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 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.

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%.”

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.

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.

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.