Stroke Alert podcast

Stroke Alert July 2021

15/7/2021
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38:29
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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.

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