Oh, jeez, more useless shit! NOTHING ON RESULTS OR RECOVERY!
Stroke Alert June 2024
On Episode 41 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2024 issue of Stroke: “Global, Regional, and National Burdens of Stroke in Children and Adolescents From 1990 to 2019: A Population-Based Study” and “Head Injury and Risk of Incident Ischemic Stroke in Community-Dwelling Adults.” She also interviews Dr. Raul Nogueira about his article “Endovascular Versus Medical Management in Distal Medium Vessel Occlusion Stroke: The DUSK Study” and highlights some of the science presented at the recent European Stroke Organisation Conference.
Dr. Negar Asdaghi: Let's start with some questions.
1) What is the global incidence rate of stroke in the pediatric population, and is this rate decreasing or increasing over time?
2) What is the latest on the subject of endovascular treatment in patients presenting with a medium or distal vessel occlusion?
3) And finally, what is the latest science presented at the 2024 European Stroke Organisation Conference?
We'll tackle these questions in today's podcast, answer a few, and create a lot more. We are bringing you the best in Stroke. Stay with us.
Welcome back to another episode of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The preparation for the June 2024 issue of the podcast occurred while the European Stroke Organisation Conference was happening live in Basel, Switzerland. To deliver on our promise of keeping you updated with the latest developments in the field of cerebrovascular disorders, we have a special hybrid podcast today to review articles published in this issue of the journal, as well as some of the late-breaking abstracts from the conference, which I'm excited to share with you.
Later in the podcast, I'm joined by Dr. Raul Nogueira to discuss the topic of endovascular therapy in distal and medium vessel occlusion patients. A pioneer in the field of neurointerventional therapies, Dr. Nogueira is a remarkable scientist, having completed multiple randomized trials and spearheaded many of the cutting-edge technologies in the field of stroke, including the use of novel thrombectomy devices, neuroendovascular robotic surgery, development of AI algorithms for stroke triage, and brain computer interface devices. Speaking about his scientific achievements, he talks about how he was first drawn to interventional neurology and the long road that began with a passion for surfing the waves in his hometown of Fortaleza in northeast Brazil. Take a listen.
Dr. Raul Nogueira: What inspired me to be a neurologist? It's a complex question. I think I was inspired to be a doctor based on the work of my father, who actually happened to be my professor in medical school and my attending mentor during my early years in internal medicine. My plan was to do interventional cardiology. I have always been fascinated by catheter therapy, endovascular techniques, and that's what I was going to do. And then I did the last semester of my medical school. I'm originally from Brazil, but during the last semester for medical school, I left my hometown, which is northeast coast Brazil, to University of Miami. And then I watched a grand rounds with Dr. Camilo Gomez back then, who was, I believe, the first and only interventional neurologist in the world, but I didn't know that.
So, I saw that he was doing exactly what I wanted to do in the heart, in the brain, and that was absolutely fascinating to me and very inspiring. Then, I decide to shift from the heart to the brain, and that was probably one of the best moves I did in my life. It's been such a wonderful and rewarding experience to work alongside great colleagues and surf the wave of acute reperfusion therapies with many other colleagues.
I said that I was originally from northeast coast Brazil. I grew up surfing, but I'm a terrible surfer. So, despite my love for surfing, I never really surfed the big waves. But then later in my life, I got to surf this great wave of the acute reperfusion therapies and thrombectomies alongside with many great people, and this has been extremely rewarding.
Dr. Negar Asdaghi: From surfing the waves of the Atlantic Ocean to riding the waves of success, the interview is worth the wait. But before we go there, let's first go to our summary section prepared by my assistant editors, Drs. Nastajjia Krementz and Eric Goldstein. You're listening to the Stroke Alert Podcast, and this is the latest in Stroke. Stay with us.
As an adult vascular neurologist, the thought of a child having a stroke makes my neurons tremble. Stroke at a young age is a daunting condition with devastating consequences, not just for the young patient itself, but also for their families. It's hard to believe that to date, much of the knowledge regarding the global burden of pediatric stroke, its prevalence, and prognosis is still derived from studies in the adult population. In this issue of the journal, Professor Yongze Li from the First Hospital of China Medical University and colleagues embark on a large study to analyze the incidence and prevalence of stroke in children and adolescents under the age of 19. For this study, the authors used the Global Health Data Exchange Tool across 204 countries over a 30-year time period from 1990 to 2019 to give us some information about the incidence and prevalence of stroke. So, let's hear what they have to say.
Overall, looking at all forms of stroke, that's hemorrhagic or ischemic subtypes, the incidence of stroke slightly increased from 1990 to 2019 in the pediatric population. That is, the incidence rate rose from 17.11 to 17.96 per 100,000. So, a 0.85 per 100,000 increase in incidence of all forms of stroke in this pediatric population, which may sound small, but if you consider the total pediatric population of the world, that is upwards of 2 billion, then we have to pay attention to these decimals.
The other point we need to pay attention to is that the incidence rates are substantially higher than the previously reported annual incidence rates for pediatric stroke, which varied depending on the different studies, but reported as high as 13 per 100,000. Now, in terms of subtypes, similar to the adult population, the incidence of ischemic stroke was almost five times higher than that of intracerebral hemorrhage and 15 times greater than that of subarachnoid hemorrhage. Importantly, the overall rise in incidence of stroke was predominantly driven by an increase in the incidence of ischemic stroke subtype. In fact, the incidence rates of hemorrhagic stroke and subarachnoid hemorrhage showed a decline in the 30 years timeframe of the study. Similar increased trends were also found in the overall prevalence of stroke and years lived with disability due to stroke.
So, this is all negative news in this young population. What are some positive news? Well, the one positive news was a notable decline in the years of life lost from stroke amongst children and adolescents. YLL, or years of life lost, at any age is measured as the number of deaths multiplied by the standard life expectancy at any given age. This was upwards of 4.7 million in 1990 and went down to 1.9 million in 2019, which, of course, translated to a statistically significant drop in the average rate of YLL from 1990 to 2019. The drop in YLL perhaps is a testament to better recognition, improved diagnostic capabilities, and improved treatment options for pediatric stroke.
Now, moving on to subgroup analyses. Analyzing global trends of pediatric stroke by sex, sadly, the increasing stroke incidence was only found in females, particularly for the ischemic stroke subtype. Next, analyzing these global trends by age groups, categorizing the pediatric population to those under the age of five, between five to nine, 10 to 14, and 15 to 19 years of age, the highest incidence rate of stroke was observed in the age category of less than five, followed by children in the five to nine years of age category. Sadly, for both of these age groups, the incidence rates of stroke also increased over the study time period.
In keeping with the overall message of the paper, it's important for practicing physicians to keep in mind that a significant association was found in the study between the age and subtypes of stroke, in that children less than five years were more apt to develop an ischemic stroke, particularly neonates under 28 days of age, and adolescents age 15 to 19 were more commonly apt to develop intracerebral hemorrhage as compared to children in all other age categories. The sad news was for the very young category of under the age of five, the incidence rates of all forms of stroke, not just ischemic stroke, but the hemorrhagic stroke, also increased in that category.
Last, the incidence and prevalence of stroke was strongly associated with countries' sociodemographic index. When classifying the 204 countries into five categories starting from high all the way to low sociodemographic index, the majority of incident cases, that's 84% of pediatric strokes, and the majority of prevalent cases, that's 83% of prevalence of stroke, and 80% of years lived with disability were all in the low- and middle-income countries. These are important information on disparities as it relates to sociodemographic differences between the various countries. Patients in the high sociodemographic countries had the highest decline in years of life lost due to stroke. But this happy news was offset by a steep incline in the years of life lost to disability from stroke, which means that with more advances in stroke care, perhaps the mortality from pediatric stroke is declining, but the morbidity continues or is on the rise due to higher rates of stroke.
So, in summary, this is an exceedingly important paper highlighting that globally, the incidence and prevalence of pediatric stroke is on the rise. And while the paper highlights a decline in mortality over the past 30 years, this was accompanied by a rise in stroke-related morbidity in the young population. These are important data to be aware of from the global public health policy perspective and to react to accordingly.
Every year, an estimated 70 million people worldwide suffer from a traumatic brain injury, or TBI. The most common causes of TBI include falls, followed by motor vehicle crashes and traffic-related accidents. TBI has a number of neurological consequences, which are the leading causes of its associated morbidity and mortality. Stroke in the acute phase of TBI has been widely recognized. Not surprisingly, there's a stronger association between TBI and development of hemorrhagic forms of stroke, whether intracerebral hemorrhage or traumatic subarachnoid hemorrhage, than the ischemic forms. Interestingly, the same mechanisms of vascular injury that can lead to intracranial hemorrhage, from the initial distortion, rotational forces, or acceleration/deceleration forces causing vascular injuries, can also cause vascular dissection or even accelerate acute plaque rupture to then lead to ischemic forms of stroke. But we have to keep in mind that ischemic stroke in the acute setting of trauma can also occur because potentially trauma is a prothrombotic state or can accelerate or cause cardiac arrhythmia. So, other mechanisms for development of acute ischemic stroke can be in play in the setting of a traumatic brain injury.
But whether TBI is associated with a higher long-term risk of ischemic stroke is not well studied. There are some suggestions in the literature that perhaps a prior history of TBI can be an independent risk for future development of ischemic stroke, up and beyond the traditional vascular risk factors. But studies on the topic have been generally limited, mostly in terms of the available follow-up data in terms of duration and the fact that most of this file of data was relying on claims data for outcomes.
In this month's issue of the journal, Dr. Holly Elser and colleagues examined the relationship between stroke and TBI in their article titled "Head Injury and Risk of Incident Ischemic Stroke in Community-Dwelling Adults." The authors use data from the ARIC study. ARIC stands for "Atherosclerosis Risk in Communities." ARIC enrolled over 15,000 community-dwelling participants between the ages of 45 to 65 from four different US communities in North Carolina, Mississippi, Minnesota, and Maryland, and essentially followed these individuals over time. In our podcast series, we've now covered a number of papers from the ARIC data on a broad range of topics, from the values of topography of cerebral microbleeds to the studies of plasma biomarkers for blood-brain barrier integrity. So, it's fair to say that ARIC study has been informing the field of vascular neurology on exceedingly diverse topics.
Now, back to our current paper. They were interested to see whether a prior history of head injury can be associated with the future risk of development of ischemic stroke. So what they did was that they included over 12,000 participants in ARIC who had no reported prior history of either stroke or head injury, then they followed these individuals over time. The median follow-up time was 27 years, during which time almost 17% of these participants had suffered at least one head injury either by self-report or from hospital or emergency department records. Ouch. That's a lot of head injuries. Basically, over the 30 years of study period, one in six middle-aged community-dwelling participants suffered a brain injury. And what makes this worse is that almost 80% of these head injuries were abstracted from hospital records, which obviously makes them a bit more reliable than self-reports.
Now, how many people had ischemic stroke in follow-up? 8.9% of the participants in the substudy of ARIC, that's 1,141 participants, developed an incident ischemic stroke during follow-up. 147 ischemic strokes occurred in participants who had suffered a head injury also during this follow-up, but prior to the index ischemic stroke. The median time from that reported head injury to development of ischemic stroke was 7.4 years. So, we're not talking about ischemic stroke occurring in the early time frames right after traumatic brain injury. In multivariable analysis accounting for the usual confounders, the hazard rate of ischemic stroke among those with a head injury was 1.3 times that of those without a head injury. In other words, the odds of development of acute ischemic stroke was increased by approximately 34% amongst those with head injury compared to those without.
Very briefly, some important points from their subgroup analysis. The severity of head injury was not necessarily a big predictor of future development of stroke, but there was a significant dose-response association in terms of the number of head injuries. In fact, repeated head injuries was strongly associated with future development of ischemic stroke. There was also a strong association between presence of a prior head injury and presenting with a more severe ischemic syndrome. That's severity of ischemic stroke equal or more than 11 on the NIH Stroke Scale.
All right, so what are the main takeaways from this article? Number one, evaluating data from over a 30-year time period, this study suggests that the hazard of acute ischemic stroke is increased by over 30% amongst those who had suffered a head injury. This is independent of all the other usual vascular risk factors that will increase the odds of ischemic stroke developments. Two or more head injuries substantially increase the future risk of development of ischemic stroke, but the actual severity of the head injury was not a big predictor of future stroke. And finally, the authors go on to discuss the importance of awareness of clinicians about this association and, of course, the appropriate interventions to prevent head injuries in general, but especially in the elderly and pediatric population that remain at the highest risk for falls.
Endovascular therapy is an effective treatment for patients with acute ischemic stroke due to a large vessel occlusion. Over the past decade and since the publication of the seminal endovascular trials, there's been a rapid succession of studies to expand indications of thrombectomy. For example, we now have positive endovascular treatment trials for patients presenting in the extended time window, those with a large ischemic core, and those with a basilar occlusion. Between 25 to 40% of target vessel occlusions are in medium-sized or distal vessels, and there's a growing recognition that strokes related to these occlusions carry substantial morbidities. So, it comes with no surprise that thrombectomy is increasingly utilized for treatment of distal and medium vessel occlusion strokes. But we have to note that endovascular treatment can be challenging for these occlusions and may lead to complications that could potentially offset any benefit of endovascular therapy.
With a rapidly evolving technology to improve access to these occlusions and six ongoing randomized trials, much is happening on the subject of endovascular versus maximal medical therapy for medium and distal vessel occlusion strokes. To keep us updated on this developing topic, I'm joined now by Dr. Raul Nogueira, a leading investigator in the field of acute stroke therapies, as we review his paper in this issue of the journal titled "Endovascular Versus Medical Management in Distal Medium Vessel Occlusion Stroke: The DUSK Study." Dr. Nogueira is the Division Chief of Cerebrovascular Medicine and the Director of the University of Pittsburgh Medical Center's Stroke Institute. He's an endowed professor of neurology and neurosurgery. He's the past president of the Society of Vascular and Interventional Neurology and the former editor-in-chief of the Interventional Neurology journal. He's had a global leadership role in many of the landmark stroke thrombectomy trials, and in recognition of his tremendous contributions to the field of stroke, he was awarded the 2023 World Stroke Organization Presidential Award. It's an absolute pleasure to welcome him to the podcast today. Good afternoon, Raul, and welcome.
Dr. Raul Nogueira: Good afternoon, Negar. Good afternoon, everyone. Thank you for the opportunity to be here to discuss one of my great passions in life, which is the endovascular treatment of stroke.
Dr. Negar Asdaghi: Great, Raul. Let's start with some definitions. What is a MeVO, and how is it different from a DMVO, and how are these entities defined?
Dr. Raul Nogueira: That's a great question, and it's definitely semantics. Theoretically, these can pretty much be assumed to denote the same entity. If you actually go to the original descriptions, there are some differences. The distal medium vessel occlusion definition comes a consensus paper led by Jeff Saver, and essentially taking consideration three elements, the distance of the vessel, the tortuosity comes with the distance, right? The more distant you are, in general, higher is the tortuosity. But also the caliber. In order to be called a medium vessel, the caliber has to be between 0.75 and 2.0 millimeters. Then, based on this concept of a medium vessel, you use the distance. So, vessels such as M3, M4, A2 to A5, P2 to P5, AICA, PICA, or SCA, they are considered distal vessels, versus proximal vessels are the intracranial ICA, M1, vertebral artery, and basilar artery.
But then we have a category of vessels that they are considered distal, but they can either be medium or large vessel occlusions based on the caliber. Those are the M2, the ACA1, and the PCAP1. Right? So, if the diameter is greater than two millimeters, you would call those a distal large vessel occlusion, which is kind of a term that most of us don't use, but we should if these vessels are large enough, versus if they are smaller than two millimeters, they would be the typical DMVO, the distal medium vessel occlusion.
The MeVO definition comes from an original paper from our colleagues from Calgary, Canada, Mayank Goyal, Michael Hill, and that group, and it's a very interesting definition. They incorporate not only anatomical aspects but also clinical function aspects. So, they say that you have to have one of these medium vessel occlusions, but you also have to have a clinical component that it's severe enough. By that they mean an NIH Stroke Scale equal or greater than five or an NIH Stroke Scale less than five but with a disabling deficit.
There are two things that I would say are suboptimal about the MeVO original definition. One is that they consider medium vessel-sized vessels that are in the two to three millimeter range, and I would say that most M1s are in the range of 2.5 to 3.0 millimeters, and we know those are not medium vessel occlusions, they are large vessel occlusions.
The other problem is, when we start to add a functional or clinical component to an anatomic definition, you create confusion. We all know about the large vessel occlusion with mild presentation. It's one of the big dilemmas that you have to solve, right? And it's been studied in two global studies, the ENDOLOW study in America, Canada, soon to be in Germany, and the IN EXTREMIS-MOSTE study in France and United States. So there, you have large vessel occlusion with NIH Stroke Scale zero to five, right? But it's still a large vessel occlusion. So personally, I don't like mixing the anatomical definition with functional definition or clinical severity aspect because I think they typically go together but they can be independent from each other.
Dr. Negar Asdaghi: All right, Raul, a lot of information. Let me just try to recap this. We are talking about the definition of MeVO or DMVO, which stands for "distal medium vessel occlusions." You nicely highlighted that basically there are variabilities in how these entities are defined. Practically speaking, we have a definition based on a consensus paper that was led by Jeff Saver and colleagues that only looked at anatomical definitions. You mentioned three things to keep in mind, caliber 0.75 mil to 2 millimeters, tortuosity of vessels. Of course, the more distal, the more tortuosity and the more branching. And distance. And that's how MeVO was described in that classification.
There is another one, consensus paper that came out of Calgary, by Mayank Goyal and colleagues, where in addition to anatomical features that were mentioned in the first classifications, clinical function by way of NIH Stroke Scale and severity was also considered. And there, these anatomical features were needed in addition to either NIH Stroke Scale severity of over five, or if it's under five and specifically three to five, was considered for definition of MeVO that had to have produced clinical dysfunction, that in the decision of the treating physician would be disability-producing. Did I get all of that?
Dr. Raul Nogueira: You did. You're absolutely correct.
Dr. Negar Asdaghi: All right. I think we already highlighted or answered part of my next question. It is, what do we know about the clinical presentation of these distal and medium vessel occlusions? Just because there's a distal occlusion, does it necessarily mean that the patient is presenting with mild neurological symptoms?
Dr. Raul Nogueira: Absolutely, and that's a key concept, right? So, patients don't understand what their NIH number is, what their site of occlusion is. The thing that they do understand, and the thing that they're going to have to cope with for the rest of their lives, is the degree of disability. Obviously, there is a strong correlation between how proximal occlusion is and how severe and disabling your stroke symptoms will be. However, that correlation is not necessarily perfect. You can have a proximal occlusion with strong collateral flow and have relatively mild disability. But you also can have a distal occlusion in a very eloquent territory with suboptimal collateral flow and have a very high clinical presentation in terms of NIH and long-term disability.
You can also have a variation of that, which is a low NIH Stroke Scale. OK? But that NIH Stroke Scale is not a good representation of the overall disability. For instance, you can have a distal occlusion involving the ACA with ischemia to the motor cortex, where you essentially have monoplegia of your lower extremity. Right? That will give you an NIH of only four. However, if you don't treat that patient and that goes into infarction, that patient will have, at 90 days, inability to walk and, therefore, we'll have an mRS of four. Right?
Again, an example of a number is not necessarily adding up, and I think that's where precision medicine has to be incorporated on our daily practice. The reason why we use numbers to code NIH, modified Rankin Scale, is because when you do population studies, you can't really use out the individual characteristics of the patients, right? But as you depart from all the knowledge that you learned from randomized clinical trials, you have to adapt this knowledge to the individual situation of the patient. And I think the distal arterial occlusion is definitely a good example of a potential disconnect between numbers and site of occlusion with the overall degree of long-term disability.
Dr. Negar Asdaghi: Raul, beautifully mentioned. Let me just briefly recap. So, you had highlighted important issues in acute stroke treatment paradigm. Number one, distal occlusion does not necessarily mean low severity of neurological presentation. Eloquence has an important play in that. Number two, our ways of measurement of neurological severity in the acute setting is perhaps not the best way of measuring disability-producing syndromes. You had given us a beautiful example of a low or relatively low NIH Stroke Scale where a person is monoplegic from an ACA stroke that is extremely disability-producing. And finally, as many leaders in the field of mild stroke have also iterated the same sentiment, when it comes to the brain, any neurological symptom, however mild, may be quite disability-producing, given the pre-existing function of that person. So with all of that, then, if these syndromes can be disability-producing, it goes with no surprise that endovascular therapy is tried for treatment of these patients. Can you walk us through some of the challenges and specifically technical challenges of endovascular treatment for these distal occlusions?
Dr. Raul Nogueira: Absolutely, Negar. A lot of the things are getting a little more complicated, right? If you have a target, I would say the low-hanging fruit of thrombectomy. Now, you have the harder targets, including the type of ENDOLOW, right, with the LVO and mild clinical presentation. Those are patients where if you decide to treat them, you can't afford any complications and the distal occlusions. However, the distal occlusions are a much more heterogeneous population. And when deciding whether or not to treat a distal occlusion through individual decisions at the bedside, one patient at a time, we can balance the risks and benefits. The risks are mostly related to anatomical factors, right?
I'll call, again, attention to those three variables. Even though you call them distal occlusions, personally, I am not worried about how far the lesion is. I think the biggest enemy is tortuosity. The more tortuosity we have, I think, the more dangerous that procedure gets. Mostly when you are talking about mechanical thrombectomy and putting stent retrievers that we will straighten and stretch the anatomy of these vessels, potentially causing avulsion of the little tiny penetrating particles, little tiny vessels, that can cause bleeding and other problems. So, tortuosity is the big enemy.
Then, I would say, after tortuosity, the second concern is caliber, and my least concern is actually the distance. I'll give you a couple of examples. I would much rather treat a distal occlusion in an angular branch, OK, than a more proximal occlusion involving a distal M2 or proximal M3 branch in the superior division of the MCA. OK? Because at that location, you have the vessel going around the operculum and you have those S-curves, and it's a lot more dangerous to perform clot retrieval or to navigate larger catheters in those locations versus going farther in a vessel that typically has a good caliber and is straight, such as the angular branch, fetal division branches of the MCA, or the ACA-based PCA, they tend to be more favorable.
So, that defines the risk, right? What is going to define the benefit is obviously how viable that tissue is. So, do you have, and not only the volume of the ischemia but the intensity, the death of the ischemia. Right? We now know that we may not be able to necessarily shrink the size of the infarct, but you may be able to improve the quality of the final infarct. Some of the recent randomized clinical trials demonstrate great benefit, independent of having changed final infarct volume. So, you know it's not only quantity, it's quality.
So, if you have a patient that has a relatively straight vessel, it doesn't matter how distal it is as long as the caliber is reasonable enough, and it has a straight course and a highly eloquent cortex with not so much well-defined ischemic injury, I think this is the ideal target, right, versus a patient that it has a more defined infarct and a less eloquent cortex with a lot of tortuosity. And there, I always call the attention to the superior division, M3 branches, M4 branches, being a particularly challenging territory.
Dr. Negar Asdaghi: Raul, can you please also comment on the rates of perforation, vasospasm, dissection, or other complications with this?
Dr. Raul Nogueira: So, when you look at the retrospective data, the safety data has been looked by many groups, including our groups a couple of times. The safety data included in the DUSK study, a retrospective study we just are about to publish, it looks very good. OK. But we know from clinical practice, we know from common sense, from biological plausibility, that going more distal should be more dangerous than staying proximal. Right? I think, again, there is emerging data to support that tortuosity, it's a factor that contributes to hemorrhage, whether it's important subarachnoid hemorrhage or parenchymal hemorrhage. I think when you do the randomized clinical trials, one of my main concerns is safety. Right? If you can be safe, we should be beneficial.
Dr. Negar Asdaghi: Perfect. Let me briefly recap and then jump to the next question. So, we are talking about technical challenges and safety issues related to endovascular treatment of these distal vessels. We're back to those three anatomical issues that you mentioned earlier. Tortuosity, it was your number one concern when accessing these distal vessels, followed then by vessel diameter being the second most important concern. And then the last of concerns for you is actual distance to getting to that clot. In terms of safety data, you mentioned that what is published so far, majority of it retrospective data, seems to have shown a reasonable safety profile in terms of odds of vessel dissection, perforation, etc. However, data is needed from randomized studies.
Now, speaking of randomized studies, we had mentioned earlier that close to 40% of all target vessel occlusions are indeed in distal or medium vessels. But yet, these patients were obviously underrepresented or entirely excluded from the original large randomized trials. What was the actual frequency of MeVOs in those pivotal studies? And can you briefly tell us about the clinical angiographic outcomes of those subgroup patients?
Dr. Raul Nogueira: Unfortunately, the representation of MeVOs in the previous randomized clinical trials was very poor. Most of these trials, they, on purpose, planned to exclude the MeVOs. Many of them also planned to exclude M2s, but some M2 patients end up being enrolled in these trials. Some of these M2s are M1-like M2s, meaning largely dominant M2s that functionally may behave much closer to an MCA M1 than an M2.
But we had enough M2s that this great paper, published by Bijoy Menon from the Calgary group in the HERMES meta-analysis, that could identify patients that had M2 occlusions and seem to benefit from treatment. It's specifically those with the dominant M2s and proximal lesions were the patients that had statistically significant benefit with thrombectomy in subgroup analysis of randomized clinical trials. I personally don't think that if you have a disabling deficit, forget the score in the NIH, right? I think if you have an NIH of three or four with a significant aphasia and an M2 occlusion, that's a tough patient to exclude from thrombectomy even though it's not Class 1A guideline, versus there are many patients that were not well-studied in these trials, specifically ACA and PCA were not well-represented. There were few ACAs in the MR CLEAN trial. We can't really come up with any conclusions about the MeVOs on either the HERMES or AURORA meta-analysis. So, the trials that are ongoing and hopefully soon to be completed are very much needed, and we will find out as to whether any risks that are theoretically higher in this vascular target will be outweighed by the greater benefits of reperfusion in these smaller territories.
Dr. Negar Asdaghi: Or so we hope, obviously. So, let me recap. So basically, we're talking about under-representation or entire exclusion of some MeVOs or DMVOs from the large trials. You mentioned that we have to keep in mind that data that we currently have from randomized trials that suggest the benefit from endovascular therapy essentially all entirely comes from almost dominant M2s. So, these are M2s that are acting as an M1 almost. And in those sub-analyses, mostly from the HERMES collaboration, we found a benefit from endovascular treatment over maximal medical therapy. But one has to note that data is almost very scant, if not non-existent at all, when it comes, for instance, for A2 occlusions. So, the ongoing randomized trials would be very informative for benefit versus not of endovascular therapy in those patients.
Now, this is a great background to bring us to the paper you have in this issue of the journal from the DUSK collaboration. Raul, please do tell us what does DUSK stand for, and tell us about the methodology of your paper.
Dr. Raul Nogueira: Sure. So, DUSK, it was an attempt to give us another expansion of thrombectomy following the idea of the DAWN trial. It stands for a "Distal MediUm Vessel Occlusion StroKe" trial. In this DUSK retrospective paper, it was a multinational collaboration involving a total of seven institutions, including six North American centers and one center in Spain, Barcelona. We pulled together 321 patients, out of which 179 patients underwent mechanical thrombectomy, and 142 were treated with medical management alone. Overall, 41% of the patients received intravenous thrombolysis. OK? And here, I would make a small comment about intravenous thrombolysis. I am very excited about exploring mechanical thrombectomy for distal arterial occlusions, but I strongly believe that we need to explore better ways to perform intravenous thrombolysis in these patients. I think we now have data from TIMELESS. While the trial was negative, there was no efficacy of TNK in late large vessel occlusion-presenting patients, but it was safe, right?
So, I really think we need to concentrate our efforts in expanding the window and the FDA label for intravenous thrombolysis beyond four and a half hours because endovascular thrombectomy mostly in the distal territory, it's not going to be something that it's going to be readily available in most stroke centers across the world. The benefit, it's going to be smaller, the risk is going to be higher, even if these trials are positive. I think intravenous thrombolysis might be a way where you penetrate more stroke centers and offer a greater benefit to more people.
With that in mind, I will go back to our paper. Again, 41% of the patients received intravenous thrombolysis, which is very important for us to know because even though intravenous thrombolysis works better for lower clot burden situations as the distal occlusions, you see a lot of the cases still fail. In fact, when you look at the literature, thrombolytics only recanalize about 50% of these distal occlusions, of these MeVOs, 50%, which is quite disappointing, I think. But we need to understand that you're coming up with adjunctive therapy, better thrombolytics, things like von Willebrand factor antagonists, things like nanotechnology, right? Nanodevices. You're about to start the field of nanothrombectomy where you're going to infuse iron beads that are as small as 90 nanometers, way smaller than a red blood cell, in the brain. And with the help of a magnet, you can guide these nanometer microbeads across the clot and have mechanical thrombolysis of small clots, and perhaps even clean up the microcirculation and prevent no-reflow phenomenon.
But going back to our paper again, it's hard to contain the excitement with all the new technologies and everything that is coming up. But going back to our paper, so this is a retrospective review. We had, again, a relative good sample size, understanding that it's 321 patients and it is retrospect. Most of the ongoing clinical trials that are trying to show a benefit, we all assume that the sample size should be around 500 to 600 patients. So, this is not only retrospect, but we need to accept that it's also underpowered. So, our best hope here is to see signals. The results, as we are going to detail, they didn't show anything statistically significant. But let's look at the signals, and the importance of these results to what is currently happening is that it will maintain the equipoise we should still have in this patient population.
So, we perform a multivariable regression model, and more importantly, we did better adjustment use and inverse probability treatment weighting, which is the more interesting analysis of our patient population. Our primary outcome was the ordinal shift at 90 days. So, jumping to the results, we did fail to show a benefit in terms of our primary endpoint. Our primary endpoint, there was a direction of potential benefit, but that didn't reach a statistical significance. Specifically, what we found was that we had an odds ratio of 1.25, which is acceptable in the direction of favoring distal thrombectomy. But the P-value was 0.11, which is even short of a 0.10, which is when you start to get more excited about at least seeing a trend. But I'll remind everyone that, again, the calculated sample size of the randomized clinical trials that we expect to potentially show a benefit, it's almost twice what you're seeing here. So, yes, the study is negative, but it's likely underpowered as well.
Interesting, there was a trend towards a benefit. Again, a P-value that is not less than 0.05, but it's between 0.05 and 0.10, we call that a trend. It's exciting, it's hypothesis-generating. In terms of functional independence at 90 days, mRS is 0 to 2 with an adjusted odds ratio of 1.32 favoring the intervention. And that same number, 1.32, favoring the intervention was seen in terms of excellent outcomes, mRS 0 to 1 at 90 days.
So, some potential signals here, but overall you need to call what it is, the analysis is negative. Not only it's retrospective, it's underpowered, it couldn't show a benefit. And I think they should add to this important issue of, we don't really know what you're doing when you are treating these patients and you need these randomized clinical trials. Equipoise is retained, and I think that on its own, it's a very important contribution of this work, but let's keep those numbers in mind. We may have odds ratio in this range of 1.3, 1.25. And if you have large enough of a sample size, and it may not even be the 600, 500 to 600 from any single trial, but it means the pooled analysis of all these trials with perhaps a couple of thousand patients, we may see numbers like that. I suspect that the treatment effect size of distal thrombectomy, it's not going to be as high as what you are used to see with proximal thrombectomy.
Finally, I want to say there was no signal of safety concerns. Right? So, the rates of symptomatic intracranial hemorrhage and mortality did not significantly differ across the two groups.
Dr. Negar Asdaghi: Wow. A lot of information. Let me see. So, we're talking about the DUSK study, which was a multi-center retrospective study that included six centers from North America, one from Spain. You had a total of just over 300 patients, so a small sample size, and the treatment decision was left to the decision of the treating physician. So interesting, Raul, as part of routine care, over 50% of the total sample size, 179 patients out of 321 patients, received endovascular treatment. The remaining 142 received maximal medical therapy that included, in either arm, IV lytics. A total of 41% received IV lytics. But that alone is an important observation from your study because we just spent the first part of the interview talking about how there is lack of robust data from randomized trials on going after these occlusions with endovascular therapy. And here, an observational study of routine practice shows that the majority of your sample size actually received endovascular treatment. So, that was interesting for me.
You nicely highlighted the salient findings. So, the primary results was whether there was an ordinal shift of modified Rankin Scale at day 90, and your study failed to show a shift in favor of thrombectomy in the study. But reassuringly, there were some favorable trends sort of towards a benefit for thrombectomy that didn't reach a statistical significance for achieving good functional outcomes, that's an mRS of zero to two, or excellent functional outcome, that's a zero to one mRS. These are promising results, but hypothesis-generating. P-values were not significant. And very importantly, you did not find a major safety concerns in terms of risks of symptomatic intracerebral hemorrhage or other safety concerns in patients treated endovascularly. Did I get all of it?
Dr. Raul Nogueira: Absolutely. A great summary. The only thing I failed to mention, Negar, is that something that has a very high biological plausibility is, obviously, the more eloquent territories with higher clinical severity are the targets that potentially can lead to higher chances of a benefit. We did see that. We didn't see a treatment effect modification for any subgroup analysis in terms of shift, but for both mRS zero to one and mRS zero to two, the subgroup of patients with NIH equal or greater than eight actually had a statistically significant benefit.
Jump from a trend to actually statistical significance. It's a subgroup analysis. If you do a Bonferroni correction for multiple hypothesis that you look into the subgroup analysis, that effect will disappear. But it is a very strong interaction with a P-value of 0.001. So, it sounds like the patients with higher disability might be the ones that will have a higher chance of a benefit, which is very similar to what you saw in the LVO situation as well.
Dr. Negar Asdaghi: Great, Raul. Let me recap what you just mentioned. In the subgroup analysis of patients who presented with more severity-producing strokes that's captured by NIH Stroke Scale of equal or greater than eight, there was a trend towards benefit from endovascular therapy for the outcomes of good functional outcome, that's mRS zero to two, and excellent functional outcome of zero to one.
So, this is really interesting data that points to that equipoise regarding best treatment for these patients. And Raul, we already alluded to the ongoing trials. We have six ongoing trials now on the subject of medium or distal vessel occlusion. Let me see if I have all the acronyms correct. So, we have DISTAL, DISTALS with an "s," DISCOUNT, ESCAPE-MeVO, FRONTIER, and your trial, the DUSK trial. Can you please briefly tell us about these trials?
Dr. Raul Nogueira: Sure. So these trials, fortunately, share a lot of common aspects, which will be very important for the data poolability. In general, we are looking at primary endpoints that involve the 90-day modified Rankin scale, with the exception of the DISTALS trial that is seeking to get the device approval with the mini Tigertriever stent retriever. All the other trials, they're really exploring the clinical benefit of this therapy either using ordinal shift or dichotomized mRS at 90 days.
Then, there are small differences across the different trials in terms of the minimum size of vessels, in terms of the time from stroke onset to treatment that it's included, whether it's 12, 24, so on and so forth. Also, to the way they deal with intravenous thrombolysis. Whether intravenous thrombolysis is accepted or not, whether you have to fail intravenous thrombolysis before randomization, or you just go and get randomized immediately after intravenous thrombolysis. We have noticed that some of these trials, talking to colleagues, patients that undergo intravenous thrombolysis and go for an angiogram, there are a lot of cases of reperfusion. So, you know that. Intravenous thrombolysis for MeVOs was about 50% reperfusion.
So, what I think is great about having so many trials is maybe because you are potentially looking at much smaller treatment effect sizes, what you saw with the trials with odds ratio of 2.5 or even higher sometimes, that is the low-hanging fruit. The ideal candidates, right? It's the antibiotics in sepsis situation. Now, I think we are looking at the patient population that hopefully will still benefit, but it's perhaps a more modest benefit. So, having all these trials potentially giving us the equivalent of a HERMES meta-analysis, AURORA meta-analysis, that has been done in LVO, for a distal occlusion. So, it's very important. And I suspect that subgroups such as the NIH equal or greater than eight, as well as those patients that have not received or have failed intravenous thrombolysis, those subgroup analyses might be specifically important. And in order to have a high chance of having statistical significance, we need high numbers. So, it's very fortunate that we have not necessarily a global collaboration in the sense of the same trial, but a lot of parallel trials with similar objectives.
I would add to all these trials, a trial called ORIENTAL-MeVO. That's a trial that I'm collaborating with one of my colleagues in China, in Hefei, China, Wei Hu, the same collaborator from the ATTENTION trial for basilar artery occlusion. That trial is moving very quickly in China, and we are hoping to be able to contribute on top of these six trials with a seventh trial, which will bring some novelty because it's going to be focused on the Asian population where you may have a little bit of differences in terms of stroke etiology, as we all know.
Dr. Negar Asdaghi: Great, Raul. So, the correction to an earlier statement was that we actually have more trials than six, and another trial is the ORIENTAL-MeVO, run in China. You highlighted the importance of having these parallel trials all in various completion states, and being able to pull data from all of them as the benefit from endovascular therapy is likely going to be a more modest benefit as compared to the original LVO trials. So, we look forward to the completion of these trials and having robust data for treatment of patients with distal and medium vessel occlusion. Thanks so much, Raul. What should be our top takeaways for this topic?
Dr. Raul Nogueira: I think the most important message is, one, if you can contribute to a randomized clinical trial, please do so. Also, do it without any cherry-picking. It will contaminate the results of these randomized clinical trials, and you really need to know without any doubts who are the patients that you are benefiting in the future. If you can contribute to a randomized clinical trial or if the patient's not a candidate, please remember about the points we discussed in terms of risk-benefit, specifically in those distal superior division branches that are very tortuous. Think about using intraarterial thrombolytics or being conservative with your stent retriever aspiration catheter as much as possible. That's a dangerous territory, and we can't afford complications because the natural history of these patients are better than LVO.
Finally, we can now hope that these seven randomized clinical trials will show a benefit or at least identify the subgroup of patients. And again, we suspect that the higher NIH Stroke patients, as demonstrated here in the DUSK retrospective cohort, and/or the patients that fail or have not received intravenous thrombolytics might be the even better target for this therapy.
Dr. Negar Asdaghi: And these are the words of wisdom. Dr. Raul Nogueira, thank you very much for joining us on the podcast.
Dr. Raul Nogueira: Thank you, it's been an absolute pleasure.
Dr. Negar Asdaghi: And this concludes our podcast for the June 2024 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications. Now, as promised, we will end this month's podcast with the developing news of science coming out of the 2024 European Stroke Organisation Conference, which is live now in Basel, Switzerland. With over 4,600 stroke providers and participants attending this year's conference, ESOC is one of the largest scientific platforms in stroke. This year, the scientific committee planned for an additional fourth plenary session in ESOC to accommodate the large number of clinical trials and late-breaking abstracts submitted for presentation. And what we've heard so far was certainly not disappointing.
On the topic of acute ICH, we have the long-awaited results of the ANNEXA-I trial. Presented at the conference and published simultaneously in the New England Journal of Medicine, ANNEXA-I studied the efficacy of andexanet alfa over standard of care in patients with anticoagulant-associated ICH in the setting of a factor Xa inhibitor use. ANNEXA-I was the result of an incredible multi-center collaboration between June 2019 to May 2023. A total of 550 patients with factor Xa-associated intracerebral hemorrhage from 130 sites in 23 countries were enrolled. The most common Xa inhibitor use was apixaban. In over 60% of participants, apixaban was used. Patients were then randomly assigned to two treatment groups: 263 patients were assigned to receive andexanet alfa, and 267 to receive the usual care. A quick note that the majority of those in the usual care group received prothrombin complex concentrate for reversal of coagulation.
The primary efficacy was a new outcome of hemostatic efficacy that was defined if all of the following criterion were met. Now, please bear with me. This is a complex primary outcome, which included expansion of the hematoma volume by less than 35% of the original volume at 12 hours after baseline, or an increase of NIH Stroke Scale of less than seven points during the same time point, which is 12 hours, or no receipt of rescue therapy. Now, that's a little bit complex, rescue therapy had multiple meanings, but essentially the patient would have met this criterion if the patient would not have required any further reversal agents or a patient did not need surgical treatment, that's decompressive surgery for their presenting intracerebral hemorrhage. This criterion was basically measured between three hours to 12 hours from baseline.
So, if all these three metrics were met, then the person would have met the primary outcome of hemostatic efficacy. A very quick note for our listeners that this is a very different and a bit unusual primary outcome for ICH trials. In general, the typical intracerebral hemorrhage primary outcome is modified Rankin at six months.
So, what did they find? The primary outcome was actually met in the andexanet group. In fact, the hemostatic efficacy was met in 67% of participants receiving andexanet alfa versus 53% receiving usual care, a difference that was statistically significant, mostly driven by the difference in the hematoma expansion rate. So, that's all great. But sadly, the primary safety outcome, which was the rate of thrombotic events by 30 days, was also higher in the andexanet group. 10.3% of patients receiving andexanet alfa versus 5.6% of patients receiving the usual standard of care suffered from a thrombotic event in that timeframe. Ischemic stroke occurred in 6.5% of andexanet alfa-treated patients versus only 1.5% of those receiving the usual care. There was no statistically significant difference in the rate of death at 30 days between the two groups.
So, we truly have mixed emotions about the ANNEXA-I results. On one hand, andexanet resulted in better control of hematoma expansion, which, as we know, is an important predictor of outcomes in intracerebral hemorrhage. But it did increase the risk of thrombotic events by 30 days, including the rate of ischemic stroke. So, the risk-benefit of andexanet should be weighed in this setting.
Next in ESOC, we have the primary results of the SWITCH trial presented and simultaneously published in Lancet to look at the efficacy of decompressive craniectomy versus best medical management in patients with spontaneous deep intracerebral hemorrhage. As we know, the recently published ENRICH trial showed a benefit from minimally invasive surgery in patients with intracerebral hemorrhage, but the benefit was predominantly derived from treatment of patients with a lobar hemorrhage rather than deep intracerebral hemorrhage. So, the SWITCH trial looked at a different population than ENRICH. Now, before we go through the results, we have to note that SWITCH was early terminated for funding issues, so this has to be kept in mind when reviewing the results. They had 201 participants from 42 centers across Europe with severe deep spontaneous intracerebral hemorrhage either in basal ganglia or thalamus were included and randomly assigned to either decompressive craniectomy, of course, in addition to best medical therapy, or best medical therapy alone. The primary outcome of the trial was a score of five or six on the modified Rankin Scale at 180 days.
So, what did SWITCH show? The primary outcome occurred in 44% of patients in the surgical arm versus 58% in the best medical treatment arm. So, less patients were dead or severely disabled in the surgical arm. This was almost statistically significant in the complete case approach analysis with P-value of 0.057, barely passing the 0.05 line, but statistically significant in their multi-imputational model, which effectively translates into a weak evidence in favor of decompressive craniectomy in the population of patients with a severe and deep supratentorial spontaneous intracerebral hemorrhage.
Finally, before we end, we're going to review one more trial. That's the INTERACT4 trial, also presented at ESOC and published simultaneously in the New England Journal of Medicine. INTERACT4 was exceedingly interesting. It studied the effects of intensive ambulance-delivered blood pressure reduction in the hyperacute state of stroke. The trial was completed in China. A total of 2,404 patients with suspected acute stroke that had caused a motor deficit and had elevated systolic blood pressure of equal or greater than 150 were eligible to be randomized. If the patient had used an ambulance, obviously, to come to the hospital, and they had to have been within two hours from their symptom onset, they were randomized to the usual care group versus to an intensive blood pressure reduction group with a target blood pressure of 130 to 140.
Now, we have to note that they had stroke-like presentation but not yet imaged to have this diagnosis confirmed. Stroke was subsequently confirmed upon arrival in over 2,200 of these patients, and almost half of these patients, that's 46.5% to be exact, had a hemorrhagic form of stroke. At the time of arrival to the hospital, the mean systolic blood pressure in the intervention group was 158 compared to 170 millimeter of mercury in the usual care group. So truly, that time in the ambulance and the invasive blood pressure reduction did help to reduce the blood pressure acutely.
Overall, their primary outcome of mRS at 90 days was basically similar between the two groups of intensive versus standard blood pressure treated groups. But the odds of good functional outcome, that's mRS of zero to two, was significantly higher in patients who ended up having an intracerebral hemorrhage that, as we mentioned, was about 50% of their population upon hospital arrival. So, INTERACT4 emphasizes the importance of early reduction of blood pressure in patients with hemorrhagic stroke, and once again, reminds us that imaging tools are badly needed to distinguish between ischemic and hemorrhagic forms of stroke in the pre-hospital setting.
So with that, we close our June 2024 issue of the podcast. Of course, this is just a fraction of science presented at ESOC, and we'll do our best to cover more in our future podcasts. Until then, I invite you to stay alert with Stroke Alert.
This podcast is produced by Wolters Kluwer and supported by the editorial team of Stroke. Our Stroke Alert podcast and production staff includes Eric Goldstein, Nastajjia Krementz, Luis Paixao, Ishara Ratnayaka, Fernando Henry, Erinn Cain, Rebecca Seastrong, and Negar Asdaghi. This program is copyright of the American Heart Association, 2024. 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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