Stroke Alert

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.

On Episode 12 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2022 issue of Stroke: "Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study" and "Cumulative Concussion and Odds of Stroke in Former National Football League Players." She also interviews Dr. Mike Sharma about his article "Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial." Dr. Negar Asdaghi: 1) Can repeated concussions increase the risk of stroke in professional athletes? 2) Does stem cell therapy enhance the recovery from ischemic stroke? 3) ESUS stands for "embolic stroke of unknown source." Is ESUS just a fancy new term, or is there more to it than meets the eye? These are some of the topics that we will discuss in today's podcast. We're covering the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome to a new year of Stroke podcasts. 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 January 2022 issue of Stroke covers a host of topics, from molecular biomarkers and drug targets in brain arteriovenous malformation to examining the role of calcium in atherosclerotic carotid disease, which I encourage you to review in addition to listening to today's podcast. Later in the podcast, I have the honor of interviewing Dr. Mike Sharma from McMaster University in Hamilton, Ontario, on his work with embolic stroke of unknown source and some of the therapies to soon be studied in this population, including the new Factor XI inhibitors. But first with these two articles. Dr. Negar Asdaghi: Stem cells are truly the new kids on the block of therapies to potentially enhance stroke recovery. There's now four decades worth of experience with preclinical research and studies with animal models to evaluate the safety and efficacy of stem cell therapies and stroke. Now, this is a complex topic, and I will try to simplify it as much as possible. So, what are the things that we need to know about stem cell therapy and ischemic stroke? Well, first, in humans, the bone marrow has emerged as the widely used source of stem cells, primarily because of its long track record of safety profile. In fact, bone marrow derived cell populations, some examples being mesenchymal stem cells, mononuclear cells, endothelial progenitor cells, are the leading candidates for stem cell therapies in ischemic stroke. Number two, stem cells can be practically delivered to the brain through a variety of pathways. Intravenous and intra-arterial treatments have been and are currently being studied, but stem cells can also be delivered intranasally and, of course, surgically transplanted in the brain. Dr. Negar Asdaghi: So, with these in mind, there are two recently concluded clinical trials of mesenchymal stem cells in adult stroke patients. The STARTING-2 trial, which stands for the Stem Cell Application Researches and Trials in Neurology-2, was one of those two trials. This trial evaluated the safety and efficacy of intravenous autologous, meaning from the same individual, mesenchymal stem cells in patients with moderate to severe neurological deficit originating from the middle cerebral artery territory infarct within 90 days of symptom onset. The primary results of the trial was published in Neurology very recently in February of 2021, and if you missed it, well, luckily, you are listening to the podcast today. So, here's a quick recap of the trial. Fifty-four patients were enrolled in the trial with mean stroke onset to randomization of 20 days. Patients were randomized 2:1 to either receive intravenous mesenchymal stem cell treatment or placebo. Dr. Negar Asdaghi: Well, in terms of the primary outcome, stem cell therapy did not improve the primary outcome, which was improvement of modified Rankin Scale at 90 days after treatment. So, disappointing, but secondary analysis showed a significant improvement in lower extremity motor function in the stem cell group as compared to the control group. So, in the current issue of the journal, in the study titled "Efficacy of Intravenous Mesenchymal Stem Cells For Motor Recovery After Ischemic Stroke: A Neuroimaging Study," the STARTING-2 collaborators, led by Dr. Jungsoo Lee from the Department of Physical and Rehabilitation Medicine from Sungkyunkwan University School of Medicine in Seoul, South Korea, aimed to look at this improved motor recovery in more detail using advanced neuroimaging. So, of the original 54 patients in the trial, 44 were eligible for the current neuroimaging study. Participants underwent a variety of testings, including diffusion tensor imaging and resting-state functional MRI studies, at the time of enrollment and then 90 days afterwards. Dr. Negar Asdaghi: So, not surprisingly, at baseline, patients in both the stem cell and control group had comparable demographics, clinical characteristics and infarct volumes, as well as similar motor function, which was measured by the Fugl-Meyer, or the FMA, score. So here's a look at their main findings. So, number one, the FMA scores that were comparable at baseline were significantly higher at follow-up in the stem cell-treated group. Number two is the interesting results; they looked at the motor pathways using diffusion tensor imaging. So, they looked at fractional anisotropy values of the corticospinal pathways and the posterior limb of the internal capsule. Now, just a quick review of a somewhat complex concept of the fractional anisotropy for our listeners. In general, FA is one of the calculated parameters in DTI with a value between zero to one, and what it does is that it defines the degree of diffusion directionality. Dr. Negar Asdaghi: A value of zero means that the diffusion is isotropic, meaning it is unrestricted or equally restricted in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all the other directions. So, it's easy to understand in terms of axons creating white matter tracts. When the tracts are intact, then the FA values would be high because the diffusion is occurring only in one direction as the tract is intending it to do so, whereas if the white matter tracts are damaged, then the uni-directionality of the tract would be disrupted and the molecules would diffuse freely in various directions and the FA values for that white matter tract is then, as expected, reduced. So, in the stroke model, for example, if a neuron in the motor cortex is damaged, the white matter tract related to that region will, over time, degenerate, a process which we know as Wallerian degeneration and, as such, the FA values of that tract is expected to decrease as we go from the acute to the chronic stages of stroke. Dr. Negar Asdaghi: So, back to the current study. At time zero, FA values for the corticospinal tract and the posterior limb of internal capsule were fairly similar between the two groups, but interestingly, at 90-day follow-up, those in the control group had a significant and expected drop in their FA values, whereas those who had received stem cell therapy did not show a significant drop, meaning that intravenous administration of mesenchymal stem cells did modulate and perhaps prevented degeneration of the motor tracts after stroke. The third and final interesting finding of the study was the findings of the resting-state functional MRI. They used RS, or resting-state, fMRI as a measure of functional motor connectivity and found that stem cell treatment increased the strength of ipsilesional connectivity in the motor network and prevented a drop in the strength of intrahemispheric connectivity, whereas these findings were not seen in the control group. Dr. Negar Asdaghi: So, what does this all mean? We now have some detailed neuroimaging evidence that indeed stem cell treatment can facilitate motor recovery possibly by reducing degeneration, which is what their DTI data showed, and potentially by leading to positive motor network organization or reorganization, which is what the resting-state fMRI findings showed. So, obviously, lots still to come in this topic and a reminder to our listeners that there are ongoing clinical trials on this topic. So, we will stay tuned as the neuroprotection and regeneration paradigm is truly changing for ischemic stroke with stem cell therapy. Dr. Negar Asdaghi: Sports-related concussive symptoms typically resolve within a few weeks of the injury, but there is now ample scientific evidence to suggest that repeated concussion can cause long-term neurological disorders extending way beyond the short-term post-concussive period. How can traumatic brain injury, or TBI, be a cause for stroke? Well, in the more severe forms of TBI, it can actually cause damage to the large vessels and cause dissection, but there is more and more research showing that even milder trauma can lead to microvascular disruptions and even alterations in coagulation pathway, which will then increase the risk of stroke. So, how about repeated mild trauma or repeated concussion in professional athletes? Is concussion a risk factor for stroke in this population? Dr. Negar Asdaghi: Well, in the current issue of the journal, in the study titled "Cumulative Concussion and Odds of Stroke in Former NFL Players," Dr. Benjamin Brett and Zachary Kerr from Department of Neurosurgery, Medical College of Wisconsin, and Department of Exercise and Sports Science, University of North Carolina at Chapel Hill, and colleagues report on a cross-sectional study that included professional football players who had at least played for one year in the National Football League and were over the age of 50 at the time of the study. Dr. Negar Asdaghi: Now, before we go over the results, there are a few important definitions from this study to note. Number one, concussion was defined as a blow to the head followed by a variety of neurological symptoms, such as headache, dizziness, loss of balance, etc. Getting knocked out or being unconscious was not necessary to define concussion. For our listeners, this is an important shift from the original definition of concussion that required some alteration of level of consciousness. Number two, the participants were asked as part of the study survey about a history of stroke, which was defined as any health provider giving the participant the diagnosis of stroke at some point in their life. So, there were no mandates of any neuroimaging or particular testings to confirm this diagnosis as part of the study. So, with these in mind, 979 participants met the study inclusion criteria and were included in the study. The mean age was 65 years ranging from 50 to 99, self-reported lifetime concussion history was recorded, and the participants were then divided into five categories of zero, meaning never had experienced concussion, to those with over 10 concussions. Dr. Negar Asdaghi: So, the first important finding was that over a quarter of their study population actually were in the over 10 concussions category. The second finding was the overall prevalence of stroke was 3.4% amongst the pro-NFL players, which was significantly lower than that expected from age-matched normative population, meaning the prevalence of stroke amongst U.S. men over age of 50. So, in simple words, being athletic is a good thing and not surprisingly is associated with a lower risk of vascular disease. But what they found was that NFL players with a history of 10 or more prior concussions had five times the odds of stroke as compared to those with no prior concussions in the adjusted models. So, what we learned from this study is that traumatic brain injury, specifically repeated TBI, however mild, seems to be an independent risk factor for stroke. Microvascular disruptions and potentially alterations in coagulation pathways have been proposed as potential mechanisms for this association. Dr. Negar Asdaghi: About a quarter of patients with ischemic stroke do not have a clear cause for the stroke and fall under the cryptogenic or unknown category. In 2014, an international panel of experts developed a criteria to define a group of patients with cryptogenic stroke that are likely to have an embolic, but yet undefined source for their ischemic event and called them ESUS, which stands for "embolic stroke of unknown source." These were operationally defined as non-lacunar brain infarcts without significant proximal arterial stenosis or known cardioembolic sources of infarct. Now, the idea behind the development of this new term, ESUS, was to identify a more homogenous subgroup of cryptogenic stroke patients that would perhaps benefit from preemptive anticoagulation therapy over the standard antiplatelet treatment for secondary prevention of stroke. Dr. Negar Asdaghi: Indeed, since 2014, ESUS has become a rather commonly used terminology in the stroke literature with multiple ongoing and a few already completed randomized trials examining the efficacy and safety of the newer oral anticoagulants in patients with ESUS over antiplatelet therapy. Similarly, much has been done to further study the clinical and radiographic characteristics of patients with ESUS. In this issue of the journal, in the study titled "Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source," the NAVIGATE ESUS randomized control trial investigators set out to examine the radiographic characteristics and infarct patterns of ESUS patients enrolled in the NAVIGATE ESUS randomized trial. Dr. Negar Asdaghi: Joining me now is the first author of the paper, Dr. Mike Sharma, to discuss the findings of this paper. I always say that my guest needs no introduction, and today's guest is, of course, no exception to that. Dr. Sharma is well known to our Stroke readership. He is a stroke neurologist and a scientist at the Population Health Research Institute at McMaster University in Ontario, Canada. He is truly a leader in the field of clinical epidemiology in secondary stroke prevention with an interest in randomized trials, covert stroke, and economics of stroke care. He holds the Michael G. DeGroote Chair in Stroke Prevention and is the immediate past chair of the Canadian Stroke Consortium and also leads the Hamilton McMaster Stroke Program. Good morning, Mike. It's so good to connect with you after so many years. Thanks for being with us. Dr. Mike Sharma: Good morning, Negar. It's a pleasure to talk to you again, and thank you for that kind introduction. Dr. Negar Asdaghi: Well, thank you so much. Can you please start us off with a brief summary of what the NAVIGATE ESUS trial set out to do, and what were the main findings of the trial? Dr. Mike Sharma: So, in NAVIGATE, we really wanted to advance the care of patients with cryptogenic stroke. Cryptogenic has been a somewhat nebulous term for decades, and care really hasn't advanced beyond using aspirin. The problem with that term is, there is no agreed upon criteria to define cryptogenic stroke. Sometimes it means that the workup is incomplete, where there are multiple competing causes or indeed there is a disagreement as to what the cause is. So, in NAVIGATE, we took a different approach, which was to look for markers which would identify patients who had strokes which were embolic. Our feeling was that they might respond better to anticoagulation than antiplatelet therapy. So that was the main goal in NAVIGATE, was to use this construct of ESUS to test the hypothesis that anticoagulation will be more effective in preventing stroke recurrence than antiplatelet therapy. Dr. Negar Asdaghi: And what did the trial find? Dr. Mike Sharma: So, NAVIGATE randomized over 7,000 patients with ESUS, and it was stopped, unfortunately, at the time of the second interim analysis after about 67% of primary events had occurred. At that point in time, our mean follow-up was only about 11 months. It was stopped because there was a difference in the risk of bleeding between the rivaroxaban arm and the aspirin arm and, at that point in time, no evidence of benefit. So, the DMC reasonably halted the trial. So, at that point, we saw an excess of hemorrhage with rivaroxaban without an offsetting benefit in preventing recurrent ischemia. Dr. Negar Asdaghi: Okay, so to recap for our listeners, NAVIGATE is an early terminated randomized trial that basically looked at the safety and efficacy of rivaroxaban over aspirin in secondary prevention of stroke in ESUS. Now, the dose of rivaroxaban used in NAVIGATE ESUS was slightly lower than the current standard of care for treatment of embolic stroke patients with known atrial fibrillation. So, you used 15 milligrams per day rivaroxaban, whereas the standard is 20 milligrams per day. Was there a reason why a slightly lower dose of rivaroxaban was chosen for the trial? Dr. Mike Sharma: That's a great question. So, 20 milligrams a day in atrial fibrillation is approved in the U.S. I must say that many guidelines, including the AHA guidelines, suggest 15 milligrams for patients with renal impairment and creatinine clearance that is less than 50. Now, in other countries, as the label is slightly different recommending the lower dose. So, in planning this very large international trial, we had a variability in dosing and the complexity of possibly having to change the dose during the course of the trial if a patient's renal function changed. When we looked at the drug exposure between the 15 and 20 milligrams, it turns out that they were very similar. So, taking 15 milligrams, you get very close to the drug exposure with 20 milligrams. The lower dose, we felt, would eliminate the need for dose adjustments during the course of the trial and make running the trial simpler and possibly have a slightly lower risk of hemorrhage than the 20 milligram dose. So, for all those reasons, 15 milligrams was chosen. Dr. Negar Asdaghi: Mike, I love these interviews mainly because of these valuable background information we get on trials that is otherwise impossible to easily access. Now, coming back to your current paper, the current paper in the January issue actually is an MRI sub-study of the NAVIGATE ESUS trial. Can you please walk us through the details of the current study? Dr. Mike Sharma: Sure. You know, in NAVIGATE, in the parent trial, we included people who had embolic strokes of uncertain source, and those were operationally defined as either visible on imaging, the majority were, or having symptoms that lasted greater than 24 hours. You couldn't have atrial fibrillation, and we required at least 20 hours of monitoring. Now, 20 hours sounds like a funny time period to request. Originally, we asked for 24 hours, but it turns out that when you put a monitor on for 24 hours, it's never exactly 24 hours. It's often just slightly less. So, we had to make a practical decision as to how much was enough, and in addition, you had to have less than 50% extracranial stenosis. We didn't require imaging of the intracranial vasculature; however, if it was imaged, the stenosis had to be less than 50% to the affected area. Dr. Mike Sharma: You needed an echocardiogram. We didn't specify a transesophageal echo. Most were transthoracic, which excluded left ventricular thrombus or left atrial appendage thrombus. People who had prosthetic mitral valves were excluded as well. So, from that population of about 7,000, our aim was to select 1,000 patients who met those criteria, but in addition had no contraindication to MRI, and the plan in the MRI sub-study was to look at what happened to covert infarcts, infarcts we didn't identify clinically during the course of the trial, if there was a treatment effect on those and also with MRI, a very sensitive, I would say, exquisite measure of hemorrhage that occurs in the brain. Because the trial was closed early, we ended up at baseline having 918 usable images and participants from 87 sites across the world, less than our original target. You know, our goal really was to see what would happen to these MRI lesions and if treatment affected them. Dr. Negar Asdaghi: Okay. So we are talking about baseline MRIs of a subpopulation of the patients who were enrolled in NAVIGATE ESUS, and I think we are ready now to hear about your main results. Dr. Mike Sharma: Thanks very much. I'm bursting to talk about them. You know, in spite of the fact that this was a subset of the whole ESUS population, 918 out of 7,000, roughly 13%, the characteristics of these patients was very similar to the main trial. So, I think that with the usual caveats of the subgroup, I think it's reasonable to think that what we found is representative of the ESUS population in general. The most exciting finding for us was that, so we set out to define clinically a group that would be embolic. The majority of the MRIs that we had first off had visible infarcts, and secondly, 70% of these were multiple infarcts often in multiple vascular territories. So, the clinical construct, I would say, worked. We did identify a group of patients who have embolic lesions and often proximal sources, as we see with these multiple vascular territories affected. Dr. Mike Sharma: So, this clinical construct works really very well in identifying them. The second thing we found, which shouldn't have been overly surprising but really stood out, were the number of lesions that these people had. The ones with multiple lesions, on average, had four infarcts visible on their MRI, and these were present even in patients who did not have a previous history of TIA or stroke. So, this was their first symptomatic event, and I think that tells us a lot about what's happening in this condition. It's an embolic disease with multiple events, which seems to be very active over time, even when these lesions aren't identified symptomatically. Dr. Negar Asdaghi: So, Mike, you've already alluded to what I was going to ask you in this question, but I want to recap and repeat for our listeners again, some very pretty impressive findings you have in the study, 93% of ESUS patients with evidence of infarcts, 70% in multiple vascular territories. What I find very interesting is that two-thirds of your patients without even a history of TIA or stroke had multiple infarcts on their neuroimaging. Does that represent to you this clinical radiographic dissociation in the ESUS population? Dr. Mike Sharma: You know, I think that's a really great question. So, it certainly does. What we know in the number of other covert studies and some other work that colleagues have done epidemiologically is the proportion of covert infarcts. These are infarcts without clinical symptoms that have been identified as stroke, is roughly 5 to 10 times symptomatic events. And we are seeing this recapitulated in this population. Dr. Mike Sharma: In looking across literature, I suspect that some of these and perhaps a majority had symptoms which were transient, which they didn't appreciate the significance of, or were not identified as stroke at the time. So, this is similar to what's been seen in other populations, just more striking, I think, because of the embolic nature of this condition. You know, I think this really points to the significance of identifying these patients. We expect them to continue to have these covert infarcts, and I prefer the term "covert" to "silent." Silent means it's not really having any manifestation, whereas covert indicates a hidden and nefarious purpose. So, these things do detract from cognition, from motor function, they correlate with disability and recurrent stroke. So, this condition seems to us to be very dynamic and really needs to be addressed. Dr. Negar Asdaghi: So, striking indeed and definitely concerning findings, Mike, as you pointed out. I think it goes along with all the continuous efforts of increasing public awareness about mild or transient neurological symptomatology along the lines of what you were mentioning. For our listeners, what should be the top two takeaway messages from your study? Dr. Mike Sharma: So, you know, I think from this study, the really important things are when you identify one of these patients where there is an infarct that you cannot comfortably identify the etiology of, please know that it is likely to be embolic often from a proximal source, but not exclusively, and that patient has an ongoing risk of recurrent infarcts, which may not present symptomatically. So, I think that what this underscores is the need to pay a very serious attention to these patients, look carefully for underlying causes, and we really do need a better treatment. Dr. Negar Asdaghi: Fair enough. Now I want to end by something that I derived from your study, and I wanted your opinion on that. ESUS is truly proving to encompass a more heterogeneous group of ischemic stroke patients than I think previously recognized. Can you please tell us what's the future for the ESUS trials? Are you going to more elaborate on the etiology of ESUS, again truly cardioembolic versus others, and can you please share with our listeners some of the work that you are currently doing in this field? Dr. Mike Sharma: Very exciting future, I think, for this. If you consider where we are with this condition, it's similar to where we were with mechanical thrombectomy with the early trials, which were negative but taught us a lot, and so has this one. Our approach with mechanical thrombectomy, we did two things. First, we honed in on the patient population that was likely to respond, and secondly, we improved the treatments, and I think our approach to ESUS, and this goes along with what we are doing currently, is along the same lines. So, in terms of honing down on the population likely to respond, there is now a number of interesting trials being done. One of these is ARCADIA, and I would encourage everybody to refer patients for this trial. In a post hoc analysis of NAVIGATE, we found that patients with markers of atrial myopathy, particularly a large left atrial diameter, seemed to respond to anticoagulation. Dr. Mike Sharma: So, in ARCADIA, which is being run from Columbia University through NIH StrokeNet, is looking for patients with ESUS who have markers of atrial myopathy, randomizing to anticoagulation or aspirin. So, really honing in on a population likely to respond. The other thing that we are working on are better treatments. So, at the same time NAVIGATE was being done at our institute, we were doing COMPASS. Now, COMPASS used low dose rivaroxaban 2.5 milligrams BID with aspirin, and one of the startling findings in COMPASS was a 50% reduction in ischemic stroke occurrence in that trial. And if you think about it, emboli can be fibrin rich or platelet rich or some combination and we really don't know. So, if there is a safe dose to combine aspirin with an anticoagulant, that is a promising approach. So, currently what we are doing is a trial using Factor XI inhibitors. Dr. Mike Sharma: Now, you know, if you think broadly across stroke prevention, we have made advances using dual antiplatelet therapy, but they seem to be hitting a ceiling in terms of efficacy with some risk of hemorrhage, and it certainly seems to be the case from NAVIGATE and also RE-SPECT ESUS, which used dabigatran, that anticoagulation by itself won't work. So, from COMPASS, we have this dual pathway approach combining anticoagulation and antiplatelet agents. The novelty here that we are pursuing is using anticoagulants, which have a much lower risk of hemorrhage. So, Factor XI, unlike Factor X, which is affected by rivaroxaban, is not involved in hemostasis, but rather amplifies thrombi, and we know that Factor XI-deficient patients have a low rate of stroke, lower than matched controls, and really no significant spontaneous hemorrhage. Dr. Mike Sharma: So, there's a number of trials currently in DVT. We are running really the first trial ever done in stroke at phase two to develop an appropriate dose of anticoagulation for these patients. So, I think the future is going to be combining anticoagulants with antiplatelet agents to reduce these patterns of embolic stroke. Holds a lot of promise after what we saw in COMPASS, and indeed we did a similar MRI study in COMPASS, which taught us a lot about how to do these trials. So, currently, we are working on those, and the first results from two trials using Factor XI inhibition. This approach should be available to us next year. Dr. Negar Asdaghi: So, wow, a lot of information, and we look forward to reading about all of this and perhaps collaborating with you on this. Now, Mike, one question that came up along the lines of what you were mentioning is that, what about the duration of therapy? Do you think that much like CHANCE and POINT, where dual antiplatelet therapy is beneficial for shorter period of time and not for long period of time, that you might choose that as well for ESUS patients, that a short period of anticoagulation or combined anticoagulation and antiplatelet therapy might be beneficial and then not continuing them indefinitely for this population? Dr. Mike Sharma: You know, it's an entirely reasonable approach to consider. The problem really is what we found in the MRI study, which is that infarcts continue to occur over the long period. We have data now for about a year. But, in other trials and COMPASS, we saw it over many, many years. So, I think that if we focus on the short term, we will have success in reducing the recurrence rate, and the payoff might be a lower risk of hemorrhage, but at the cost of leaving patients vulnerable to recurrences over the long term, you know, and NAVIGATE, we saw recurrence rate of about 5% per year. So quite a significant recurrence rate of symptomatic stroke, and we won't have touched the occurrence of covert infarcts and all that means for the brain. Dr. Negar Asdaghi: Dr. Mike Sharma, thank you so much for joining us on the podcast this morning. We look forward to covering more of your work in the future. Dr. Mike Sharma: It's a pleasure, Negar, very nice to talk to you. Dr. Negar Asdaghi: And this concludes our podcast for the January 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including an organizational update from the European Stroke Conference, which highlights some of the top science presented as part of the plenary sessions at this year's meeting to give us that extra motivation to start the year. Now, speaking of motivation, starting the year, in my view, is much like running a long distance race. Anyone who has done it would tell you that this is as much about mental fitness as it is about physical fitness. So, I think it's only fitting to end the beginning of this year's podcast remembering one of America's inspirational distance runners, Steve Prefontaine. Dr. Negar Asdaghi: As a kid, he was told that he's too short and perhaps too slow to be played in any of his school's sport teams. Later, when he became a runner, people would say that they had never seen anyone run like him, a runner who never slowed down nor paced himself. And he famously said "to give anything less than your best is to sacrifice a gift." All of 2022 is now ahead of us. Let's not sacrifice the gift. There is no time to pace ourselves, 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 11 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the December 2021 issue of Stroke: "Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial" and "Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial." She also interviews Dr. Mark Parsons about his article "Stroke Patients With Faster Core Growth Have Greater Benefit From Endovascular Therapy." Dr. Negar Asdaghi: 1) Can the presence of a high-grade asymptomatic carotid stenosis result in development of early dementia? 2) Have you ever wondered if a random poststroke urinary tract infection or hospital-acquired pneumonia can impact the 90-day poststroke outcome? 3) When it comes to the beneficial effect of endovascular thrombectomy, what is the concept of late window paradox, and why do we need to know about this and its relation with the speed of infarct growth? These are the questions that we will tackle in our December podcast. We're covering the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to 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 December 2021 issue of Stroke, we have a large selection of topics, from whether adjusting antiplatelet therapies after stenting for intercranial aneurysms can potentially reduce ischemic events, to studying the outcomes of patients with reversible cerebral vasoconstriction syndrome and analysis from a nationwide study in the United States, which I encourage you to review in addition to listening to our podcast today. Later in the podcast, I have the pleasure of interviewing Dr. Mark Parsons, from the University of New South Wales in Sydney, Australia, on his work suggesting that the beneficial effect of endovascular thrombectomy may be modified based on the speed of infarct growth, from the time of symptom onset to the time when the patient is being considered for reperfusion therapies. But first with these two articles. Dr. Negar Asdaghi: It has been suggested that the presence of chronic high-grade carotid stenosis can result in early cognitive decline, even in the absence of ischemic stroke secondary to the carotid disease. Multiple mechanisms for this decline have been proposed, including an alteration of cerebrovascular reactivity and ipsilateral hemispheric hypoperfusion. Now, if this is true, then asymptomatic patients harboring a high-grade carotid stenosis would have a lower cognitive status than their age and risk factor in matched counterparts. And this is the exact topic that Dr. Ronald Lazar from the Department of Neurology at the University of Alabama and colleagues studied in this issue of the journal, in their article titled "Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial." Dr. Negar Asdaghi: Now, a very quick recap of the CREST-2 Trial. You will recall that CREST-2 is an ongoing randomized trial of patients over 35 years of age with asymptomatic carotid disease of equal or greater than 70%. Asymptomatic is defined as absence of ipsilateral stroke or TIA symptoms within 180 days prior to randomization. Also, a reminder, that to be able to be enrolled in the CREST-2 Trial, patients had to be independent, with no diagnosis of dementia, and they were then randomized to either intensive medical management versus carotid artery stenting, or intensive medical management alone versus carotid endarterectomy. It's important to keep in mind that a secondary outcome of CREST-2 is to see whether carotid intervention over intensive medical management is better in reducing cognitive decline over time in this patient population. Dr. Negar Asdaghi: Obviously, we'll have these results after the completion of the CREST-2 trial and its follow-up completion, but in the current study, the authors were interested to compare the baseline cognitive function of the CREST-2 candidates, and they were able to compare this baseline cognitive status to participants of the REGARDS population-based study. Now, the acronym for REGARDS stands for "Reasons for Geographic and Racial Differences in Stroke." This was a population-based study in the United States that included over 30,000 community-dwelling White and Black adults over the age of 45. So, think about the REGARDS cohort as the stroke-free participants without the high-grade carotid stenosis. Dr. Negar Asdaghi: So, to match the two populations, the authors included only CREST-2 participants that were older than 45 years of age and did not have any prior strokes. So, that gave them a sample size of 786 patients for the current analysis with a complete neurocognitive battery of four tests administered over the phone, in the same order in both studies. So, let's go over these cognitive tests. The test included the Word List Learning Sum, assessing the cognitive domain of learning; the Word List Recall, which is a test of memory; and the two tests for executive function, Word Fluency for animal names and fluency for the single letter 'F'; and a brief screen for depression. Dr. Negar Asdaghi: So, simply put, we have four cognitive tests assessing the three cognitive domains of learning, memory, and executive function. And depending on how the person did on each test, it gave the investigators Z scores for each participant in each category and then they compiled the Z scores in a percentile tabulation for the CREST-2 population and compared these percentiles to the normative data obtained for the REGARDS population. Dr. Negar Asdaghi: So, what they found was that, well, not surprisingly, the population of CREST-2 had a higher prevalence of cardiovascular risk factors, things like hypertension, elevated lipids, smoking and diabetes. Slightly more than half, exactly 52% of the CREST-2 patients, had a target carotid stenosis vessel on the right side. And then they did some complex statistical models, adjusting for age, race and educational level, and then further adjusting for some vascular risk factors, such as hypertension, diabetes, dyslipidemia, and smoking, for each cognitive test, and they found that the overall Z score for patients in CREST-2 was significantly below expected for higher percentiles and marginally below expected for the 25th percentile for all four cognitive tests, as compared to the normative population. Dr. Negar Asdaghi: For example, if they were expecting that 90% of the CREST-2 population would score in the 75th percentile for a particular test, or at 95th percentile on a different test, these percentages were significantly lower in the CREST-2 candidates. The greatest cognitive differences were detected for Word List Delay, which is a test of memory, followed with the Word List Learning, which is a test for learning. And the results really did not change when they adjusted for the vascular risk factors, and importantly, unchanged when they adjusted for right- or left-sided stenosis of the carotid, which is important, as language plays an important role in assessment of memory function. Dr. Negar Asdaghi: So, what did we learn from this study? Well, number one, poor cognition is associated with harboring high-grade asymptomatic carotid occlusive disease, an effect that was only modestly attenuated by further adjustment for other risk factors. Number two, patients with high-grade carotid stenosis showed a significantly lower cognitive performance in the learning and memory domains. This profile of cognitive decline is different than what was typically expected to be seen in the case of vascular dementia, where abnormalities are predominately seen in the test of executive function. Number three, though we don't know the precise mechanism for cognitive impairment in the setting of carotid stenosis, cerebral hypoperfusion seemed to be the leading plausible cause as hippocampus and amygdala are known to be susceptible to hypoperfusion, and the findings of the current study show that the predominant impairment seen in patients with carotid disease seemed to be involving memory and learning. So, really important findings, and lots to still learn on this topic. Dr. Negar Asdaghi: The occurrence of adverse events during acute treatment and within the first few weeks of acute ischemic stroke are common and can negatively influence the course and clinical outcomes of stroke patients. Serious adverse events, or SAEs, are defined as life-threatening events resulting in death or requiring hospitalization, prolongation of hospitalization, or resulting in significant disability, and they can be either neurological, such as recurrent ischemic events, hemorrhagic complications, seizure disorders, but also can include a myriad of systemic complications, including, but not limited to, occurrence of deep vein thrombosis, pulmonary emboli, cardiac arrhythmias, various infections, GI bleeds, to name a few. Dr. Negar Asdaghi: In a setting of a clinical trial, patients are regularly and systematically monitored for SAEs, and from these studies we know that, indeed, both adverse events, or AEs, and SAEs are quite common poststroke and are reported in up to 95% of participants of prior randomized trials. Intravenous thrombolysis increased the risk of symptomatic intracerebral hemorrhage, but in general, the rate of SAEs are similar in thrombolyzed and non-thrombolyzed patients. Which clinical characteristics prone stroke patients to what type of side effects is, of course, an intriguing subject for a stroke neurologist. Similarly, it's important to know how, for example, a seemingly indirect complication of ischemic stroke, such as a hospital-acquired urinary tract infection, can potentially affect the stroke outcomes. Dr. Negar Asdaghi: So, in this issue of the journal, Dr. Iris Lettow from University Medical Center in Hamburg, Germany, and colleagues looked at the subject in the paper titled "Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial." This was a post-hoc analysis of the WAKE-UP Trial, which was a multicenter randomized trial of MR-guided intravenous thrombolysis with alteplase in ischemic stroke patients with unknown time of onset. The WAKE-UP Trial included 503 patients, and they had 199 SAEs reported for 110 patients, meaning that one in five patients had at least one serious adverse event in the trial. Of those patients who did suffer an SAE, 20 patients, which was 10%, had a fatal outcome. Dr. Negar Asdaghi: The rate of SAEs were not different between thrombolyzed and non-thrombolyzed patients. But, when they categorized the patients based on who did and who did not experience an SAE, they found that those who experienced an SAE were older, presented with more severe strokes, and were more likely to have a large vessel occlusion. But only higher age and male sex were independent predictors of development of an SAE poststroke. So, let's pause and think about these findings. This was in contrast to the previous studies, where traditionally, the severity of stroke was a predictor of complications, and importantly, the first study to identify male sex as an independent predictor of SAE, whereas, traditionally, female sex had been identified as a risk factor for development of adverse events poststroke. Dr. Negar Asdaghi: Perhaps what we're seeing with a paradigm shift in improvement in poststroke quality of care. Now, another important finding of this study was that the presence of any SAE, whether neurological or non-neurological, resulted in reduction of favorable outcome by half and almost quadrupled the odds of poor outcome, defined as modified Rankin Scale of four to six at 90 days, even after accounting for all the known confounders. Now, the authors also looked at some interesting details. The organ most effected by serious adverse events poststroke was indeed the nervous system. Almost 50% of all SAEs were neurological in nature. This was then followed by cardiac events. Some examples would include an acute coronary syndrome, MI, various arrhythmias. And the surgical and medical procedures were the third most common category of serious adverse events in this study. Dr. Negar Asdaghi: And what they found was that SAEs by organ of involvement had a significant association with 90-day outcomes, where any neurological serious adverse events significantly affected 90-day functional outcome poststroke. When adjusting and accounting for important variables, such as age, sex, LVO, this still remained true in terms of a predictor of outcome. In contrast, cardiac serious adverse events, infectious serious adverse events, did not have any effect on the 90-day functional outcome. Dr. Negar Asdaghi: So, what are the top takeaway messages from this study? Number one, SAEs occur commonly poststroke, and in this particular study, occurred in one in five ischemic stroke patients. Number two, 10% of those who suffer from an SAE had a fatal outcome. Number three, nervous system disorders and cardiac disorders were the most frequent classes of side effects poststroke. And finally, patients suffering from at least one serious adverse event had a lower odds of reaching favorable outcome at 90 days. These findings emphasize the importance of dedicated stroke care, neurointensive care units, and all poststroke efforts to reduce preventable adverse events poststroke. Dr. Negar Asdaghi: Time is an exceedingly important concept in treatment of patients with acute ischemic stroke. As an example, in a typical stroke related to a proximal large vessel occlusion, the ischemic brain loses an average of two million neurons per minute. Now, endovascular therapy is the standard reperfusion treatment for patients with acute ischemic stroke secondary to a large vessel occlusion. It is an effective treatment to restore blood flow and reperfusion to the brain and had been shown to improve outcomes in stroke patients. Dr. Negar Asdaghi: Therefore, one would naturally anticipate that the benefits of endovascular therapy would be dramatically reduced with treatment so late. If this is true, then why is it that the beneficial treatment effect from endovascular therapy was even larger in patients treated in the late time window trials, and you will recall that these were patients included from 6 to 16 hours, or 6 to 24 hours, from their symptom onset time. This compared to treatment effects noted in patients enrolled in the early time window trials. This concept is known as the "late window paradox" and does not mean that we have to wait to provide reperfusion therapies to patients. It actually refers to those fortunate few that have robust collaterals and, as a result, have slow infarct growth, which will afford them that extra precious time to remain eligible to receive this life-saving treatment. Dr. Negar Asdaghi: Joining me now on the podcast is Dr. Mark Parsons from the University of New South Wales in Sydney, Australia, to talk to us about the concept of infarct growth. Dr. Parsons is one of the senior authors of the study published in the current issue of the journal titled "Stroke Patients With Faster Core Growth Have Greater Benefit From Endovascular Therapy," and will discuss how the beneficial effect of endovascular treatment may be modified by the speed of infarct growth in the early time window after symptom onset. As in every podcast, when I have the pleasure of interviewing a pioneer in the field of stroke, that my guest needs no introduction, but truly Dr. Parsons needs no introduction to our listeners. He's a Professor of Neurology at the University of New South Wales in southwestern Sydney. He's an internationally recognized leader in the field of stroke, stroke clinical trials, and brain imaging whose research has helped improve patient selection for acute stroke reperfusion therapies. It's truly an honor to have him on the podcast today. Welcome, Mark. Thank you so much for joining us all the way in Sydney on a Saturday morning. Dr. Mark Parsons: Yes, thank you, Negar. It's OK, I have been up for a little while. So, yes, lovely to chat with you, and we haven't chatted in person for quite a long time, and I think I actually remember the last time was in Hamburg, in Germany, at a big stroke conference. I remember it quite well. We had a very pleasant evening with a group of Canadians and Australians, and I had to present a major tenecteplase study finding the next day, and I was a little bit off my game, some of my friends said, and I think that's probably your fault, Negar. Dr. Negar Asdaghi: Mark, you did really great, and we really, truly, look forward to getting back to in-person meetings. So, let's start with the study here. Can you please tell us about the INSPIRE registry? Dr. Mark Parsons: So, the INSPIRE registry, that's an acronym. So, it's best to spell out this acronym, so that stands for the "International Stroke Perfusion Imaging Registry." So, that was something we set up quite a while ago when perfusion CT was quite considered advanced or novel. We set that up, I think, in about 2010, and because that was obviously one of my areas of interest, perfusion imaging, we started collecting perfusion CT and CT angiography , and noncontract CT, for that matter, from our stroke patients from a number of centers in several countries. And over time, that built up to over 20 centers around the world, so predominantly Australia and China, because of the close connections that we've got there, but also one site in Canada, actually two sites now. We have so many sites that I sometimes overlook a few. Dr. Mark Parsons: So, it is international. And what we do is, we collect prospective data from stroke patients, both clinical and their acute imaging, follow-up imaging, follow-up clinical information, and in the majority of patients, we also get three-month Rankin. So, there's now over 3,000 patients in that database with complete datasets from acute baseline imaging through to three months. And that was the dataset that we used for this current study. Dr. Negar Asdaghi: So, Mark, this is truly an impressive registry. It is not easy to do large-scale imaging-based registries, and this is really impressive to have so many centers involved. Can you tell us about the current study population? Who did you include in the current study paper? Dr. Mark Parsons: Firstly, we specifically looked at patients that had a large vessel occlusion, or LVO. Of course, the definition of large vessel occlusion varies a bit from place to place, but essentially, that means a clot in a proximal artery to the brain that's potentially retrievable via endovascular thrombectomy. I guess the beauty of the INSPIRE registry is, we started collecting stroke patient data well before endovascular thrombectomy was a routine treatment. We had quite a large number of large vessel occlusion patients in this study who didn't receive endovascular thrombectomy because it simply wasn't available at the time. And then, of course, with all of those big trials that came out in 2015, as you know, and beyond, with thrombectomy becoming routine at all of our INSPIRE sites and many other places around the world, we then had a, I guess, a historical cohort comparison of large vessel occlusion patients that were not given EVT and then, more recently, a cohort of large vessel occlusion patients who were treated with thrombectomy. Dr. Mark Parsons: The non-thrombectomy patients, in the vast majority, received intravenous thrombolysis because they were in the 4.5-hour time window. I guess the only other thing, the main other inclusion criteria, was we specified that patients in this particular study needed to have a relatively small infarct core, less than 70 mL, and we can talk more about that later, if you like, and a significant area of tissue that's potentially salvageable with reperfusion, the so-called penumbra. Dr. Negar Asdaghi: Thank you. Just to recap for our listeners, so your current study population included patients presenting early on, within 4.5 hours from symptom onset, with a large vessel occlusion, and because, as you mentioned, the study had been ongoing even before endovascular therapy became a standard of care, you have a group of patients in whom endovascular therapy was offered and you have the comparison to this group to those patients who had an LVO, large vessel occlusion, but simply received intravenous thrombolysis only. Can you now tell us about these two groups, basically, IV thrombolysis versus endovascular therapy group. What were the differences between the two groups, and what were the main clinical outcomes in your study? Dr. Mark Parsons: Yes. We had about 400 patients in each arm. And though reasonably well matched, I mean, of course, registry, it's not randomized, so you can't have perfectly matched groups, and indeed, in the more recent era where most patients with large vessel occlusion, particularly with this small core, big penumbra on imaging, would go to thrombectomy because they had the so-called ideal target population. So, in the modern era, if patients don't receive EVT, then there's probably a good reason for that. But, essentially, they are around 70 years of age. Their NIH Stroke score was around 15, or the median score, so that's reasonably consistent with large vessel occlusion. And then if you look at the perfusion imaging, so this was all with perfusion CT in our studies, so the core volume was quite small, 15 mL, but there was quite a large range. And the median penumbra volume was actually a bit bigger in the EVT group; it was 80 versus 65 in the penumbral group. Dr. Mark Parsons: We probably don't need to go into the details of how those core penumbral volumes are calculated, but that might be a bit over-technical for our audience, but happy to elucidate further if you want. Dr. Negar Asdaghi: Actually, I think it's important to, just briefly, talk about how those values were measured. Dr. Mark Parsons: Yes, OK. The other thing I should say is that, interestingly enough, we specified the 4.5-hour time window, but in fact, the median time from stroke onset to imaging was just under two hours in both groups, which is quite short. Dr. Mark Parsons: And indeed, some of the people that are less enthusiastic about perfusion CT than I am would say, "Well, maybe measures of core are not so reliable in that early time window with perfusion CT." I would probably debate that to some degree. But, if we talked to the technicalities, there's quite a lot of data to suggest that the cerebral blood flow threshold is probably the most robust for identifying core, or at least tissue that's destined to infarct. It may not actually be infarcted at the time we measure it, particularly at two hours, but there's quite a lot of data now showing that with perfusion CT with a cerebral blood flow threshold of 30%, depending on software variations, that's a pretty accurate estimate of the final infarct in people that have rapid reperfusion fairly quickly after the perfusion CT. Dr. Mark Parsons: So, all of these figures that we use are based on, for example, the core threshold on perfusion CT relates to, we validate that from patients, particularly that have had thrombectomy, so we know when they've reperfused. And the theory should be that if the CT perfusion core is an accurate measure of the final infarct, that there should not be much change from the baseline CT perfusion core to the follow-up infarct because there's been reperfusion not long after the perfusion scan. Now, with the penumbral volume, we use software that measures a delay time. Other software, particularly in North America, you would use a Tmax, but they're both basically direct measures of collateral flow. Dr. Mark Parsons: So, as you know, when you have a large vessel occlusion, say, of a middle cerebral artery and in one segment, the way that blood gets to the cortex, it's typically supplied from the middle cerebral, is via retrograde flow from the anterior cerebral and the posterior cerebral via leptomeningeal collateral, so you actually get blood coming back retrograde bypassing the occlusion. And these measures on perfusion CT delay time in Tmax, actually, give you a measurement in seconds of how long it takes the blood to travel to that part of the brain. And, obviously, the longer the delay in seconds means the poorer the collateral flow. And then, typically, that means the poorer the collaterals, the less time you've got to salvage the penumbra, and the quicker the infarct core will expand. Dr. Negar Asdaghi: Right. So, in your study, using these perfusion parameters. First, before even we come to the perfusion parameters, you found that overall, when you adjusted for all confounders, endovascular-treated patients had a better, or higher, odds of achieving good 90-day outcomes. This was not a surprising finding when you compare this population of endovascularly-treated patients to those treated with intravenous thrombolysis alone. But what was interesting was, indeed, those analyses related to infarct growth rate. Can you tell us a little bit about this concept of infarct growth rate, and you already mentioned how you measured infarct growth by perfusion imaging. Dr. Mark Parsons: Thanks, Negar. I guess that's the novel part in it. I guess it would have been quite surprising if we didn't show that EVT was superior to IVT in the early time window. So, that certainly wasn't unexpected, that finding. But I guess the novel part of this study is this relatively new concept of infarct core growth rate. I'm not saying we're the first that's described it because, as you know, there are a number of papers in the literature and talking about the concept of slow infarct core growers versus fast infarct core growers. And you mentioned the late time window thrombectomy studies, DAWN and DEFUSE 3, which actually showed a dramatic benefit in the later time window, up to 24 hours after stroke, in patients who had evidence of perfusion core mismatch. And the concept then was suggested that the reason that these people benefited so much in that late time window was that they had very slow infarct core growth because they had great collaterals. Dr. Mark Parsons: The treatment effect was bigger in those late time window studies than it was in the early time window thrombectomy studies, which was hypothesized might have included a lot of patients with fast infarct core growth rate, which wasn't really measured in a number of the thrombectomy studies in the early time window. We wanted to look more at, does the rate of infarct core growth have an influence on the effective treatment, with both IV and endovascular treatment? Dr. Mark Parsons: So, the way we measured infarct core growth was pretty simple, actually. It's basically, we excluded patients with uncertain time of stroke onset because we had more than double this total number of LVO stroke patients with target mismatch, but we had to exclude the patients with uncertain time of onset, which included wake-up stroke and others. So, in this group, where there was a defined time of onset, basically, the infarct core growth rate was simply measured from the volume of the infarct core measured on perfusion CT divided by the time from stroke onset. So, just simplistically, if you've got a core of 50 mL, and it's two hours after stroke onset, then the infarct core growth rate is 25 mL per hour. That's simple, but that obviously assumes a linear core growth rate. And we based that linear model on previous studies of repeated diffusion MR imaging, which is another measure of core, that showed that the core growth rate was linear. Dr. Mark Parsons: Now, of course, you could criticize that because I suspect, in some patients, the core growth rate is not linear. This is an estimate of core growth rate. Dr. Negar Asdaghi: Right. So, your study actually found something quite interesting, which I really want you to go over for us and for our listeners, and that's that the beneficial effect of endovascular therapy is superior in those with a fast infarct growth rate, and was not superior, in fact not any different, in those patients who had a slow infarct growth rate. Can you walk us through that, and also tell us how that does not contradict what we've found as part of DAWN and DEFUSE with the slow infarct growers? Dr. Mark Parsons: Thanks, Negar. It is slightly complicated, so we'll go one step at a time. So, first of all, the core growth rate varied quite a bit in this population. A number of patients, and this is because you saw that the median core in this group was 15 mL, so there was quite a large population of patients that had a core growth rate of less than 15 mL per hour. So, they're your traditional slow growers, slow core growers, who have really great collateral flow. You probably have a number of hours to save the penumbra. Now, I'm not saying that you should waste time in this group of patients, but it might be particularly relevant, for example, if you're transferring from a primary stroke center to a comprehensive stroke center. You know that you're going to have time to save that penumbra because the infarct core is going to grow slowly. Dr. Mark Parsons: In, for example, in Australia, at least half of our thrombectomy patients come from regional or out of metro centers, where there is a significant transfer time from the primary stroke center to the comprehensive center. So, that may be a particularly important finding to look at in the future for longer transfer times from primary to comprehensive stroke centers. So, then, at the other end of the scale, we had a proportion of patients who had what we call a fast core growth rate of more than 25 mL per hour. And then there were people in the middle between 15 and 25 who we called sort of moderate core growth. So greater than 25 mL per hour was a fast core growth. Dr. Mark Parsons: We categorized it into those sort of three categories. Again, that's a bit arbitrary, but the reason we did that was that if you look at the IVT group alone, those who had slow core growth rate, less than 15 mL per hour, their rates of good outcome, so a Rankin 0 to 2, so getting back to close to normal function at three months, their rates of a good outcome were almost 60% in the slow core growth rate with IVT. Then, if you go to the other end of the scale with fast core growth with intravenous therapy, the rates of good outcome in that group were only 30%. So, there was a clear decline in terms of three-month good outcomes with intravenous thrombolysis versus core growth rate. So, as the core growth rate increased, the chances of good outcome with intravenous thrombolysis decreased. Dr. Mark Parsons: Then, if you looked at the EVT group, it was quite interesting that this core growth rate effect had minimal impact on the outcome of the EVT patients. So, in the EVT patients with slow core growth rate, less than 15 mL, the rates of good outcome at three months were, again, close to 60% and identical to the IV therapy group. But, at the other end of the scale, with fast core growth rate above 25 mL with the EVT group, they had a much higher rate of good outcome compared to the IVT group. Their rates of good outcome were around 45%. So, they are a little bit lower than the slow core growers with EVT, but there wasn't much drop-off with core growth rate, and there was a significant increase in good outcomes in the EVT group who had fast core growth compared to the IVT group. Dr. Negar Asdaghi: So, I just want to summarize this so that I understand it and, of course, want to make sure that it's simplified also for our listeners. So, you found that those people, and it should be noted these are all within the first 4.5 hours. Dr. Mark Parsons: Yes. Dr. Negar Asdaghi: So, we understood in that time frame. Those people who had a fast growth rate, they had the greatest benefit from endovascular therapy in this time frame. And those people who had the slow growth rate, that is defined in your study as less than 15 cc per hour, they actually had a similar benefit from endovascular therapy as they did with intravenous thrombolysis. Did I summarize that? Dr. Mark Parsons: Yes. That's correct. Dr. Negar Asdaghi: So, Mark, how do you explain this from a pathophysiological standpoint? Dr. Mark Parsons: Fortunately, there's a relatively simple explanation. So, because of the way that we set up INSPIRE, we collected follow-up infarct volumes as well. From the time window for follow-up infarct measurement was a little bit variable, but it was around 48 hours after stroke onset. In this group of patients, we actually were able to measure final infarct volume and essentially, in the slow core group, so less than 15 cc growth per hour, in that group, with both IVT and EVT, there was minimal infarct growth by the time we measured it at 48 hours. So, both therapies basically led to minimal infarct growth after the treatment, whereas in the fast core growth group, more than 25 cc per hour, the IVT group had much greater infarct growth by 48 hours, about 40 or 50 mL more, on average, than the EVT group. Dr. Mark Parsons: I guess also, to explain that a touch more, if you look at the slow core growth EVT group versus the fast core growth EVT group, there was still more infarct growth in the fast core growth rate. And this is because you measure the core at a certain time on the CT or the MR. And then, even with the very best system, you're not going to get reperfusion with EVT for at least 30 minutes after that because you have got to get into the angio lab, you have to puncture the groin, and you have got to get up there, and you have got to pull the clot. So, even if you get complete perfect circumstances, it's still usually at least a 30- to 60-minute delay between the perfusion CT and when you're fully reperfused. Dr. Mark Parsons: But the theory should be, if there's a minimal delay from the perfusion CT to reperfusion, the core at that time should be identical to the follow-up, final infarct volume. And that's what we actually found in the slow core group. It was almost the same. The interesting thing was, it was the same in both IVT and EVT, which basically, we don't know for sure, because we don't know exactly when the IVT group reperfused, but it probably means that because the core growth is so slow in this group, even if you reperfuse later with IV therapy, which we know is the case, often with IV thrombolysis the recanalization is a bit slower than with EVT, so even if you've got delayed reperfusion, if you've got slow core growth rate, you may not get much infarct expansion at all, whereas if you've got fast core growth rate, getting reperfusion as quickly as possible after your CT is crucial to limit subsequent infarct growth before reperfusion. And that's exactly what we found in the fast core growers, that EVT substantially limited that subsequent infarct growth and led to better clinical outcomes as well. Sorry, again, that was a long explanation. Dr. Negar Asdaghi: Mark, but these are really important findings, and as you alluded to earlier, I believe that they have major implications in how the systems of care are organized and our transfers are going to be decided upon in the future. We have a few minutes before we end the podcast here, and I want to ask you, do you think it's fair to have a similar concept that's studying the infarct growth rate in the late time window, especially in the sort of past 12 hours time window in the future? Dr. Mark Parsons: Yeah, it's a fascinating question, Negar. In fact, we do have a paper somewhere under review. I think Stroke might have knocked it back. Anyway, but it's actually looking exactly at this concept, but the fascinating thing is, in the late time window, you see very few true fast growers because they actually present early. This is what the paper under review is talking about. So, in fact, most people that you see with a favorable imaging pattern in the late time window, such as DAWN and DEFUSE 3, the core is relatively small. In patients with fast core growth, by the time you get to six hours, you've got a massive core and no penumbra, so they are typically not offered endovascular therapy because there's no salvageable tissue and there's already lots of damage, even on the non-con CT. Dr. Mark Parsons: So, it would be actually really interesting to look just at the late time window, and I'm sure others are doing that, too, but I suspect what we'll find is that the distribution of core growth is pretty narrow. It's mostly the slower core growers, and it's very clear that most of the really fast, and we're actually looking at this now in people with large infarct core over 70 mL, in fact, they present, the ones that we've got at least, present very early. So, it'll be a fascinating area to look at, for sure. Dr. Negar Asdaghi: Mark, it is definitely fascinating. We look forward to covering that paper, hopefully in our future podcast. But I want to leave you, reminding you that I'm a mild stroke person, so I am definitely interested in looking at these slow grow rate infarct patients because there are also, as you know, some studies suggesting that the slow growth infarct actually can happen sub-clinically on only a radiographic basis, and especially important in the mild group patients. But, we are out of time. Professor Mark Parsons, thank you so much for joining us all the way from Sydney, and it's been a pleasure interviewing you. Dr. Mark Parsons: Thank you, Negar. Lovely to chat and hope to see you very soon in person. Dr. Negar Asdaghi: Thank you. Dr. Negar Asdaghi: And with that, we end our podcast for the December 2021 issue and close the first year of the Stroke podcast. A year ago, Dr. Ralph Sacco, the Editor-in-Chief of Stroke, approached me to talk about the importance of starting a podcast for Stroke as an accessible means to highlight the great work published in the journal, and also introduce me to the amazing Stroke editorial staff. Dr. Negar Asdaghi: One year, hundreds of reviewed papers, and 11 podcasts later, from missed deadlines to late night emails, early morning texts, and weekend recordings, our podcast has become a bit more than just a quick review of the literature. It has truly become our podcast family. Overcoming the time differences and impossible schedules, you made time to interview with us, listen to us, and work with us as we reached out to researchers across the globe who contributed to this journal and to the podcast. Lots of laughter and a few tears. Like every family, ending the year reminds us of some good times and, of course, the difficult times. Dr. Negar Asdaghi: So, I want to end our final podcast of the year with a topic that we haven't really covered in our journal, but I think may sprinkle some magic on your holiday season, and that's the topic of quantum biology. Wrapped in mysticism with a pseudoscientific flavor, physicists, neurologists, anesthesiologists, and philosophers have been hard at work deciphering whether consciousness may have similar properties to quantum particles. From superposition to entanglement and coherence, is it possible that your mind may have something to do with the epigenetics, up and down regulation of genes and presentation treatment and, importantly, outcome of various medical or neurological disorders? Now, even if this was proved to have a low scientific validity, as a stroke scientist, isn't it amazing to be working in the one field that ensures the brain, which is the home of consciousness, remains healthy? So, let's think about the power of consciousness in altering the outcome of medical conditions with our ever-excitement to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2021. 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 10 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the November 2021 issue of Stroke: "Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke" and "Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial." She also interviews Dr. S. Claiborne Johnston about "Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack." Dr. Negar Asdaghi: 1) What is the net ischemic benefit derived from combination of ticagrelor and aspirin treatment in patients with mild ischemic stroke or transient ischemic attack? 2) Is the ischemic stroke in patients hospitalized with COVID-19 associated with the rise in biomarkers of inflammation and coagulopathy? 3) What are the characteristics associated with periprocedural stroke in patients treated endovascularly for an unruptured AVM? We'll discuss these topics and much more at today's podcast. Stay with us. Dr. Negar Asdaghi: Welcome back to 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 November 2021 issue of Stroke, we have a large selection of topics, from peanut consumption reducing the risk of ischemic stroke, and the decline in the rate of progression of coronary atherosclerosis in patients on a Mediterranean diet, to how the efficacy of endovascular thrombectomy diminishes in patients with more pervious thrombus composition, which I encourage you to review in addition to our podcast today. Dr. Negar Asdaghi: Later in the podcast, I have the distinct honor of interviewing Dr. Claiborne Johnston from Dell Medical School at UT Austin on his latest work with data from the THALES trial to clarify the net ischemic benefits derived from a combination of ticagrelor and aspirin therapy in comparison with the risks of hemorrhage associated with this treatment in patients with mild and moderate stroke and TIA. But first with these two articles. Dr. Negar Asdaghi: COVID-19–associated ischemic stroke, or CAIS, is a new term that, unfortunately, stroke physicians need to be familiar with. While acute ischemic stroke can occur in parallel from, say, traditional causes of stroke in patients infected with coronavirus, ischemic stroke and other thrombotic events, such as myocardial infarction, pulmonary embolism, deep vein thrombosis, and acute limb thrombosis, can occur in the setting of overt hyperinflammation and subsequent coagulopathy that is observed in patients hospitalized with severe COVID-19 illness. Dr. Negar Asdaghi: Elevated D-dimer, although quite non-specific, has emerged as a marker of COVID-19–associated coagulopathy, but whether an elevated D-dimer in isolation or in combination with various other inflammatory and coagulation markers is associated with development of acute in-hospital ischemic stroke in those hospitalized with COVID is not known. Dr. Negar Asdaghi: So, in the current issue of the journal, in the article titled "Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke," Dr. Charles Esenwa from the Department of Neurology at Montefiore Medical Center and colleagues did an interesting analysis of over 5,000 patients with COVID-19 who were admitted to one of the Montefiore Health System hospitals between March 1, 2020 and May 8, 2020. This was a retrospective analysis, so they had to work with the available biomarkers for each patient and use a machine learning cluster analysis of these biomarkers to divide the patients basically based on five biomarkers to four clusters. Dr. Negar Asdaghi: The following five biomarkers were chosen by this machine learning cluster analysis. These included CRP, D-dimer, LDH, white BC, and PTT. So, they had to come up with some arbitrary rules to exclude biomarkers that were either missing in over 30% of their population, and they also excluded those patients that were hospitalized for a long period of time, and they chose a 30-day hospitalization and over. And they also only used the first reading for each biomarker. Again, these were arbitrary rules that were set forth by the authors, and they found some alarming findings. When they clustered patients based on similarities in these biomarkers, they came up with predicted models for combined thrombotic events and acute ischemic stroke. Dr. Negar Asdaghi: For example, in the cluster where the patients had the highest mean values for CRP, D-dimer, LDH, and white BC, and a relatively low PTT, these patients had the highest prevalence of acute ischemic stroke. They had the highest prevalence of in-hospital strokes and severe strokes and highest percentage of total thrombotic events. In contrast, the cluster with the lowest mean of all of these five biomarkers had no cases of in-hospital acute ischemic strokes; they had the lowest prevalence of composite, all thrombotic events, and patients had the least severe complications. Dr. Negar Asdaghi: So, they also tested the effects of biomarkers individually for prediction of acute ischemic stroke. And it turns out that when they used a lone marker, only D-dimer again was associated with acute ischemic stroke. Very interestingly, D-dimer was specifically elevated in those COVID-19 patients in whom the stroke was ultimately classified as cryptogenic. Dr. Negar Asdaghi: So, what does that mean? That means that it's more likely that a stroke had occurred in the setting of severe COVID-19 hyperinflammatory response, and less likely associated with other classical causes of stroke. Dr. Negar Asdaghi: So, what did we learn overall from this study? Well, hospitalized COVID-19 patients with a combination of high CRP, D-dimer, LDH, and white BC, and slight reduction in their PTT, had a 4.5-fold increase in the risk of in-hospital mortality and a fivefold increase in the risk of in-hospital stroke as compared to the COVID-19 patients with the lowest mean values for all the five biomarkers mentioned above. So, important information to keep in mind as we treat hospitalized COVID-19 patients, and we await more prospective data on this topic. Dr. Negar Asdaghi: Arteriovenous malformations, or AVMs, are congenital vascular lesions that are associated with long-term excess mortality and morbidity, essentially almost all related to their risk of intracerebral hemorrhage. Roughly half the patients with brain AVMs present with intracerebral hemorrhage, resulting in a first-ever hemorrhage rate of about 0.5 per 100,000 person years. Dr. Negar Asdaghi: Annual risk of hemorrhage is estimated at 1 to 4% for all comers with AVMs, but varies significantly, and can be as low as 0.9% in patients with unruptured, superficially located brain AVMs with superficial drainage, but may be as high as over 34% in patients with ruptured, deeply seated brain AVMs with deep venous drainage. So, treatment would entirely be dependent on the type of presentations and characteristics of each patient with an AVM. Dr. Negar Asdaghi: Whether unruptured AVMs should be managed clinically or treated either endovascularly or surgically is the subject of the ARUBA trial that is a randomized trial of unruptured brain AVMs. The enrollment of ARUBA was halted by the study's DSMB board, but medical management was found to be superior to treatment arm for the primary outcome of symptomatic stroke and death. Dr. Negar Asdaghi: Since then, there's been a lot of focus in the literature and comparison of outcomes between treated and untreated patients with unruptured AVMs, but less has been published on characteristics of patients who suffered from periprocedural stroke, an important part of the primary outcome of ARUBA. So, in the current issue of the journal, we have the study titled "Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial." Dr. Negar Asdaghi: Dr. Joshua Burks and colleagues from the Department of Neurosurgery at the University of Miami and colleagues evaluated 64 patients with unruptured AVMs enrolled in the ARUBA trial who underwent endovascular treatment as part of the trial and looked at the characteristics of those who suffered a perioperative stroke, defined as a stroke recorded at or within 48 hours of intervention, as this would represent a direct procedure-related complication rather than sequelae of, say, treated or partially treated AVM itself. Dr. Negar Asdaghi: All patients who initiated endovascular intervention, including attempted interventions in cases where therapy was aborted secondary to technical or anatomical limitations, were included regardless of randomization or subsequent withdrawal from the study beyond 48 hours following the intervention. So, what they found was that 16% of interventions resulted in stroke, 11% hemorrhagic, and 5% ischemic strokes. And they had no perioperative mortality, which is good news. Dr. Negar Asdaghi: In univariate analysis, they found many factors that were more commonly seen in patients that suffered from perioperative stroke as compared to those who did not have a stroke perioperatively. Those factors included, for instance, female sex. Over half of these patients were female. Close to half were enrolled in France. And over 40% of those who suffered a stroke in the perioperative timeframe had Spetzler-Martin grade two AVMs. Dr. Negar Asdaghi: When they accounted for all confounding variables, they found that endovascularly treated unruptured AVMs that are supplied by the posterior cerebral artery cortical feeders and those with Spetzler-Martin grade two and three had a higher perioperative stroke risk as compared to their counterparts without these characteristics. Interestingly, there are also significant geographical disparities in the risk of stroke in that patients treated in the United States or Germany had a significantly lower stroke risk than patients treated in other countries. Dr. Negar Asdaghi: So, what did we learn from this study? There are patients and lesion characteristics that increase the risk of stroke associated with endovascular treatment of unruptured AVMs. The current study suggests that AVMs with cortical arterial feeders from posterior cerebral artery and those with grade two and three Spetzler-Martin were associated with a higher risk of procedural and periprocedural stroke. Dr. Negar Asdaghi: And very importantly, as with every surgical intervention, the risk of a procedure is operator-dependent, as well as center-dependent. And these are important factors to keep in mind as technology evolves and more treatments become available to decide whether to keep or to refer patients with unruptured AVMs to a more experienced center. Dr. Negar Asdaghi: Patients with mild ischemic stroke and transient ischemic attack are at high risk of having recurrent ischemic events, especially in the immediate aftermath of their symptom onset. Early diagnosis and initiation of secondary preventive measures, such as antiplatelet or anticoagulation therapies, in the appropriate setting considerably reduce this recurrent risk. Dr. Negar Asdaghi: Multiple randomized trials have shown that as compared to treatment with a single antiplatelet agent, dual antiplatelet treatment is more effective in reducing the risk of stroke and other major vascular events in the TIA mild stroke population, a benefit that comes with an expected increase in the risk of hemorrhage. Dr. Negar Asdaghi: THALES trial is one of the latest trials to determine the efficacy of dual, which is combination of ticagrelor and aspirin, versus mono-antiplatelet therapy, that is aspirin alone, in eligible patients with non-cardioembolic acute ischemic stroke and TIA. Now, it's important to keep in mind that the primary outcome of THALES is a composite of stroke or death, which included both ischemic and hemorrhagic events. Dr. Negar Asdaghi: Now, it's important to understand that while in the setting of a clinical trial, combining the risks associated with dual antiplatelet therapy, which is hemorrhage, and the potential treatment benefit, that is reduction of recurrent ischemic events, is appropriate as part of the outcome selection. In routine practice, this type of primary outcome can obscure the actual trade-offs between the benefits of dual antiplatelet treatment and its inherent hemorrhagic risk. Dr. Negar Asdaghi: So, in this issue of the journal, in the study titled "Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack," the THALES investigators led by Dr. Claiborne Johnston sought to separate the ischemic benefits of combination of ticagrelor and aspirin therapy from its hemorrhagic risks in patients enrolled in the trial. Dr. Negar Asdaghi: I'm joined today by Professor Johnston to discuss the findings of this paper. Dr. Johnston absolutely needs no introduction to the stroke community and our readership. He's a Professor of Neurology at Dell Medical School at the University of Texas at Austin. He's a leader in the field of cerebrovascular disorders, has served as the primary investigator of multiple randomized trials and large prospective studies to evaluate the preventive treatment outcomes in TIA and mild stroke, and has pioneered the development and validation of predictive models for recurrent stroke in this population. He's authored over 700 peer-reviewed manuscripts, has won several awards for research and teaching, and is recognized for his leadership in the field of medicine and healthcare. Dr. Negar Asdaghi: Good morning, Clay. We're delighted that you could join us on the podcast. Dr. S. Claiborne Johnston: Well, thank you. It's wonderful to be here. Thank you for having me. Dr. Negar Asdaghi: Thank you. So, THALES is an exciting new addition to the most recent trials of dual antiplatelet therapy that studied mostly the role of clopidogrel and aspirin combination therapy. Can you please start us off by telling us why did we need a new trial in a very similar patient population? Dr. S. Claiborne Johnston: Well, the primary reason was, yes, clopidogrel works in combination with aspirin in the setting, but clopidogrel is actually a prodrug. It requires conversion in the liver to its active form. And polymorphisms in CYP2C19 and Cyt P450 pathways are really common and associated with an inability or limited ability to convert that prodrug into its active form. So, there are a number of people who may not benefit much, if at all, from clopidogrel. So, it's kind of surprising that it works as well as it does. Dr. S. Claiborne Johnston: Ticagrelor doesn't have that problem. It's not a prodrug. It acts directly on the P2Y12 inhibitor. And so, the hope was that we would have a more consistent and pronounced effect on risk reduction in patients after TIA and mild to moderate strokes. Dr. Negar Asdaghi: Primary efficacy outcome in THALES was different from the primary efficacy outcome chosen for the POINT trial, that was major ischemic events and death from ischemic vascular events, and that of the CHANCE trial, that was a combination of ischemic and hemorrhagic strokes in 90 days. Can you please tell us about the thought process behind choosing this particular primary efficacy outcome in THALES? Dr. S. Claiborne Johnston: Yeah, so this was encouraged by the regulatory authorities. And so the primary efficacy outcome in THALES is all stroke, hemorrhagic and ischemic, and all death, hemorrhagic and ischemic. And we teased apart just the ischemic etiologies in POINT. Dr. S. Claiborne Johnston: The rationale was that we were including all the major outcomes that the drug could impact. The problem is that people forget that it includes hemorrhagic events, and then they weigh that efficacy outcome against the safety outcome. And so there's confusion. There's sort of double-counting of safety elements in doing that comparison. Dr. Negar Asdaghi: Okay, great. And now, before we hear about how you disentangled the two safety and efficacy outcomes, can you please remind our listeners about the primary results of THALES, which was published obviously a few months ago? Dr. S. Claiborne Johnston: Yeah, sure. So, it showed that the combination of ticagrelor and aspirin works. It reduced the stroke and death by about 17% over the 30-day period of treatment. So robust effect. There were some increased hemorrhages, and looking at severe hemorrhage as defined by the GUSTO definition, there was almost a fourfold increase, but it was tiny in absolute terms of 0.4% increase. Dr. Negar Asdaghi: Okay. So, now it's very important, as you mentioned, this disentangling of recurrent ischemic, again, safety from efficacy outcomes. Your current study that is published in the November issue of Stroke clarified these results. And we're excited to hear about those results. Dr. S. Claiborne Johnston: That's right. So, there were two problems with the way people have interpreted the results of the THALES trial. One is this entanglement of safety events and both efficacy outcome and the safety outcome. The other was the use of relative risks as opposed to absolute risks, because a high relative risk for a rare event is less important than a small relative risk for a more difference between more common events. And so we wanted to deal with both of those issues. Dr. S. Claiborne Johnston: So, we defined new outcomes that were not entangled. So, we defined major ischemic events, similar to what we had done in POINT, and then we defined major hemorrhage as being basically irreversible hemorrhage, and compared outcomes in the two groups. And what we found was that when we did it that way, for every 1,000 patients treated, we avoided 12 major ischemic events and produced three major hemorrhages. So, about a four-to-one ratio of ischemic benefit to hemorrhage risk. And that was true at various cutpoints for disability. Dr. S. Claiborne Johnston: So, if we said, "Okay, yes, you had an event, and are you disabled at last follow-up at 30 days?" Then if we said that, there was also a four-to-one difference in disabling events, ischemic versus hemorrhagic. And if we said a two or greater, so moderate disability or worse, it was the same ratio, four-to-one. Dr. Negar Asdaghi: Okay, so four-to-one ratio of benefit. That's an important number to keep in mind. Also reassuring to see that this net clinical benefit or net clinical impact of the combination of therapy was practically the same across all the pre-specified subgroups in the trial. Were you at all surprised by the subgroup analysis? Dr. S. Claiborne Johnston: Well you know if you do enough subgroup analyses, you're going to find differences, right? And thankfully, we have the looking at interaction terms to keep us honest, but even so, you look at 20 and you're going to have some significant interaction terms, as well. But yeah, it was reassuring that the effects were so consistent across groups. Dr. S. Claiborne Johnston: I think there's been a tendency to over-interpret results from subgroup analyses. We don't have any evidence to suggest that we should be doing that here. I'm sure we can pick out groups that do better, and we've done that actually. The group with atherosclerosis does particularly well, but is that a chance event or is that real? I think we just have to be super-cautious about subgroup analyses. Dr. Negar Asdaghi: So, absolutely. One of the subgroups that I'm personally very interested in is just the time subgroup. So, all of the patients in THALES were enrolled within the first 24 hours, and the subgroup analysis did not show that there were any differences in terms of the net benefit between those that were enrolled earlier, within the first 12 hours, and those that were enrolled later, between 12 and 24 hours. But in routine clinical practice, we often see patients with TIA and mild stroke actually presented to us later than that timeframe entirely. Should we be giving them dual antiplatelet treatment? Dr. S. Claiborne Johnston: That's a great question. So, we did an analysis in POINT where we modeled out, would we still have an important significant net benefit if we had started the trial later? And we didn't start the trial later, right? So, this was just pretending like anybody who had an event early on was not in the study in starting at a later timepoint and modeling that out. And basically what we found was that for out to three days, there was still a benefit. And, in fact, if you look at that data and look at those tables, you could even say, even out to five days. Dr. S. Claiborne Johnston: I would say it's not unreasonable to do that given that the risks are so small and they're going to be even later with later treatment. But I would say, too, that even though we're not seeing greater impact within that first 24 hours versus 12 to 24, it just makes sense with event rates being as great as they are early on that if you don't treat with a preventive medication before an event occurs, it doesn't work. So, it just makes sense that as much as possible we ought to treat people as early as possible after their events. Dr. Negar Asdaghi: Very important findings and things to keep in mind. I want to ask you about the top two takeaway messages from the study. Dr. S. Claiborne Johnston: One is that there's a favorable benefit-to-risk ratio for ticagrelor/aspirin in mild to moderate actually ischemic stroke and high-risk TIA from THALES. So that would be number one. Dr. S. Claiborne Johnston: And then number two is watch your endpoints carefully. Think carefully, too, about whether balancing safety to efficacy events really makes sense and also whether focusing on relative risks really makes sense. I would encourage us, even though our journals tend to push us towards relative risks and we're more familiar with those, I'd encourage us to get more comfortable with using absolute risks in the way we look at data, but also in the way we talk to patients about their impact. Dr. Negar Asdaghi: Fair enough. I remember a few years ago, you visited us here at the University of Miami to deliver the annual Cerebrovascular Scheinberg Lecture. And you had mentioned that the idea of dual antiplatelet therapy treatment of patients with TIA mild stroke had come to you many years back when you were still in training, but it took many years for that idea to turn into reality, into randomized trials, and now translated into clinical practice. Dr. Negar Asdaghi: At the time, if you recall, this was right before you went to Europe to present the primary results of POINT at the European conference. And the trial results were not publicly available, so you were sworn to secrecy. You couldn't tell us about the results. It's been a few years since then. You've already completed yet another trial on this topic. Can I ask what's next for you and your team as it pertains to acute treatment of patients with TIA and mild stroke? Dr. S. Claiborne Johnston: Well, there are a few things. So, CHANCE-2 is a really interesting trial. My role in that was peripheral, just really advisory, but it's an exciting trial. So, basically it's looking at people with those CYP2C19 polymorphisms that I mentioned before, people who don't rapidly and readily convert clopidogrel to its active form, and randomizing them to clopidogrel versus ticagrelor. Dr. S. Claiborne Johnston: So, it's going to give us some head-to-head data on the two drugs and the people who may benefit the most from ticagrelor. And that is complete, and that will be published in the next few months. So, I that's going to be an important trial in people's thinking about how best to approach these patients. Dr. S. Claiborne Johnston: The second is, you know, we're not done. We still have a 5% risk of events, even in those three dual antiplatelet therapy. And so we need more agents. And we need to think about secondary prevention extending to other groups as well, just as you said, longer periods of time, more severe strokes, people after thrombolysis/thrombectomy. Those are big groups of patients at extreme risk for secondary events, and we have no agents and no data right now. Dr. S. Claiborne Johnston: I would be concerned about dual antiplatelet therapy in those patients, just given what we've seen about the risks of hemorrhage in the existing groups, which are again manageable and shouldn't change people's decision about treatment. But for the groups I just mentioned, risks of hemorrhage start to get greater. And so one worries about whether dual antiplatelet therapy's the right thing or whether other agents make more sense. So, yeah, we're interested in looking at other agents, some novel, for those other indications as well. Dr. Negar Asdaghi: Professor Johnston, thank you for your time, and we look forward to covering more of your research in the future. Dr. S. Claiborne Johnston: Well, thank you. It's been a pleasure. Dr. Negar Asdaghi: Thank you. Dr. Negar Asdaghi: And this concludes our podcast for the November 2021 issue of Stroke. Please be sure to check out the November table of contents for a full list of publications, including two important topical review articles, one on thrombus composition after thrombectomy, and one on pearls and pitfalls of perfusion imaging in acute ischemic stroke, as advanced neuroimaging continues to play a critical role in decision-making for acute stroke therapies. Dr. Negar Asdaghi: Now, speaking of advanced neuroimaging and the immense role that neuroimaging plays in our day-to-day practice, let's take a moment as we end our November podcast to remember how the concept of medical imaging first began over 120 years ago with the discovery of X-ray by German professor of physics Wilhelm Röntgen. Dr. Negar Asdaghi: On Friday, November 8, 1895, while experimenting with electricity, Röntgen accidentally discovered a new kind of rays that he referred to as X-rays. He soon realized that X-rays were capable of passing through most substances, including the soft tissues of the body, but left bones and metals visible. Dr. Negar Asdaghi: One of his earliest photographic plates of his experiments was a film of his wife Bertha's hand with her wedding ring clearly visible. This was the first time that the inside of human body was seen without performing surgery. Dr. Negar Asdaghi: From Röntgen's first X-ray image to the advanced neuroimaging that we review today on our portable devices, I can't help but wonder, what will your accidental discovery on a Friday fall afternoon in November do to advance the field of science and stroke 100 years from now, as we continue to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2021. 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 9 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2021 issue of Stroke: "Endovascular Therapy of Anterior Circulation Tandem Occlusions" and "Automated Perfusion-Diffusion Magnetic Resonance Imaging in Childhood Arterial Ischemic Stroke." She also interviews Dr. Sepideh Amin-Hanjani about her article "Outcome Following Hemorrhage From Cranial Dural Arteriovenous Fistulae." Dr. Negar Asdaghi: 1) Should perfusion imaging be incorporated into routine neuroimaging for stroke-like presentation in the pediatric population? 2) Is performing emergent cervical carotid stenting beneficial in patients undergoing endovascular thrombectomy for a tandem occlusion? 3) What are the outcomes of patients with intracranial hemorrhage secondary to dural AV fistula? These are the questions that we will answer in our podcast today. Stay with us. Dr. Negar Asdaghi: Welcome back to 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 October 2021 issue of Stroke, we have a comprehensive list of publications, from studying the role of C-reactive protein in outcome prediction after subarachnoid hemorrhage to studying the association of over 81 classes of routinely prescribed drugs with the risk of ischemic stroke, which I encourage you to review in addition to our podcast today. Later in the podcast, I have the pleasure of interviewing Dr. Sepideh Amin-Hanjani on her work with outcome prediction in patients with dural AV fistula–related intracranial hemorrhage. But first, with these two articles. Dr. Negar Asdaghi: Between 10-20% of patients with an anterior circulation large vessel occlusion have tandem occlusions. That means that they have a concurrent cervical carotid occlusion or significant stenosis in addition to their target intracranial occlusion. Performing endovascular therapy for a tandem occlusion is often difficult, providing technical and access challenges for the operator. Dr. Negar Asdaghi: In practicality, we have two options for carotid treatment in the acute setting. One option is doing nothing, or do carotid angioplasty predominantly to gain access to that target intercranial occlusion. But the second option is to do an emergent carotid stenting. Currently, we have two ongoing clinical trials to assess the very question of whether emergent cervical carotid stenting is an option in tandem occlusions. One is the ongoing TITAN trial out of France, and the second one is a Canadian trial, Endovascular Acute Stroke Intervention - Tandem OCclusion Trial, or EASI-TOC. Dr. Negar Asdaghi: And while we await the completion of these trials, the treatment option for cervical carotid remains a contentious subject. Though performing emergent cervical ICA stenting is feasible, the opponents of the procedure highlight that emergent stenting is associated with higher rates of intracranial hemorrhage, a high risk of in-stent thrombosis, iatrogenic artery-to-artery embolization, and hemodynamic instability during stent deployment. Not to mention that it will increase time to reperfusion if stenting is done prior to the intracranial recanalization. In contrast, the proponents of emergent cervical ICA stenting argue that leaving the carotid alone can lead to an increased risk of infarct recurrence and infarct progression. Of course, it goes without saying that the current practice pattern is widely variable. So, in the current issue of the journal, Dr. Mohammad Anadani, from the Department of Neurology at Washington University School of Medicine, and a group of international collaborators from the TITAN and ETIS registries compared the outcomes of endovascularly treated patients with tandem occlusions in the anterior circulation who received concurrent carotid stenting to those who did not receive stenting of the carotid. Dr. Negar Asdaghi: It is important to note that the no-stent group included those with either no cervical carotid intervention or angioplasty alone. So, the authors identified 760 patients with a tandem occlusion that were included in the pooled analysis of TITAN and ETIS registries. TITAN stands for Thrombectomy in Tandem Lesions and endovascular treatment in ischemic stroke. That included EVT-treated patients; these are endovascularly treated patients with tandem occlusions from 18 comprehensive stroke centers across Europe and United States. And ETIS is an ongoing prospective multicenter registry that enrolls all patients treated with endovascular thrombectomy at six large comprehensive stroke centers in France. In both cohorts, treatment of cervical ICA was left at the discretion of the treating physician. Overall, cervical ICA stenting was performed in 56% of total patients with tandem occlusion. In the adjusted model, they found that the odds of favorable outcome and successful reperfusion were higher in the stent group. In contrast, the risk of any hemorrhage was higher in the stent group, but the rate of symptomatic hemorrhage was not different within the two groups. Dr. Negar Asdaghi: Some very important findings from their subgroup analysis include a stronger benefit from emergent carotid stenting, unfavorable outcome in patients with lower NIH Stroke Scale, and in patients in whom the etiology of carotid stenosis or occlusion was deemed to be related to atherosclerosis rather than dissection. Dr. Negar Asdaghi: So, what are the top three things we learned from this paper? Number one, we learned that emergent carotid stenting overall increased the odds of favorable outcome in patients with tandem occlusion. Number two, emergent cervical ICA stenting came with a cost of increased hemorrhage, perhaps related to the necessity of administering antiplatelet therapies in the angiosuite. Number three, benefit from emergent carotid ICA stenting in the setting of endovascular therapy was confined to patients with carotid occlusion or significant stenosis in whom the etiology was deemed to be related to athero and not dissection. And of course, people seem to benefit from emergent cervical ICA stenting in whom the presenting NIH Stroke Scale was mild. So, many things to keep in mind, and most important of all, that these results are from registry-based data, and we still have to wait for the results of the two ongoing trials to confirm these findings. Dr. Negar Asdaghi: Diagnosis of stroke in children is often delayed beyond the conventional thrombolytic and endovascular time windows. In 2018, randomized trials in adults showed that patients with an ischemic mismatch, that is the presence of a large ischemic penumbra in a setting of a small ischemic core, can significantly benefit from endovascular therapy. Whether these results can be directly applied to the pediatric population from simply the adult population is, of course, unknown. In this issue of Stroke, Dr. Mark Mackay and Melissa Visser, from the Department of Neurology, Royal Children's Hospital of Melbourne, and colleagues present the results of a retrospective, observational cohort study of 29 children who underwent MRI diffusion and dynamic susceptibility contrast perfusion imaging within 72 hours of stroke onset. Perfusion-diffusion mismatch was estimated using the RAPID software with the same criteria used in adults, which was defining ischemic penumbra as regions with a Tmax delay of more than six seconds and core as defined by diffusion positive lesions with corresponding low signal on the apparent diffusion coefficient, or ADC, map with values less than 620. Dr. Negar Asdaghi: Favorable mismatch profile was defined the same way that they are defined in the adult population, that is, core volumes less than 70 mL and mismatch volumes of over 15 mL with a mismatch ratio of over 1.8. Now, the primary goal of this paper was to demonstrate feasibility of assessing automated perfusion-diffusion mismatch in childhood stroke. So, among 187 children with confirmed stroke on MR imaging, 58 underwent perfusion imaging in the study and only 29 fulfilled the inclusion criteria. Most cases had cryptogenic stroke followed by local cerebral arteriopathy as part of their etiology of stroke. Vessel occlusion was confirmed in 12 cases, two of which involve the posterior circulation. So, RAPID detected an ischemic core in 66% of patients only, remembering that the remaining diffusion positive cases were excluded from this finding simply because either the ADC values were not below the 620 value or they had a smaller infarct core, at which point determining the ADC values becomes very difficult. Dr. Negar Asdaghi: Overall, three patients only had favorable mismatch profile as we defined earlier and we use to guide us for thrombectomy in the adult population. Of the three children who met the target mismatch criteria, only one received IV alteplase and none underwent thrombectomy, which makes this difficult to validate the penumbral thresholds that are used in the adults for the pediatric population. Dr. Negar Asdaghi: So, what are the top two points from the study? Number one, in this large cohort of children with confirmed ischemic stroke, only a third had perfusion imaging, and most cases received their neuroimaging more than 72 hours after their symptom onset. Number two, the ischemic mismatch as defined by the adult criteria was present in children even as late as 23 hours from symptom onset. So, in summary, this study and others confirm the feasibility of performing perfusion imaging in the pediatric population, but there remains a necessary reluctance in adoption of perfusion imaging as part of the stroke protocols in pediatric centers. Dr. Negar Asdaghi: There are a number of concerns that we should keep in mind, including contrast-induced nephrogenic systemic fibrosis and gadolinium deposition in the brain, which are major concerns in the pediatric population, especially in those kids with impaired renal function or those requiring multiple scans over time. You have to also consider unfamiliarity with stroke imaging protocols, given that the majority of stroke-like presentations in children are non-ischemic in origin, in which case, perfusion imaging performance is of little or no value. And there should also be technical considerations, including uncertainty regarding the optimal bolus injection dose, rate, and scan duration of kids. Lots to learn, but still, studies like this represent the first step forward to further our understanding of the role of perfusion imaging in pediatric stroke. Dr. Negar Asdaghi: Dural arteriovenous fistulas, or dural AVFs, are intracranial vascular malformations defined by abnormal communications within the dural leaf that's between meningeal arteries and dural venous sinuses and/or cortical veins. Dural AV fistulas represent approximately 10-15% of all intracranial vascular malformations and can remain asymptomatic or have a variety of neurological presentations, the most feared of which is intracranial hemorrhage. It is important to remember that much of the research on the topic is focused on high-risk features of dural AV fistulas associated with the risk of either initial or recurrent hemorrhage, things such as the pattern of venous drainage or location of the fistulas. But less is known about the clinical outcomes of these patients after they present with a bleed. Dr. Negar Asdaghi: The CONsortium for Dural arteriovenous fistula Outcomes Research, or CONDOR, Registry is an international multi-institutional database to study the outcomes of dural AV fistulas. In the current issue of the journal, in the study titled "Outcome Following Hemorrhage After Cranial Dural Arteriovenous Fistulae: Analysis of Multicenter CONDOR Registry," Dr. Matthew Koch, from the Department of Neurosurgery at the University of Illinois in Chicago, and colleagues used this registry to determine the morbidity and mortality of dural AV fistula–related intracranial hemorrhage. I'm joined today by the senior author of the study, Dr. Sepideh Amin-Hanjani, to discuss this paper. Dr. Negar Asdaghi: Dr. Amin-Hanjani needs no introduction to the Stroke readership. She's a Professor of Neurosurgery and Co-Director of Neurovascular Surgery at the University of Illinois. She's the past Chair of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons Cerebrovascular Section. She serves on multiple national and international cerebrovascular committees, including serving as the Chair of the Neurovascular Intervention Committee for the American Heart Association Stroke Council. Good morning to you, Sepi, and thank you for joining us on the podcast. Dr. Sepideh Amin-Hanjani: Good morning, Negar. I really appreciate the opportunity to have time to discuss this paper a little bit with you and the folks listening in today. Dr. Negar Asdaghi: Great, Sepi, let's start off with discussing the prevalence of dural AV fistulas. In the current era of increased availability and accessibility of vascular imaging, how often are these malformations found? And importantly, what are the known predictors of so-called bad neurological behavior or intracranial hemorrhage in these fistulas? Dr. Sepideh Amin-Hanjani: So, I would say these are rare lesions, which is, I think, what makes it particularly useful sometimes to pay a little bit more attention to them because they're less frequently encountered, and so there's not as much thought about looking for these lesions when a patient presents with neurological symptoms or hemorrhage. And so I think highlighting it here is important. They are rare. They're probably, as you mentioned, only about 10-15% of all vascular malformations. The crude incidence is probably somewhere around 0.5 per 100,000. So, again, infrequently encountered. Dr. Sepideh Amin-Hanjani: Because of the nature of the lesion, they're not as easily, I would say, identified incidentally. Unlike AVMs that will show up on routine MRI or aneurysms that'll show up on routine MRA, fistulas may or may not be apparent because of their nature. They're fed by dural arterial feeders; the fistula itself is within the dural leaflets. They can have venous drainage or ectasia associated with them. So, the secondary phenomenon of the venous congestion may show up on MR, but the actual fistula may be hard to identify. And I think, in some ways, that's why we tend to see them a little bit less incidentally, at least in my own practice, in my own experience, than we do when they present with symptoms, either non-hemorrhagic or hemorrhagic symptoms. Dr. Sepideh Amin-Hanjani: There are some features of these fistulas that tend to predict if they're going to be bad actors, so to speak, if they're going to have those more aggressive symptoms of neurological dysfunction from venous congestion. Things like seizures, headaches, even dementia as a prolonged effect of venous congestion, or the most dreaded complications, in some ways, hemorrhage, which relates to if there is evidence of significant cortical venous reflux from the fistula itself. Dr. Negar Asdaghi: Perfect. So this is a great start to get us now to the topic of the registry. What was the overall purpose of the CONDOR Registry? Please tell us a little bit about the patient population, specifically the population of your interest that you included in your study. Dr. Sepideh Amin-Hanjani: So, given the rarity of the condition, you find that in the literature, there's lots of kind of relatively smaller case series, and it's hard to make broader assessments of outcomes and treatments, etc., when you're looking at small retrospective series. So, the idea behind CONDOR, which was really launched by one of my colleagues, neurosurgeon Greg Zipfel at Wash. U. in St. Louis, was the idea of getting together a consortium of centers who have either previously published or have a particular interest in dural AV fistulas to collate our series and get a larger cohort of patients together that could be analyzed for just the kinds of interventions and outcomes that would be of interest in looking at a larger sample size. Dr. Sepideh Amin-Hanjani: So, the consortium now is up to, I think, 16 or 17 centers. The data that was collected and analyzed for the purposes of this particular manuscript came from 12 centers and was over a thousand patients. So, really a large cohort that allowed us to do a deeper dive analysis on a number of topics, including looking at folks who had presented with hemorrhage. There's a number of other studies that have come out of this registry, and the collaboration to form the registry has also been published as well. And it's retrospective data, but the hope is that CONDOR will eventually transform into a prospective database that will allow us to get even higher level data for this condition. Dr. Negar Asdaghi: So, perfect. Sepi, I was going to ask this question of whether the registry's ongoing, so thank you for clarifying that, but coming back to your paper. So, you included those patients who have bled. This was data up until 2017. And it's important to look at this number, 25% of patients with dural AV fistulas in the CONDOR Registry up until the time that you looked at the data. That's 1 in 4 patients presented with an intracranial hemorrhage. Is this an overall good estimate of the risk of hemorrhage for this malformation, especially when we're counseling patients on this? Or do you think this number is higher than routine practice and that it's just basically biased because it's a hospital-based registry? Dr. Sepideh Amin-Hanjani: I think both things are true in some ways, meaning that because this is a consortium of tertiary care centers, obviously there's a referral bias. Patients who are symptomatic or who have hemorrhage are more likely to be cared for in that setting. So, we are going to tend to see a higher proportion of the patients that are presenting with aggressive symptoms or with hemorrhage within this kind of cohort. Dr. Sepideh Amin-Hanjani: But along with that, similarly, if you look at the features of these fistulae, they're the ones that have the cortical venous reflux, the high-risk features. So, in as much as to say, "do 25% of all fistulas hemorrhage?" No, because presumably there's a lot of more benign fistulas, ones that aren't discovered or aren't worked up that are low risk for hemorrhage that don't show up. But within the paradigm of, again, the construct of a consortium where you're looking at centers who are really taking care of patients presumably presenting more actively with neurological symptoms, I think this proportion is fairly representative. And it, again, speaks to the fact that depending on the type of fistula and the features of the fistula, it's going to be more or less likely to present in an aggressive manner, hemorrhage being one of those presentations. Dr. Negar Asdaghi: Perfect. So now let's talk about treatment modalities. A majority of patients in your study had undergone surgical intervention of the fistula. What was the most common intervention in this registry? And can you briefly tell us about the current treatment modalities, whether endovascular or surgical, that are available for dural fistulas? Dr. Sepideh Amin-Hanjani: So, I think what we found with this registry, and these were centers both within the U.S. and internationally, that the most common treatment paradigm is endovascular, so embolization of AV fistulas. And I think that very much reflects current practice because of the relative, I think, being not an endovascular person, I probably shouldn't comment on the ease or lack thereof, but the ability to access these fistulae endovascularly and use a number of agents, including glue or other embolization materials to obliterate them. So, we certainly found that in the series, embolization, either alone or in combination with other modalities, was the most prevalent. Dr. Sepideh Amin-Hanjani: Having said that, surgical intervention still has a significant role. Sometimes these fistulas can be difficult to access, depending on their supply or drainage endovascularly, and then the surgical option for obliterating them becomes important as well. And then, more rarely, lesions that are not amenable to either of those modalities can be treated with radiosurgery, although the concern there always with a hemorrhagic lesion is that the effect is not immediate, as opposed to embolization or surgery, where your goal is to obliterate the fistula and remove the source of hemorrhage, which is really the cortical venous reflux, immediately to make sure that there's not a risk for recurrence. Dr. Negar Asdaghi: Thank you. This is a great review of AV fistulas. So, coming back to the paper now to recap, you had a highly selected group of AV fistulas that presented with an intercranial hemorrhage, the majority of which underwent embolization in this cohort. So, what were the outcomes? And let's start with just a brief overview of what outcomes are actually collected in your study, and what did you find? Dr. Sepideh Amin-Hanjani: Yeah, so we were interested to see, in kind of the current paradigm of management of these fistulae, when they present with hemorrhage. As you said, the great majority were treated. So, this is not a natural history study in the sense that it's not looking at untreated malformations after hemorrhage. It's looking at patients in the real world who pragmatically are going to present into tertiary centers with hemorrhage. What is their overall outcome with the current state of interventions that are available and with whatever primary injury is caused by the hemorrhage itself? Dr. Sepideh Amin-Hanjani: That's really what the study is looking at, is what is morbidity and mortality after hemorrhage from a lesion like this, and current management paradigm for these fistulas. And in that context, we were looking to see if there were predictors of worse or better outcome in that situation following the hemorrhage itself, and defining morbidity as Modified Rankin score of 3 or greater, with the idea of looking at independent versus dependent outcome, and also looking at mortality. Dr. Sepideh Amin-Hanjani: In other words, how severe are these patients in terms of their neurological outcomes if they do suffer hemorrhage event? We were able to define and look at a variety of potential predictors of outcome. The hemorrhage from dural AV fistulas can be either intraparenchymal intracranial hemorrhage or it can be subarachnoid, or it can be a combination thereof. There can be intraventricular hemorrhage, all depending on the venous congestion pattern related to the fistula. And the idea was, do any of those hemorrhage subtypes matter? Do the comorbidities of the patient matter? Do the specific angio-architecture or location of the fistula matter as relates to the outcome from the hemorrhage? Dr. Negar Asdaghi: Perfect. So, at 13% morbidity and 3.6% mortality associated with AV fistula hemorrhages in your study, tell us please about some of the independent factors associated with this primary outcome. Dr. Sepideh Amin-Hanjani: Yeah. So, after we analyzed the features that were available within the database, really age emerged as a predictor of poor outcome. And I think that's not surprising. That's very true for the full range of cerebrovascular conditions. If we thresholded at age 65, folks older than 65 had a twofold risk of a worse outcome. Dr. Sepideh Amin-Hanjani: The other things that we found, really a lot of the other features fell out on multivariate analysis, but the couple that remained strongly associated with poor outcome were folks who were on anticoagulants at the time of the hemorrhage. It was a small number within the cohort, but nonetheless, a very robust effect in that those folks did worse following their hemorrhage and certainly recurrent hemorrhage. Dr. Sepideh Amin-Hanjani: Now, a lot of these fistulae were treated, but in the instance where recurrent hemorrhage did occur prior to treatment, or if the patient had not undergone treatment, recurrent hemorrhage certainly had a really significant effect on worsening outcome as well. That age effect, as I said, has been seen in other vascular conditions. Anticoagulant use as a predictor of poor outcome at the time of hemorrhage has also been seen as a predictor of worse outcomes and other conditions like aneurysmal hemorrhage, things of that nature, and, similarly recurrent hemorrhage. So we're finding similar features as have been described for other cerebrovascular conditions as relates to hemorrhagic lesions as being important predictors of poor outcome. Dr. Negar Asdaghi: Perfect. Very important features to keep in mind when we are dealing with patients with intracranial hemorrhage that are found to have these fistulas. So, things that you mentioned that I want to repeat just for our listeners were: age; recurrent hemorrhage that occurs if a patient is not treated and presented with a hemorrhage initially and added a recurrent one prior to receiving the appropriate therapy; and obviously, and not surprisingly as you mentioned, being on anticoagulants at the time of presentation with their hemorrhage. So, 1 in 6 patients, in summary, with dural AV fistula–associated hemorrhage in your study is dead or dependent follow-up. How does this morbidity and mortality, Sepi, compare to the outcomes from other vascular malformations, say, for instance, that of AVMs? Dr. Sepideh Amin-Hanjani: Yeah, I think that's one of the things we're particularly interested to kind of compare and contrast. Now, one end of the spectrum, you have aneurysmal subarachnoid hemorrhage. I think out of all hemorrhagic vascular lesions, that has the worst outcome. We know morbidity and mortality of that far exceeds 50%. For AVMs, it's been pretty well described even from prospective series that you can have 10-15% mortality and about 30% morbidity related to an AVM hemorrhage. Dr. Sepideh Amin-Hanjani: And we were interested to see if that was similar profile for fistulas. I think our results show that it's somewhat better than the AVM hemorrhage. The mortality is lower at about 3-4%, like you noted, and the morbidity is around 13% for survivors. But all in all, if you aggregate that, that is, as you say, a 1 in 6 chance of a very poor outcome. So, it's not trivial by any means and certainly much higher than the hemorrhagic consequences of something like cavernous malformations, where hemorrhages from cavernous malformations are rarely fatal. These dural AV fistula hemorrhages can be fatal and can result in long-term morbidity. I think that has implications in terms of how we think about risk-benefit profile of treatment for a malformation, an AV fistula that's discovered and has predictors that would indicate it's at high risk for hemorrhage. Dr. Negar Asdaghi: Thank you very much, Sepi. I think you've already eloquently summarized all of this, but I want us to leave our listeners with your top two or three takeaway messages on the topic. Dr. Sepideh Amin-Hanjani: Thanks, Negar. So, I think the key takeaways that we took from looking at this analysis is that we now at least have some idea about what the morbidity and mortality related to dural AV fistula hemorrhage is. That 1 in 6 number, as you indicated, really benchmarks what morbidity and mortality for the condition is. Now, what's the relevance of that? I think, by inference, we can take this into practice in a couple of different ways. Dr. Sepideh Amin-Hanjani: First would be that if a patient presents with a fistula with high-risk features for hemorrhage, that knowing this morbidity and mortality related to hemorrhage certainly informs that discussion about treatment and certainly favors the idea of treating fistulas at high risk for hemorrhage based on cortical venous drainage early to prevent this morbidity and mortality from occurring. Dr. Sepideh Amin-Hanjani: Secondly, I think it argues towards making sure that there's a thorough workup done when a dural AV fistula is suspected, even if it's presenting with more benign symptoms like tinnitus, for example, or is discovered incidentally, and that workup really should be thorough enough to determine if there are high-risk features from this fistula. And that workup really entails catheter angiography because that's truly the way to determine if these cortical venous reflux and other features that are most associated with hemorrhage are present or not. So, I think those two key elements should be kept in mind. Dr. Sepideh Amin-Hanjani: And finally, given the rarity of the condition and because these are complex and heterogeneous lesions, I think it makes sense upon discovery or suspicion of a dural fistula to really refer these to tertiary centers that manage these conditions frequently enough to be able to determine those risk features and to offer the appropriate type of treatment for it, whether it be, as we discussed, mostly embolization or surgery. Dr. Negar Asdaghi: Dr. Sepideh Amin-Hanjani, congratulations on this work, a huge collaboration and a great addition to the existing literature of vascular malformation–related intracranial hemorrhage. It was a pleasure having you on the podcast today. Dr. Sepideh Amin-Hanjani: Thank you so much, Negar, much appreciated. Dr. Negar Asdaghi: And this concludes our podcast for the October 2021 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including two articles published online in September simultaneous with their presentation at the European Stroke Conference, which appear in the October issue of Stroke. The first article is on clinical outcome of thrombolysis with tenecteplase, and the second one discusses the effects of fluoxetine on outcomes after acute stroke, results from EFFECTS randomized controlled trial. Dr. Negar Asdaghi: Now, for a second year in a row, the European Stroke Conference was entirely online, bringing a wealth of knowledge and stroke expertise from all over the world to a completely virtual audience. Now, we hope to soon return to our good old times when we traveled for conferences, but let's take a moment and think about the magnitude of this virtual accomplishment, the incredible role that technology plays in our abilities to do research and provide healthcare. And we owe this to the men and women that pioneered the development and the ever-growing fast-paced progress of computer sciences. Dr. Negar Asdaghi: Ten years ago in October, the world lost one such pioneer. Steve Jobs, the father of mobile technology and digital revolution, is recognized not just for his technical creations but also for his way of life, his incredible mind that led to the seemingly utopian ideas for how things should be. In a powerful commencement speech he delivered at Stanford University a few years before his death, he talked about his life experiences, the power of mind, and the power that lies in doing every part of one's work with absolute perfection and love. So, in honor of his genius and the legacy he left behind, we end our October podcast with his parting words of wisdom to the graduating class of 2005: "Stay hungry, stay foolish." And, as always, stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2021. 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 8 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the September 2021 issue of Stroke: "Risk of Fractures in Stroke Patients Treated With a Selective Serotonin Reuptake Inhibitor" and "Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression." She also interviews Drs. Jukka Putaala and Markku Kaste about their article "Should Tenecteplase be Given in Clinical Practice for Acute Ischemic Stroke Thrombolysis?". Dr. Negar Asdaghi: 1) Are we ready to say goodbye to our old friend alteplase and replace it with a new one, tenecteplase, for acute stroke thrombolysis? 2) Does treatment of depression with SSRIs increase the risk of fractures in stroke patients? 3) When it comes to carotid intervention, should we continue offering treatment based on the degree of luminal stenosis, or are there better biomarkers in the horizon? These are some of the questions that we'll tackle in today's podcast. We're covering the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to 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 September 2021 podcast, we have an exciting program where we discuss some of the controversies in stroke therapies. The September issue also contains a Focused Update with a set of articles and comprehensive reviews on the topic of genetics and stroke, organized by Professor Martin Dichgans, which I encourage you to review in addition to our podcast today. Later in today's podcast, I have the pleasure of interviewing Drs. Putaala and Kaste, from Helsinki Institute, to help us with a burning question of whether there's enough evidence now to use tenecteplase instead of alteplase for ischemic stroke thrombolysis. But first with these two articles. Dr. Negar Asdaghi: Over a third of stroke survivors either have depressive symptoms or a formal diagnosis of depression. Selective serotonin reuptake inhibitors, or SSRIs, are the mainstay of depression treatment and the most common antidepressants prescribed in the U.S. In addition, in 2011, we had the results of the FLAME trial suggesting that early poststroke treatment with fluoxetine, a commonly prescribed SSRI, improves motor recovery and functional independence in stroke patients with motor deficit. Though these results were not replicated in the subsequent larger FOCUS trial, the use of SSRIs poststroke dramatically increased over the past decade. So what are the side effects of using SSRIs poststroke? It's a known fact that adult stroke survivors are more likely to experience bone fracture, and that there's some evidence that SSRIs may increase this risk. Dr. Negar Asdaghi: So, in the current issue of the journal, Dr. Graeme Hankey and Joshua Jones, from Faculty of Health and Medical Sciences, University of Western Australia, in Perth, and colleagues aimed to answer this question with a systematic review and meta-analysis of randomized controlled trials that included an SSRI treatment for an adult patient with a previous hemorrhagic or ischemic stroke and included incident fractures, either as a primary or secondary study outcome, amongst other criteria. So they found four randomized controlled trials that fulfilled their research criteria. Three of them looked at the effects of fluoxetine, used at a dose of 20 mg per day for six months duration, on functional recovery and outcomes after stroke. And one trial, which has studied neuroregeneration in vascular protection by citalopram, either at a 10 mg or 20 mg daily dose also for six months duration, in patients with acute ischemic stroke. So three studies included with fluoxetine and one study included citalopram. Dr. Negar Asdaghi: So, what they found was that although the risk of falls, seizures and recurrent stroke were not statistically increased with SSRI treatment, it was actually a significant increased risk of fractures with a risk ratio of 2.36 in patients treated with SSRI as compared to the placebo. Now, how the SSRIs will increase the risk of fractures is still unknown. There are multiple postulated mechanisms that are discussed in the paper, such as SSRIs potentially increasing spastic motor activity, causing orthostatic hypotension, dizziness, delayed reaction time or temporary imbalance or sleep disorders. But the most important mechanism to keep in mind is the possibility of SSRIs lowering bone mineral density. It's also important to note that the duration of exposure to SSRIs is an important predictor of factors. It's worth noting that the usual SSRI exposure in patients with the primary diagnosis of depression is a lot longer than the exposure time in these trials. Dr. Negar Asdaghi: So, what are the top two takeaway points for stroke physicians? Number one: Fluoxetine and citalopram SSRIs, used for six months poststroke, double the risk of fracture as compared to placebo in this meta-analysis. Number two: While the mechanism of this association is still debated, fracture prevention should be an important discussion point when considering prescribing an SSRI to stroke patients. Dr. Negar Asdaghi: We all know that carotid disease is a major cause of ischemic stroke. Now we have to keep in mind that the bulk of the literature in carotid disease are practically concentrated on the association between the degree of luminal stenosis and the risk of recurrent stroke. So, in practice, we constantly counsel and discuss risk of future ischemia in symptomatic and asymptomatic carotid disease based on the degree of stenosis that's less than 50%, or between 50% to 70%, or over 70%. Dr. Negar Asdaghi: But what if we learn that some plaques can be active despite causing small or little stenosis? And conversely, some may be active despite being very large. There seems to be a growing literature that much of the recurrent strokes are occurring in destabilized plaques. And it turns out that there are actually biomarkers that could cause this destabilization, and we can actually measure them. Xanthine oxidase, or XO, is one of these biomarkers. XO is a key enzyme involved in degradation of purine into uric acid. Now I'm trying to simplify a complex subject here. Xanthine oxidase oxidizes the conversion of hypoxanthine into xanthine and xanthine into uric acid. Along the way, it also does create a whole bunch of reactive oxygen species such as superoxide and hydrogen peroxide, which can create tissue damage. Dr. Negar Asdaghi: Now, how is XO and serum uric acid levels related to carotid disease? Well, it turns out that XO is enhanced in carotid arteries with evidence of atherosclerosis. Better yet, in animal models, inhibition of XO is associated with reduction in progression of atherosclerosis. So, in the current issue of the journal, Drs. Morsaleh Ganji and Valentina Nardi, from Departments of Cardiovascular Medicine and Anatomic Pathology of Mayo Clinic in Rochester, Minnesota, and colleagues set out to investigate whether carotid plaques from symptomatic patients had increased expression of xanthine oxidase than their asymptomatic counterparts. So, what they did was they looked at 88 patients undergoing carotid endarterectomy for symptomatic or asymptomatic carotid disease, part of the routine clinical practice, and then measured the XO expression by immunohistochemical staining in CA obtained specimens. Dr. Negar Asdaghi: In addition, they collected a number of serum samples and other demographics and vascular risk factors from the participating patients. They found four major findings in their paper. Number one: XO expression was indeed higher in symptomatic carotid arteries. Number two: Symptomatic patients had a higher serum uric acid levels. Number three: Higher XO expression was inversely associated with the serum levels of HDL. Number four: The symptomatic plaques had higher amount of macrophages expressing XO. Dr. Negar Asdaghi: Very interesting, but these findings were irrespective of the actual degree of luminal stenosis. In fact, the asymptomatic carotid plaques patients, as routine practice dictates, had a higher degree of luminal stenosis, but they had lower expression of XO and other associated findings. So what did we learn from this study? Well, there seems to be a strong association between certain biomarkers, in this case xanthine oxidase, and symptomatic state of carotid plaques, suggesting that perhaps in future we'll have other ways of measurements that may help us decide on carotid intervention rather than just the symptomatic state of the artery and the degree of stenosis. Dr. Negar Asdaghi: It's been over 25 years since alteplase was approved as the thrombolytic agent of choice for treatment of patients with acute ischemic stroke. But in the past decade, tenecteplase, a genetically modified variant of alteplase with regulatory approval for treatment of ST-segment–elevation, myocardial infarction, has gained interest as an alternative reperfusion therapy for treatment of patients with acute ischemic stroke. Whether tenecteplase is ready to completely replace alteplase in clinical practice is certainly a burning question faced by the stroke community today. This was the subject of a lively debate at the most recent and entirely virtual 2021 International Stroke Conference, where a panel of experts reviewed the current evidence regarding the use of tenecteplase in acute ischemic stroke, examining data from animal models, preclinical studies to dose escalation studies and randomized trials, directly comparing tenecteplase with alteplase, as well as the collective clinical experience to date with this thrombolytic agent. Dr. Negar Asdaghi: The proponents of change point out the many advantages of tenecteplase over alteplase, including its ease of use, increased fibrin specificity, longer half-time and its non-inferiority to alteplase in the head-to-head trials. On the other hand, the opponents caution stroke physicians, drawing attention to the inherent issues with the already completed clinical trials of tenecteplase, and argue that more data is needed before tenecteplase is considered as a thrombolytic agent of choice in routine clinical practice. Continuing on this debate in the September issue of the journal as part of the Controversies in Stroke series, Drs. Jeffrey Saver and May Nour provide opposing views to Drs. Dawn Kleindorfer and Mollie McDermott on the present evidence and current guidelines around tenecteplase use in acute ischemic stroke. Dr. Negar Asdaghi: Acting as moderators, the senior authors of paper, Dr. Jukka Putaala, Head of Stroke Unit at Neurocenter, Helsinki University Hospital, and Dr. Markku Kaste, Emeritus Professor of Neurology at the University of Helsinki and past chairman of Neurocenter, Helsinki University Hospital, in Finland, provide us with the balancing remarks on the issue. I'm joined today by Professors Putaala and Kaste to give us an overview on the debate of tenecteplase versus alteplase. Is it time to make the switch? Good morning from sunny Florida and good afternoon to you both in Finland. Thank you for joining us on the podcast. I hope the weather is as beautiful in Helsinki today as it is here in Miami. Dr. Jukka Putaala: Here it is not as warm as you have, but we have had a really beautiful summer, and at the moment, although it is also autumn, temperature is around 20 Celsius, so it's just great. Dr. Negar Asdaghi: It's great to have you both. The paper outlines a generally recognized criteria to support the use of any new pharmacotherapy. Can you please start us off by reviewing the components of this criteria and tell us, please, how many checkmarks does TNK get on this checklist when considered as a reperfusion therapy in acute ischemic stroke? Dr. Jukka Putaala: These eight criteria include a well-characterized mechanism of action; strong preclinical data; evidence of benefits and safety in a closely related clinical condition, which here is myocardial infarction; important practical advantages over existing agents; the clinical efficacy in how the patient has demonstrated in randomized trials; and endorsement by national practice guidelines. Also, support from regulatory authorities. And finally, clinical effectiveness, which has demonstrated in routine care. We think that tenecteplase for acute ischemic stroke meets actually all of these eight criteria. But we could also think that a smaller number of criteria will be enough to satisfy or meet, would be sufficient. Dr. Negar Asdaghi: Perfect. So definitely many important steps, starting with the basics all the way to post-marketing clinical experience. Markku, now over to you. Can you remind us about the mechanism of action of tenecteplase? And what are some of the similarities and differences in terms of pharmacodynamic and pharmacokinetics with alteplase? Dr. Markku Kaste: So alteplase catalyze plasminogen cleavage to plasmin and, in turn, degrades fibrin in thrombi, yielding clot lysis. TNK, compared to alteplase, is 14-fold greater fibrin activity and 80 times higher resistance to plasminogen activator inhibitor-1, which means it has a longer half-life, which is a major advantage. Patients need only one injection. In case you're compared to alteplase, when you had to have third dose injection and then one-hour infusion, which delay the care of patient, if the patient need thrombectomy. So it takes an hour for the infusion before patient can be transferred to thrombectomy, and time matters in brain infarction. So the faster you are, the better it is for patients. Dr. Negar Asdaghi: Perfect. So more fibrin specificity, as you mentioned, and longer half-time for TNK. And in addition, TNK is not a new drug. In fact, there is over two decades' worth of experience with this in cardiology. Can you also tell us about this? And also some of the preclinical and animal studies that make TNK a potential candidate as a thrombolytic therapy in stroke? Dr. Markku Kaste: In animal studies, both in vitro model of mural platelet deposits under arterial flow and a rabbit model using extracorporeal arterial-venous shunts, TNK was more potent, showing benefits up to three hours versus one hour when alteplase was used. So, it's a major benefit already in animal experiments and in the code team, of course, it will be transferred in clinical practice. So, in myocardial infarctions, in three randomized trials, including our 17,000 patients, TNK showed significant reduction for bleeding rates and similar intracerebral hemorrhage rates and 30-day mortality. Dr. Markku Kaste: So, these facts support the use of TNK, also in ischemic stroke, the results from myocardial infarction, some steady encouraging. Although we have to keep in mind that myocardial infarction is very homogeneous disease, it's arterial occlusion, while ischemic stroke can be caused by the local occlusion just like myocardial infarction, but also from artery-to-artery thrombi or from a cardiac emboli. And these three [inaudible 00:17:43] mechanisms generate different kind of thrombi, so we need a better drug than alteplase, which really is effective, whatever is the etiology of the occlusion of brain artery. Dr. Negar Asdaghi: Right. Thank you. Jukka, now over to you. Before we review the data from randomized trials of tenecteplase, can you please tell us about some of the practical advantages of tenecteplase over alteplase? We're comfortable with alteplase. Why should we make the switch? Dr. Jukka Putaala: The key practical advantages arise from the fact that tenecteplase can be given as one single dose; it takes only one minute. And if you compare that to alteplase, you'll have to give the bolus first, and then following the bolus is 60 minutes infusion. And that also has many advantages in clinical practice, for example, if you have a patient with large vessel occlusion in a remote hospital, which is not thrombectomy-capable, you can give tenecteplase and then put the patient in the ambulance and transfer swiftly the patient to the thrombectomy center. While, when using alteplase, you have to start infusion, which you have to have the nursing staff that is capable of monitoring the infusion and taking care of any complications arising during the infusion and so forth. Dr. Jukka Putaala: With tenecteplase, you can immediately transport the patient to a thrombectomy site after the bolus without any infusion-capable paramedics staff. Another practical advantage is that by using tenecteplase, you avoid the potential gap between the bolus and the infusion, which means that there is at least several minutes or longer gap in four out of five patients treated with alteplase. You can also think the other scenarios during this coronavirus era, and you have 15 patients with suspected or very fast coronavirus infection. By using bolus, you don't need to put nurses in the same room with the patients many times with the infusion if you use alteplase. Instead, you can use tenecteplase, it's only one single bolus, and you can go away and you don't have to be exposed to potential coronavirus infection. Dr. Negar Asdaghi: So, many important advantages, as you mentioned. It seems very reasonable, then, to use tenecteplase in routine practice if it is indeed non-inferior to alteplase. Jukka, what dose of tenecteplase should be used for treatment of acute ischemic stroke patients? And we're definitely excited to hear about the head-to-head trials with tenecteplase versus alteplase. Dr. Jukka Putaala: Well, the trial, the dose is 0.25 mg/kg or 0.4 mg/kg. It depends if you have LVO, if you review the evidence what we have now available, you have to use the lower dose in LVO patients. But you can use the higher dose in non-LVO patients. All of this arises from the evidence we have available right now. So, basically, five randomized trials have been completed, to date, comparing tenecteplase with alteplase in acute ischemic stroke. And shortly, if they pull out these five trials and compare primary outcome, which is modified Rankin Scale 0 to 1 versus prior, which means excellent outcome. Dr. Jukka Putaala: So, when pulling out these five trials, 58% percent of patients rates excellent outcome versus 55% of alteplase, and this satisfied the criteria for non-inferiority. Regarding safety and secondary outcomes, major intracranial bleeding, mortality, this meta-analysis according to five trials shows similar results for tenecteplase and alteplase. You have to consider some details of this trial. I think Markku was going to quickly review some of the details of the science and doses used in these trials later on. Dr. Negar Asdaghi: So, yes, this sounds great for tenecteplase, but so now over to you, Markku. As Jukka mentioned, do we hear a "not so fast for tenecteplase"? Is the current data enough to say goodbye to alteplase entirely and completely turn over to tenecteplase? What are some of the issues with the already completed trials? Dr. Markku Kaste: It's not today, we cannot say goodbye to alteplase. As Jukka referred to those trials, there's no reason to go into these really deep details because the trials are quite small compared to ordinary clinical randomized trials studying stroke care. Like I don't want to give neuroprotection agents, for example. One larger trial was, let's say, reasonably well designed. But as to say that most of these trials are not really double-blind randomized clinical trials. And so the results which can be generated is not as reliable as double-blind trials because, of course, there are reasons, I mean, colleagues randomizing cases may think that, OK, a randomizing case and I'm not totally convinced about TNK. And I think this gentleman or this lady really needs effective thrombolytic agents, so I give alteplase, while if another patient with a mild symptom, same physician may think, OK, this stroke patient will recover no matter what, so let us randomize the patient. Dr. Markku Kaste: So, it means these kind of unbalanced randomization provides data which is not really reliable. We had to have lots double-blinded randomized trials before it's time to say goodbye, if this double-blinded randomized trial verified that TNK beats alteplase. And, of course, we need also meta-analysis of those advanced trials, and these things can take time, although many guidelines, like AHA guidelines, European Stroke Organization guidelines, Chinese guidelines, Indian guidelines, they, in a way, how do you say, might recommend use of TNK, but I think we need more reliable scientific evidence before it's time to say goodbye to alteplase. Dr. Negar Asdaghi: So, Jukka, Markku already alluded to this. I wanted you to review this for our listeners, the national practice guidelines and drug regulatory authority guidelines around the globe with regards to the issue of tenecteplase versus alteplase. Dr. Jukka Putaala: Yeah, actually, already American, European, Chinese, Australian and Indian guidelines are recommending tenecteplase into the guidelines, which were recently published in 2019, between 2019 and 2021. What we can read from the guidelines is that tenecteplase can be considered over alteplase. But we have to remember that the strength of the recommendation will remain weak at present and quality of evidence is by the facts that we discussed of these five completely randomized trials and meta-analysis pulling out the data. Qualitative evidence remains slow, and, therefore, the wording in the guidelines is that it may be reasonable to choose or consider alteplase. Tenecteplase might be considered as an alternative to alteplase in certain conditions. Dr. Jukka Putaala: The recommendations are a little bit mixed in the guidelines, but generally, in large vessel occlusions, the guidelines say that you could consider TNK over alteplase or even that you should consider TNK over alteplase in large vessel occlusion before proceeding to thrombectomy. However, in cases without large vessel occlusion, the statements are more mixed and they say tenecteplase might be considered or even that alteplase is preferred over tenecteplase until we have more evidence. Dr. Negar Asdaghi: Thank you, Jukka. Markku, what should be our final takeaway message for the practicing stroke physicians at this point considering the use of tenecteplase in routine practice? Dr. Markku Kaste: Before your paper has been accepted and published in high-quality journal, it takes weeks, mostly it takes months, even a half a year. While in Stroke Conference, you get the most recent data, which is, let's say, generated last week or even the same day. So, when you want to really provide high-quality care of your patient, keep you updated. And then it's best for you and her, and it's better, of course, for your patient. International Stroke Conference and also European Stroke Conference, they are excellent places to get the most recent, yet unpublished, reliable information. Dr. Negar Asdaghi: Professors Jukka Putaala and Markku Kaste, thank you for summarizing a large body of evidence for our listeners. We're definitely excited to learn how tenecteplase will ultimately stand against the old competitor and perhaps learn that both may be reasonable thrombolytic options, depending on the specifics of the clinical setting. Dr. Negar Asdaghi: And this concludes our podcast for the September 2021 issue of Stroke. Please be sure to check the September table of contents for the full list of publications, including two special reports on consensus recommendations from the 11th STAIR Consortium, that is, Stroke Treatment Academic Industry Roundtable. Dr. Negar Asdaghi: The first report is intended to enhance patient, clinician and policymaker comprehension at modified Rankin Scale findings in clinical trials and quality improvement initiatives. The second report from the STAIR Consortium is on top priorities for cerebroprotective studies, an important manuscript where the roundtable considered and presented a new paradigm for evaluation of putative therapies that may work together with recanalization treatments to improve outcome after ischemic stroke, with special attention to using the correct nomenclature, such as replacing the term "neuroprotection" with "cerebroprotection" when the intention of an investigation is to demonstrate that a new treatment benefits the entire brain, rather than neurons alone. Or replacing the term "time window" with "tissue window" or "target window" when selecting patients for recanalization therapies to enhance the notion that various elements of the neurovascular unit show vulnerability to ischemia evolving over different time scales in different brain regions. An important paradigm shift in ways we think of the brain under ischemic attack. With that, we invite you to continue to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2021. 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 7 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2021 issue of Stroke: "Stroke Risks in Adult Survivors of Preterm Birth: National Cohort and Cosibling Study" and "Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm." She also interviews Drs. Nirav Bhatt and Diogo Haussen about their article "Reliability of Field Assessment Stroke Triage for Emergency Destination Scale Use by Paramedics: Mobile Stroke Unit First-Year Experience." Dr. Negar Asdaghi: 1) Can preterm birth be associated with increased risk of stroke in adulthood? 2) Can a plant-based diet high in phytoestrogens reduce the risk of aneurysm formation and aneurysmal rupture in postmenopausal women? 3) What is the predictive ability of FAST-ED score in detection of large vessel occlusion? We will review these questions in today's podcast. You're listening to the Stroke Alert Podcast. Stay with us. Dr. Negar Asdaghi: From the Editorial Board of Stroke, welcome to 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 2021 issue of Stroke covers a wide range of topics from examining if the presence of spot sign modifies the treatment effect of tranexamic acid in patients with intracerebral hemorrhage to the results of the PRESERVE randomized clinical trial examining whether intensive blood pressure lowering in patients with severe cerebral small vessel disease can be associated with progression of white matter damage as detected by diffusion tensor imaging or MRI studies, which I encourage you to review in addition to our podcast today. Dr. Negar Asdaghi: Later in today's podcast, I have the pleasure of interviewing Drs. Diogo Haussen and Nirav Bhatt from Emory University on their work on reliability of FAST-ED scale when used by the paramedics in mobile stroke units and learn about the implementation of mobile stroke units in Atlanta. But first with these two articles. Dr. Negar Asdaghi: Preterm birth, defined as birth prior to 37 weeks of gestation, affects approximately 11% of births worldwide. Today, with the advent of modern neonatal and pediatric care, the majority of preterm babies survive into adulthood. Multiple studies have shown that adult survivors of preterm birth are at increased risk of developing vascular risk factors, such as diabetes and hypertension, and have a higher incidence of ischemic heart disease as compared to their age-matched individuals born at term, though the association between preterm birth and risk of stroke is not well studied. Dr. Negar Asdaghi: In the current issue of the journal, Dr. Casey Crump from Departments of Family Medicine and Community Health and Population Health Science and Policy at Icahn School of Medicine, Mount Sinai, New York, examined whether preterm birth is associated with an increased risk of stroke and its major subtypes in adulthood. The authors use the prenatal and birth information obtained from the Swedish Birth Register, which contains information for nearly all births in Sweden since 1973. The study cohort included over 2,200,000 singleton live births in Sweden from 1973 to 1994. These years were chosen to allow for sufficient follow-up into adulthood. The study cohort was examined for the earliest diagnosis of stroke from the time the participants turned 18 through September 31, 2015, and the maximum age of included population is 43 years. Stroke was identified using ICD codes from all primary and secondary diagnosis in the Swedish Hospital and Outpatient Registries and all deaths attributed to stroke in the Swedish Death Register. Dr. Negar Asdaghi: Cosibling analyses assess for potential shared, familial confounding factors, such as genetic and environmental factors, that could contribute to development of stroke. In 28 million person-years of follow-up, 4861, or 0.2% persons, were diagnosed with stroke between 18 to 43 years of age. The authors found that low gestational age at birth was associated with a significantly higher risk of first-time stroke in adulthood. In their adjusted model, as compared to those born at full-term, the hazard ratio for any stroke associated with early preterm, that is birth between 22 to 33 weeks of gestation, was 1.4, and the hazard ratio for late preterm, that is birth between 34 to 36 weeks of gestation, was 1.22, both of which were statistically significant. Interestingly, each additional week of gestation was, on average, associated with a 3% lower risk of first stroke in adulthood. Dr. Negar Asdaghi: Similar associations were found in men and women and for both hemorrhagic and ischemic strokes. These findings were only partially explained by shared genetic or environmental risks of preterm birth and stroke within families, suggesting important direct effects of preterm birth on risk of stroke. Multiple putative mechanisms that could potentially link preterm birth with increased stroke risk were discussed in the paper as well, including interaction of fetal angiogenesis during the critical developmental period leading to reduced capillary density and increased arterial stiffness, to persistently elevated levels of anti-angiogenic factors, which are correlated with increased blood pressure development and development of hypertension in adulthood. In summary, the study findings suggest that preterm birth should be recognized as a risk factor for stroke later in life, and survivors need early preventive evaluation and long-term clinical follow-up into adulthood to reduce their lifetime risk of stroke. Dr. Negar Asdaghi: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women, suggesting estrogen may be protective against aneurysm formation or aneurysmal rupture. However, estrogen-containing hormone replacement therapy is also associated with an increased risk of other significant adverse outcomes, such as increased risk of breast cancer and ischemic stroke, and is not routinely recommended for primary prevention of chronic conditions in postmenopausal women. Isoflavones, a type of phytoestrogen, are plant-based, diet-derived compounds with properties similar to estrogen. Two types of isoflavones, genistein and daidzein, are found in soybeans, chickpeas, and lentils and are thought to be the most potent phytoestrogens that exert estrogenic activities with tissue and receptor specificity. Regular consumption of isoflavones has been shown to alleviate the vasomotor symptoms of estrogen deficiency and associated with reduced incidence of estrogen-dependent diseases in postmenopausal women. Daidzein, once ingested, is converted to its bioactive metabolite, equol, which preferentially binds to estrogen receptor beta, a receptor subtype responsible for the protective effect of estrogen against the formation and rupture of intracranial aneurysms. Dr. Negar Asdaghi: In the paper titled "Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm," Dr. Tomoki Hashimoto from the Barrow Aneurysm and AVM Research Center, Departments of Neurosurgery and Neurobiology, the Barrow Neurological Institute, and colleagues investigated whether the phytoestrogens daidzein and its bioactive form, equol, are protective against the formation and rupture of intracranial aneurysms in ovariectomized female mice. Intracranial aneurysms were induced by combining systemic hypertension and a single injection of elastase into the CSF at the right basal system. Ovariectomized mice were fed with an isoflavone-free diet. The systemic treatment with equol delivered via an implanted mini-osmotic pump in the treatment group (0.5 mg/kg/day) or vehicle (in the control group) began one week before aneurysm induction and was continued for four weeks thereafter. So, what they found was that equol treatment significantly reduced the incidence of aneurysm formation compared to vehicle, and there was a trend for equol-treated mice to have a lower incidence of aneurysmal rupture than control mice, while there was no difference in the blood pressure noted between the two groups. Dr. Negar Asdaghi: Furthermore, systemic treatment through equol decreased mRNA expression of proinflammatory cytokines, such as IL-6 and interleukin-1β. Importantly, equol seems to require estrogen receptor beta, as the observed protected effects of equol against aneurysm formation was not duplicated in ovariectomized estrogen receptor beta knockout mice. The authors further demonstrated that dietary daidzein reduced the incidence of aneurysm formation, an effect that was dependent on the conversion of daidzein to equol as the beneficial effect of this dietary supplement was abolished in mice that were fed vancomycin, which prevented the intestinal microbial conversion of daidzein to equol. In summary, this study showed that both dietary oral daidzein or the systemic use of its bioactive metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor beta and subsequent suppression of inflammation. These results indicate a potential therapeutic value of phytoestrogen in prevention of intracranial aneurysm formation and related subarachnoid hemorrhage. Dr. Negar Asdaghi: Early recognition of stroke-like symptoms, combined with increased utilization of revascularization therapies, have greatly improved the clinical outcomes of patients with acute ischemic stroke, but have similarly resulted in an ever-growing demand on the stroke systems of care. In the era of endovascular thrombectomy, a prehospital scoring tool with predictive abilities for detection of a target vessel occlusion can greatly assist in the appropriate triage, transfer, and activation of the endovascular team for eligible patients, all the while preventing the inevitable fatigue that accompanies the overuse of the system by properly triaging out those who have a lower likelihood of needing endovascular therapy. For any scoring system used in the prehospital setting, the need for precision needs to be balanced with notions such as ease of administration, time consumption, and reproducibility, as decisions made in the field are invariably fast and frequently made in unstable situations. The Field Assessment Stroke Triage for Emergency Destination, or the FAST-ED scale, is one such stroke scale that meets many of the above-stated criteria in patients with stroke-like presentations to predict a possible large vessel occlusion. Dr. Negar Asdaghi: In the paper titled "Reliability of FAST-ED Scale Use by Paramedics: Mobile Stroke Unit First-Year Experience," Drs. Nirav Bhatt and Diogo Haussen and colleagues, from the Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, and the Department of Neurology at Emory University School of Medicine in Atlanta, report on the reliability of the FAST-ED score in the prehospital setting when used by the paramedics in a mobile stroke unit. I'm joined now by Drs. Bhatt and Haussen to discuss this paper. Good afternoon, Nirav and Diogo. Thank you very much for joining us. Dr. Nirav Bhatt: Thank you so much for the invitation. I'm very happy to be here. Dr. Diogo Haussen: Thank you very much. It is a great pleasure to join you. Dr. Negar Asdaghi: Right. In this paper, the FAST-ED score was administered by the paramedics in a mobile stroke unit. So Nirav, to get us started, please tell us about the concept of a mobile stroke unit, how long it's been implemented in Atlanta, and what it means for patients with stroke-like symptoms who would possibly have a large vessel occlusion. Dr. Nirav Bhatt: The mobile stroke unit, or the MSU, is an ambulance equipped with a CT scanner and state-of-the-art telemedicine capabilities and is operated by the Grady Emergency Medical Services that covers majority of Metro Atlanta and many of its suburbs, caring for a population of a little over 500,000. It was specifically incorporated to expedite care amongst patients with suspected strokes and went into operations on 30th May, 2018, Monday through Saturday, 12 hours a day, 8 a.m. through 8 p.m. It is operated by a group consisting of an EMT driver, a paramedic, an emergency medicine registered nurse, and a CT technician. So, when a patient has symptoms suspicious for a stroke, the MSU is activated either through 911 dispatch or by an ALS ambulance crew evaluating a possible stroke alert patient in the field. After the initial stroke triage performed by the MSU crew, if there is a persistent suspicion for stroke, the patient is transferred to the MSU and a noncontrast CT scan of the brain is immediately performed. Dr. Nirav Bhatt: These CT images are transmitted via the telemedicine platform and are available for review by the vascular neurologist and neuroradiologist in real time. With the help of telemedicine technology, a remotely located vascular neurologist then examines the patient. So, with the help of telemedicine and CT scanner, it allows the remotely located vascular neurologist to identify patients who may qualify for IV alteplase, which is then administered in the MSU to qualifying patients, and these patients get subsequently transported to a stroke treatment center. Now, if the neurological exam is concerning for a large vessel occlusion and the non-contrast CT scan does not show corresponding early ischemic changes, these patients get transferred specifically to a comprehensive stroke center for consideration of thrombectomy. At our centers, some of these patients get directly transported to the neuro-angio suite for further imaging and possible thrombectomy. Thus, the MSU serve a very important goal of expediting critical neurological care for a stroke patient, not only by administering IV alteplase in the field to qualifying patients, but also early triage and transport of qualifying patients to the neuro-angio-suite and with earlier activation of neuroangiosuite. Dr. Negar Asdaghi: Perfect, Nirav. An important and a growing concept, bringing treatment to patients and helping with triaging them appropriately, as you mentioned, which I'm sure we'll see more of in the United States and across the world. Now, Diogo, over to you. Can you tell us about the FAST-ED score, its components, then about the reliability of FAST-ED score in the prehospital setting prior to your current study? Dr. Diogo Haussen: So, the landmark trials published in 2015 defined mechanical thrombectomy as this very effective and powerful treatment of large vessel occlusion stroke patients, and the clinical and the public health impact of this treatment are certainly highly dependent on the rapid triage of these folks into the appropriate destination. So, this involves the prompt identification of patients with severe symptoms by the emergency medical system personnel, and obviously the transportation of them for a thrombectomy capable center. So, some scales had been proposed earlier on, and the FAST-ED was then developed, and it aimed to help with the identification of patients with a higher probability of having a large vessel occlusion stroke. So, in 2017, we validated the scale on stroke patients that had undergone contrast-enhanced vascular images, which had not been done before, in this publication led by Fabricio Lima and Raul Nogueira in Stroke, in the Stroke journal. Dr. Diogo Haussen: So, this paper demonstrated that FAST-ED had higher accuracy than RACE and CPSS. The main limitation at the time was the fact that the FAST-ED score derived from the NIH Stroke Scale and, therefore, had to be validated in the field. The FAST-ED scale stands for the important features that are involved with stroke care and recognition and triage, such as facial palsy, arm weakness, speech changes, and time. Then we complimented this with findings of critical dysfunction illustrated by eye deviation and also denial/neglect. So, the FAST-ED has the following scoring system: So, facial palsy scored from zero to one; arm weakness from zero to two; speech changes, which is aphasia, from zero to two; time is just for documentation, but not for really any decision-making in terms of the scale itself. So, eye deviation goes from zero to two, and denial/neglect from zero to two, and again, was designed based on the items of the NIH Stroke Scale with higher predictive value for large vessel occlusion strokes. I think Nirav is going to discuss a little bit more about why we chose those cutoffs, but they're all designed in a specific way. Dr. Negar Asdaghi: Perfect. So a quick score that can be administered easily by different healthcare personnel. So, please tell us, before we go back to Nirav, about your paper's methodology. What were you hoping to expand on the existing knowledge with this paper? Dr. Diogo Haussen: I'm just going to repeat a few things, but our mobile stroke unit is equipped obviously with a CT machine and is staffed by an EMT driver and emergency medicine registered nurse, a paramedic, and a CT technician. So, a remote evaluation of patients by a vascular neurologist is then performed through this video-based telemedicine platform. The MSU, as he mentioned, is routinely accompanied by an Advanced Life Support–staffed ambulance, which responds to the suspected stroke calls, and sometimes then calls in or calls off the potential of our stroke code. And as part of this MSU evaluation, the FAST-ED is then administered by the MSU paramedic via the FAST-ED smartphone application that was designed. And then an independent NIH is performed by the registered nurse within the MSU. So, subsequently, the patient is transferred into the MSU itself and a non-conscious CT is performed. Once the scan is completed, the patient is evaluated by the vascular neurologist in a two-way video conference where the FAST-ED is then estimated by the physician. Dr. Diogo Haussen: So, all patients are then transferred to the comprehensive stroke center, where further evaluation, including vascular imaging, is performed. The vascular imaging data was formerly read by neuroradiology and then followed by an independent read by the vascular neurologist for the identification of large vessel occlusion strokes, which we define in this paper as an intracranial occlusion off the internal carotid, the M1 or the M2 branches of the middle cerebral artery or the basilar artery. The study encompassed our initial experience, which was from May of 2018 till August of 2019. And we have some other goals, but the initial experience was planned to allow us to investigate, once again, this most important feature, which is the potential reliability of the estimation of the FAST-ED score by paramedics in the field. Dr. Negar Asdaghi: Perfect. Thank you for this background, Diogo. Now Nirav, we're ready to hear about the study results. Dr. Nirav Bhatt: So, in the first 15 months of operation of the mobile stroke unit, we analyzed data on 173 eligible patients. We had an almost equal distribution of our patients in terms of gender. We had 52.6% females, and the majority of our patients were Black. We found that FAST-ED scores matched perfectly between paramedics and vascular neurologists 56% of the time, and there was only a zero to one point difference in 91% of the cases. Cases in which the discrepancy of the FAST-ED score between the paramedic and vascular neurologist was two points or higher were less than 9%. Overall, the intraclass correlation of FAST-ED score between the paramedic and the vascular neurologist was 0.94, indicating excellent interrater reliability. Dr. Negar Asdaghi: Thank you. You found a higher interrater reliability between the paramedics and vascular neurologists for scores of three or above on the FAST-ED scale. Higher FAST-ED scales also were more specific in terms of detection of a target vessel occlusion. How should your results be interpreted in our day-to-day practice, Nirav? Dr. Nirav Bhatt: That is correct. When vascular neurologists recorded a FAST-ED score greater than or equal to three, paramedics also recorded a FAST-ED score greater than or equal to three in 87.5% of the instances, and when a vascular neurologist recorded a FAST-ED score of greater than or equal to four, the paramedics also recorded a FAST-ED score of greater than or equal to four in 92% of the instances. This is suggestive that when the patients presented with a moderate to a severe stroke, that EMS paramedics were highly reliable in identifying the neurological severity of these patients. This provides a sound basis for more widespread utilization of FAST-ED as a simple and reliable tool that can be utilized by paramedics to identify stroke severity in the field. Dr. Negar Asdaghi: Thank you, Nirav. Simple indeed. I know Diogo briefly alluded to this, but can you also tell us a little more about how FAST-ED compares to the other prehospital scoring systems in terms of their interrater reliability and LVO prediction? And what should be our takeaway message from your paper? Dr. Nirav Bhatt: Yes, absolutely. So, just to give you an example, the Los Angeles Motor Scale, LAMS, tests for facial droop, arm drift, and grip strength, but does not really test for cortical signs. We know that a lot of patients with subcortical strokes will have those features, meaning facial droop, arm drift, and decreased grip strength. Similarly, while RACE is very similar to FAST-ED, it tests for leg weakness in addition to what FAST-ED does. It also puts a lot more emphasis on the facial droop as compared to FAST-ED. And with that, I want to draw your attention to a study that we cited in our paper where these scales were compared head to head, and while the accuracies of all the prehospital scales were found to be acceptable, the accuracy of RACE and LAMS were slightly higher than that of FAST-ED. However, it should be noted that in almost 35% of the cases, a complete FAST-ED score could not be reconstructed largely due to data and availability regarding patients' neglect. Dr. Nirav Bhatt: This percentage for data and availability for RACE was even higher, meaning we have to consider the feasibility of these scales when we recommend the widespread adoption of these scales into our communities. Overall, the takeaway from this entire study is we strongly believe that there needs to be a system in place for prehospital stroke triage in order to identify and transport the patients to the right destination rapidly. However, the choice of individual scales should be made after consideration of the geographical characteristics of a particular community, and also that experience and that comfort with the level of training required for reliable performance of each of these scales by the EMS personnel. Dr. Negar Asdaghi: Thank you so much, Nirav. More to come on this, I'm sure, in the future. Thank you for joining us on the podcast today. Dr. Nirav Bhatt: Thank you so much. It was our pleasure. Dr. Negar Asdaghi: Thank you, Drs. Nirav Bhatt and Diogo Haussen. Thank you for joining us on the podcast today, and we look forward to covering more of your work in the future. This concludes our podcast for the August 2021 issue of Stroke. Please be sure to check out the August table of contents for the full list of publications, including a special report on the safety of the mobile stroke units and a descriptive review of the amount of radiation exposure to the public, patients, and staff from these mobile units. With that, as our work to save every brain cell from ischemic and hemorrhagic damage continues, we invite you to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2021. 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.