it, in what timeframe after endovascular thrombectomy, and also how much. So, as an example, as we were discussing this earlier, before we did the podcast recording, is if you started a systolic blood pressure at 190 and then reduced that patient quickly to 130, is that the same as if starting blood pressure was 150, and then you reduce it to, again, 130? So, delta, or the magnitude of change in blood pressure, and also time intervals, that how long after thrombectomy you were able to reduce that blood pressure, are all important factors in terms of determining the outcome. That's a nice summary of what this current study aimed to do. Perfect. So, with that, we're ready to hear the results of your study. Dr. Mohammad Anadani: We included 267 patients, 137 in the intensive arm and 130 patients in the standard arm. And then, when we compared patients who had poor outcome at 90 days to patients who had good outcome at 90 days, we found that the patient who had poor outcome had less systolic pressure reduction, meaning these patients had less systolic pressure reduction compared to the baseline than the patient who had good outcome. And then, when we controlled for other confounders, their association remained significant, especially for the one- to six-hour period and six- to 24-hour period. And the same results were when we had our outcome as intraparenchymal hemorrhage, we found the same results. The patient who had intraparenchymal hemorrhage had less systolic blood pressure reduction than patients who did not have intraparenchymal hemorrhage. And, again, the association remained significant even after we adjusted for possible confounders, like age, the degree of recanalization, and the stroke severity. Dr. Mohammad Anadani: And then we wanted to see, if we looked at the blood pressure change as categorical variable, meaning we want to see if there is a difference between large systolic blood pressure reduction compared to minimum or no systolic blood pressure reduction. So, we divided the systolic blood pressure reduction into three categories: the minimal, which was just zero to 10 systolic blood pressure reduction; the moderate, which was 10 to 20; and large, which was more than 20 millimeter mercury systolic blood pressure reduction. And when we looked at that, a patient who had more than 20 millimeter mercury systolic blood pressure reduction had significantly lower risk of poor outcome than patients who had no systolic blood pressure reduction or just minimal systolic blood pressure reduction. And the difference was striking. There were the patients who had more than 20 systolic blood pressure reduction, they had almost 62% lower risk or lower odds of having poor outcome than a patient who did not have significant systolic blood pressure reduction. Dr. Negar Asdaghi: These are some very interesting findings. Let me try and to summarize this for our listeners and make sure that I understood the study results correctly. So, in other words, if we had a patient that at the end of a successful revascularization treatment, say, had a systolic blood pressure of 150, and that was reduced to 140, so there's a 10 millimeter mercury difference, that patient, in this particular study, had a higher risk for development of intracerebral hemorrhage than the person that finished at 180, so finished endovascular therapy at 180 millimeter of mercury. But then with rapid reduction, we dropped the blood pressure to, say, for example, 140, so that 40 millimeter of mercury of reduction carried a higher weight or higher impact on reduction of intracerebral hemorrhage than the absolute target of blood pressure, because your results did not look at which category were these patients under, were they under intensive category or standard, but they looked at just the magnitude of that drop, which showed a bigger implication on effective blood pressure reduction on outcomes. Dr. Mohammad Anadani: Yeah, that is correct. Now, the primary outcome for our study and really what we want to look at here is the functional outcome, more than the intraparenchymal hemorrhage. And, like you said, if we have, let's say, patients who started with 160 and they dropped to 120 or started with 180 and they dropped to 150, these patients had better functional outcome than patients who started, let's say, with 160 and remained 160 or even their blood pressure increased after reperfusion. We did not look at absolute numbers, but we did look at if the patients were presented, let's say, above 180 or patient presented less than 180, and both of these patients had the same, or both of these groups had the same results, meaning systolic blood pressure seems to be beneficial for both of these patients. And also we looked at the patients who were in the standard arm or in the patients who were in the intensive arm, also both of them have the same results. The systolic blood pressure reduction remained associated with poor outcome. Dr. Negar Asdaghi: Mohammad, the current American Heart Association guidelines and also the European stroke guidelines both recommend a target systolic blood pressure of under 180 or 185 after successful recanalization. What do you think the optimal target blood pressure should be based on BP-TARGET trial and based on your post hoc analysis? Dr. Mohammad Anadani: Yeah, that's a difficult question. We learn from the BP-TARGET trial, that's lowering systolic blood pressure is safe. And our study added to that, that significant reduction, especially in the first hour after reperfusion therapy, may be beneficial because patient had lower risk of poor outcome. However, I don't think we will have a one number that we will be able to say, this is the optimal blood pressure that fits all patients. I think the optimal blood pressure needs to be tailored to individual patient based on their admission blood pressure, based on their comorbidities, and also based on the degree of reperfusion. I don't think patients who have TICI 2b, for example, should be treated exactly the same as patients who had TICI 3. Dr. Negar Asdaghi: So, a lot still to come on this topic, and we are still learning. So, on that topic, can you tell us a little bit about the currently ongoing randomized trials on the topic of blood pressure controlled post-thrombectomy? Dr. Mohammad Anadani: Yes. I think there are three main trials that are ongoing now and trying to assess the safety and efficacy also of intensive blood pressure reduction. The first trial is the Second Enhanced Control of Hypertension and Thrombectomy Stroke Study, or ENCHANTED2 study. And this study is being conducted now in China. And it's comparing systolic blood pressure less than 120 target to systolic blood pressure less than 180. And the study has the primary outcome here, is the shift in mRS score at 90 days. The study is estimated to be completed in 2023, so, hopefully next year, we will have some results. The second study is the Outcome in Patients Treated With Intraarterial Thrombectomy - optiMAL Blood Pressure Control, or OPTIMAL-BP. And this study is being conducted in South Korea, and it's comparing systolic blood pressure target of less than 140 to systolic blood pressure target of less than 180. Dr. Mohammad Anadani: And the primary outcomes of this study are mRS zero to two at 90 days and symptomatic intracerebral hemorrhage. The study here is estimated to be completed in 2024. And the last trial is the Blood Pressure After Endovascular Stroke Therapy-II, or the BEST-II trial. And this is being conducted here in the U.S. and comparing three different blood pressure cohorts: less than 160 and less than 140 as the experimental group to less than 180 as the standard group. And the primary outcome of this study is final infarct volume. And also the co-primary outcome is utility-weighted mRS at 90 days. And this study is estimated to be completed next year, in 2023. Dr. Negar Asdaghi: So, a diverse group of randomized trials from Korea, China, and the United States. Hopefully, we'll have a lot more answers in the next two years then on this topic. So, just the last few minutes of our recording here. Mohammad, can you please summarize for our listeners, what should be our top two takeaway messages from your study and what we know from collectively in the field on the topic of blood pressure control post-thrombectomy? Dr. Mohammad Anadani: I think the main home message that one, we found a leaner association between blood pressure change after endovascular therapy and poor functional outcome, and two, effective and significant systolic blood pressure reduction, which we defined in our study as a more than 20 millimeter mercury in the first hour after endovascular therapy, is potentially beneficial, and these patients had significantly lower risk of poor outcome than the patient who did not have significant blood pressure reduction. Dr. Negar Asdaghi: Thank you so much, Dr. Mohammad Anadani. Thank you for joining on the podcast today, and we look forward to having you back and covering more of your work in the future. Dr. Mohammad Anadani: Thank you for having me, and I look forward to learning more about the Stroke studies from your podcast. Dr. Negar Asdaghi: Thank you. Dr. Negar Asdaghi: And this concludes our podcast for the March 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including a series of Focused Updates on the topic of health equity and reduction of disparities in stroke, organized by Dr. Bruce Ovbiagele. It's hard to believe that we're already in March, and coming off the heels of one of our largest cerebrovascular annual meetings, the International Stroke Conference, which coincidentally concurrently happened with one of the biggest sports events of the year, the 2022 Winter Olympics in Beijing. Now, what do these two very different events have in common? Well, I think they both represent the extraordinary stories of talent and grit on the world stage. So, let's end our Stroke podcast with an inspirational story of the Olympian swimmer Yusra Mardini. Dr. Negar Asdaghi: In August 2015, after her family home was invaded and destroyed in the Syrian civil war, the 17-year-old Yusra and her sister, Sarah, fled Syria to Beirut, Istanbul, and finally İzmir, in Turkey, where they managed to squeeze onto a dingey crossing the Mediterranean to the Greek island of Lesbos. Carrying 20 people, rather than just six or seven, they found their boat sinking less than 30 minutes into their journey. Yusra, Sara, and another woman were the only ones on board who knew how to swim. Fighting for their life and that of the other refugees on board, they would swim the cold open water of the heavy seas for three and a half hours before reaching the shore. Less than a year later, Yusra became one of the top 10 athletes worldwide to qualify and compete in the 2016 Summer Olympics, as part of the first refugee Olympic athletes team. She won the opening heat of women 100-meter butterfly race, but did not make it to the podium in the Olympic Games. And that is, of course, only part of her story. Dr. Negar Asdaghi: Very much like the story of many scientists, doctors, engineers, and staff who make the international stroke meeting possible. Many stories are not celebrated on a podium, but nevertheless are the essence of the success of our stroke community. So, wherever you are in the field of neurosciences, whatever the challenge, and however cold the waters, know that while we don't share the same border, the same flag, or even a common language, together we push the field of cerebrovascular disorders forward. And, as always, we stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 13 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the February 2022 issue of Stroke: "Cannabis Use and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage" and "Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women: A Systematic Review and Meta-Analysis." She also interviews Dr. Pierre Amarenco about his article "Intracranial Hemorrhage in the TST Trial." Dr. Negar Asdaghi: 1) Can marijuana use increase the risk of ischemic stroke in patients with aneurysmal subarachnoid hemorrhage? 2) Is there an association between infertility or miscarriage and development of stroke later in life? 3) Does lowering the bad cholesterol increase the risk of intracerebral hemorrhage? We will cover these and much more in today's podcast. This is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome to another exciting Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. Dr. Negar Asdaghi: The February 2022 issue is the second installment of Stroke's annual Go Red for Women issue. This is to highlight the journal's continuous effort to bring to attention the research which focuses on reduction of sex disparities and enhancing inclusivity in stroke care. This issue of the journal features a number of articles from sex disparities in enrollment in randomized trials of stroke, to sex-related differences in ischemic stroke presentation, outcome of endovascular therapy, plaque composition of carotid stenosis, and the sex-dependent rupture rate of cerebral aneurysms and the risk of subarachnoid hemorrhage, which I encourage you to review in addition to listening to today's podcast. Dr. Negar Asdaghi: Later in the podcast, I have the distinct honor of interviewing one the leaders in the field of secondary stroke prevention, Dr. Pierre Amarenco from Bichat University in Paris, to discuss the latest analysis of the association between LDL cholesterol levels and intracerebral hemorrhage risk in a sub-analysis of the Treat Stroke to Target trial, and what is next to come on cholesterol-lowering therapies post-ischemic stroke. But first with these two articles. Dr. Negar Asdaghi: It should come at no surprise to our listeners that the use of marijuana in its variety of forms is increasing not only in the United States, but also across the globe, both for recreational purposes and also for treatment of a range of medical conditions. There's also a growing body of evidence to link marijuana use to cerebrovascular disorders, including ischemic and hemorrhagic strokes. In fact, national surveys in the United States show that over two million Americans with established cardiovascular disorders currently use or report having used marijuana in the past. Dr. Negar Asdaghi: Aneurysmal subarachnoid hemorrhage is a hemorrhagic stroke subtype that is frequently complicated by cerebral vasospasm and delayed cerebral ischemia, or DCI. Now, we know that development of DCI can significantly increase the neurological morbidity and mortality related to the disease. So, the question is, can marijuana use increase the risk of DCI in subarachnoid hemorrhage? And what is the difference between cannabis and marijuana? And how are they even related to the brain and vascular disorders? Now, to answer these questions, we first have to do a quick review of three key points. Dr. Negar Asdaghi: Key point number one: The word "cannabis" refers to all products derived from the plant cannabis sativa. This plant contains about 540 chemical substances. The word "marijuana" refers to parts of or products from the plant with substantial amounts of tetrahydrocannabinol, or THC. THC is the active ingredient of marijuana responsible for mediating its psychoactive effects through activation of G protein-coupled cannabinoid receptors, which are easier to remember as CB1 and CB2 receptors. Dr. Negar Asdaghi: Key point number two: CB1 and CB2 receptors are diffusely expressed throughout the brain, but interestingly, CB1 receptors are also richly expressed across various vascular beds, including the cardiac and cerebral vessels. So, there we have it, a connection between marijuana and the blood vessels. Dr. Negar Asdaghi: Key point number three: The differential activation of CB1 receptors in cerebral vessels may lead to vasoconstriction or vasodilation, potentially linking marijuana to vasospasm seen in aneurysmal subarachnoid hemorrhage, which then leads to DCI. But it should be noted that THC can also lead to ischemia through other mechanisms, such as altering the brain's oxidative capacity, impairing mitochondrial respiratory chain complexes, and increasing reactive oxygen species in free radicals. So, causing brain ischemia through mechanisms other than vasospasm. Dr. Negar Asdaghi: So, with these three points in mind, in the current issue of the journal, in the study titled "Cannabis Use and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage," Dr. Joshua Catapano from the Department of Neurosurgery at the Barrow Neurological Institute and colleagues report on the outcomes of 1,014 aneurysmal subarachnoid hemorrhage patients treated over a 12-year period at their institution from August 2007 to July 2019. Dr. Negar Asdaghi: The primary exposure was cannabis use, which was detected by routine urine toxicology at the time of hospital presentation with subarachnoid hemorrhage. Patients were also screened for the use of other vasoactive substances, including cocaine, amphetamines, and also tobacco use. The primary outcome was DCI defined as cerebral infarction detected either by CT or MRI or proven on autopsy after exclusion of procedure-related infarctions. Dr. Negar Asdaghi: And here's what they found. Number one: Overall, 36.2% of their patient population with aneurysmal subarachnoid hemorrhage developed DCI. 50.2% of their total population had poor functional outcome defined as modified Rankin Scale of over two by the time of discharge, and 13.5% died. These are important reminders that aneurysmal subarachnoid hemorrhage remains a deadly form of stroke, despite modern neurosurgical and neurocritical care advances in treatments. Dr. Negar Asdaghi: Number two: 4.5% of their patient population tested positive for cannabis. And here's the alarming finding of their study. The rate of DCI was significantly higher in those who were positive for cannabis, that was 52%, versus only 35% in those negative for cannabis. This association was not seen with other vasoactive agents such as cocaine and methamphetamine. Now, radiographic vasospasm was also significantly more common in cannabis users, the rate of which was 88% in cannabis users than in non-users, which was 70%. Dr. Negar Asdaghi: Now, number three: When they adjusted for baseline patient characteristics, presenting Hunt and Hess classification, and other vasoactive substances and active smoking, cannabis use was independently associated with an increased likelihood of development of DCI. So, what did we learn from this study? Active cannabis users were 2.7 times more likely to develop ischemic stroke post-aneurysmal subarachnoid hemorrhage as compared to their non-user counterparts. This is one of the largest studies to potentially link marijuana to development of cerebral ischemia in this population. Dr. Negar Asdaghi: There is now ample scientific evidence to connect some pregnancy-related complications, such as gestational hypertension, gestational diabetes, preeclampsia, and some pregnancy outcomes, such as preterm birth or having small-for-gestational-age infants, to an increased long-term risk of cerebrovascular events in the mother. Infertility, miscarriage and stillbirth are also common abnormalities in the process of conceiving and being pregnant, but whether there is an association between these abnormalities and development of future vascular disorders in women is not clear. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women," Dr. Chen Liang from the School of Public Health at the University of Queensland in Brisbane and colleagues report on the results of a systematic review and meta-analysis on this topic. So, let's dive into it. Dr. Negar Asdaghi: First, a brief look at their methodology. After a comprehensive literature search, a total of 18 studies were included in this meta-analysis, including over 7,800,000 women between the ages of 23 to 63 with a mean follow-up of 3.8 to 19 years. So, a big study. Five studies evaluated the association between infertility and stroke. Infertility was defined in broad terms as either a formal diagnosis or receiving fertility treatment or testing through databanks or medical records. And the other 13 studies explored the association between a history of either miscarriage and/or stillbirth and the main outcome of the study, which was stroke. Dr. Negar Asdaghi: In 11 studies, the outcomes of ischemic and hemorrhagic strokes were specified, four studies only reported on the ischemic stroke, and the rest did not identify the stroke subtype. So, what did they find? Well, their first finding was on the association between infertility and stroke. Overall, the five studies included over 4,600,000 women, and this association was inconsistent due to heterogeneity of the results between the different studies. But, when excluding the one study from Asia, which created most of the heterogeneity in results, infertility was indeed found to be associated with a 17% increase in the risk of stroke in the mother. In terms of possible causes, well, they looked at common infertility etiologies and vascular risk factors, and not surprisingly, they found many connecting points. Dr. Negar Asdaghi: For example, polycystic ovarian syndrome is a common cause of infertility and is frequently associated with insulin resistance and type 2 diabetes. Endometriosis, another cause of infertility, is commonly associated with hyperlipidemia and hypertension as a result of chronic systemic inflammation. Another example is premature ovarian insufficiency that could increase the risk of stroke through elevated follicle-stimulating hormone, a lower level of estrogen, and a relatively elevated level of androgen. Dr. Negar Asdaghi: So, their next finding was on the association between miscarriage and stillbirth in stroke. As you know, both of these conditions, so miscarriage and stillbirth, describe pregnancy loss at various stages. A stillbirth is the loss of fetus after the 20th week of development while a miscarriage refers to a loss of pregnancy before the 20th week of gestation. Women with a history of miscarriage had a 7% increased risk, and those with a history of stillbirth had a 38% increase in the risk of stroke later in life. Now, since having a miscarriage is a very common occurrence, it's important to pay attention to their dose response sub-analysis. When data was available on the number of miscarriages or number of stillbirths, increased risk of stroke was apparent among women with three or more miscarriages, but not two or less. For stillbirths, similarly, a history of repeated stillbirths was associated with increased risk of stroke, but evidence on association for a single stillbirth with stroke was insufficient. Dr. Negar Asdaghi: These are important findings to keep in mind when reviewing these results, and importantly, when counseling patients in routine practice. Now, in terms of causes, the authors discuss a variety of associated mechanisms, such as persistent endothelial dysfunction, a common cause for both pregnancy loss and vascular disease, elevated level of homocystine, autoimmune disorders, including presence of antiphospholipid antibodies and a cause for both pregnancy loss and development of arterial stenosis, noting that especially for the autoimmune conditions, specifically in the case of the APS syndrome, pregnancy loss is likely to be repeated, which is consistent with the findings of their subgroup analysis and dose response analysis in the paper, showing that repeated miscarriages and stillbirths are more likely associated with a higher risk of stroke rather than a single event. Dr. Negar Asdaghi: So, bottom line, what my takeaway from this study is, that many factors that can cause infertility, miscarriage and stillbirth can also cause vascular disorders, and these associations should be kept in mind when treating women at a younger age for fertility and pregnancy-related complications. Dr. Negar Asdaghi: Intensive therapy to lower serum lipid levels with the use of statins is recommended after transient ischemic attack or ischemic stroke of atherosclerotic origin. Treatment with statins has been shown to reduce the risk of major vascular events in the stroke population, but there remains a concern regarding an increased risk of development of intracranial hemorrhage with this therapy. Whether this increased risk of ICH is a class effect related to treatment with statins, or is associated with a certain low target levels of LDL cholesterol, is uncertain. Dr. Negar Asdaghi: The Treat Stroke to Target randomized trial tested the hypothesis that a target level of LDL cholesterol of less than 70 milligram per deciliter would be superior to a target range of 90 milligrams to a hundred milligram per deciliter in reducing the overall cardiovascular events after an ischemic stroke or TIA in patients with evidence of atherosclerosis. The primary results of the trial was published in New England Journal of Medicine in early 2020. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Intracranial Hemorrhage in the Treat Stroke to Target Trial," the trial investigators report the results of a pre-specified analysis of the TST trial to evaluate the baseline and on-treatment predictors of incident ICH. I'm joined now by Dr. Pierre Amarenco, who's the first author of the study and one of the primary investigators of the TST trial, to discuss this paper. Dr. Amarenco is an internationally renowned neurologist who absolutely needs no introduction to the Stroke readership, but as always, an introduction is nice. Dr. Negar Asdaghi: He's a Professor of Neurology and the founder of the Department of Neurology and Stroke Center, as well as the SOS-TIA Clinic, at Bichat University Hospital in Paris. He's a leader in the field of secondary prevention of stroke with special interests in treatment of patients with TIA and mild stroke. He has served as the primary investigator of multiple randomized trials of antithrombotic therapies, lipid modifying agents, and acute revascularization treatments. Dr. Amarenco leads the international TIA registry involving centers from 21 countries around the globe. Welcome to our podcast, Pierre. Thank you so much for joining us all the way from Paris. Dr. Pierre Amarenco: Good afternoon, Negar. Thank you for asking me. Dr. Negar Asdaghi: Well, thank you for being here. Let's start with the Treat Stroke to Target trial. It addresses an important gap in the secondary prevention of ischemic stroke literature. Can you please start us off with an overview of the trial? Dr. Pierre Amarenco: Yes. The objective of Treat Stroke to Target trial was to evaluate in 2,860 patients with ischemic stroke of atherosclerotic origin randomized into a target LDL cholesterol less than 70 milligram or a target LDL cholesterol 90 to 110 milligram per deciliter to see the benefit in the lower target group as compared to the higher target group. That was the purpose of the TST trial. Dr. Negar Asdaghi: And the trial, Pierre, was terminated early. Do you mind commenting for our listeners as to why this happened? Dr. Pierre Amarenco: Yes. The TST trial had a very long duration. It was an academic trial with low funding, funded by the French government, which is not quite the same as the NIH-funding trials. To give you an example, patient cost was $1,500 for the whole duration of the trial per patient. Around $1,500 per patient. So, it was a very low funding, and because of that, after nine years, we had to stop. But we had recruited all patients, and we had a three-year follow-up, so we could have a meaningful result. Dr. Negar Asdaghi: So, perfect. So, just to recap for our listeners: Over eight-year period of time, despite the early termination, you had 2,860 patients enrolled, and so the termination of the trial was administrative reasons alone, as you mentioned. And so what were the primary outcomes of the trial? Dr. Pierre Amarenco: The primary outcome of the trial was a reduction of 22% in this primary outcome, which was the composite of ischemic stroke and non-stroke, microinfarction, vascular death, and urgent revascularization for coronary or carotid ischemic event. Dr. Negar Asdaghi: Okay, so the primary outcome was reduction of vascular events, truly, whether cardiac or in the brain. But now coming to the issue that is going to be addressed in your current paper, there remains a concern in the secondary prevention literature regarding an increased risk of intracerebral hemorrhage with statin therapy. Before we talk about the paper again, I want to give us a little bit of a background regarding the roots of this concern. Where does this all stem from? Dr. Pierre Amarenco: In fact, when you do a meta-analysis of all statin trials, there is no increase of hemorrhagic stroke, particularly trials in primary prevention of stroke. However, in trials in secondary prevention, which include mostly HPS trial with simvastatin and SPARCL trial with atorvastatin, there was a 60% increase in hemorrhagic stroke. That did not outweigh the benefit observed in this trial, but there was a concern about statin in secondary prevention, particularly high dose statin. Dr. Pierre Amarenco: So, in SPARCL, we did a post-stroke analysis looking at predictors of hemorrhagic stroke, and we found that, as usual, age and male sex increase risk of hemorrhagic stroke, but the most important was uncontrolled hypertension and atorvastatin. Atorvastatin stayed into the model. We know that atorvastatin reduce LDL cholesterol, that low LDL cholesterol in SPARCL was not associated with hemorrhagic stroke. So, there was a paradox because atorvastatin stayed into the model and we know that atorvastatin lower LDL cholesterol importantly. It is possible that something goes wrong between statin and vascular disease in the brain. In SPARCL, we looked at stroke subtypes at the baseline, and we found that atherosclerotic stroke, TIA and cryptogenic stroke were not associated with hemorrhagic stroke. But we found also that patients randomized with brain hemorrhage, 2% of the sample, and patient randomized with lacunar stroke were at increased risk of hemorrhagic stroke. Dr. Pierre Amarenco: So, altogether, we can say that small vessel disease of ischemic type or hemorrhagic type were associated with hemorrhagic stroke, and we know that small vessel disease is associated with high blood pressure. So, the fact that we found uncontrolled hypertension as a predictor of hemorrhagic stroke in SPARCL was logical since also we found that small vessel disease was a predictor. Dr. Negar Asdaghi: So, very important points that you mentioned, and I, again, want to repeat them for our listeners. And I think it's one of my questions later on to ask about independent predictors of hemorrhage, but based on the cumulative literature for what we knew before the current study, you had mentioned uncontrolled hypertension, small vessel disease, which is sort of a marker of both ischemic and hemorrhagic events in the brain, were all independent predictors of development of ICH. Whether statin therapy or low target level of LDL adds to that fueling, that fire, or not was something that you wanted to really decipher in the TST trial. I think we're ready to hear about the methodology of your current paper, if you could tell us, please. Dr. Pierre Amarenco: So, in TST, of course, because of this background, we pre-specified an analysis of incident hemorrhagic stroke. So, we looked at patients with incident hemorrhagic stroke versus those without, and we did a multivariable analysis to look at predictors, and that was the methodology of the paper we use for this specific paper. Dr. Negar Asdaghi: And what were the primary results? Dr. Pierre Amarenco: So, the primary result was that after a median of three years follow-up, we found 31 hemorrhagic stroke in the lower target group and 28 hemorrhagic stroke in the higher target group, and the difference was not significant. In the paper, we show a graph with a distribution of hemorrhagic stroke according to the level of LDL cholesterol three months before the hemorrhagic stroke, and it is striking to see that half of the events occurred for an LDL cholesterol above 100 milligram per deciliter and half of the events occurred for an LDL cholesterol below 100 milligram per deciliter. So, clearly, in TST trial, like in SPARCL trial, we did not find a relationship between low LDL cholesterol and incident hemorrhagic stroke. Dr. Negar Asdaghi: So, very important information for all practicing neurologists and stroke neurologists out there. I want to recap, again, very important numbers that you mentioned. Achieving low LDL cholesterol target, even very low numbers, as you mentioned, was not a predictor of development of intracerebral hemorrhage in the trial. And, as you mentioned, half of them, actually it occurred even before achieving the target LDL for the trial. But you did find some other significant predictors of ICH in the study. Can you please elaborate on those? Dr. Pierre Amarenco: Yes, we found predictors, and the only predictors we found, in fact, were uncontrolled hypertension, exactly what we found in SPARCL. So, uncontrolled hypertension is really something important, and anticoagulant treatment, which was not found in SPARCL. So they were the only predictors, uncontrolled hypertension and anticoagulant treatment with of use therapeutic implications. When you put patients on a low level of LDL cholesterol, when you target the low level, you have to tightly control blood pressure, which is always a case in secondary prevention of stroke, but particularly when you target the low LDL cholesterol, and then anticoagulant treatment, of course, you have to monitor closely blood pressure and also the level of anticoagulation. Dr. Negar Asdaghi: So, it's, again, I want to repeat what you mentioned, because it seems like we've been blaming the wrong person all along, concentrating on this issue of statins or low LDL levels being associated or the causative reason for development of intracerebral hemorrhage, and forgetting about the obvious, which is uncontrolled hypertension and now the new finding of being on oral anticoagulants, which is not unexpected. Pierre, my next question was on SPARCL trial, but you've already alluded to the SPARCL study. I'm going to repeat and ask the question regarding SPARCL, because for years and years as practicing neurologists, we've referred to the results of SPARCL, and you already alluded to some of the similarities between the two trials, but is there something else as you compared TST with SPARCL that you want to mention in terms of patient population included in both studies or the differences in the results? Dr. Pierre Amarenco: The most important difference was that in SPARCL, there was a placebo group, which was not the case in TST since we compared two levels of LDL cholesterol. So, literally all patients were on statins in TST trial, which was not the case in SPARCL since half of the patients were on statins. So, that was the main difference, but the concept of TST clearly came from SPARCL sub-analysis. In SPARCL sub-analysis, we found that achieving an LDL cholesterol less than 70 milligram was associated with a benefit compared to patients with an achieved LDL cholesterol of 100 milligram per deciliter. But that was a post-stroke analysis in SPARCL, and so we had to confirm this, which is why we did the TST trial, which was clearly a follow-up of the SPARCL trial. And then we confirmed what we found in SPARCL, that is low LDL cholesterol was not associated with incident hemorrhagic stroke while there was a benefit of achieving a low LDL cholesterol target compared to a higher target. Dr. Negar Asdaghi: All right, so just the follow-up question on the LDL levels. Statins are, of course, not the only agent to use to achieve a lower level of LDL cholesterol. There's a growing literature with the PCSK9 inhibitors, especially in patients with acute coronary syndrome, to lower the LDL levels. How are the findings from those studies of PCSK9 inhibitors on the risk of ICH compared to your study? Dr. Pierre Amarenco: The findings of four-year trial with evolocumab and ODYSSEY OUTCOMES trial with alirocumab was that going to less than 40 milligram per deciliter or even 30 milligram in mean per deciliter in four-year trial was not associated with an increased risk of hemorrhagic stroke. For example, in four year, the risk of hemorrhagic stroke was 0.21% in the evolocumab group versus 0.18% in the placebo group. And in ODYSSEY OUTCOMES trial, it was 0.2% in both groups. So, clearly, going to a very, very low level of LDL cholesterol was not associated with an increased risk of hemorrhagic stroke. To give a comparison, in TST, in the lower target group, we had a 1.25% risk of incident hemorrhagic stroke versus 0.9% in the higher target group. There was a slight increase, but that was not reaching statistical significance, and it was not associated with low LDL cholesterol. Dr. Negar Asdaghi: Perfect. So, quite reassuring, these results from various trials, again, showing and reassuring that the risk of intracerebral hemorrhage seems to not be significantly associated with lower target levels of LDL cholesterol. Now, we do have time, Pierre, I want to digress a little bit from your current study and ask a question that comes up rather frequently in routine practice. And that is the association between statin therapy, lower levels of LDL and incident ICH in the setting of microbleeds that are found typically incidentally on an MRI study. Do you think there is any possible interaction between the two, or are there plans to look at this as part of TST? Dr. Pierre Amarenco: Yes. I would like first to say that I don't like the term "microbleeds" or "microbleeding" because it is scary for the patients. I have plenty of patients coming to my outpatient clinic because they are afraid of what they have read on the radiologist report, "microbleeds." "Doctor, my brain is full of microbleeds." I prefer to use the term "microdeposit of hemosiderin," which is descriptive, which is associated with small vessel disease. Dr. Pierre Amarenco: So, regarding the relationship between microdeposit of hemosiderin and incidence of intracranial hemorrhage on statin, in fact, we don't know the relationship, but we can't say that in SPARCL, there was an association between small vessel disease of hemorrhagic or ischemic type with incident hemorrhage on atorvastatin 80 milligram per day. So, these patients with microdeposits of hemosiderin have small vessel disease, and then they may be at risk of more hemorrhagic stroke. So, in these patients, I would be cautious, and on high dosage of statin. I prefer to use low dosage associated with ezetimibe or with PCSK9 inhibitor to go low for LDL cholesterol, but not with statins. So, this is the way I'm used to do when there is a lot of microdeposit of hemosiderin in my patient, but it has not been tested in clinical trials. Dr. Negar Asdaghi: So, very important, again, to repeat and recap what you mentioned. First of all, love the term "microdeposit of hemosiderin," and I'm going to use that with my patients. I totally agree with you that telling someone, "Oh, there's tons of blood in your brain," is not quite a good start. But definitely, again, as you mentioned, these are markers of small vessel disease, both for ischemic stroke and hemorrhagic. So, it's important to, again, address the causes of small vessel developments and etiologies very aggressively. And, as you mentioned, the jury's still out whether the statin class affect an association with incident ICH or an association between low target levels of LDL cholesterol, and more to come on that in the future. Pierre, just to end our podcast, what would be your top two takeaway messages for our listeners on the topic of target LDL and incident ICH? Dr. Pierre Amarenco: Well, the message is simple. Targeting an LDL cholesterol of less than 70 milligram per deciliter in atherosclerotic ischemic stroke non-significantly increases the risk of subsequent intracranial hemorrhage. Incident intracranial hemorrhage were not associated with low LDL cholesterol level. And we found two predictors of incident intracranial hemorrhage, which were uncontrolled hypertension and anticoagulant therapy, which has important clinical implication for our patients. Dr. Negar Asdaghi: Dr. Pierre Amarenco, it's been a pleasure interviewing you on the podcast today, and we look forward to having you back with more on this topic. Dr. Negar Asdaghi: And this concludes our podcast for the February 2022 issue of Stroke. Please don't forget to check out this month's table of contents for the full list of publications, including a series of Focused Updates on vascular brain health organized by Dr. Steve Greenberg. Dr. Negar Asdaghi: February is also a special month for our stroke community, with our annual International Stroke Conference, which this year is held as a hybrid event, both face-to-face in New Orleans and simultaneously as a virtual event for those who cannot attend it in person, as the fight against the COVID-19 pandemic continues. Reminding us all that with every challenge, there comes new ways to live, to cope, and to rise above it all. And we're here to do just that with staying alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.