Stroke Alert December 2022

On Episode 23 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the December 2022 issue of Stroke: “Direct, Indirect, and Combined Extracranial-to-Intracranial Bypass for Adult Moyamoya Disease” and “Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States.” She also interviews Drs. Koji Tanaka and Andrew Demchuk about article “Significance of Baseline Ischemic Core Volume on Stroke Outcome After EVT in Patients Age ≥75 Years.” Dr. Negar Asdaghi:         Let's start with some questions. 1) Is direct bypass better than indirect bypass in preventing the future risk of vascular events in adult patients with moyamoya disease? 2) What is the contemporary incidence of cerebral venous sinus thrombosis in the pediatric population? 3) And finally, is endovascular therapy beneficial for patients presenting with a large ischemic core? We have the answers and much more in today's podcast. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us. 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. In our final podcast for the year, I'm thrilled to announce that Drs. Nastajjia Krementz and Eric Goldstein have joined our podcast as assistant editors to help us cover the latest and the best in the field of cerebrovascular disorder. And together, here's our article selection to close the year. As part of our Advances in Stroke, in the article titled "Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation," we get an update on current evidence from randomized controlled trials on the use of direct oral anticoagulants or vitamin K antagonists in patients with valvular heart disease that are mechanical valves, moderate to severe mitral stenosis, or bioprosthetic valves from the perspective of stroke physicians. What that means is that data from randomized trials was analyzed based on whether the patient had a prior history of stroke or TIA. In this review, we learned that direct oral anticoagulants may be used in patients with bioprosthetic valves who have atrial fibrillation, although DOACs have never been shown to be superior over vitamin K antagonists. We also learned that vitamin K antagonists should be used in patients with rheumatic moderate to severe mitral valve stenosis or patients with mechanical valves with or without atrial fibrillation and, of course, sometimes during the first few months after either surgical or transcatheter aortic valve replacement in patients without atrial fibrillation. And finally, patients with bioprosthetic valves without AFib don't have any other indications to be treated with anticoagulants should be treated with antiplatelet monotherapy in the long run. In a separate article in this issue of the journal, from Dr. Yang and colleagues from China, we learn about the pathophysiology of radiation-induced brain injury with special attention to radiation-induced vasculopathy. These investigators show that hyperactivity of notch signaling pathway that in normal state is essential in vascular morphogenesis and maintenance of arterial identity actually results in abnormal accumulation and disturbance of vascular smooth muscle cells, resulting in arterial muscularization and arterial dysfunction seen in radiation-induced vasculopathy. What's interesting is that inhibition of the notch signaling pathway in their study resulted not only in a measurable reduction in radiation induced vasculopathy, but also an overall improvement in radiation-induced brain injury as measured by the cognitive function of the mice exposed to radiation in their study. This study takes us a step closer to possible therapeutic options for radiation-induced vasculopathy and radiation-induced brain injury using compounds that can potentially inhibit the notch signaling pathway. As always, I encourage you to review these articles in detail in addition to listening to our podcast. For our interview today, I have a special guest who's not only a prominent researcher and a pioneer in the field of acute stroke therapies, but also, he's an experienced educator who has trained many of the current leaders in the field of vascular neurology and has been influential in shaping the careers of many vascular neurology fellows over the years. Take a listen. Dr. Andrew Demchuk:   I've had the privilege of training fellows. I've been the director since 2004, and we've trained close to 100 fellows in Calgary over 20-some years now. Really, it's frankly an honor and privilege to be able to do that. These individuals come from all over the world. They're here to dedicate themselves to learning a subspecialty really, really well, and it's just a fantastic experience to interact with them all and all their cultures to help them learn those things, and doing it in a fun, enjoyable, comprehensive way. Dr. Negar Asdaghi:         And those are the words of Dr. Andrew Demchuk, who's incidentally my own vascular fellowship director as well. Andrew joins me all the way from Canada to talk about his latest paper on the very hot topic of outcomes of endovascular therapy in patients presenting with a large ischemic core. And true to form, he's accompanied by one of his current vascular fellows. The interview is definitely worth the wait after we review these two articles. Most of us have heard of the term "moyamoya." First described in Japan in 1950s, the term refers to occlusion or stenosis of the terminal portion of the internal carotid artery and is associated with dilated collateral vessels of the proximal middle cerebral artery. These collaterals have a hazy appearance on angiography resembling the puff of smoke, which is Japanese for "moyamoya." Moyamoya is categorized into two broad categories of moyamoya syndrome and moyamoya disease. Syndrome refers to the situations where the occlusion occurs due to another condition. Conditions such as Down syndrome, sickle cell disease, neurofibromatosis type one have all been recognized as associated with moyamoya syndrome. Of course, moyamoya syndrome can occur due to a secondary insult to the blood vessels, anything from radiation vasculopathy, as we reviewed earlier in the podcast, to autoimmune vasculitis, or even good old advanced intracranial atherosclerosis involving the distal ICA region can cause moyamoya syndrome. Now, in contrast to moyamoya syndrome, the term "moyamoya disease" is reserved for individuals with no vascular risk factors or known moyamoya predisposing conditions other than, of course, some potential genetic factors. The most recognized genetic association for moyamoya disease is polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17. But we also have to keep in mind that the majority of moyamoya disease patients have no identified genetic abnormalities. So, moyamoya is truly a complex condition, and the physicians have to navigate the many possible etiologies that may cause or be associated with this condition. But when it comes to treatment options, we're really limited here. Antiplatelets are generally used and have been shown to reduce mortality in both moyamoya disease and syndrome, and especially cilostazol, which is the favorite antiplatelet therapy of our own assistant editor, Eric, has been shown to be significantly associated with increased survival rate in patients with moyamoya disease. Eric really wanted me to talk about a recently published study out of Korea, which included over 9,000 patients, and that showed that patients treated with cilostazol had a better survival rate than any other antiplatelet therapies. Apart from antiplatelet therapies, medical treatment includes optimizing all other vascular risk factors, which, as we mentioned, are rarely present in this population. So, it all comes down to most cases, at some point, needing surgical treatment, with bypass surgery being the most commonly surgical intervention for this population. Three flavors of bypass are used: indirect, direct, or combination of the two. Indirect bypasses are kind of like long-term investments where the surgeon moves vascular tissue to the surface of the brain in hopes of promoting angiogenesis. Several procedures, such as performing multiple burr holes, pial synangiosis, dural inversion, or omental transposition, among other methods, are used. And broadly speaking, we can think of indirect procedures as angiogenesis-dependent methods, the effect of which takes months to recognize and, in general, are thought to be more efficacious in the pediatric population than the adult population. The direct bypass, in contrast, commonly referred to as extracranial-to-intracranial, or ECIC, bypass, is more of an immediate reward where the surgeon stitches a vessel directly from a donor extracranial branch, typically the superficial temporal artery, to a recipient artery, typically the middle cerebral artery, to provide a direct anastomosis between the two vessels. There are technical variations, of course, especially with regards to the number of donors and recipient arteries used, but essentially this method is an angiogenesis-independent method that results in a quicker revascularization, but it's unclear if this strategy is long lasting. A combination of direct and indirect bypass can also be used. So, the question is, which method is better, especially in the adult population? In this issue of the journal, in the study titled "Direct, Indirect, and Combined ECIC Bypass for Adult Moyamoya Disease," Dr. Nickalus Khan and colleagues report on a meta-analysis and systematic review of those with adult moyamoya disease who underwent either direct, indirect, or a combination bypass. The main study question was whether there's a difference in the rates of early ischemic or hemorrhagic strokes, defined as strokes occurring within 30 days of bypass, or late strokes, defined as strokes occurring after 30 days of bypass, in this population when comparing the different surgical techniques. They also compared the "favorable" outcome rate; however, this outcome was defined in each study between the various broad techniques of direct, indirect, and combined bypass. So, with that, let's take a very quick look at their methodology. They screened more than 4,000 articles and identified 143 articles for their pooled analysis, the majority of articles being from Eastern Asian-based regions, and they had close to 4,000 combined, 4,000 direct, and 4,000 indirect bypass procedures for this analysis. And they had an average follow-up of over three and a half years. So, this is a great sample size for this large, pooled analysis. But they also performed a smaller meta-analysis where they were much more stringent with article selection, excluding pediatric papers, excluding articles containing only one surgical modality, or articles with insufficient outcome data. So, for that meta-analysis, they only had 43 articles qualified and were included in that meta-analysis. So, what did they find? In the larger pooled analysis, a significant benefit in favor of both direct and combined bypass techniques were noted in reduction of early and late ischemic strokes and late intracerebral hemorrhage. Also, a higher rate of that sort of vague favorable outcome was noted with both the direct or combined methods as compared to when indirect bypass techniques were used alone. So, everything in the large, pooled analysis pointed towards the direct bypass or combined technique performing better than all indirect bypass techniques, with only one exception, which was a lower incidence of early intracerebral hemorrhage rate in indirect bypass cases. So, that's one point to keep in mind. The second point was when they compared combined techniques to direct bypass. Overall, these procedures had more or less the same outcomes with the exception that the rate of late ischemic stroke was lower in the combined group than the direct bypass group. So, this is sort of the overall summary of what they found in that large, pooled analysis. When they were much more stringent with their selection criteria, focusing on the smaller meta-analysis portion of the study, what they found was that in the short term, there were no differences in outcomes of any type of stroke between any of these methods. So, basically, people, regardless of the type of bypasses they received, did the same with regards to the risk of intracerebral hemorrhage and ischemic stroke recurrence within the first 30 days after the bypass. But for the late stroke outcomes, whether ischemic or hemorrhagic, those with indirect bypass were nearly twofold more likely to develop late stroke after 30 days compared to those who've undergone the direct bypass. A similar pattern was found comparing combined bypass versus indirect bypass, in general, beyond the 30 days, with combined bypass doing better. Comparing direct versus combined bypass showed no difference regardless of timeframe. So, in summary, overall, it appears that combined or direct bypasses may be the best surgical strategies for treatment of adult patients with moyamoya disease. This study, of course, has many limitations, as does any meta-analysis, but most importantly, the authors focused on moyamoya disease in their analysis. It is presumed, but really unclear if patients with moyamoya syndrome would respond similarly to these different techniques. So, the question is, what surgical procedure are you using at your institution for treatment of adult moyamoya disease patients? And, of course, Eric wanted me to ask if your antiplatelet of choice is cilostazol for this population, yes or no. Leave us your comments, and let us know. Venous sinus thrombosis, or CVST, is a less common form of stroke most commonly affecting women and young individuals. In our past podcast, we've covered many aspects of CVST, especially when it comes to therapy with anticoagulation, anticoagulant of choice, and duration of therapy. In the October podcast, we reviewed a systematic review and meta-analysis comparing direct oral anticoagulants to vitamin K antagonists in the adult patients with CVST. But there are many aspects of this disease that we have not yet covered. For instance, you may ask, how common is this relatively uncommon condition? In the adult population, the incidence of CVST varies depending on the age of individuals studied, and ranges between 1.3 to 2.7 per 100,000 in women between the ages of 31 to 50, which is the adult population at highest risk for this disease. But the incidence of CVST, for instance, in the pediatric population is largely unknown. Some studies suggested an incidence rate of 0.67 per 100,000 in the pediatric population. That's roughly less than half the incidence rate in young female adults, but these reports are from the 1990s and are likely very outdated. Nowadays, many of the pediatric conditions, especially infectious conditions, that can predispose children to CVST are more readily diagnosed and treated. On the other hand, we now perform a lot more imaging than 30 years ago. Our neuroimaging modalities are more accurate, so we are more likely to diagnose CVST than before. So, the question is, what is the contemporary incidence of pediatric cerebral venous sinus thrombosis? In this issue of the journal, in the study titled "Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States," Dr. Fadar Otite and colleagues conducted a retrospective analysis of the New York State Inpatient Database, or SID, from 2006 to 2018, and the National Kids Inpatient Database, referred to as KID, from 2006 to 2019, for all hospitalized CVST cases. KID is the largest publicly-available pediatric inpatient care database in the United States, containing about 3 million pediatric discharges. They included over 700 hospitalized CVST cases from the SID database and 6,100 hospitalizations from the national KID database for the current analysis. And here's what they found. Number one, in terms of significant risk factors associated with CVST, congenital circulatory system anomalies, infections, head trauma, dehydration, and anemia were amongst the top CVST risk factors in the pediatric population. So that's very good to know. Number two, in terms of presentation, seizures were the most common presentation among all pediatric age groups, with close to half of infants with CVST presenting with seizures. Number three, in terms of outcomes, the rate of mortality was twice higher in the infants group as compared to all other age groups. And finally, the overall incidence of CVST, which was the main question of the paper, in this population was 1.1 per 100,000 per year, with a peak incidence during infancy of 6.4 per 100,000 per year. Interestingly, incident admissions also increased annually by 3.8% throughout the study period, which was close to 15 years in this paper. And the national burden of hospitalization dramatically and exponentially grew during the study period. So, here are the top three points from this study. Point one: Girls included less than half of all admissions nationally and statewide, and the overall burden of CVST was higher in boys than girls. That's a dramatic difference between the pediatric and adult populations. Point two: Incidence of CVST in infants was higher than five times that of other age groups at 6.4 per 100,000 compared to overall incidence in children, which was 1.1 per 100,000 people per year. Mortality was also two times higher in infants than in any other age group. And finally, point 3, incident admissions and national burden of hospitalization have dramatically increased over time, but it remains unclear whether true incidence has been on the rise or if simply more cases are recognized nowadays due to heightened awareness of this condition and our advanced neuroimaging capabilities. This study, of course, has some limitations. Data was only obtained on patients admitted, so many patients that may have had CVST but not admitted are not captured in this database. So, in summary, CVST can have catastrophic consequences in children and lead to long-term neurological deficits. Having a high clinical suspicion and early recognition remain crucial for prompt treatment and improved outcomes in this population. Dr. Negar Asdaghi:         Endovascular treatment, or EVT, is an effective method to achieve recanalization and to improve clinical outcomes in ischemic stroke patients with a target vessel occlusion. Both advanced age and having a large infarct volume at the time of presentation are negative predictors of beneficial outcomes post-EVT. Despite this, the neurological benefits of EVT seem to persist across the spectrum of age, and the same has been observed for a range of ischemic core volumes. But it's important to note that, in general, patients presenting with large ischemic core volumes were excluded from the original thrombectomy studies, and currently there's several ongoing trials to determine whether EVT is beneficial for the large core population. Now, the question that everyone is interested in answering is whether there is an actual ischemic core volume beyond which endovascular therapy is either futile or potentially even harmful, and if this magic futile core volume is the same for all patients, or does it differ depending on the age and other factors. In a previous podcast, in an interview with Dr. Osama Zaidat, we learned about that important interaction between the presenting ischemic core volume as measured by ASPECTS score and advanced age in an analysis of patients enrolled in the STRATIS registry. In that study, no one over the age of 75 achieved functional independence post-EVT if the presenting ASPECTS score was under 5 regardless of the angiographic outcomes. In that interview, we also discussed the limitations of STRATIS registry as a non-randomized, single-arm study, and the issues surrounding using ASPECTS score to define ischemic core. In today's podcast, we're going to revisit the important interaction between the presenting ischemic core volume and age while reviewing a pooled analysis of seven endovascular clinical trials in the paper titled "Significance of Baseline Ischemic Core Volume on Stroke Outcome After Endovascular Therapy in Patients Age 75 Years or Older." I'm delighted to be joined today by the first and senior authors of this paper, Drs. Koji Tanaka and Andrew Demchuk. Dr. Tanaka is an Assistant Professor of Neurology at Kyushu University in Japan. With his experience working at the leading center for conducting stroke clinical trials in Osaka, he has now joined the Calgary Stroke Program as a research fellow. And he's accompanied today by his fellowship director, Dr. Demchuk. Dr. Demchuk, of course, needs no introduction to our Stroke readership and our podcast audience. He's a Professor of Neurology at the University of Calgary Cumming School of Medicine. He's a stroke neurologist and a leader in the field of cerebrovascular research who has been involved in multiple clinical studies and randomized trials, including the seminal studies that led to the approval of EVT as the standard of care for treatment of stroke. And, of course, he's a very special guest of this podcast this morning as he was my very own fellowship director. Top of the morning to you both, Andrew and Koji. Welcome to the podcast. Dr. Andrew Demchuk:   Thanks, Negar. It's great to be here. Dr. Koji Tanaka:               Thank you very much for your invitation. That is a great honor to be here. Dr. Negar Asdaghi:         Thank you both. Andrew, let's start with you. Can you please provide us some background on the pooled analysis and the HERMES collaboration, please? Dr. Andrew Demchuk:   Yeah, HERMES is a really, it's been a really fun journey. Years back, when these trials all came out roughly at the same time, right? There was a real quick succession of trials, the MR CLEAN trial was obviously first, and ESCAPE and others quickly followed it. It became very clear to us that it just made total sense to collaborate. And so we got together as a group and decided we will pool the data. We'll do it in a very careful scientific way with basically an independent statistical analysis, and develop a core imaging lab, and really actually share the workload amongst us. I remember one of the really interesting tidbits about HERMES is when we got together, in order, I think, to really build trust in the group, one of the important things we decided early was we were going to have a snake draft. If you don't know what a snake draft is, Negar, it's essentially where you take turns selecting a topic through each of the trials. So, every trialist got an opportunity to pick a topic, and we just went down the list until everyone had their turn, and then we'd start over again and do it again. And I think that really worked very well to be as democratic as possible with this, and as fair. And it really allowed for a lot to get done because whoever was motivated in the collaboration was able to do an analysis. Dr. Negar Asdaghi:         So, what a great summary of this collaboration. So, it's true collaboration between the trialists that basically gave us those seven original randomized trials. Andrew, can I just stay with you, and can you tell us a little bit about the patient population that were enrolled in those trials? Dr. Andrew Demchuk:   Yeah, I think one of the important things to know, and I think a limitation for any kind of analysis like this, is the trials generally were small core trials, right? I mean there are some, MR CLEAN was certainly a more generalized population, but many other trials, including ESCAPE, I mean the "S" and the "C" in ESCAPE is "small core," right? And so a lot of these trials were small core. So, we don't have a lot of data in larger core patients. But, as you can imagine when you do core lab analysis, you realize that some of the stroke patients weren't as small core as we thought they were when we enrolled them. So, there is some sufficient data to hypothesize. I would consider this paper very much hypothesis-generating. So, yeah, it is a limitation to be considered here. I mean, our sample size isn't very large in the big core patients. Dr. Negar Asdaghi:         Perfect. Thank you, Andrew. So, again, a recap for our listeners, that we are looking at pooled analysis of seven original trials of thrombectomy, but keeping in mind that those patients that were enrolled in the trials had, generally speaking, small presenting ischemic core. So, now, Koji, on to you. Can you walk us please through the current study, and what was the premise of it, and who was actually included in this study? Dr. Koji Tanaka:               Yes. In this study, we aimed to evaluate association between baseline ischemic core volume and the benefit of endovascular therapy over the best medical treatment on functional outcomes. Patients were categorized age over 75 years, and less than 75 years old. The primary outcome of interest was a modified Rankin Scale of three or less, and we included 899 patients who underwent this baseline ischemic core volume measurement, which corresponds to 51% of our patients in the HERMES collaboration dataset. Dr. Negar Asdaghi:         All right. So, just a quick recap of what you said. Thank you for this. So, we have 899 patients. Those patients were all included in the HERMES collaboration, but, of course, these are patients in whom we had presenting ischemic core measurements. And that will get me, actually, Koji, to my second question. Can you please walk us through how you did analysis of ischemic core volume measurements in this study? Dr. Koji Tanaka:               In this study, ischemic core volume was measured by CT perfusion in 591 patients and by diffusion-weighted imaging in 309 patients. We defined the ischemic core volume as a relative cerebral blood flow of less than 30% in CT perfusion and diffusion coefficient of less than 620 square micrometers per second in diffusion-weighted imaging. Previous studies showed ASPECTS moderately correlate with ischemic core volume in both CT perfusion and diffusion-weighted imaging. For example, ASPECTS of eight can be considered as ischemic core volume of 20 milliliters. But underlying [inaudible 00:28:21] were different between CT perfusion and diffusion-weighted imaging, and previous studies suggested CT perfusion occasionally overestimates the ischemic core volume was on diffusion-weighted imaging. In this study, the results did not change when analyzing CT perfusion and diffusion-weighted imaging separately. Dr. Andrew Demchuk:   Yeah, that's a really important point Koji makes, is that because we had sort of a, not quite a 50/50 split, we had a 60/40 split of CTP and DWI, we did analyze them separately, and the odds ratios of treatment effect were pretty similar at different core thresholds. So, they're fairly similar when you separate them out, but obviously the methodology is a little different between a CTP and a diffusion. And to Koji's point, he's absolutely right, the CTP has a tendency to slightly overestimate core when you compare to diffusion. Dr. Negar Asdaghi:         Yeah, and thank you. I think you already sort of alluded to what I was going to ask you and Koji, because, in reality, we have different ways of measuring core. We have the ASPECTS score, which is just a quick and dirty way of estimating or guesstimating core, and then we have CT perfusion, and we also have diffusion that sometimes is available to us, but not always. And the question is, in the heat of it, how we're going to measure the volume. With post-processing softwares, with CT perfusion, we get a quick potential ischemic core volume, but we don't have that capability with diffusion even if we did get diffusion. So, I think it's important to know that what Koji mentioned, an ASPECTS of eight can, more or less, in a quick fashion, be thought of as about 20 cc of core. And the other point that Koji raised was that CTP, again, this is sort of ballpark, can tend to overestimate ischemic core if you were to compare that with diffusion-weighted data. So, with that, now we have a study in which we have core volumes, and we're going to look at outcomes from endovascular thrombectomies compared to best medical management and see whether there is a correlation or interaction between ischemic core presentation, especially age. So, my next question would be to Andrew, can you walk us please through the main findings of the paper? Dr. Andrew Demchuk:   The whole goal of this paper was really to understand, are there thresholds in the older patients? When we looked at overall, and Bruce Campbell and the team wrote an important paper with HERMES and the CTP cohort overall, and the sort of message there was if you looked at shift analysis, there wasn't actually a core threshold found at all in HERMES for lack of benefit. There was a benefit across all the core volumes, but, of course, that's all ages. So, we were really interested in looking at the older patients because we felt there's more likelihood the core volume will matter in the elderly than in the younger patient. We know the younger population, it benefits overwhelmingly with EVT, it's hard to even find a core volume threshold. So, that was a premise. Essentially, we had 247 patients over 75 in the overall cohort, of which 98 had EVT. So, it was a decent population, and not a huge sample, but a decent sample. And so we looked at various things. The first thing that was interesting we found was that infarct volumes, the average infarct volume to achieve an mRS three or less, was lower in the older patients, significantly lower, was 23.9 for younger patients under 75 and 10.7 for the older patients. You tend to have much smaller infarcts to achieve good outcome. And so that was kind of interesting, and I think that's been shown by others. Then we got into the weeds to try to figure out, OK, what are these thresholds? And if there's one figure that matters, Negar, you know me to always point out that there's always one figure or table in a paper that's kind of where the money is, where the real learning is, and that's Figure 2 on this paper in my opinion, beautiful figure with four figure A, B, C, and D. And it really sort of nicely highlights these issues and these cutoffs. But what we saw is that in the older patients who received EVT, around 50 mils seemed to be a threshold to achieve zero three, you had to, to see treatment effect, you had to have a baseline infarct volume less than 50 mils for a zero three outcome advantage. For zero four, it was 85 mils. And then we looked at this issue of what we called futility, true futility. And that's a very controversial thing. What is futility, or how do you measure futility? And really, I think, we even had a debate about this as a HERMES group when we were designing the analysis, and we sort of landed on mRS five six. A 90% chance of mRS five six, right? That's quite the bar, right, to say true futility because some people argue mRS four is still not a horrible outcome. Culturally, that is an OK outcome in some situations. But when we did use that five six 90% threshold, it was 132 mils. So, you're getting up to these really large volumes. But here's the catcher in the whole thing, and Koji will probably speak to this a bit more. I don't want to steal his thunder too much, but this issue of reperfusion seemed to matter in this. And we'll come back to that maybe with another question. Reperfusion matters a lot when you think about these thresholds. Dr. Negar Asdaghi:         OK, so, Andrew, a lot of information, I don't know if I need a recap myself to recap, but basically what you mentioned is that for the older patients who received EVT, if we keep our eyes on the outcome of mRS of zero to three, it seems to be the magic core volume for that outcome post-endovascular therapy that it lands on the magic volume of 50 cc core. Did I get that right? Dr. Andrew Demchuk:   That's correct. Dr. Negar Asdaghi:         Then if you're still a bit more lenient with the definitions of what is favorable outcome, what outcomes we're looking at and so on, so forth, for an mRS of five to six, then when we talk about futility of endovascular thrombectomy, the volume that you mentioned, and again I want to ask you this, this volume is for elderly over the age of 75, is 130 mil. Dr. Andrew Demchuk:   132, but yeah, absolutely. But there's a real catcher here, and we need to really emphasize the catcher in this. Dr. Negar Asdaghi:         Okay. I will ask you one more question before I go to Koji, which I'm sure is going to tell us more about that catcher. Andrew, can you please tell us about the factor of time? I feel like that is something that we need to discuss, as well. Your study included patients early on in their stroke onset, but we're talking about an important interaction. The question is, do you think the results of this interaction would be different or impacted by the value of time? Dr. Andrew Demchuk:   Hypothetically? It must, right? I think that that must be the case. We don't have any data specific to this. That would be an interesting Aurora analysis to do. Now, of course, the challenge with late window analysis is, we are really small core in our late window trials, we probably have even a much smaller proportion of large cores. So, to be able to even tackle that question in the late window is, I don't know if we have the data yet, to be honest. But it makes sense that you would expect the thresholds to be a bit lower the later you are in the window. But that is a hypothetical opinion. Dr. Negar Asdaghi:         Right, so, I want to take that and come to Koji. I want to digress a little bit to Koji and see how we can understand the finding of this current analysis of this paper. So, small core patients early on into their onset, we're looking at the interaction between age and their core volume and coming up with numbers 50 cc for the elderly population. If you're looking at the outcome of zero to three or 132, as Andrew pointed out, for an MRS of much higher, four or five. Dr. Andrew Demchuk:   Actually five, six, 90% chance of five, six. So, it's there. It's like almost everybody got five, six, took 132 mils to get there. So, it's like this extreme outcome. Dr. Negar Asdaghi:         Right, so, exactly, and I have to correct it, again, mRS of five or six or dead or almost dead mRS basically. Dr. Andrew Demchuk:   In 90% of patients. Dr. Negar Asdaghi:         90% of patients. So, we have these important numbers here, and I want us to basically understand these numbers in these volumes in the context of the recently published RESCUE-Japan LIMIT study. Can you tell us a little bit about that study and how we can make sense of these volumes in the setting of that paper? Dr. Koji Tanaka:               In the recent RESCUE-Japan LIMIT trial, the median ASPECTS was lower, and baseline ischemic core volume was greater than those in our study. And surprisingly, the median ischemic core volume in that trial was close to our threshold to predict less than 10% of patients achieve a modified Rankin Scale of four or less after endovascular therapy. We thought this is due to much higher complete reperfusion rate in HERMES patient. We have much interest in their additional analysis for outcomes in elderly patients by reperfusion status. This potential benefit of endovascular therapy in the area is promising for the future clinical trials. Dr. Andrew Demchuk:   I think just to add to that, it was actually really interesting, Negar, because when we were analyzing all of this and then the trial came up and it was actually really nice because we're like, OK, how does our data relate to their data? And that's where Table 2 comes in, and it would almost be worth putting on the pod, whatever, I don't know if you have on your podcast website, you have one figure that you can sit there with as you listen to the podcast, because that would be the figure. Dr. Negar Asdaghi:         We'll work on that Andrew, but tell us a little bit more because, really, when I read the trial results, the way I understand it is that people enrolled in RESCUE-Japan that were older than 75, and these are all large core patients, benefited more from endovascular therapy than their younger counterpart. How do I understand that? I don't know how to wrap my head around that finding. Dr. Andrew Demchuk:   You want to try to answer that, and then I'll add? Dr. Koji Tanaka:               As I mentioned previously, we want to know about the exact patient population just only for elderly patients, whether they have a exactly larger ischemic core volume or as well as their functional outcome. How many patients achieved modified Rankin Scale four or less or three or less, or more than five or six? Dr. Andrew Demchuk:   Koji's point's very important. We actually don't have the breakdown of the mRS, so we don't know if they created a lot of fours, or threes, or what. So, that's one issue. But I think that the key to this whole thing is to understand that this is a 2022 trial. HERMES data is essentially a 2015 equivalent where we're looking at a number of clinical trials who roughly ended between 2014, 2016. So, the technology, the technique, the operators, are just at a different level back then than now. And quite frankly, EVT is an improving treatment. We probably don't even fully understand how much, I mean, we're just getting better at it. And I think what's happened here is the reperfusion rates have improved. And our HERMES reperfusion rates, remind me, Koji, I think they're about half, we think, in HERMES, than like the TICI 2bs, threes, are half in HERMES what they got in RESCUE-Japan LIMIT. So, when you achieve successful reperfusion, what were the numbers here? TICI 3 was 43% in the Japan RESCUE LIMIT, and 8.6% in HERMES. Okay, TICI 3s were not ... Now that may be slight differences in core lab interpretation, but we were just starting to get good at 3s. We were getting a lot of 2bs and some 2cs, but we weren't getting a massive number of 3s back in 2015. Well, voilà, now we are, right? We're hitting home runs when we didn't before. And I think that has really shifted the goalposts on the large core. If you open the vessel, they can still do well if they're elderly, but you've got to really open that vessel. And in HERMES, we only did that in a small portion of patients. So, these thresholds are sort of representative of 2015 skill. Dr. Negar Asdaghi:         Golden points, Andrew and Koji, both of you. I want to recap what you mentioned here. A note to all of our audience and listeners that we are looking at an analysis with RESCUE-Japan, an analysis of a 2022 study. And the patient population that were enrolled were also treated much later in terms of time than the patient population that was enrolled in the HERMES collaboration and in all of the trials that contributed to HERMES. So, we've got to remember that EVT is this fluid, ongoing, everyday-improving therapy, from our techniques to everything else, you know, how fast we get patients to the angiosuite. And the point that you raise, I want to repeat that, the percentage or the odds of achieving a perfect reperfusion was, in RESCUE-Japan, was 43% odds of TICI 3 reperfusion, whereas only 8.6%. So, when we're talking about all of these predictive modeling or predictive factors that will tell us who's going to do well, who's not going to do well, it also is predicated on the angiographic success. And perhaps in the earlier trials or even the early study that we covered as part of the STRATIS registry, we put everybody, TICI 3s with TICI 2b or better, whereas nowadays we accept the best, TICI 3s, and maybe that improved percentage in the most recent trial, the RESCUE-Japan, really did what it had to be done for the elderly population to keep that in mind. And Andrew, before we end our interview, I want us to get your top two takeaway messages from this paper. Dr. Andrew Demchuk:   Clearly, elderly patients do better when their strokes are smaller, that we know, compared to younger patients. But it's all about hitting the home run. It's all about hitting the home run. Figure 2C and 2D, you can see that if you achieve that high TICI score, a significant proportion of elderly patients potentially could still benefit, 30–40% reasonable outcomes with bigger cores if you get those high TICI scores. So, it is about hitting the home run in reperfusion in the elderly. You need to go for it, and hopefully you're successful, because if reperfusion isn't successful, then generally the outcomes are not ideal and they certainly worsen as the core volumes become larger, bigger. Dr. Negar Asdaghi:         Before I ended the interview, given Andrew's tremendous experience as a longtime fellowship director and seeing that he was flanked by two of his fellows, one past, myself, and one present, Koji, I had to ask him one final question of what his philosophy is as an educator. Dr. Andrew Demchuk:   I have a sort of philosophy on life with fellows. I always look for the special power in a fellow. I realized a long time ago we’re all, we’re not perfect, nobody’s perfect, I’m not perfect, but there’s usually a special power in people, and if you spend the time to get to know them, you identify that special power, and you really help harness it because you know that if they can harness it when they go back to their faculty job, they’re going to really contribute something special to their team, right? You can imagine six special powers from six different people in a team. Now you’ve got a real team, right? If you know what your power is, you know your limitations, but you know where your strengths you can add to the group, and that’s what we try to do here when we can. It’s not always, you know, special powers, you have to kind of seek them out. But they’re there in most people, and that’s really important for career down the line. Dr. Negar Asdaghi:         And this concludes our podcast for the December 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including our very interesting Stroke Images series. In this month, we have a case of progressive cervical myelopathy secondary to a dural AV fistula supplied by the anterior inferior cerebellar artery. We also have a separate case of carotid rete mirabile imaged with a four-dimensional flow MRI study. And with these cases, we bring our 2022 Stroke Alert Podcast series to an end. Over the past 12 months, we've ended our podcasts with various inspirational tales. From the moving account of the American runner Steve Prefontaine and the remarkable journey of the Syrian refugee and Olympian swimmer Yusra Mardini, to the discovery of positron and Commander Armstrong's landing on the moon, our podcast stories have but one thing in common, which is the story of human perseverance and consistency in the face of hardship. So, as we end 2022 to start 2023 anew, Andrew's comments on finding that special power in each of us resonate with our resolution to stay alert with Stroke Alert. 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.