Stroke Alert podcast

Stroke Alert October 2021

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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.

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    Stroke Alert November 2021

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    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.
  • Stroke Alert podcast

    Stroke Alert October 2021

    33:35

    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.
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    Stroke Alert September 2021

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    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.
  • Stroke Alert podcast

    Stroke Alert August 2021

    26:31

    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.
  • Stroke Alert podcast

    Stroke Alert July 2021

    38:29

    On Episode 6 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2021 issue of Stroke: “Prevalence and Clinical Correlates of Intracranial Dolichoectasia in Individuals With Ischemic Stroke” and “Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation.” She also interviews Dr. Osama Zaidat about his article “Impact of Age and Alberta Stroke Program Early Computed Tomography Score 0 to 5 on Mechanical Thrombectomy Outcomes.” Dr. Negar Asdaghi: 1) Is intracranial dolichoectasia the new intracranial atherosclerotic disease? 2) What is the latest on collateral flow improvement through sphenopalatine ganglion stimulation in patients with acute ischemic stroke? 3) Is endovascular therapy futile in patients presenting with a low ASPECTS score? These are the topics that we will cover 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. Dr. Negar Asdaghi:         For the July 2021 issue of Stroke, we have a systematic review and meta-analysis of safety and efficacy of dual antiplatelet therapy with P2Y12 inhibitors and aspirin versus aspirin monotherapy in patients with mild ischemic stroke or high-risk transient ischemic attack, which I encourage you to review in addition to today's podcast. Dr. Negar Asdaghi:         Later in the podcast, I have the pleasure of interviewing Dr. Osama "Sam" Zaidat, Professor of Neurosurgery and Neurology at Bon Secours Mercy Health Neuroscience Institute. Dr. Zaidat will speak to us about his work on endovascular therapy in patients presenting with a large ischemic core as determined by a low ASPECTS score on presentation. But first with these two articles. Dr. Negar Asdaghi:         In the setting of acute ischemic stroke, intracranial large-vessel disease is often equated with processes which result in narrowing of the intracranial vessels, such as what is seen in the setting of intracranial atherosclerotic disease, or ICAD, where much research has focused on the degree of noumenal stenosis. Less is known about intracranial dolichoectasia, or IDE, which is characterized by ectasia, that is dilation, or dolichosis, which is increased length or tortuosity of the intracranial arteries. Dr. Negar Asdaghi:         IDE can occur due to inflammatory, infectious, or genetic abnormalities. But much like its stenotic counterpart, or ICAD, most cases of IDE are diagnosed in the setting of uncontrolled vascular risk factors. Keeping in mind that the pathophysiology of ICAD and IDE are entirely different. Dr. Negar Asdaghi:         Despite recent advances in recognition of IDE beyond an arteriopathy involving the basilar artery alone, the prevalence of IDE in patients with acute ischemic stroke is unknown, in part related to the lack of a unified diagnostic criteria for this condition. In this issue of the journal, Dr. Victor Del Brutto from the Division of Cerebrovascular Disease at the University of Miami and colleagues studied the prevalence and clinical correlates of IDE among 211 consecutive acute ischemic stroke patients admitted to a tertiary care hospital during a four-month period. IDE was defined as either ectasia or dolichosis of at least one proximal intracranial artery equal or greater than two standard deviations from the study population mean as measured by semi-automated segmentation method. Dr. Negar Asdaghi:         So, what they found was that IDE was identified in 24% of stroke cases: a small percentage, which was only 5%, with only isolated ectasia; 9.5% with isolated dolichosis; and the rest with both ectasia and dolichosis. Anterior and posterior circulation were equally involved, but not surprisingly, the basilar artery was the single most common affected artery by IDE. After a complete stroke work-up, stroke was classified as cardioembolic in 25.5% of their population, large-artery atherosclerosis in 30%, small-artery occlusion in 14.5%, and undetermined in 25.5% of cases. Using cardioembolic stroke as a reference, the prevalence of IDE was significantly higher across strokes of undetermined etiology with odds ratio of 2.8. And there was a trend towards higher IDE prevalence in those whose stroke was classified as small-vessel disease. Dr. Negar Asdaghi:         Furthermore, IDE was considered the most likely pathogenic mechanism in 6% of the entire cohort, which represented over 23% of strokes initially categorized as undetermined etiology and 21% of those with strokes categorized in small-vessel disease category, suggesting a likely causal correlation between parent vessel dolichoectasia and occlusion of the small vessel perforators in these patients. Dr. Negar Asdaghi:         The authors concluded that IDE is an arteriopathy frequently found in patients with acute ischemic stroke and likely responsible for a sizable fraction of strokes initially categorized as undetermined etiology and those with small-vessel ischemic disease. Dr. Negar Asdaghi:         The concept of freezing ischemic penumbra refers to either pharmacological or non-pharmacological interventions that aim to reduce tissue energy requirements for increased oxygen delivery and collateral perfusion to the tissue at risk for ischemia while awaiting revascularization therapies. Sphenopalatine ganglion, or SPG, electrical stimulation via an injectable implant had been previously shown to augment collateral flow and improve clinical outcomes in patients with acute ischemic stroke. Dr. Negar Asdaghi:         The benefit of SPG stimulation is likely conferred not only from its potent collateral augmentation properties, but also from other mechanisms, such as blood-brain stabilization, direct neuroprotection and enhancement of neuroplasticity, though the need to implant the device diminishes its applications in the hyperacute stroke setting. Dr. Negar Asdaghi:         Capsaicin, the pungent ingredient in hot chili peppers, is an SPG chemical stimulator, which affects the trigeminal vascular system, resolving in vasodilation and improved collateral flow. In the paper titled "Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation: A Pilot Study," Dr. Juan Manuel Marquez-Romero from IMSS Institute in Mexico and colleagues completed a dose escalation study of capsaicin ranging from 33 to 165 micromole topically applied to the posterior surface of the subject's hemi-palate in 30 healthy volunteers. By applying capsaicin in the palate mucosa, the SPG can be stimulated directly through the greater and lesser palatine nerves while minimizing that pungent sensation. Dr. Negar Asdaghi:         During the 20-minute applications, the investigators used transcranial Doppler to study various flow parameters, including the mean velocity, positivity index, and the CBF index, or cerebral blood flow index, over the middle cerebral artery. The median age of participants in the study was 21. All reported having consumed capsaicin in their diets sometimes in the past. So, what they found was, at baseline, TCD measurements and the calculations were all within normal limits. All the tested doses of capsaicin reduced augmentation of the MCA mean velocity while reducing the positivity index. The effects peaked between the five and the 10 minutes measurements and then returned to basal levels for all doses of capsaicin, except for the 66 micromole dose group, in which the effect remained stable with the same pattern. There were no side effects reported, and the investigators found no correlation between the perceived pungency and the dose of capsaicin administered. Dr. Negar Asdaghi:         The authors noted that capsaicin appears to produce a hemodynamic response in the intracranial circulation, similar to the one achieved with SPG electrical stimulation. Understanding that this is data from a small pilot study, the results are hypothesis-generating at this point, and further research is required to measure the safety and efficacy of capsaicin in the elderly stroke population. Dr. Negar Asdaghi:         Endovascular thrombectomy is an effective evidence-based treatment to improve outcomes in patients with acute ischemic stroke. Studies to expand the applications of this therapy to late-presenting patients, those with large ischemic cores, or distal occlusions are leading to major changes in clinical practice worldwide. Whether the ischemic core is measured by volumetric methods or by ASPECTS score, the presenting infarct core beyond which endovascular therapy is futile, or even potentially harmful, has not been established. Dr. Negar Asdaghi:         So, the commonly encountered question in routine practice is whether thrombectomy should be offered to patients with presenting low ASPECTS. In other words, what are the characteristics of patients who continue to benefit from thrombectomy despite presenting with a large ischemic core? In the paper titled "Impact of Age and ASPECTS of 0 to 5 on Mechanical Thrombectomy Outcomes: Analysis From the STRATIS Registry," we learn about the outcomes of thrombectomy-treated patients stratified into low and high ASPECTS categories and the specific interaction between increasing age and low ASPECTS. Dr. Negar Asdaghi:         I'm joined now by the first author of the paper, Dr. Osama "Sam" Zaidat, who's one of the principal investigators of the STRATIS Registry. Dr. Zaidat, of course, needs no introduction to our listeners. He's the past president of the Society of Vascular and Interventional Neurology. He's a leader in the field of neurointerventional therapists and currently is the neurology residency director and the endovascular fellowship director at the Bon Secours Mercy Health Neuroscience Institute. Welcome Sam. Welcome to our podcast. Thank you for joining us. Dr. Osama Zaidat:           Thanks for having me. I really appreciate Dr. Negar and the Stroke journal team for featuring our research and our results and sharing it with your listeners today. Thank you for having me. Dr. Negar Asdaghi:         Thank you very much. So, let's start by learning about the STRATIS Registry. Can we please hear an overview of the registry? Dr. Osama Zaidat:           Yes, that's a good question because this is kind of the database where we really go and mine for questions that we still need answers for in the stroke field. For example, and specifically in the thrombectomy field, the STRATIS Registry was designed to evaluate post-marketing, real-life experience and results using Solitaire device stent retriever as the first mechanical thrombectomy choice. So, if you have enrolled a patient, that means the first attempt to take the clot out was using the Solitaire device for large vessel occlusion that presented with acute ischemic stroke. Dr. Osama Zaidat:           We planned about 1,000 patients, so we needed a bigger patient population than the randomized trial. So, we have 1,000 patients treated with Solitaire device within eight hours from symptoms onset with large vessel occlusion presenting with acute ischemic stroke. To do that, we needed 55 medical centers with various clinical experience, various volume, and various operator experience because that really reflects a little bit of not a selection bias, meaning that data can be reproducible and can be validated across different spectrum of centers and neurointerventionalists and stroke neurologists for that matter. Dr. Osama Zaidat:           This also, the aim of it — the spectrum — in addition to validate and reproduce randomized clinical trial data, to try to address questions that are hard to address with a clinical trial. For example, what's the outcome in nonogenarians? What's the outcome in tandem lesion? What's the outcome in different technique we use in the lab? What's the outcome of large infarct sites? Until we find the randomized trial, we can have some signals from those large registry to really inform future randomized trial. Dr. Osama Zaidat:           So that's kind of the scope of the STRATIS Registry. Dr. Negar Asdaghi:         Perfect. So truly a real-life, large cohort of endovascularly-treated patients, allowing us to look at the many aspects of this therapy in real life, rather than in a randomized setting. Dr. Negar Asdaghi:         So, now coming to the current paper, we often think of low ASPECTS as a phenomenon of late presenters. Yet the current paper included endovascularly treated patients in a relatively early time window, within eight hours of symptom onsets. Please walk us through what percentage of your study patients actually had low ASPECTS, and what were their baseline characteristics as compared to high ASPECTS of patients? Dr. Osama Zaidat:           That's an excellent question. STRATIS was basically a core lab adjudicated. So, independent, experienced core lab have read all the angiogram outcomes and have read all the CT scan, all the MRI, so he doesn't know about what's going on at 90 days functional outcome. And we wanted to restrict the analysis to the available baseline CT scan that was evaluated by the core lab, like you mentioned. So, from the 984 evaluable patients, only 763 patients, almost 75%, had the CT scan available for the core lab and the core lab blinded to the functional outcome and blinded to the angiographic outcome have read the ASPECTS. Dr. Osama Zaidat:           So, this is a centrally read ASPECTS score by experienced interpreter that read them. So, 75% has available CT, or 763 patients. From those 763 patients, as a clinical practice out there, 92.5% had an ASPECTS of six to 10, consistent with the guidelines that we all treat on everyday basis. If the CT scan looks good, we treat. STRATIS is consistent with that. 92.5% had an ASPECTS of six to 10, or 706 patients. 7.5%, close to 8%, of the site had enrolled patients with low ASPECTS, or 57 patients have low ASPECTS, zero to five. So, about one out of maybe eight, less than one out of 10 patients, had low ASPECTS at the time the STRATIS was conducted between 2014 and 2016. Dr. Osama Zaidat:           People were following the AHA/ASA guideline, with an ASPECTS of six to 10 the majority of the time, like in the STRATIS. It came up to 92% with ASPECTS and 8%, very low ASPECTS, for example. Dr. Osama Zaidat:           So, kind of really what we like about the STRATIS, the real-life practice tried to adhere to the guideline for most of the time. However, we managed to find good sample size, 57, that people kind of did not necessarily, for one reason or another follow the guidelines. Dr. Osama Zaidat:           And I feel like the first things, when you asked me the second question, the baseline characteristics, is there is a difference between the low ASPECTS group and the good ASPECTS. The first thing, really, that stand out-- the young age. So, the age was 62 years versus almost 69. So there's absolute difference of about seven years between low ASPECTS and good ASPECTS, six to 10 versus less than five. And the P value was significant. The listener can look at the paper, but it was a very statistically significant ASPECTS. Dr. Osama Zaidat:           My feeling and my interpretation to this difference is that the physician felt, even with the low ASPECTS, he wanted to give the younger population a chance and take the clot out and see if they do well. So, I think they were more aggressive to take a low ASPECTS in a young patient than not necessarily offering them a mechanical thrombectomy, which probably mirrors what you do and what I would do in real life. If you have 55 years old and ASPECTS of four, you want to say, "Let me take the clot out and see how the functional status pans out." So, that's one thing. Dr. Osama Zaidat:           The other difference, besides the difference in age, slightly more diabetic in the low ASPECTS, but it didn't reach statistical significance. Slightly less AFib than the ASPECTS of six to 10. What really also makes sense, besides the age, is the stroke scale, the stroke severity scale. The stroke severity scale was higher in the low ASPECTS, which makes sense. The infarct is completed, the patient had a worse stroke scale at baseline. So, their stroke scale was almost 20 versus 17, consistent with literature and the good ASPECTS. So, 17 in the good ASPECTS, the average score, and 20 in the low ASPECTS, slightly higher stroke severity scale. Dr. Osama Zaidat:           What also makes sense in the low ASPECTS is you have more ICAT occlusion. When you have an ICAT occlusion, will lead to loss of collateral, will lead to more tissue, and more core infarct volume with a completed stroke. Dr. Osama Zaidat:           So, I feel like also that's consistent. So, the difference between the baseline characteristic can be summarized with younger age, higher proximal occlusion, and more severe stroke than usual. And then the general anesthesia use was more often because now you have more severe stroke, now you have more core infarct volume, you are more likely to need anesthesia than not. So again, that's also consistent. Dr. Osama Zaidat:           The onset to puncture time, because you may need more anesthesia, the patient was sicker to stabilize, the onset to puncture time was also more prolonged in the lower ASPECTS group versus the good ASPECTS. Dr. Osama Zaidat:           So, those are the differences at baseline, Negar, as you can see. Not sure how you think about it, how you feel about them as well, but kind of the best way to explain them. But I'm curious also to hear your thought about them, if you have any comment or questions. Dr. Negar Asdaghi:         Yeah, I think I want to repeat just what you said and the point you raised because it's, as you mentioned, it is not surprising to see that low ASPECTS patients are presenting with more severe strokes with higher NIH Stroke Scale, have more tandem occlusions or more proximal occlusions. They're obviously sicker patients. So, those differences were not surprising at all to a reader of your paper. What was surprising is that age gap that you mentioned within your low ASPECTS and high ASPECTS category, and that from the registry-based study is actually, exactly what you mentioned, is a signal that clinicians are more comfortable to push the guidelines boundaries in the younger population. That's something that has to be taken with a grain of salt, because we're not talking about a population-based study where we're comparing age groups between low ASPECTS and high ASPECTS. We're talking about a highly selected group of individuals who've already received endovascular therapy, and now we're comparing the age groups depending on their lower ASPECTS. So that's an important distinction that you beautifully outlined for our listeners. Dr. Negar Asdaghi:         Now, coming to your primary outcomes, please tell us about the reperfusion rates in the study and comparing the low to high ASPECTS categories. Dr. Osama Zaidat:           That's an excellent question, to try to see — in spite of you're taking the chances — and treating patients with low ASPECTS. How did they do functionally and angiographically? The angiographic outcome and revascularization success can be a surrogate of functional outcomes. So, let's try to review with your listeners and readers the reperfusion outcome, like you mentioned. If you look at the reperfusion outcome in the paper, and I direct the readers and the listeners to Table 2. Specifically, what stands out is the rate of complete reperfusion because that's the one with the highest difference and significance between the two groups, which is TICI 3. The frequency of obtaining TICI 3 was 83 patients out of 662 that had an angiographic outcome with a good ASPECTS was zero out of the 55 patients; none of them had a TICI 3 complete occlusion. Dr. Osama Zaidat:           What's really astonishing in the result is the fact that there's a statistical difference between complete reperfusion, TICI 3, between the low ASPECTS group and cohort versus the good ASPECTS cohort of six to 10, and the theory and explanation, one of the explanations at least that may be plausible, is the fact that you probably had a good collateral in the good ASPECTS to have less core infarct, and the good collateral reduced the clot length, because the pial flow goes all the way backward into the clot in a retrograde fashion and makes it probably more likely to have a successful removal of the clot and hence achieving a TICI 3. Dr. Osama Zaidat:           So, but overall, if you just lump TICI 2b or higher, the standard definition of successful reperfusion as TICI 2b or higher, there was no statistical difference between the group. It was 85.5% in the low ASPECTS and 87.6% in the good ASPECTS group. So, that was not statistically different. Dr. Osama Zaidat:           When we looked at the first-pass effect, there was a trend toward more first-pass effect in the good ASPECTS group, but 61% and 57% in the low ASPECTS. That's defining first pass as TICI 2b from the first attempt, and not TICI 3, for example. Dr. Osama Zaidat:           So again, you can see that your success of reperfusion probably related to the ASPECTS in an indirect way, as a surrogate of collateral. Poor collateral tissue dies quickly, low ASPECTS and higher core infarct volume, and hence low success of reperfusion, but again, the only statistical significance here is in the complete reperfusion and TICI 3. Dr. Osama Zaidat:           So, if you kind of evaluate if the reperfusion outcome translated to a difference in the functional outcome, yes, indeed. In the low ASPECTS group, three out of 10 patients achieved independence at 90 days, or to be precise, 28.8% of that cohort and population had mRS of zero to two at 90 days in comparison to 59.7% in the good ASPECTS group. Dr. Osama Zaidat:           So, it's almost six out of 10 patients in the good ASPECTS versus three out of 10 patients in the low ASPECTS group. Still, they achieved a good outcome because we don't have a control group, but in comparison to the good ASPECTS, it's lower outcome, as you can see on Table 2, as well. Dr. Osama Zaidat:           The mortality is higher; it's almost 31% in the low ASPECTS versus 13.4% in the good ASPECTS group. The symptomatic hemorrhage rate was 7% versus almost 1% only in the good ASPECTS group. So, functional outcome across the board is lower than the good ASPECTS, but since this is not a randomized trial, we don't know if doing nothing to those low ASPECTS will necessarily yield similar results. Dr. Osama Zaidat:           So, it could be better than control, but clearly it's the likelihood of the patient doing better correlates with a better ASPECTS, which we all kind of already know, but we want to try to identify the group beyond which, like you started, Dr. Negar, beyond which the mechanical thrombectomy may be futile. Dr. Negar Asdaghi:         Right. So a very unfortunate vicious cycle almost, that those who needed the first-pass effect, TICI 3 perfusion the most actually ended up achieving it less than their high ASPECTS counterpart, as you mentioned. And again, it's important to understand that these observations are based on an observational large registry study. Dr. Negar Asdaghi:         Now, you found an important interplay between age and low ASPECTS in the clinical outcomes from thrombectomy in your study. Can you please elaborate on those findings? Dr. Osama Zaidat:           Absolutely. That's an excellent question because that's kind of the unique part of our research and our paper is we're trying to really combine the low ASPECTS with another variable that we all know as a clinician and people who treat stroke on a daily basis, that influence outcome. If you combine two poor predictors of good functional outcome. A good predictor that they could predict the outcome one way or another in either direction, good or bad outcome, you know ASPECTS was one of them, and age. So, we wanted to see if there's a threshold beyond which, if you combine the two, you can identify the patients that are almost less likely to benefit and the resources and the, if you may say, the resources and the message to the patient and their families should be with this consideration to try to provide guidance to the clinician nowadays. Dr. Osama Zaidat:           So, based on the previous data, we kind of wanted to really trichotomize the age into young, less than 65, 65 to 75, and 75. Dr. Osama Zaidat:           There is enough signal in the literature out there that 75 with low ASPECTS is a good cutoff to see. And indeed, we looked at that and we compared those three cohorts. We compared less than 65, 65 to 75, and more than 75 in the low ASPECTS group to see which one stands out. Now, the sample size is fairly small. So, I want to caution the reader and the listener to us today that this is a good signal, this is a good hypothesis-generating result; however, it needs to be reproduced in, again, large sample size and see if other researchers and investigators can have similar results. Dr. Osama Zaidat:           What we've found in this group of more than 75 and less than 65, I feel like the equipoise should remain between 65 and 75, but less than 65 is probably beneficial more than 75. Unfortunately, we could not find a strong signal of good functional outcome in those people more than 75. Dr. Osama Zaidat:           We had 12 patients; none of them achieved (mRS of) zero to two at 90 days, 0% at zero to two. And their mortality was close to 60%, and their symptomatic hemorrhage was close to 15%. So, when you treat a low ASPECTS (zero to five), and they are older than 75, the current data or the current signals suggest that the likelihood of good outcome is 0%, if you consider good outcome as (mRS) 0-2, and the likelihood of mortality close to 60%. More than half of them will die, and the likelihood of symptomatic hemorrhage is going to be higher, close to 16%. Dr. Osama Zaidat:           So, that's the cohort that we have to be very cautious about. I think the younger cohort had even better outcome than the overall zero to five. If you recall, from the previous question of Dr. Negar, discussion that the overall was 28.8%. If you restrict the analysis to the young, they have probably a good plasticity, good recovery, good rehab potential. If you look at those less than 65, their mRS zero to two went up to 44.8%, which is decent, acceptable, functional outcome in those young patients, and their mortality went down from 30% or 31% to 20%, and the symptomatic hemorrhage from 7% to 6%. So, it seems that there is a good signal in those less than 65 for being aggressive and try to provide them with a therapy, less aggressive with 75, and in between, where we really have no clear answer, and their mRS score was close to 20% versus 44 and 0%. So 44%, 18%, and 0%; less than 65, 65 to 75, and older than 75. Dr. Osama Zaidat:           Hopefully, this will shed the light and make the decision-making in the middle of the night probably more informed to the best of our knowledge nowadays. Dr. Negar Asdaghi:         Right. And how do these rates, the symptomatic intracerebral hemorrhage rates and mortality rates, compare in the low ASPECTS group as compared to those reported from the randomized trials? Dr. Osama Zaidat:           This is an excellent question because the randomized clinical trial had the advantage of having a control group, and the HERMES meta-analysis in all patient-level meta-analysis have looked at the CT ASPECTS. However, they combined it with the MRI ASPECTS, so kind of a heterogeneous population. It's not exactly the same, like the STRATIS low ASPECTS study that we're discussing today, and they have a very small sample size. What they found in that group from three to five, that 31%, so almost identical- if you think about -it to our outcome in the ASPECTS group. HERMES group didn't go to the 24 hour; they did up to six hours. Maybe the ESCAPE was 12 hours, the only one with the expanded time window, but interesting that their three to five ASPECTS had a good outcome of mRS zero to two at 31% versus 16% in the tPA group with an absolute difference about 15%. Dr. Osama Zaidat:           So, again, our result is consistent with the HERMES patient-level meta-analysis. However, in the (ASPECTS) zero to two group, they found the futility in the zero to two. They found 0%  (90 day mRS) in the mechanical thrombectomy. We didn't have that much of a sample size of zero to two (ASPECTS), and we didn't obtain a 0% (90 day mRS) similar to them, but we did obtain a 0% (mRS) if you are zero to five (ASPECTS) and older than 75. They have not really looked at the intersection and the interaction with the age like we looked at it, for example. So again, in their trial, the three to five (ASPECTS) is consistent with the ASPECTS with our low ASPECTS trial at 28.8% (90 day mRS) versus 31% in the HERMES meta-analysis, for example. Dr. Osama Zaidat:           MR-CLEAN group, however, even they have a better outcome, zero to four (ASPECTS), than us and HERMES, at about (90 day mRS) 36.7%. Their sample size was very small, less than 30 patients in the whole cohort, almost half the size of our sample size. So MR-CLEAN showed also, so if you think about it, the registry is close to 30% (mRS of 0-2 at 90 days), the randomized trial 31% to 35%. So, we are within the confidence interval of what's the likelihood of good outcome, which is almost one-third of the patients with low ASPECTS would have a good outcome. Dr. Osama Zaidat:           The good news that the standard care therapy with tPA gives you half of that outcome almost. So, there's a good signal that future randomized trial may be positive if they follow the STRATIS registry, HERMES, or MR-CLEAN data. Dr. Negar Asdaghi:         So, Sam, very important information and percentages to keep in mind as we counsel patients and family members, especially those elderly patients we see with large ischemic cores and low ASPECTS in the early timeframe from stroke onset. Dr. Negar Asdaghi:         I know you alluded to the future randomized trials, but I want to end with our takeaway message from your study, and how do you see these randomized trials in low ASPECTS population unfolding in the future? Dr. Osama Zaidat:           I mean, this is an excellent question that has two aspects about it. One is, can we use some of this data to guide us nowadays until we have future randomized trial? And I think each patient is individual, each family's individual family. I want the listener and the readers to take their time to explain the data to the patient. They have to keep in mind that there is a small sample size and also how definitive they feel about their reads with ASPECTS score, how definitive they feel about the large core infract, and is this plus minus one, is five the cutoff, in the elderly? Is it four or zero? Dr. Osama Zaidat:           So, I think if you are confident that your score may be zero to three, and the patient is more than 75, is more justifiable, kind of, at that extreme and to say this is less likely to benefit (from endovascular therapy) based on collective data. Dr. Osama Zaidat:           Again, without randomized trial, it's hard to strongly send a message, don't treat them (endovascularly) and futile. But based on HERMES, based on our analysis, extreme ASPECTS in older than 75, probably you have to be cautious taking them to the (cath) lab, for example. Now that's been said, the future trial will answer that. We are running the randomized trial ourself, myself and my co-PI, Dr. Albert Yoo, are doing an international TESLA trial. We are close to 125 patients randomized from two to five ASPECTS score and up to 85 years of age. So, we have almost 60-plus randomized in each arm, and we are hoping if we continue at this rate in the next two years to complete the enrollment and have some answer. Dr. Osama Zaidat:           Our sample size-it's an adaptive design trial called TESLA Trial--and our sample size is 300 patients. In Germany, there is an ongoing Tension trial. In U.S., there is another trial that mixed a CT scan with the perfusion for large core infarct called SELECT 2. That's ongoing, as well. And then a fourth trial, which is the IN EXTREMIS trial in France, that also going to answer it, and hopefully we can do a meta-analysis among those four large core infarct trials. Dr. Osama Zaidat:           Some of them allowed diffusion MRI, as well as CT scan; some of them allowed perfusion. And this way, if we combine all our data together, we can have probably a more reliable and precise answer to this important clinical question that has been identified by the National Institutes of Health [inaudible 00:36:43] as priority number one for thrombectomy following what we know so far. It's ranked as the next question that needs answer. Dr. Negar Asdaghi:         Dr. Sam Zaidat, congratulations on this work, and we look forward to the completion of TESLA results and the results of other randomized trials. Thank you for being with us today. Dr. Osama Zaidat:           Thank you for having me, and I appreciate the listener tuning in, and I appreciate the ASA and the journal team for having me. This is on behalf of my co-authors, the sponsor of the registry. Thank you very much. Dr. Negar Asdaghi:         Thank you. Now, before we end the July podcast, I want to draw your attention to a special invited report prepared by the Stroke Council Leadership on behalf of the American Heart and Stroke Associations on diagnosis and management of cerebral venous sinus thrombosis, or CVST, with vaccine-induced immune thrombotic thrombocytopenia. Dr. Negar Asdaghi:         This report is to heighten clinicians' awareness regarding the six cases of CVST, with thrombocytopenia in patients who received the Johnson & Johnson vaccine in the United States. Similar thromboembolic events were reported in Europe following the administration of AstraZeneca vaccination. These are adenoviral vector–containing vaccines, which are mechanistically different from the mRNA SARS-CoV-2 vaccines produced by Pfizer and Moderna. Dr. Negar Asdaghi:         The putative mechanism of vaccine-induced thrombotic thrombocytopenia is believed to be related to the leakage of DNA from the adenovirus-infected cells that subsequently binds to the platelet factor 4 and triggers the production of auto-antibodies against platelets. Dr. Negar Asdaghi:         The authors emphasize that while we wait for further research on the causal nature of the relationship of vaccines to CVST with thrombocytopenia, it is important to keep in mind that the reported risk of CVST associated with COVID-19 infection itself is far greater than that associated with vaccination. Dr. Negar Asdaghi:         And with that, we conclude our podcast for the July 2021 issue of Stroke. On behalf of the Editorial Board, I want to thank you all for listening and a special thanks to our healthcare providers and clinicians who continue to work on the front lines of this pandemic. We hope that you find this information useful, and until our next podcast, stay alert with Stroke Alert. 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.
  • Stroke Alert podcast

    Stroke Alert June 2021

    24:45

    Stroke Alert June 2021 On Episode 5 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2021 issue of Stroke: "Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke” and “Body Mass Index in 1.9 Million Adolescents and Stroke in Young Adulthood.” She also interviews Dr. Shyam Prabhakaran, from the University of Chicago, about his article "Predictors of Early Infarct Recurrence in Patients With Symptomatic Intracranial Atherosclerotic Disease." Dr. Negar Asdaghi: 1) Do people with mild cognitive impairment receive the same quality of stroke care as their cognitively normal counterparts? 2) Is there a causative relationship between the alarming rise in adolescent obesity and the rise in the incidence of stroke under the age of 50? 3) What are the independent predictors of radiographic recurrence in patients with symptomatic intracranial atherosclerotic disease? These are the topics that we will cover 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. For the June 2021 issue of Stroke, we have a range of publications that cover a variety of topics from activation of neuroinflammatory pathways and intracerebral hemorrhage to predictors of outcome in patients with mild and rapidly improving ischemic stroke, which I encourage you to review, in addition to our podcast. Later in today's podcast, I have the privilege of interviewing Dr. Shyam Prabhakaran from University of Chicago on his work with various radiographic biomarkers as predictors of outcome in patients with symptomatic intercranial atherosclerotic disease. But first, with these two papers. Dr. Negar Asdaghi:                        In the United States, one in five adults over the age of 65 have mild cognitive impairment, and one in seven have a formal diagnosis of dementia. With our aging population, these numbers are estimated to triple by year 2050. Prior studies suggest that patients with dementia are less likely to receive evidence-based stroke care as compared to those with normal cognition. Less is known about the quality of stroke care amongst patients with mild cognitive impairment. In their paper titled "Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke," Dr. Deborah Levine from Departments of Neurology and Internal Medicine at the University of Michigan and colleagues studied the quality of care in acute ischemic stroke patients with mild cognitive impairment, or MCI, and preexisting dementia as compared to patients with normal cognition. Dr. Negar Asdaghi:                        This was a cross-sectional analysis of prospectively obtained data on adults with acute ischemic stroke included in the Brain Attack Surveillance in the Corpus Christi project from 2008 to 2013. Primary outcome of the study is a composite quality measure of defect-free care calculated by dividing the number of treatments that a patient received by the number of treatments they were eligible to receive. Defect-free care was defined as receipt of seven stroke performance measures when eligible, and included administration of IV tPA, use of antithrombotic therapy by end of hospital day two, administration of DVT prophylaxis, assessment for rehabilitation, discharge on antithrombotic therapy, discharge on lipid-lowering therapy, and discharge on anticoagulation therapy for atrial fibrillation. Dr. Negar Asdaghi:                        Amongst 836 adults included in this study with a median age of 65, 58%, that's over half of the patients in this study, had some degree of cognitive impairment prior to their presenting stroke. 44% of patients with preexisting dementia received defect-free care as compared to 55% with either normal cognition or mild cognitive impairment. The difference, they did not reach statistical significance after adjusting for the sex, vascular comorbidities, and BMI in multivariate analysis. However, preexisting MCI remain an independent factor to be negatively associated with receipt of IV tPA echocardiogram and assessment for rehabilitation. Similarly, after adjusting for all confounders, preexisting dementia remained negatively associated with receipt of antithrombotic therapy by day two, lipid-lowering therapy at discharge, and receiving an echocardiogram. The authors highlighted their findings as a call to action to improve the overall delivery of stroke care and measures to all stroke patients, and caution that disparities noted in their study might contribute to differences in post-stroke outcomes, such as functional disability and recurrent stroke in the growing population of patients with mild cognitive impairment and dementia. Dr. Negar Asdaghi:                        Having a stroke at a young age has profound personal, societal, and economic implications. For the young stroke survivors, a long life expectancy after stroke, and the cost of long-term care pose huge challenges to healthcare systems, which are different than that encountered in the elderly stroke population. Over the past two decades, the incidence of ischemic stroke has substantially increased in the young, with adults under the age of 50 now comprising 10% of all ischemic stroke cases. This comes in parallel with the continuous rise in the prevalence of adolescent obesity in many Western countries, but the association between the two remains unclear. In the current issue of the journal, Dr. Aya Bardugo from the Department of Military Medicine, Hebrew University, in Jerusalem, and colleagues studied the association of adolescent body mass index, or BMI, with first stroke event in young adults as part of a nationwide population-based study of 1.9 million adolescents, followed for a cumulative 9.48 million person-years. BMI values were categorized in five groups of underweight, low-normal, high-normal, overweight, and obese. Dr. Negar Asdaghi:                        So, what they found was that the incident rate of any stroke and ischemic stroke increased gradually across the five BMI categories. Importantly, the hazard ratio for ischemic stroke became significant, even in the high-normal BMI group at 1.4, and increased to 2 for the overweight and 3.5 in the obese category. Though a similar increase in the rate of hemorrhagic stroke was noted, there was no significant association between BMI and hemorrhagic stroke in the study. Not surprisingly, many vascular risk factors, including high blood pressure and diabetes, were also elevated in the higher category BMI adolescents. However, alarmingly, these trends remain significant even after adjustment for age, sex, sociodemographic factors, and when the data was limited to otherwise healthy adolescents, those without diabetes and those without high blood pressure. Overall, the authors found that overweight and obese adolescents had approximately two- to threefold increased hazard for ischemic stroke that could present prior to the age of 30 irrespective of sex, race, ethnicity, and socioeconomic status. Dr. Negar Asdaghi:                        The authors detailed various mechanisms in which increased adolescent BMI may lead to stroke in the young, including progressive risk of large vessel intra and extracranial atherosclerotic disease, increased cardiovascular disease, and a shift to young onset heart failure and atrial fibrillation, as well as a strong association with being high BMI in children and adolescents, and that of obesity in adults. These findings are important observations as we face a growing epidemic of childhood and youth obesity worldwide with the potential to increase the future burden of stroke in young adults. Dr. Negar Asdaghi:                        Intracranial atherosclerotic disease, or ICAD, is an important cause of ischemic stroke worldwide. In addition to neurological deficits caused by index event, patients with ICAD remain at high risk for development of recurrent ischemic events. The risk of clinical recurrence is estimated to be between 12% to 20% at one year based on prior studies, despite best medical management. But recent studies have shown that up to 25% of patients with symptomatic ICAD have evidence of radiographic recurrence on follow-up MRI imaging. Dr. Negar Asdaghi:                        Who will remain stable and who will have more events with symptomatic ICAD is a common question that practicing clinicians struggle with in routine practice. The Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease, or the MYRIAD study, aimed to get us closer to that answer. Joining me now is Dr. Shyam Prabhakaran, Professor of Neurology and Chair of the Department of Neurology at the University of Chicago, who was one of the principal investigators of the MYRIAD study and the first author of the paper in the current issue of the journal titled "Predictors of Early Infarct Recurrence in Patients With Symptomatic Intracranial Atherosclerotic Disease." Good afternoon, Shyam. Thank you for joining us. Dr. Shyam Prabhakaran:              Thank you, and good afternoon to you. Dr. Negar Asdaghi:                        Thank you. Shyam, can you please start by telling us how MYRIAD's design was different from prior studies of symptomatic ICAD? And what were the main objectives of the study? Dr. Shyam Prabhakaran:              Sure, so MYRIAD was conceived as a study to really unravel and study the mechanisms of recurrent stroke after symptomatic ICAD presentation. Prior studies, I think, have really helped in many ways, obviously to understand the natural history of the disease, including through clinical trials, where we learned about the different interventions that could be applied, medical and endovascular, through WASID and then SAMMPRIS. However, both of those studies, which provided probably the bulk of information about the disease in multi-center study, did not really focus on mechanisms, per se, understanding it through biomarkers, understanding whether certain subsets of patients have higher or lower risk of recurrence. So, MYRIAD was conceived to try to tackle that particular aspect of research that we felt was understudied. Dr. Negar Asdaghi:                        Yes, thank you. Traditionally, as you mentioned, the location and the degree of stenosis have been considered as important radiographic factors to predict outcomes in symptomatic ICAD. MYRIAD looked at many more imaging biomarkers than just degree of stenosis and the location. Can you please elaborate on those radiographic biomarkers that were included in MYRIAD? Dr. Shyam Prabhakaran:              Yeah. So, again, MYRIAD wanted to explore these imaging biomarkers, and we split them into three categories. One was biomarker of antegrade flow. What would help us understand the amount or volume of flow through a particular diseased artery? And we used quantitative MRA for that, which is a technique that's been around a long time, a phase contrast MR approach, to get vessel-specific flow measurements. And aim two thought of the distal flow beyond the stenosis and aimed to look at two types of imaging biomarkers that might answer the question of flow in the distal territory, one through perfusion imaging. So looking at CT or MR perfusion, but MR was the one that we selected, where we would measure the tissue flow through Tmax measurements, and then the other using TCD, transcranial Doppler, and vasomotor reactivity testing of the distal arterials. So that was aim two. Can we look at those biomarkers potentially as predictors of recurrence? And then the third was emboli detection, so the plaque vulnerability or instability biomarker. So, could we look at distal emboli in the territory and assess its role in predicting recurrence? So, those were really the main biomarkers tied to the objectives of the grant. Dr. Negar Asdaghi:                        Perfect. So, obviously, great, and a comprehensive various biomarkers looking at different imaging predictors of early recurrence. We're excited to hear about your primary results. So, what did your study find? Dr. Shyam Prabhakaran:              So, in MYRIAD, we enrolled 105 subjects who had symptomatic intercranial stenosis at 10 centers across the US. And we were able to track them for both the primary outcome, which was stroke in the territory of the stenosis, clinical stroke at one year, and the secondary outcome, which was radiographic occurrence of new infarcts on six- to eight-week MRI. So that was a prespecified outcome. In the primary analysis of the clinical outcome, we did find a fairly high rate of recurrent events. Roughly 10% of patients in the cohort had a recurrent clinical event at one year, consistent with findings from, say, SAMMPRIS, which with maximum medical or aggressive medical management found a roughly 12% recurrence. So, we were able to confirm that there is a high rate of clinical recurrence. However, none of the biomarkers that we were looking at, quantitative MRA, profusion imaging, transcranial Doppler for BMR or emboli detection were predictors of the clinical outcome at one year. So, that was our main results. Dr. Shyam Prabhakaran:              Our secondary outcome was recurrent infarcts on study-specific research MRIs performed at the sites, and looked for recurrences compared to baseline MRIs that were performed at the time of their index stroke or TIA. So, in this paper, we were really interested in looking at whether there were any specific predictors of recurrent radiographic infarct, and that really was an interest of ours because we did find such a high rate of radiographic recurrence. Roughly 24% of our cohort had a recurrent infarct on brain imaging at six to eight weeks. So, we recognized right away that this is potentially an unrecognized phenomenon, that there's potentially an excess of radiographic events to clinical events. And there could be, obviously, a potential consequence of this radiographic accumulation of disease. Particularly, it might be important to prevent those radiographic occurrences in the future if they are affecting an individual's performance on cognition or even physical function as a result of accumulating lesions. So, we were really interested in seeing whether there were some early predictors of this six- to eight-week recurrence that we saw at a high rate. So, the paper looked at clinical factors, as well as imaging factors, that were available in the MYRIAD cohort, really trying to delve into a model that we could use to identify a subset that is at the highest risk of these early recurrent infarcts. Dr. Negar Asdaghi:                        Right, so very, very important findings. So, just to reiterate for our listeners, one in four patients in your study had evidence of radiographic recurrence despite clinically seemingly having no clinical events. So, this clinical radiographic dissociation would have absolutely gone unnoticed had it not been for these early MR images that were performed in the study. So, I want to clarify this from a pathophysiological standpoint. Is it hypoperfusion, plaque rupture, or both? Based on your results, what is the driving factor in development of new ischemia in symptomatic ICAD? Dr. Shyam Prabhakaran:              So, one of our main findings here, which is reported in this paper, is that those with multiple infarcts at their index stroke, so a pattern on diffusion-weighted imaging that was more than a singular infarct lesion, was a strong, independent predictor of having a recurrent event, recurrent infarct at six to eight weeks. And the part that isn't really highlighted in the paper, but is true, is the other factor that was co-mingled with multi-lesion, multi-infarct and index was borderzone pattern. They were co-linear, and they were essentially the same patients who were borderzone also had multiple lesions. So, one way we've interpreted this, and I can speak to a little bit about the different biomarkers that were studied in addition to the infarct pattern, but one way we've interpreted this is that multi-lesions can probably fall under two subsets. Dr. Shyam Prabhakaran:                           It could either be in this borderzone pattern, where you have multiple lesions due to hypoperfusion mechanisms, typically within either cortical or internal borderzones. And that may be then telling us about a mechanism of low flow. On the other hand, some of these patients could also have scattered lesions that are embolic in etiology and suggest a plaque that was unstable and potentially showered at their index event, resulting in that pattern that we saw. So, both of them probably are mixed in. We're favoring the borderzone because they were so co-linear that that probably was the more likely mechanism. And we're probably concerned that that could also be a factor that leads to early recurrence because flow failure typically is associated with critical hypoperfusion and imminent recurrence. Dr. Shyam Prabhakaran:              But, interestingly, in the paper, we talk about this, none of the specific prespecified biomarkers that were looking at flow, perfusion imaging, vasomotor reactivity were significant by themselves as predictors of recurrent infarct. So, it's a little hard for us to know why. It could be that the technology that we use, perfusion imaging, is still not quite picking up the kind of flow failure that we need to. Maybe it's more subtle than even we found because we looked at different cut points of Tmax and other parameters on perfusion imaging, and yet, we're not able to find a cutoff that was predictive, likewise with vasomotor reactivity. So, it could be that those are not quite good enough surrogates of hypoperfusion. And yet, borderzone or multi-infarct patterns may have been a surrogate of hypoperfusion. So, I think the short answer here is that it could be both mechanisms, plaque instability and hypoperfusion, although we're maybe favoring hypoperfusion because there was a strong co-linearity with borderzone pattern. Dr. Negar Asdaghi:                        Understood. Now Shyam, recurrent events on maximum medical therapy, this is not what we like to hear. Where do you see the future of symptomatic ICAD therapy? Now in your view, is there a role for interventional treatment or other therapies in a select group of ICAD patients? Dr. Shyam Prabhakaran:              I think that's really where we still face real challenges. I think the work done by many of the investigators before us on maximum medical therapy and interventional therapies have found, obviously, that there are some benefits to the medical approaches that we now consider standard of care. The dual antiplatelet therapy, the lipid-lowering therapy, the lifestyle management that SAMMPRIS also implemented and successfully showed some benefits of physical activity. So, those things clearly matter. And yet, the clinical event rate is still very high, and the radiographic event rate is even higher. So, you have this real challenge facing clinicians and patients of a disease that has a very high rate of recurrence, much higher than the other subtypes of ischemic stroke, and certainly higher than, say, AFib patients even, where we sometimes obviously are concerned and adopt strategies to lower risk. So, we are in a position, I think, today where we have to go back to the well and think about novel strategies. Dr. Shyam Prabhakaran:              Now, flow is a component of this, and I do think that SAMMPRIS, albeit now almost a decade ago, tested an interventional approach. It may be worth revisiting interventional strategies. Of course, we know from endovascular therapy for ischemic stroke, try once and fail, and try again, and you might find a different result because technologies get better, practitioners, proceduralists get better. So, that's one angle that I think people are very interested in, is whether or not an interventional approach for flow failure patients is a path forward. And that, I think, will get a lot of attention in the years to come with new studies that are being designed. Dr. Shyam Prabhakaran:              I think the other important point here is that aggressive medical management in the current day and age may still have room for improvement. Maybe the drugs that we're using, especially with DAPT and lipid-lowering therapies, they're not as quick or necessarily universally responsive for every patient. So, we know that about clopidogrel, that there's a certain rate of non-responders. We could probably do better than that with other choices, antiplatelet choices or even anticoagulant choices, which are being considered. And we know that lipid-lowering therapy with statins works well, but perhaps PCSK9 drugs could be considered in this population to lower cholesterol levels even more rapidly and more aggressively. So, all of these, I think, should be on the table as we move forward. Dr. Negar Asdaghi:                        Dr. Shyam Prabhakaran, thank you for joining us on the podcast today. We look forward to having you back here and covering more of your work in the future. Dr. Shyam Prabhakaran:              Thank you for having me. Dr. Negar Asdaghi:                        Thank you. And this concludes our podcast for the June 2021 issue of Stroke. Please be sure to check out the June table of contents for the full list of publications, including an important update from the American Stroke Association and the Stroke Council on how cerebrovascular disease is expected to temporarily fall from the fifth to the sixth leading cause of death in the United States in 2020. Sadly, this is not because of advances in stroke prevention and therapies, but rather because mortality from COVID-19 will displace stroke as a leading cause of death, a grim reminder of the year we put behind us and the many lives lost to this global pandemic. And yet we look ahead with hope, and with the promise that science has the power to resolve and the ability to push the human race forward. Every small step, every question will get us closer to learning more, answering more and knowing more. So, as we end this podcast today, we look forward to asking more at our next, and our promise to stay alert with Stroke Alert. 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.
  • Stroke Alert podcast

    Stroke Alert May 2021

    21:29

    On Episode 4 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two featured articles from the May 2021 issue of Stroke: “Association of Serum IL-6 With Functional Outcome After Intracerebral Hemorrhage” and “SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group.” This episode also features a conversation with Dr. Alvaro Garcia-Tornel Garcia-Camba to discuss his article “Ischemic Core Overestimation on Computed Tomography Perfusion.” Dr. Negar Asdaghi: 1) Can a pro inflammatory marker predict the hematoma size and clinical outcomes in patients with intracerebral hemorrhage? 2) What are the characteristics of stroke patients infected with coronavirus? 3) Is ischemic core reliably represented by the current established cerebral blood flow thresholds on CT perfusion imaging? Or are we underestimating the importance of perfusion overestimating the ischemic core? We will discuss these topics in today's podcast. You're listening to 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. For the May 2021 issue of Stroke, we have an exciting program today, as we cover topics from the predictive role of inflammatory markers in intracerebral hemorrhage to characteristics of stroke patients infected with SARS-CoV-2 virus. Later in the podcast, I have the privilege of interviewing Dr. Alvaro Garcia-Tornel Garcia-Camba from Autonomous University of Barcelona on the topic of ischemic core overestimation by CT perfusion imaging. I hope you enjoy our podcast. Dr. Negar Asdaghi:                                     Intracerebral hemorrhage is an aggressive form of stroke with high morbidity and mortality rates. Increased systemic inflammation may be correlated with more severe neurological presentation, larger hematoma volume, and worse clinical outcome in these patients. Elevated levels of interleukin 6, or IL-6, have been found in the experimental models of ICH and may represent a therapeutic target to reduce the inflammatory response in ICH if similar findings were replicated in clinical studies of patients with ICH. Dr. Negar Asdaghi:                                     In the May issue of the journal, in the study titled “Association of Serum IL-6 With Functional Outcome After Intracerebral Hemorrhage,” Dr. Kevin Sheth from Department of Neurosurgery at Yale University and colleagues performed a pre-specified exploratory analysis of the patients enrolled in the FAST trial, testing the association of admission levels of serum IL-6 with baseline neuroimaging and functional outcome at 90 days. Dr. Negar Asdaghi:                                     But just a reminder for our listeners that FAST trial was a multicenter randomized trial of the recombinant factor VIIa administered in two doses versus placebo in patients with spontaneous nontraumatic intracerebral hemorrhage presenting within three hours of symptom onset. Dr. Negar Asdaghi:                                     So, in the current analysis, amongst 841 patients enrolled in the trial, 66% were included who had both baseline IL-6 measurements and the follow-up modified Rankin Scale on day 90. Patients were stratified into four quartiles based on their admission IL-6 serum levels from low/normal in quartile one to very high levels in quartile four. And their baseline characteristics, neuroimaging and outcomes were then compared. Dr. Negar Asdaghi:                                     So, what they found is that patients with a poor outcome, defined as modified Rankin Scale of four or higher at 90 days, had a higher median admission IL-6 level than those with a favorable outcome. In their multivariate analysis, for each one nanogram per liter increase in IL-6 level, there was a 30% increase in the odds of a poor functional outcome after adjustment for various factors, such as age, intracerebral hemorrhage volume, baseline Glasgow Coma Scale, presence of intraventricular hemorrhage, hematoma expansion, ICH location, and recombinant factor VIIa treatment allocation. Dr. Negar Asdaghi:                                     So, a higher IL-6 level at baseline was also found to be independently associated with higher baseline hematoma volume and was a predictor of perihematomal edema, an association that was stronger in patients with lobar rather than subcortical  ICH. Dr. Negar Asdaghi:                                     Now, whether there is a causal relationship between IL-6 and outcomes in ICH, and importantly, whether the growing number of anti-IL-6 therapies have a role in the reduction of inflammation and improvement of clinical outcome in this population, are important subjects to consider and study in the future. So please stay tuned. Dr. Negar Asdaghi:                                     We now move on to our next paper, examining the characteristics of stroke in COVID-positive patients. In the study titled “SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group,” Dr. Ramin Zand from Geisinger Neuroscience Institute and colleagues from across the globe examine the characteristics of COVID-infected patients with neuroimaging-confirmed stroke from 71 centers across 17 countries. Patients were included in the study if presented to the hospital with stroke-related chief complaints and asymptomatic COVID infection, or had a stroke while being hospitalized for COVID, or patients with stroke-related admission who had confirmed prior diagnosis of COVID infection. Dr. Negar Asdaghi:                                     A total at 432 stroke patients were included in the study. 75% of those had acute ischemic stroke, 21% with intracerebral hemorrhage, and the remainder had cerebral venous sinus thrombosis. The authors found that, in general, stroke characteristics and subtypes were different in COVID-infected patients as compared to non-COVID stroke patients based on the prior population-based studies for both ischemic and hemorrhagic stroke. Notably, amongst COVID-infected patients with acute ischemic stroke, a third had only asymptomatic COVID. They had an overall male predominance with a young median age, and that a quarter of ischemic stroke patients were younger than 55 years of age, and a similar percentage had no known identifiable vascular risk factors. Among those with available vascular imaging, close to 50% had evidence of a large vessel occlusion on vascular imaging. In considering the etiology of stroke as defined by the TOAST classification, only 10% of COVID-positive stroke population had small vessel disease in contrast to typically 30% of the general ischemic stroke population. Dr. Negar Asdaghi:                                     Now, when considering the hemorrhagic stroke, despite smaller number of patients included in the study, similar differences in general classification of hemorrhagic stroke patients was noted. Specifically, 25% of hemorrhagic strokes had evidence of subarachnoid hemorrhage, over two thirds of which was non-aneurysmal, a much higher percentage than that reported amongst non-COVID infected patients. A third of hemorrhagic strokes in this population is related to cerebral venous sinus thrombosis, an observation that is in keeping with the general notion that COVID infection can create a hypercoagulable state. Dr. Negar Asdaghi:                                      In summary, this study adds to the growing literature regarding the complex interplay between COVID infection and vascular disease, and the importance of understanding how this virus may play a role in clinical presentation of stroke. Dr. Negar Asdaghi:                                      Various imaging modalities, including diffusion-weighted imaging, MR perfusion, and CT perfusion, are used to define the extent of ischemic core in patients presenting with acute ischemic stroke. In contrast to restrictions and delays associated with acquisition of an MRI study in the acute setting, CT perfusion is readily accessible with relatively fast acquisition times and is easily incorporated in the stroke-alert workflow. As a treating stroke neurologist, you make the decision not to proceed with endovascular therapy in an otherwise eligible patient due to presence of a large volume of ischemic core, as measured by CT perfusion, only to find out that perfusion overestimated the ischemic core. How often do we encounter this scenario? And what are the factors associated with ischemic core overestimation as determined by CT perfusion? Joining me now is Dr. Alvaro Garcia-Tornel Garcia-Camba from Autonomous University of Barcelona, who's the first author of the study titled “Ischemic Core Overestimation as Measured by CT Perfusion: Collateral Status, Time and Its Interaction.” Good afternoon, Alvaro. Thank you for joining us from Barcelona. Dr. Alvaro Garcia-Tornel Garcia-Camba: Good afternoon, Negar. It is a pleasure to be interviewed in a Stroke Alert Podcast to talk about our work with you. Dr. Negar Asdaghi:                                      Great, Alvaro. Endovascular treatment is routinely offered to patients with a target intracranial occlusion, or between 6 to 24 hours from symptom onset, or those without a known time of onset if they're determined to have a small ischemic core. Can you walk us through the evolution of stroke endovascular therapies from time-based to imaging-based decision-making, please? Dr. Alvaro Garcia-Tornel Garcia-Camba: Yeah, well, I remember when I started my neurology training, that was nearly 10 years ago, that the most important biomarkers that we took into account in decision making was time and stroke severity. For decades, time had been the tool to select patients for thrombolysis. It was no different for patients that were considered for endovascular treatment at the beginning. And we did a variety of scales and scores for acute stroke infarct assessment on non-contrast CT and MRI, like ASPECTs score and the routine use of non-invasive angiographics tests for the selection of patients with large vessel occlusion and the new generation stent-retrievers, and in basic framework for patient selection started to grow, and this led to positive progress for endovascular treatment trials back in 2015. Perfusing imaging developed in parallel with SWIFT-PRIME and EXTEND-IA being the early window trials that used perfusion imaging to select patients for endovascular treatment, with the aim to estimate the ischemic core, the already infarcted tissue, and penumbra, the ischemic tissue that is still viable if reperfusion is achieved, on computed tomography perfusion as an effort to mimic the accuracy of diffusion imaging MRI core estimation. Multiple studies for the development of thresholds applied to computed tomography perfusion role data to estimate core and penumbra using diffusion imaging as the gold standard. And the mismatch concept was the finite and it was successfully applied in the extended window that was above six hours in DEFUSE 3 trial. Dr. Alvaro Garcia-Tornel Garcia-Camba: And DAWN trial, the other late window endovascular treatment trial, used a slightly different approach using the core clinical measurements, taking into account clinical severity and age rather than the penumbral tissue to select patients for endovascular treatments. Both the studies had positive results and a number needed to treat comparable to early imaging trials. And we have learned in the past years that time is one of the most important prognostic factors in patients with an acute stroke. But the clock runs at different speeds depending on the specific patient that we evaluate. Tissue analysis on imaging is the way to calibrate this state. Dr. Negar Asdaghi:                                      Thank you, Alvaro, for this nice review of the literature. Can you please tell us about the concept of ischemic core overestimation, specifically by CT perfusion? What was known in the literature before, and what prompted you to look into this in more detail in the current study? Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, we consider ischemic core overestimation is present when the estimated score by computed tomography perfusion imaging is actually larger than the real core, which is the not salvageable tissue at the time of imaging. Most of the studies that have focused on computed tomography perfusion accuracy considered both types of error, that the estimated score is larger or smaller than actual real core normal using diffusion imaging as the ground truth. We wanted to focus on overestimation because of two reasons. The first one is because it might deny endovascular treatment for patients in which reperfusion might lead to better outcomes. And because the ground truth is that the core should increase its size over time, not decrease. The study that prompted me to further investigate on this concept was an article that was published back in 2017, that is ghost infarct core concept that it was published by the unit that I work in nowadays. Dr. Alvaro Garcia-Tornel Garcia-Camba: And this is the two main factors succeeded with overestimation. In this case was slightly different because they consider core overestimation to be when the estimated core was 10 milliliters larger than the follow-up infarct where reperfusion that was achieving more than 50% of reperfusion after endovascular treatment for more than mTICI 2B or earlier imaging in time. We consider the main limitation of this specific study was the small size because it only included 70 patients. And that the software used for computed tomography perfusion analysis was not as validated at this time as RAPID is, the one that is used in our actual study. Dr. Negar Asdaghi:                                      Right. Now, very important concept to keep in mind, especially because RAPID is now used worldwide everywhere in many institutions. And as you mentioned, we make therapeutic decisions based on volumetric assumptions of ischemic core that's given to us by RAPID. Alvaro, we're excited to hear about your study. Can you please tell us about your patient population, and how you define ischemic core and CT perfusion, and what measures were used to determine the final ischemic volume in your study? Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, we included 407 patients from a single center retrospective database that was from 2014 to 2019. They had to have an anterior circulation intracranial large vessel occlusion, including in portions of M1, M2 of middle cerebral artery or terminal intracranial carotid artery occlusion. And they had to have baseline computed tomography perfusion, and they must have achieved reperfusion after endovascular treatment that we have defined as mTICI 2B at the end of the procedure, with a follow-up non-contrast CT at 24-48 hours, in order to measure the final infarct volume. Dr. Alvaro Garcia-Tornel Garcia-Camba: Patients with unwitnessed stroke onset were included, and the estimated core and hypoperfusion intensity ratio that it's a perfusion imaging output that it strongly correlates with collateral flow were determined using RAPID automated software with default thresholds. That is a relative reduction of cerebral flow below 15%* as compared to contralateral hemisphere for estimated core and the ratio of tissue with a Tmax delay above 10 seconds in areas with a Tmax delay above six seconds for hypoperfusion intensity ratio. Dr. Alvaro Garcia-Tornel Garcia-Camba: The final infarct that was the ground truth for comparison was calculated as the mean from two observers’ measurements using a semiautomatic method for non-contrast CT and patients with a parenchymal hemorrhage type 2 hemorrhagic transformation on follow-up imaging were excluded from the analysis. Ischemic core overestimation was considered when estimated core was larger than final infarct volume. Dr. Negar Asdaghi:                                      Perfect. Can you please tell us about the main findings of the study? Dr. Alvaro Garcia-Tornel Garcia-Camba: We found out that ischemic core overestimation is a phenomenon that is more prevalent in patients with earlier window time and that the influence of poor collateral status are measuring using hypoperfusion intensity ratio with a cutoff point of 0.4. Previously as stated to discriminate between good and [inaudible 00:16:02] collaterals was stronger in patients with earlier window time. Patients with poor collateral status in the first four hours window had twice the odds of ischemic core restoration, as compared to patients that presented above four hours from symptom onset. Dr. Negar Asdaghi:                                      Very interesting, Alvaro. CT perfusion overestimated the volume of ischemic core in 20% of your study population. What was the median volume of core overestimation, and what were the factors associated with this overestimation in your multivariate analysis? Dr. Alvaro Garcia-Tornel Garcia-Camba: 83 patients presented with ischemic core overestimation. The median volumetric overestimation was 12 milliliters with an interquartile range of 56 milliliters. Apart from hypoperfusion intensity ratio and time from onset to imaging, terminal internal carotid occlusion location and complete reperfusion that was more than 90% of the people with modified TICI 2C–3 were independently associated with ischemic core overestimation on multivariate analysis. Within the [inaudible 00:17:12] and independent association with time from imaging to reperfusion, a variable that had been previously reported to influence the accuracy of core overestimation on computed tomography perfusion, and we believe that differences in baseline characteristics between the studies and the low variability in imaging reperfusion time in the core will explain why it was not statistically significant. Dr. Negar Asdaghi:                                      Very important findings, Alvaro. Just reminding clinicians to pay attention to factors such as location of the occlusion and, as you mentioned, the hypoperfusion intensity ratio, in addition to the volume of the tissue with relative cerebral blood flow of less than 30% to define the ischemic core. So, definitely many important learning factors for all of us here. Alvaro, I want to finish by just a question that in routine clinical practice, CT perfusion is not commonly performed in those under six hours. And yet ischemic core overestimation seems to be a phenomenon most notably found in earlier presenters. So, what is the clinical implication of the ischemic core overestimation by CTP in late presenters? Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, the rate of ischemic core overestimation was low in patients presenting above four hours from symptom onset. And I do not personally believe that clinically relevant overestimation is present in late presenters with witnesses at the stroke onset. Nonetheless, a high proportion of this population with late presentation do not actually have a clear symptom onset times. And it was witnessed in this group of patients, they [inaudible 00:18:46] not to perform in the vascular treatment for a large score on CTP only should be carefully taken given the results of our study. As taken solely in accountable volumetric estimation of core on computed tomography perfusion might lead to deny treatment to patient that could benefit from it. Dr. Negar Asdaghi:                                      Very important, Alvaro. Again for our listeners, keep that ischemic core overestimation in mind when relying on CT perfusion in waker-upers and those with ischemic stroke of unknown time of onset. So, Alvaro, please tell us what's the most important takeaway message from your study, and what does the future hold for you in terms of your research? Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, it's a global message. I believe that contemporary perfusion imaging construct is based on fixed thresholds to estimate ischemic core. Those thresholds rely on [inaudible 00:19:37] patients with relatively small cores and early imaging. These models might have overfitted to those specific population characteristics. Different studies, including ours, have pointed that the accuracy of computed tomography perfusion core estimation is dependent on many variables. Some of them are known at the time of imaging, like degree of the perfusion after endovascular treatment or time from imaging to reperfusion. In order to improve our prediction accuracy for both core and prognosis estimation, further research should be focused on a multi-parametric approach that takes into account both clinical and imaging parameters, not only imaging parameters. Dr. Negar Asdaghi:                                      Dr. Alvaro Garcia-Tornel Garcia-Camba, thank you for joining our podcast, and we look forward to covering more of your work in the future. And this concludes our podcast for the May 2021 issue of Stroke. Please be sure to check out the May table of contents for the full list of publications, including original contributions on clinical and basic and translational sciences, brief reports, editorials, comments and opinions, and much more. And remember that every breakthrough in science started somewhere from an idea that was then cultivated with care, determination, perseverance, and collaboration. A simple idea that someone might've heard somewhere in passing or on a podcast. So, keep working on your ideas, and until our next podcast, stay alert with Stroke Alert. *Dr. Alvaro Garcia-Tornel Garcia-Camba confirmed following the interview that “15%” should be “30%.”
  • Stroke Alert podcast

    Stroke Alert April 2021

    21:20

    On Episode 3 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two featured articles from the April 2021 issue of Stroke. This episode also features a conversation with Dr. Simon Nagel, from Heidelberg University in Germany, to discuss his article “Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.” Dr. Negar Asdaghi:                       1) Is Andexanet a cost-effective treatment for the reversal of coagulopathy in factor Xa-associated intracranial hemorrhage? 2)  Are statins safe and efficacious in secondary prevention of stroke in the elderly population? 3)  What are the predictors of futile recanalization amongst successfully treated patients with endovascular therapy? We have the answers to the above and much more in today's podcast. You're listening to 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. For the April 2021 issue of Stroke, we have an exciting program today where I have the privilege of interviewing Dr. Simon Nagel from Heidelberg University in Germany on predictors of failure of early neurological improvement or futile recanalization after successful thrombectomy. But first I want to review these two interesting articles. Dr. Negar Asdaghi:                       Factor Xa inhibitors, such as apixaban, edoxaban and rivaroxaban, are commonly used for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Bleeding is a serious adverse consequence of treatment with anticoagulants, including factor Xa inhibitors, with intracranial hemorrhage representing the most devastating form of such adverse events. Dr. Negar Asdaghi:                       Anticoagulant-associated intracranial hemorrhage typically results in larger hematoma volumes, higher risk of expansion, and worst clinical outcomes as compared to their spontaneous counterparts and requires immediate reversal of coagulopathy. Andexanet alfa is a recombinant modified factor Xa protein which is an effective antidote to reverse this coagulopathy, though it comes with an increased risk of thromboembolic events, either from Andexanet itself or delayed or lack of resumption of anticoagulation in the setting of intracranial hemorrhage. Dr. Negar Asdaghi:                       It is important to note that the estimated cost of Andexanet is between $25-50,000 US dollars, depending on the standard versus high dose used, and this medication is currently not available in many countries, including in Canada, and even in the United States, it's still not accessible in many centers mainly due to its high cost. Now, when Andexanet is not available, the non-specific antidote of prothrombin complex concentrate, or PCC, is used, carrying an approximate cost of $4-8,000 US dollars, depending on the dosage used. Dr. Negar Asdaghi:                       PCC, which is a combination of various clotting factors, together with protein C and protein S, have a limited efficacy and reversal of Xa inhibitors coagulopathy. In the absence of randomized control trials to directly compare Andexanet to PCC, there remains a significant gap in knowledge with regards to comparative efficacy, adverse events, and cost-effectiveness of these therapies for life-threatening bleeding, specifically intracranial hemorrhage, in the setting of Xa inhibitor use. Dr. Negar Asdaghi:                       In the current issue of the journal, Dr. Andrew Micieli and colleagues from the Division of Neurology, Department of Medicine, Universities of Toronto and Calgary, in Canada, did a comparative analysis between Andexanet and PCC in a study titled “Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Factor Xa-Associated Intracranial Hemorrhage.” Using a patient population on chronic factor Xa inhibitor treatment, when presenting with an intracranial hemorrhage, the authors applied a probabilistic Markov model over a lifetime horizon for each patient to evaluate the cost and benefits if either Andexanet or PCC was administered to reverse the coagulopathy. Dr. Negar Asdaghi:                       Estimates of outcomes, dosing, and administration protocols for Andexanet were derived from the ANNEXA-4 study and from the UPRATE study for the PCC. These are two previously published large cohorts of treatment for these agents, respectively. Dr. Negar Asdaghi:                       So, what they found was an overall reduction in the occurrence of fatal intracranial hemorrhage with Andexanet therapy, estimated around 18%, as compared to PCC, estimated at 34%, specifically if the antidote was administered in the first cycle, which is the first 30 days following intracranial hemorrhage. This, of course, came at a cost of a higher thromboembolic event rate measured as composite outcome of myocardial infarction, TIA stroke, deep vein thrombosis or pulmonary embolism of approximately 10% in the Andexanet-treated group as compared to 5% in the PCC-treated group. Dr. Negar Asdaghi:                       Now, the cost analysis of the study is very interesting. The authors found that Andexanet, for its incremental effectiveness in gaining quality-adjusted life year, had an incremental cost over PCC. This cost-effectiveness ratio was close to $220,000 US dollar per quality-adjusted life year gain for Andexanet. Dr. Negar Asdaghi:                       And as such, as things stand today, this therapy is not cost-effective and represents low value for reversal of factor Xa–associated intracranial hemorrhage over the standard of care, which is PCC. So, this study provides an important insight, not only for the physicians, but also for health policymakers, as they critically evaluate the merits of Andexanet therapy compared to the current standard of care. Dr. Negar Asdaghi:                       So, moving on now from oral anticoagulants to statin therapies and other medication commonly used in the secondary prevention of ischemic stroke, the second article we will discuss today in our podcast looks at the use of statins poststroke in the elderly population. About a third of stroke patients are over the age of 80, and with the aging population and increased life expectancy, this proportion is estimated to double by year 2050. Dr. Negar Asdaghi:                       Stroke survivors who are over the age of 80 have increased 30-day and one-year mortality rates and remain at higher risk for recurrent cardiovascular events as compared to their younger counterparts. Statin therapy has been shown to reduce the risk of composite cardiovascular events in stroke survivors, but randomized data regarding their safety and efficacy in the elderly population is limited. Dr. Negar Asdaghi:                       Treatment with statin is not without its own challenges in the elderly population. These patients are more likely to be on multiple medications that can interact with statins, and there's also some evidence that the frail population may be more prone to statin side effects such as muscle pain, risk of rhabdomyolysis, increased blood glucose levels, increased risk of diabetes, and liver problems that have all been reported in the setting of statin use. Dr. Negar Asdaghi:                       In this issue of the journal, Drs. Lefeber and colleagues from the Department of Geriatrics in Utrecht University in Utrecht, Netherlands, study this subject in their paper titled “Statins After Ischemic Stroke in the Oldest: A Cohort Study Using the Clinical Practice Research Datalink Database.” This was a retrospective analysis of over 5,900 patients aged 65 years and older who were hospitalized and then discharged for a first ischemic stroke during a 17-year study period from 1999 to 2016 who were not on statin prescription in the year prior to their index hospitalization. Dr. Negar Asdaghi:                       The authors compared the primary outcome, which was a composite of recurrent stroke, myocardial infarction, and cardiovascular-related mortality, within the elderly patients, those over the age of 80, to the younger population, those over 65 but under 80 years of age, based on the number of years that they had a statin prescription poststroke. That is comparing at least two years of statin prescription time with no statin treatment or less than two years of prescription time compared to no treatment at all. Dr. Negar Asdaghi:                       So, what they found was that 53% of their population were actually over the age of 80, and in over half of these elderly patients, a statin was prescribed within 90 days of the index date. And not surprisingly, 38% of this elderly population had moderate to severe frailty, an index that has been linked to statin intolerance and its common myalgia side effect. Now, in terms of their main finding, more than two years of statin prescription compared to no statin prescription was significantly associated with a lower risk of the primary endpoint for both the over and the under 80 age groups. Dr. Negar Asdaghi:                       This association remained true in their adjusted model, not only for the primary outcome, but also for all-cause mortality rates, which was significantly lower in the statin-treated patients. After a correction for the mortality rate of close to 24% during the first two years, the number needed to treat for reduction of composite recurrent stroke, myocardial infarction, and cardiovascular-related mortality was 64 and the number needed to treat for reduction of all-cause mortality was 19 in the group over 80 on a statin prescription during a median follow-up of 3.9 years. Dr. Negar Asdaghi:                       So, in the absence of data from randomized controlled trials, this study provides reassuring results regarding the efficacy of statins in reduction of cardiovascular events in the patients aged 80 and older, keeping in mind that a third of the elderly population in the study was significantly frail, at risk for development of possible statin-related adverse effects. Dr. Negar Asdaghi:                       Much has changed in the field of reperfusion therapies since the publication of the positive results of the thrombectomy trials in 2015. Advances in patient selection processes, rapid access to advanced neuroimaging, the use of newer generations of thrombectomy devices, and improvement in systems of care have all played important roles in the growing success of endovascular therapy. Dr. Negar Asdaghi:                       But even with today's rigorous selection criteria and fast thrombectomy timelines, there remains a significant proportion of endovascularly treated patients in whom the successful radiographic recanalization do not translate into early neurological improvement. In our previous podcast, we report how the odds of favorable outcomes with thrombectomy decreases with an increase in the number of retrieval attempts during the procedure amongst successfully recanalized patients. Today, we dive deeper and look into other independent variables that may predict odds of futile recanalization. Dr. Negar Asdaghi:                       Joining me now is Dr. Simon Nagel from Department of Neurology at Heidelberg University Hospital in Germany, who is the senior author of the study titled “Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.” Good morning, Simon, and thank you for joining us. Dr. Simon Nagel:                           Good morning, or even good evening, from Germany. Thank you, Negar. It's a pleasure to be here, of course, especially in these times when you don't get to personally speak to a lot of international colleagues. Dr. Negar Asdaghi:                        That's great, Simon. Can you start us off, please, with some background on futile recanalization? What do we know about this medical work, and what prompted you to look into this topic in more detail? Dr. Simon Nagel:                           I guess, in most studies, futile recanalization is defined as a technically successful recanalization by a TICI score of 2b upwards, but an outcome on day 90 of only three to six points on the modified Rankin scale. And many papers have examined a selected number of parameters for the association with futile recanalization being either clinical, radiological, laboratory or procedural, which is why we wanted to be very comprehensive in our approach by including 38 different variables from the above-mentioned spectrum in our own analysis from our monocentric registry in Heidelberg. Dr. Negar Asdaghi:                        Perfect, so a very important concept to keep in mind in light of the increased demand to perform endovascular therapy. So, can you tell us, you alluded to it, but can tell us a bit more about the study design, the population you studied, and specifically why you choose failure of early neurological improvement at the time of discharge as opposed to that more conventional outcome measure of modified Rankin scale at day 90 poststroke? Dr. Simon Nagel:                           That's a good point, Negar, and you're right, we did maybe choose an unconventional end point since the definition of early neurological improvement is usually based on the NIHSS at 24 hours, but this study was driven from a very clinical perspective, that is the one from the stroke physician on the ward who is receiving the patient after the procedure, after all the acute decisions have been made. And then we have to do our best during the following days managing the complications, the deficit, and finding out why the stroke happened in the first place, until the patient is then either discharged home or back to the referring facility or to a normal board or to rehabilitation. Dr. Simon Nagel:                           But a considerable amount of patients, we found, did not improve until this discharge, although the procedure was a technical success. So some reasons for that are obvious, but some of them are not, and we wanted to find more about this, especially since early neurological improvement has been proposed as a surrogate for good outcome later on. Dr. Negar Asdaghi:                        Right. So we're very excited, Simon, to hear about the main study results. What were some of the predictors of failure of early neurological improvement in your study, and were you at all surprised by any of those developments? Dr. Simon Nagel:                           A lot of known factors that have been previously described to show an association with early neurological improvement or failure of that were found in our univariate analysis, namely 21 of 38, but only a few remained independent predictors after selecting with the elastic net approach and logistic regression modeling. Some of them are obvious by definition, which is symptomatic intracranial hemorrhage. Then, of course, the ASPECTS on follow-up was a predictor, and this obviously beat the baseline ASPECTS and also potentially the collateral score, which was significant in univariate analysis, but we included also over 20% of patients with a premorbid disability of more than two on the Rankin scale so premorbid condition was an independent predictor. Dr. Simon Nagel:                           We had eight patients with end stage renal failure in our analysis, so we did include that as well, and dialysis is a very strong predictor of failure of early neurological improvement. But also, admission glucose was, so higher levels of that, and then procedural parameters like reaching thrombolysis. So, if you do imply this, this was a factor that was positively associated with early neurological improvement. And then, also, the time from groin puncture to final recanalization was associated, so the longer it took, and this obviously beat also the stent retriever attempts in the analysis, the longer it took, the more likely that it was that failure of early neurological improvement was observed. And last but not least, general anesthesia was associated with that, but there is a sense of bias in this analysis because we have a SOP that we generally perform awake sedation. That means only patients that are not eligible for that, that are not doing well, will be treated under general anesthesia, so this variable has to be interpreted with caution. Dr. Negar Asdaghi:                        So, very interesting, Simon. I want to emphasize to our listeners that in your study, 20%, that is one in five successfully recanalized patient, did not clinically improve post-thrombectomy up until discharge. This is a considerable percentage to keep in mind. Now, in our day-to-day practice, many of us also accept a TICI 2b as a measure of a successful recanalization. In your study, you included a more rigorous definition of successful recanalization. How do you think your results would have changed had you included those who have achieved a TICI 2b, and why did you exclude that population? Dr. Simon Nagel:                           According to the mTICI definition, 2b means that more than half of the previously occluded vessel is reperfused, which also means that almost 50% is not. That might have been a success in the advent of thrombectomy and when this was defined in 2013, but I don't think it's adequate to call this a successful recanalization these days. When this was re-defined by David Liebeskind in 2018 with a eTICI score, 2b is still not considered anything more than two-third of the territory, and only 2c is a nearly complete reperfusion, leaving just 10% of the vessel territory occluded or not reperfused. Dr. Simon Nagel:                           This is why we thought it is a more appropriate definition of successful thrombectomy, and this is what we think should be attempted in day-to-day practice. In our cohort, almost 50% achieve TICI 2c or 3, and if we would have included 2b, 83% of patients would have achieved that. I can't tell you what our analysis would have looked like if we included 2b, it might have been different, but I can tell you that that would require a new analysis of the data. Dr. Negar Asdaghi:                        Yes, and we keep that in mind for sure that the new way of definition is to keep 2c or better. So Simon, I agree that definitely your study has given us a clear roadmap regarding early outcome expectations in patients undergoing thrombectomy. What should be our final take-away from your study? Dr. Simon Nagel:                           I guess, before I can tell you, you have to bear in mind that this is a monocentric retrospective analysis, hence, there is bias to be expected, and choosing a different definition of early neurological improvement then may be useful, might have given us a different result. It is also important to be clear from what perspective you are looking at the data. For example, this analysis does not necessarily help with predictors for outcome that help you make a decision if you should treat the patient or not since we included many parameters that are not yet available at that point in time when you need to make the decision to treat the patient. Dr. Simon Nagel:                           But, I think it's fair to say that you should, according to our results, apply thrombolysis whenever indicated, that you should be as quick as possible with your procedure, and that you should manage blood sugar well, as well as other medical complications, and that you should not expect too much early improvement in case the patient has a premorbid condition or if the motor cortex is involved, which was also a significant outcome, which I didn't mention earlier, and, of course, by definition, if symptomatic hemorrhage occurs. Dr. Simon Nagel:                           Hemorrhagic transformations, on the other side, do not seem to independently influence failure of early neurological improvement. Dr. Negar Asdaghi:                        Dr. Simon Nagel, it's always a pleasure speaking with you, and thank you for being with us. And this concludes our podcast for the April 2021 issue of Stroke. And as I leave you today, I want to remind us all that for every minute left untreated a brain under an ischemic attack loses an average of 1.9 million neurons. So whether you're just starting off or you're a well-established clinician or researcher in the field of vascular neurology, your work and that of your colleagues are part of a quest to save the most valuable commodity of human life, which is the brain, and, for that, we're proud to review your work in stroke and highlight the best in vascular neurology in our future podcasts. So until our next podcast, stay alert with Stroke Alert.
  • Stroke Alert podcast

    Stroke Alert March 2021

    17:08

    On Episode 2 of the Stroke Alert podcast, host Dr. Negar Asdaghi highlights two featured articles from the March 2021 issue of Stroke. This episode also features a conversation with Dr. Joan Montaner from Neurovascular Research Laboratory at the Universitat Autònoma in Barcelona, Spain, to discuss his article “D-Dimer as Predictor of Large Vessel Occlusion in Acute Ischemic Stroke.” Dr. Negar Asdaghi:           Can your microRNA profile predict your future risk of stroke? Is stroke that wake-up call to finally live a healthier lifestyle, better diet, exercise more, and stop smoking? Can a simple blood test improve our clinical predictive models for presence of a large vessel occlusion in patients with suspected ischemic stroke? We have the answers and much more in today's podcast. You're listening to Stroke Alert. 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 the host of the monthly Stroke Alert Podcast. In today's podcast, I'm going to interview the senior author of the study on the values of D-dimer and predicting the presence of large vessel occlusion in stroke. But first with these two articles. Dr. Negar Asdaghi:           DNA noncoding sequences and introns, once thought to represent the, quote, junk DNA, quote, have been found to play an important role in the modulation of gene expression at the post transcriptional level through coding for regulatory molecules, such as microRNAs, or miRNA. Whether the presence of certain miRNAs can signal a future risk of development of stroke is unknown. In their paper titled “Circulatory MicroRNAs as Potential Biomarkers for Stroke Risk: The Rotterdam Study,” Dr. Michelle Mens and colleagues from the Department of Neurology, University Medical Center, in Rotterdam, Netherlands, discuss their findings related to microRNA samples collected between 2002 and 2005 from over 1900 stroke-free participants of the Rotterdam Study. Participants were assessed for incident stroke through continuous monitoring of medical records until January 1, 2016. Dr. Negar Asdaghi:           At baseline, using next-generation sequencing, they measured expression levels of over 2083 miRNAs in plasma samples. During a mean follow-up of close to 10 years, the incidence of stroke was 7% in their study population, and they found, in total, 39 miRNAs were at least nominally related with that incidence of stroke. In their fully adjusted model, they found significant association between expression level of three particular microRNAs and risk of stroke, with the hazard ratio ranging between 1.1 to 2.6. Interestingly, the area under the curve for the longitudinal predictive models improved when the miRNA data was added to the vascular risk factor model. And in conclusion, they found miRNA 6124, 5196-5p and 4292 were associated with future risk of stroke in their population. The elevated levels of these miRNAs may serve as plasma biomarkers for predicting future risk of stroke in combination with other known vascular risk factors for stroke. Dr. Negar Asdaghi:           So, speaking of vascular risk factors, let's move on to our second paper for today's podcast. There's a growing emphasis on adherence with pharmaceutical interventions, such as diabetic and blood pressure treatments, statin therapy, to control the risk factors for stroke and prevent recurrent vascular events. All the while, the non-pharmaceutical interventions, such as smoking cessation, diet control, and increased physical activity, seem to represent the somewhat easy or implied aspect of our secondary preventive efforts. But how well are stroke survivors doing with regards to making these healthy lifestyle modifications? In the March issue of Stroke, Dr. Chelsea Liu and colleagues from Johns Hopkins School of Public Health presented their findings on lifestyle and behavioral changes pertaining to cardiovascular health in the study titled, “Change in Life’s Simple 7 Measure of Cardiovascular Health After Incident Stroke: The REGARDS Study.” Dr. Negar Asdaghi:           So, this was a population-based, epidemiological study of over 7,000 stroke-free participants between 2003 and 2007, who had data on Life's Simple 7, what the author called “LS7 measures,” which studied seven different domains. Four of them behavioral, including smoking, diet, physical activity, body mass index, and three medication-controlled, including blood pressure, total cholesterol, and fasting glucose, both at study entry and their follow-up visit. At which point, either they did not have a stroke or had an ischemic stroke and were included if that stroke had happened more than one year before the follow-up visit. And so the study authors hypothesized that those with a stroke would have had a significant improvement in their Life's Simple 7 data poststroke as compared to the stroke-free participants. Dr. Negar Asdaghi:           But what they found was completely the opposite. At 10 years follow-up, a total of 149 patients had suffered a stroke in their study. On a scale of zero to 14 at study entry, all participants scored low or relatively low in these seven simple measures, but those participants who would ultimately suffer a stroke scored significantly lower at baseline. What was alarming, though, was that after adjusting for all confounders, at follow-up, participants who had experienced an ischemic stroke showed a significantly further decline in their total LS7 score at 10-year follow-up. And the greatest declines were noted in behavioral domains, most notably physical activity and diet scores. The authors noted a non-significant improvement, in other words, improvement in weight in the BMI score among stroke survivors, but they caution that that may indeed be actually related to muscle loss, a downstream effect of decreased physical activity poststroke, rather than representing active dietary interventions with weight loss. So, in summary, this important paper highlights, on a population level, the urgent need for behavioral interventions to improve secondary prevention after a stroke event up and beyond our efforts to improve medication adherence. Dr. Negar Asdaghi:           So now moving on from secondary preventative measures to the acute phase, our next paper discusses ways in which we can improve our diagnostic accuracy in the acute setting. Identification of large vessel occlusions is the first step in determining patients' eligibility for endovascular thrombectomy, a highly effective treatment to improve outcomes in acute ischemic stroke. But without vascular imaging, which may not be readily available in the small or community hospitals, the decision to transfer patients to thrombectomy-capable centers is entirely dependent on clinical scales, which, as we all know, may have suboptimal sensitivity and specificity. So the question is, could a simple blood test improve the predictive capabilities of our current clinical scales for presence of a target LVO, or large vessel occlusion? Joining me now is Dr. Joan Montaner from Neurovascular Research Laboratory at the Universitat Autònoma in Barcelona, who is the senior author of the study titled “D-Dimer as Predictor of Large Vessel Occlusion in Acute Ischemic Stroke.” Good morning, Joan, all the way from the sunny Florida to the beautiful Barcelona. Good to have you with us, and thank you for joining us. Dr. Joan Montaner:         Hello. Nice to talk with you on blood biomarkers for stroke management. Dr. Negar Asdaghi:           Thank you, Joan. Your study touches on the importance of improving the ways in which the systems of care are set up in triage and transfer of patients with thrombectomy-capable centers. Can you please tell us briefly about the stroke systems of care in Catalonia where you practice and where your study is based out of? And what clinical scales are currently used for transfer of patients with suspected acute stroke to a comprehensive stroke center? Dr. Joan Montaner:         Yes, Catalonia, it's a region of about 7.5 million inhabitants. And when we did this study, most of the comprehensive stroke centers were located in Barcelona itself, in the capital. So it's true that there are several areas of the region that are far away from Barcelona. It took more than two hours to bring some patients from those distant regions to Barcelona. That's why we began to use these clinical scales that you are talking about. Mainly they are RACE, it's like a simplification of the NIHSS subscale. And, in fact, a large study RACE card that was presented last year in the European Stroke Conference was done to try to see if we could, by using these scales, RACE, select the right patients to come directly to the thrombectomy centers instead of going to the closest hospital. But, unfortunately, the results were neutral. So, we were a little bit disappointed, and we think, as you were saying, that these neurological scales are suboptimal, probably not enough sensitivity and specificity for identifying LVO. That's why we think that these biomarkers could improve the accuracy of those scales. Dr. Negar Asdaghi:           Perfect. I totally agree with you. And now, before you tell us about the biomarkers, can you just briefly tell us about the Stroke-Chip study, your study population, and what prompted you to look at these various biomarkers that you addressed in the paper? Dr. Joan Montaner:         Stroke-Chip was a lot, it was really a massive collaborative effort among all the public hospitals in this network here in Catalonia. We were able to collect more than 1,300 patients in this particular study that we are talking about. Dr. Anna Ramos-Pachón and Elena Cancio were leading the analysis on the relation of these biomarkers with LVO. But I have to say that this was not the original intention of our study. Really, and perhaps we were naive at that time, we were looking for biomarkers to differentiate ischemia from hemorrhagic strokes or from stroke mimicking conditions to try to give TPA or TNK in the ambulance. But, as I was saying, perhaps that was a little bit naive, and we know how difficult that would be and perhaps with some liabilities. That's why it came this idea of, "Well, if we use those markers, not for giving a drug in the ambulance, but for doing triage and sending the patient to the right hospital, that could be more simple and more useful even." Dr. Negar Asdaghi:           Thank you very much. Can you briefly tell us about the study? What were your inclusion criteria? Dr. Joan Montaner:         Well, in this study, we selected all consecutive acute stroke patients attending the stroke unit of all these hospitals. We were including all stroke suspicions, if their symptoms onset happened within six hours. So, it's really hyperacute patients. And we were able to collect, like this, more than 1,300 patients. And then at the hospital, with the angio CT or duplex, we were able to categorize those with LVO, and we measured a panel of different biomarkers in the blood stream of those patients and trying to associate which of these markers were related with having or not having an LVO. Dr. Negar Asdaghi:           Very interesting. So tell us, please, your study’s main finding? Dr. Joan Montaner:         The main finding, what we liked more, let's say, of our results was that some of those markers, specifically NT-proBNP and D-dimer, were really high among patients with a large vessel occlusion. When we combined these results, for example, having high levels of D-dimer, those patients above fourth quartile of D-dimer with more stroke severity, patients with NIH of more than 10, the accuracy was really good. It was very specific, 93% specificity, 34% sensitivity, to predict an LVO. So this means that without almost any mistake, you select more than one third of the patients that have an LVO, that could be very useful. To bring those patients, we were talking from far away of these thrombectomy centers, to the right place. And perhaps we could be doing a thrombectomy one or two hours before with these technologies. Dr. Negar Asdaghi:           Perfect. So basically, just to reiterate what you're saying, is that D-dimer, as non-specific as it is and as important as it is to note that it can be elevated in the setting of aging or increase NIH Stroke Scale severity, this increase in D-dimer noted in patients with LVO was just not a factor of just age simply or increased severity of the stroke scale. Can you tell us about your multivariate analysis and what other factors you adjusted for in your final model? Dr. Joan Montaner:         You are right that D-dimer can be modified by many things, as you were saying. That's why we took a lot of care about the multivariate analysis and all factors, all clinical factors that were related with LVO were included in the model. And finally, only eight NIH Stroke Scale scores D-dimer and the vast history of atrial fibrillation were included in the model. Odds ratio for D-dimer was 1.59 that I think it's quite acceptable. And it's true that in that model, NT-proBNP was not included anymore, probably because it's related with a fee. So, that's something interesting if perhaps in the ambulance, you don't know about the story, the history of a patient, of a fee, we could use NT-proBNP, so I think this opens the possibility of using different clinical neurological scales biomarkers in combination to make the prediction of LVO. Dr. Negar Asdaghi:           Yes. Very, very exciting results for sure. So what is our main takeaway from your study? Are we thinking that D-dimer or a particular level of elevations of D-dimer will one day become the, quote, Troponin equivalent of LVO for stroke? Dr. Joan Montaner:         Well, it sounds nice, but I know it's several technical issues here. You are right that there is variability among labs in the measurement of D-dimer so now what we are doing is really, in a prospective study called BIO-FAST in the south of Spain, in Seville, in a large network of ambulances, we are measuring D-dimer, but in a rapid fashion with a rapid point of care test in the ambulance itself. We think that we are not going to have a magic biomarker. Not that Troponin you are talking about. Probably we need to combine it with others. We think that the marker of brain damage would add a lot on top of D-dimer, probably D-dimer is very good for the clot burden, but we think other markers could improve the accuracy of the test. And we are measuring them together with these. Our dream would be really to have cost utility study in the future and to see if really we are able to randomize patients based on these biomarkers in the ambulance, will have an impact on outcome if we are able really to do thrombectomies much faster. Dr. Negar Asdaghi:           Well, we certainly look forward to covering your future studies on this topic of biomarkers. Dr. Joan Montaner, thank you for joining us and congratulations on your work. Dr. Joan Montaner:         Thanks a lot. Dr. Negar Asdaghi:           And this concludes our podcast. Don’t forget to check online for the full list of publications, including two papers on the state of pediatric thrombectomy and a study on the association between stroke and subsequent risk of suicide that are published online ahead of their presentations at the International Stroke Conference. Until our next podcast, stay alert with Stroke Alert.
  • Stroke Alert podcast

    Stroke Alert February 2021

    19:39

    On Episode 1 of the Stroke Alert podcast, host Dr. Negar Asdaghi highlights two featured articles from the February 2021 issue of Stroke. This episode also features a conversation with Drs. Fabian Flottmann and Matthew Maros from the Department of Diagnostic and Interventional Neuroradiology, University Medical Center, in Hamburg, Germany, to discuss their article “Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy: Beyond the First-Pass Effect.” Dr. Negar Asdaghi:          Are women more likely to suffer from stroke than men? Are oral anticoagulants safe in atrial fibrillation patients with a prior history of GI bleeding? Does pregnancy increase the risk of intracerebral hemorrhage in patients with cavernous malformation? Does the number of retrieval attempts during thrombectomy affect the outcomes of stroke patients in whom successful reperfusion is achieved? In today's podcast, we address some of these topics and much more. 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 the host of the monthly Stroke Alert Podcast. We're starting our podcasts with the February 2021 issue of the journal, which also features a special section on Go Red for Women stroke, a comprehensive American Heart Association platform to improve the vascular health of women globally. I hope you enjoy it. Dr. Negar Asdaghi:         Cavernous malformations or cavernomas are angiographically called vascular abnormalities, which can pose an increased risk for intracerebral hemorrhage. Cavernomas can have diverse neurological presentations ranging from mild neurological symptoms to seizures, but in some cases may remain entirely asymptomatic and are diagnosed incidentally as part of routine neuroimaging completed for other reasons. Earlier studies had reported higher rates of intracerebral hemorrhage from cavernomas during pregnancy, and have postulated a hormone-related increased expression of vascular endothelial growth factor or basic fibroblasts growth factors to explain this increased rate. Subsequent studies, however, have failed to demonstrate either progesterone or estrogen receptors in cavernomas. So the question is, should presence of cavernous malformation, whether symptomatic or asymptomatic, influence the reproductive choices of women of childbearing age? In the “Influence of Pregnancy on Hemorrhage Risk in Women With Cerebral and Spinal Cavernous Malformations,” Dr. Nycole Joseph and colleagues from the Departments of Neurology and Neurosurgery from Mayo Clinic Rochester in Minnesota evaluated 365 pregnancies and 160 women with brain or spinal cord cavernomas. They found that during the cumulative 402 years of study follow-up, the risk of hemorrhage amongst non-pregnant patients in the study was 10.4% per year. They found only four patients with clinical hemorrhage during pregnancy, all of which resulted in the cavernomas being first diagnosed. None of the hemorrhages occurred during delivery, and all of the four patients had functionally independent outcomes by three months. Importantly, they found that no patient who became pregnant after the diagnosis of cavernous malformation had a hemorrhage while pregnant. They had a total of 33 pregnancies in the study, including one patient who had previously bled during a prior pregnancy and also patients with brainstem lesions and those who presented with hemorrhage at diagnosis. Both of these are factors for hemorrhage in cavernomas. So, in summary, in this prospective study, pregnancy did not increase the risk of hemorrhage in women with a known brain or spinal cord cavernous malformation. And the vaginal delivery was safe in this population. The authors concluded that the presence of cavernous malformation should not influence the reproductive choices in women or their type of delivery. Now, speaking of hemorrhage risk, let's move on to our next paper on anticoagulation therapy in patients with atrial fibrillation. The decision to start anticoagulants for atrial fibrillation can often be challenging in those who have suffered from a prior gastrointestinal bleeding. Prior studies have shown that the non–vitamin K antagonist oral anticoagulants, or NOACs, can carry a comparable and, in some cases, even a higher risk of GI bleed than warfarin. It should be noted that patients with a prior GI bleed were generally excluded from the pivotal randomized control trials that approved NOACs. And importantly, the risk of bleeding may also be higher in certain race/ethnic groups, such as the Asian population. In the article titled “Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Prior Gastrointestinal Bleeding,” Dr. Soonil Kwon from the Department of Internal Medicine, Seoul National University Hospital, in Seoul, Republic of Korea, studied over 42,000 anticoagulant–naïve patients with nonvalvular atrial fibrillation and prior GI bleed from 2010 to 2018 as part of a retrospective, observational cohort study in Korea. They evaluated the risk of ischemic stroke, major bleeding and combined outcomes in this population. What they found was that, not surprisingly, close to 60% of patients were initiated on a NOAC, with rivaroxaban leading dabigatran, apixaban, followed by edoxaban in terms of frequency of agents used. Just over 40% of patients were started on warfarin. Now, over the study follow-up, when they looked at the safety by looking at major bleeding rate and effectiveness by assessing ischemic stroke rates, NOACs generally did better as compared to warfarin, resulting in 39% risk reduction in recurrent stroke, 27% risk reduction in major bleeding and 34% risk reduction in composite outcomes as compared to warfarin. And the rates of upper and lower GI bleed were similar in NOACs versus warfarin users. NOACs still did better as compared to warfarin amongst patients who suffered from GI bleed as they had a lower transfusion rates and shorter hospital stay. NOACs were also associated with lower risks of fatal clinical outcomes except for fatal GI bleed. So the authors concluded that contrary to some of the prior reports, NOACs may be a better option than warfarin for stroke patients and atrial fibrillation patients with prior GI bleed. Dr. Negar Asdaghi:         Moving from secondary prevention to acute stroke therapy, our last article discusses how the technical details of endovascular thrombectomy may affect the outcomes in patients with ischemic stroke. So, achieving a successful reperfusion is the cornerstone of improving clinical outcomes in patients undergoing endovascular therapy, but how many retrieval attempts should be made by the interventionist to obtain that desired successful reperfusion is still unclear. Importantly, if successful reperfusion is ultimately achieved, it's still not clear if there's a relationship between the number of retrieval attempts and favorable clinical outcomes.  Joining me now are doctors Fabian Flottmann and Matthew Maros from the Department of Diagnostic and Interventional Neuroradiology, University Medical Center, in Hamburg, Germany, who are the first and senior authors of the study titled “Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy: Beyond the First-Pass Effect.” Good morning from Florida, and good afternoon, Fabian and Máté, in Germany. Thank you for joining us. Dr. Fabian Flottmann:    Thank you very much, Negar, for the nice introduction. Good afternoon from Hamburg. At the moment, it's really, really cold here. It's -4 degrees Celsius. I can't translate it to Fahrenheit, but it's pretty cold, let me assure you. And thank you very much for having us today. Dr. Negar Asdaghi:         It's great to have you. So I start with Fabian. This is a very interesting and timely study as we're learning more that the way in which we achieve a goal in acute stroke reperfusion therapies is almost as important as the goal itself. Can you tell us a bit about the background of your study, Fabian, and why you felt the need to look at these granular details, which unfold inside the angio suite during endovascular thrombectomy? Dr. Fabian Flottmann:    Of course, that's a question that's highly relevant for a neurointerventionalist. This research topic developed from our clinical practice, because quite often we have the situation in the angiography suite, where we try to open a vessel, a patient with a large vessel occlusion, and everything is very easy if the vessel opens after one retrieval attempt, because everybody is happy and you can end the procedure. But what happens if the vessel doesn't open? Then you try again. And what happens if the vessel doesn't open? You try it again, and so on and so on. So the question is, when should you stop? And we ask ourselves, are these maneuvers that we do, like three or four or five maneuvers, are they as successful or as beneficial for the patient as the first maneuver? We did an analysis of our data in Hamburg, and that led to the first paper that we published in Stroke in 2018. And our finding was that the third or fourth retrieval, they were successful in achieving recanalization, but the clinical outcome of those patients was not as good as those patients that you opened with just one retrieval attempt. That was the first finding that we had with our data and our center. And then in the same year, the first pass effect was described. The first pass effect, being the finding that the first retrieval attempt is the most important for the patient. This data was very interesting. And then there were other publications that said, no, there's no connection between the number of retrieval attempts and the clinical outcome. So, as always, in science, when there's more than one opinion, things begin to get interesting. And we said we want to investigate this further. And we decided to do a multicenter study with more patients. And we decided to look at each retrieval attempt separately, to not look just at a first retrieval attempt versus the others, but at each retrieval attempt. Dr. Negar Asdaghi:         So interesting indeed. Please tell us, before you tell us about the study findings, about the German Stroke Registry. How many years has the registry been active, and how many centers are involved, and please walk us through your study population and the selection process of your study? Dr. Fabian Flottmann:    Germans Stroke Registry. It's a systematic observational registry study from Germany. It's academic, it's independent, prospective, multi-central, there are 25 centers who participate in this registry. And its goal is to have a systematic evaluation of endovascular stroke treatment in Germany. There are stroke centers from all around the country who consecutively enroll their patients. All patients with an intention to treat in the angiography suite are included. All the patient data are collected at the center and all these data are then centralized and we have a central quality check. And what is important that we also try to include the clinical follow-up information for every patient at day 90. So, the modified Rankin Scale at day 90 is also included. And in our work, we did an analysis of the first 2,600 patients of this German Stroke Registry, and our goal was to eliminate bias. So, for example, we wanted to include data on the stroke severity, the NIHSS score, the amount of early infarction, the ASPECTS score and the location of occlusion, the age of the patient. We selected all the patients that had these data entered. So, we were able to select about 1,200 patients from the German Stroke Registry that fulfilled our inclusion criteria for the present study. To our knowledge, this is the largest multicentric, retrospective study that investigated this effect of retrieval attempts on clinical outcome. Dr. Negar Asdaghi:         This is really nice because we are really not used to getting granular details and radiographic details in such large numbers. So, the multicenter nature and the large number of patients included in your study are certainly important strengths of your paper, and that should be noted. Now, Matthew, over to you. Please tell us the main findings of the paper. Dr. Matthew Maros:     So, one specialty of our applied methodology is that we used a generalized mixed-effects models, if we didn't know logistic regression framework. That means that our target variable was the mRS90 and the good functional outcome, defined by zero to two scores by mRS. We also implied this framework to be comparable to the HERMES meta-analysis by Goyal et al. And we investigated, in our primary analysis, the effect of age, the baseline stroke severity NIHSS score, ASPECTS score, and also the main explanatory variable that we investigated was the successful reperfusion at N-th retrieval attempt. And we found that, so as one would expect, a younger age and the less severe stroke clinical manifestation, like NIHSS score, was inversely associated with a good functional outcome. So, younger patients and less severe stroke were associated with a favorable outcome. And also, a less severe ischemic changes on a non-contrast head CT, so ASPECTS score eight, nine or ten, were also independent predictors for a good function outcome at 90 days. Our main finding was that the success at the first, second, or third retrieval attempts were significantly and independently associated with a good functional outcome. And interestingly, the effect of the consecutive retrieval attempts were gradually diminishing from an odds ratio from six (around) to three. Dr. Negar Asdaghi:         This is interesting. So, basically, what you found is that you go in with the first attempt, second and third, you don't achieve that successful recanalization. If you achieve your successful reperfusion after the third attempt, it's good, but not so good, meaning that it doesn't translate to that beautiful, favorable outcome at 90 days as it did for the first three attempts. Dr. Matthew Maros:      So, for four or more retrieval attempts, this positive effect on the outcome has flattened, so the curve is more like a sigmoid curve that was asymptotic to a virtual threshold. Dr. Negar Asdaghi:         Understood. So, I find it very interesting that this decline in the odds of favorable outcome, despite successful reperfusion, was not simply a factor of time, meaning that, if you tried once and you achieve reperfusion right away, it's so much faster. And of course, time is brain, but if you try five times, it would take longer. It is interesting in your results and your multivariate analysis that even if you adjusted for the factor of delay in time, the results persisted. Could you please tell us about your multivariate analysis and what other factors and co-founders you adjusted for? Dr. Matthew Maros:      Exactly. So, as a sensitivity analysis, we also included the time from groin puncture to flow restoration and also sex, and also to be almost identical or highly similar to the model applied in the HERMES meta-analysis. We also included the site of the intracranial occlusion and better intravenous thrombolysis was administered or not. And in the sensitivity analysis, we had almost 90% of our dataset. So almost a thousand one hundred patients. And we found that all the effects of age and NIHSS score stayed significant, and also the effect of the first, second and third retrieval attempts associated with good functional outcome at 90 days were also significant. While interestingly, the effect of intravenous thrombolysis, and also the ASPECTS score, had diminished, but also just narrowly escaped a significant threshold. And interestingly, the effect of time, so time from groin puncture to flow restoration, seemed to be not relevant or be interpreted that way, that the number of retrieval attempts and the effect that we see is not a surrogate of time, that it simply takes longer to perform the interventions, but it's the true effect of achieving recanalization at a certain attempt. Dr. Negar Asdaghi:         So, what should be our takeaway from your study, Fabian? Is three that magic number? Are we asking the interventionalist to stop the procedure after the third retrieval attempt if they're unsuccessful, and what should the future hold in terms of studies on this project? Dr. Fabian Flottmann:    That's the most important question. Of course, we have to keep in mind that every patient and every intervention is different. The decision to continue or stop the thrombectomy procedure is a very important decision, which is taken by the neurointerventionalist together with his team. And they will take into account multiple factors, including patient's biography, medical history at time from symptom onset, image data, and so on. Our study can provide some guiding information when making this decision. And yes, three could indeed be called a magic number in the following sense. We would like to encourage interventionalists to make at least three attempts in case of persistent occlusion, because we can see a clear benefit even when reperfusion is achieved after the third attempt. Then, in patients with younger age and/or, for example, a good ASPECTS score, even more retrieval attempts are probably warranted regardless of IV thrombolysis, site of occlusion and potentially increased procedure time. Of course, in all these retrospective studies, a bias remains. We don't know why the procedure was stopped in each case. The best thing would be a randomized controlled trial with the following design. You could, in case of persistent occlusions, after two retrievals, randomize to continue or to stop the procedure. And then we would know what the right answer is. So, taken together, our study suggests that in EVT for anterior circulation strokes, at least three retrieval attempts should be performed in cases of persistent occlusion, and up to five attempts of beneficial association with good clinical outcome is expected. Dr. Negar Asdaghi:         Doctors Fabian Flottmann and Matthew Maros, thank you very much for joining us and congratulations on this work. And this concludes our podcast today. Don't forget to check the February table of contents for the full list of publications, including original contributions, brief reports, editorials, and our special section on Go Red for Women stroke. Until our next podcast, stay alert with Stroke Alert.

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