Stroke Alert June 2025

Let's start with some questions. Does intensive blood pressure lowering in the setting of acute ischemic stroke reduce the odds of development of post-stroke cerebral edema? Does a degree of hypodensity on non-contrast CT of the brain predict thrombectomy outcomes in patients with a large ischemic core? And finally, what is the difference between futile recanalization and the no reflow phenomena?

We'll tackle these questions in today's podcast, answer a few, and create a lot more. You're listening to the Stroke Alert Podcast, because this, without a doubt, is the best in Stroke. Stay with us. Welcome back to another issue of the Stroke Alert Podcast. My name is Nagar Azdagi. I'm an associate professor of neurology at the University of Miami, Miller School of Medicine, and your host for the monthly Stroke Alert Podcast.

For the June 2025 issue of the podcast, we're picking up where we left off in May, continuing on the topic of minimally invasive hemotoma evacuation in patients with spontaneous interstereal hemorrhage. This time, as part of a study from the Get with the Guidelines Registry. In this paper, Dr. Santosh Mursi from Whale Cornell Medicine and colleagues.

Studied the outcomes of seven hundred and three patients with spontaneous interstrebal hemorrhage who underwent minimally invasive surgery, three hundred and twelve underwent stereotactic surgery, and three hundred and ninety-one endoscopic surgery. within the average of two days after intercerebral hemorrhage onset, and they compared these outcomes to the outcomes of over 550,000 spontaneous intercerebral hemorrhage patients who were conservatively managed.

between twenty eleven to two thousand twenty one. After propensity matching for demographics and ICH severity, minimally invasive hematoma evacuation was associated with significantly lower in-hospital mortality rate. That's 13.5% versus 23.5% in the conservatively managed RM. and a higher likelihood of favorable discharge disposition, as well as lower risk of death or hospice discharges, as again compared to the conservatively managed population. Very cold and reassuring.

Staying on the topic of hemorrhagic stroke, in a separate paper in the Social The Journal, doctor Huan Wen Chen from the Department of Neurosurgery at the University of Maryland and colleagues. Take us through an analysis from the nationwide readmission database of the United States. On outcomes of non-traumatic, non-surgical subdural hematoma patients who have either received standalone middle meningeal artery embolization or MMAE or treated conservatively.

We all know that recent randomized trials have shown that MMAE is effective and safe when used alongside surgical evacuation or treatment of non-acute subdural hematoma patients. But what about those who are not deemed to be surgical candidates? After all, a challenging aspect of subdural hematoma management is its persistence over time, with up to twenty percent of conservatively managed Chronic subdural hematomas eventually requiring rescue surgical evacuation.

So the role of MMAE as a standalone treatment in patients not undergoing surgery and its impact on the eventual need for having a rescue hematoma evacuation deserves more research. Which brings us to a paper in this issue of the journal where the authors analyzed data from over 24,000 non-surgical and non-traumatic subdual hematoma patients. That were included in the nationwide readmission data set in the United States between 2019 and 2021.

Then they compared outcomes of 2,228 patients who received standalone MMAE to outcomes of over 6,000 patients who were managed conservatively. And what they found was that at 180 days, the MMAE group had a significantly lower risk of the composite outcome of death. or the need for rescue surgical hematoma evacuation, an improvement that was practically driven by lower all-cause mortality rate in the MMAE group over the conservatively managed group.

The survival benefit from these real world data in both the subdural and interestrual hemorrhage patients is highly encouraging as the results of recently completed anonymized trials are adopted into routine care. As always, I encourage you to review these articles in detail in addition to listening to our podcast today.

Later in the podcast, I'm joined by Drs Samantha Rivert and Felix Ng to discuss the very timely and exceedingly relevant topic of post thrombectomy noriflow phenomena. And get an update on the latest randomized trials in this space, including the one that Dr. Ying is leading himself. They say conducting a randomized trial is like raising a child with all the highs and all the hopes. Here is doctor Ing on how he feels about his trial. Take a listen.

Hello, I'm Dr. Felix. I'm the PI of the Extend Acnes TNK trial, and this stands for Post Thrombectomy Intraarterial Tenectoplase for Acute Management of Non-Retrievable Thrombus and Nodiflow in Emergent Stroke. Agnes is also the name of my three year old cheeky baby daughter, and I love both Agneses, and I hope both grow healthy and strong and will change many people's lives for the better when they grow up.

But before we go to this interview, let's first go to our summary section prepared by my assistant editors, Drs. Nastasia Kremens and Erin Shoskis. Together, we're bringing you the latest in the world of serovascular disorders. Stay with us.

Post stroke cerebral edema, comprising of cytotoxic and vasogenic components, is a major complication of acute isemic stroke, linked to worse clinical outcomes and extended duration of hospitalization. In severe cases, post-stroke edema can increase intracranial pressure, lead to herniation syndromes, resulting in rapid neurological deterioration, a form that is commonly referred to as malignant cerebral edema.

Several characteristics have been linked to development of post-stroke cerebelledema, including hypertension. In fact, elevated baseline blood pressure has long been recognized as a significant predictor for development of malignant form of cerebral edema. Together with other characteristics such as age, presence of a large vessel occlusion, and importantly, large volume of ischemic stroke.

But the effect of acute blood pressure reduction on reducing cerebral edema is not well understood. In fact, when it comes to blood pressure management in the hyperacute setting or the acute setting of ischemic stroke, The cumulative literature suggests that rapid reduction of blood pressure can be harmful. Our stroke alert listeners recall that we covered the topic. A blood pressure reduction in the past podcast when we review the results of the Interact 4 clinical trial.

showing that blood pressure reduction in the pre hospital setting of stroke results in worsening of 90-day functional outcomes in those patients who end up having an ischemic stroke. But the argument is that it is possible that the harmful effect of blood pressure reduction may be relevant to its role in reducing collateral flow and reducing cerebral profusion pressure rather than its impact on cerebral swelling. So more studies to understand this relationship is warranted.

Which brings us to a paper in this issue of the journal, where we learn about the effect of intensive blood pressure reduction on brain swelling in thrombolyzed patients with acute schemic stroke as part of a secondary analysis of the Enchanted Trial. First stop, what was the enchanted trap?

The acronym stands for the Enhanced Control of Hypertension and Thrombolysis Stroke Study. This was an international multi-center open-labeled randomized clinical trial looking at blood pressure control after thrombolysis. Over two thousand one hundred acute schemic stroke patients were enrolled from one hundred ten hospitals in fifteen countries from March 2012 to April 2018 in the Enchanted Trial.

Patients were randomly assigned to either receive intensive blood pressure lowering, that is achieving a systolic blood pressure of one hundred and thirty to one hundred and forty millimeter of mercury. within one hour of enrollment and maintaining at this range for seventy two hours, or receiving the usual care with regards to blood pressure, that is maintaining guidelines recommended systolic blood pressure of less than 180 millimeter of mercury after thrombolysis.

The main trial results were published in Lancet in 2019, which showed that 90 days functional status, that is a distribution of modified ranking score, did not differ between the two groups. However, fewer patients in the intensive blood pressure group had any intracranial hemorrhage. Now, in the current paper in the Sisha The Journal, we have a subgroup analysis of enchanted randomized trial by lead author Doctor Gyu Ben Zhang from the Department of Radiology.

at Shanghai Six People's Hospital to look at the association between blood pressure reduction and post-stroke swelling. This study included fourteen hundred seventy seven patients that were enrolled in the trial, in whom follow up brain imaging was available to look at the post stroke swelling, The participants' mean age was 67.7, and close to 40% were women with median and eye stroke scale of eight. So these were predominantly moderate severity ischemic strokes.

all of whom had received intravenous thrombolysis. Baseline characteristics and treatments relevant to cereal edema post randomization, for example, the use of endovascular therapy, use of manitol, were all similar between the intensive and guidelines recommended blood pressure management groups. However, as expected, those in the intensive blood pressure arm had a higher frequency of antihypertensive medication use.

as compared to the control arm, and the achieved systolic blood pressure in the first 24 hours was, as intended, lower in the intensive group. as compared to the conservative and guidelines recommended managed group. But the actual difference between the mean systolic blood pressure of the two groups was only seven millimeter of mercury.

In other words, the mean systolic blood pressure in the intensive group was one hundred and forty point four millimeter of mercury, versus in the conservatively managed group That means systolic blood pressure was 147 millimeter of mercury, and this small difference should be kept in mind as we review the results. So with that, they were interested to compare the follow-up scans with regards to the amount of post-stroke swelling developed in each arm.

The follow scans were on average completed about twenty seven hours after symptom onset. And they score cerebral edema in these scans using established and simple visual scoring system to rate cerebral edema with scores ranging from zero to six. Zero meaning no swelling and six indicating large cerebral edema, midline shift, and effacement of the neighboring cisterns and ventricles. So with all of this, what did they find?

They found that there was no significant difference in terms of the rate of post-stroke swelling between the two groups. However way they looked at the scores, either in the frequency of any degree of cerebral swelling, or the distribution of the swelling scores or the rate of severe swelling on follow-up imaging between the group of intensively managed blood pressure as well as guidelines recommended blood pressure.

In other words, intense and early reduction of blood pressure within the first day after ischemic stroke onset. Did not make a difference in odds of development of post-stroke cerebral edema or odds of development of severe post-stroke cerebral edema.

But we have to note that the median time from stroke onset to follow up imaging in this subgroup analysis of Enchanted was just twenty-seven hours, so the study couldn't evaluate cerebral edema in the later time frame after stroke onset, which is definitely a limitation of this study.

And another limitation being that actual difference in mean systolic blood pressure over 24 hours was just under seven millimeter of mercury or which may have not been large enough to detect a difference on impact of blood pressure reduction on post stroke swelling. And finally, enchanted in general enrolled moderate severity strokes, so likely not capturing those large volume strokes that are certainly at high risk for development of post-stroke ademia.

Keeping all these limitations in mind that The main take-home point is that this secondary analysis of Enchanted Twilight does not support the widely accepted notion that acute reduction of blood pressure lowers the rates or severity of post schemic stroke cerebral edema. in patients treated with intravenous thrombolysis.

There's now strong evidence to support that endovascular therapy is an effective treatment for patients presenting with a large skippic cord. But are all regions within the schemic core created equal? Or is it possible that some areas are too far gone and unlikely to benefit from mechanical throbectomy?

In this issue of the journal, we have a paper by Dr. Jogen Brachemar from the Ottawa Hospital and the Select Two Randomized Trial Investigators to study whether the presence of severe hypodensity in the schemic core can modify thrombectomy treatment effect in the large core population. Let's dive. Select two randomized trial was one of the six randomized studies. that evaluated the role of Navas were thrown back to me in the large ischemic core population.

The trial included schemic stroke patients with large core presenting up to twenty four hours from onset, with either an intracranial internal carotid artery or an M1 occlusion, Large core was defined as either an aspect of three to five on non contrast CT or a core volume of greater than fifty CC by CT perfusion. Overall, Select 2 showed a robust benefit from mechanical thrombectomy over medical management.

With functional independence at 90 days, that's modified ranking of zero to two, observed in twenty point three percent of patients in the thrombectomy group as compared to seven percent of patients in the medical treatment arm.

translating to a number needed to treat of seven point seven for achieving functional independence at three months with thrombectomy. Now back to the paper in this issue of the journal that similar to the first paper we just reviewed is also a secondary analysis of a randomized trial. The authors looked at the scans from three hundred and twenty two patients that had follow up imaging. Roughly half of them were randomized to receive thrombectomy, and the rest received medical management.

And they were interested in looking at the severity of hypodensity on the initial qualifying non-contrast C. For our listeners, of course, this is an audio only podcast, so I encourage our listeners to look at the figure three of the paper and figure five in the supplement. That could serve as nice pictorial examples for their methodology, but basically they used Houseville Units Threshold.

First, they manually created a region of interest mapping the entirety of the ischemic core area. The median volume of ischemic core across all patients, regardless of treatment allocation, was 89cc. The median hypodensity of the ischemia, as measured by Hansfell Unit, across all patients, was 31 Hansfall unit. So almost 90cc of core with an average hypodensity of 31 house full units.

Now the problem is when we say thirty one Hounfell units across the entirety of core, we have to realize that not all voxels within the schemic core have the same degree of hypodensity. We know that isemic changes follow a slow gradient. We go from regions with early schemic changes to subtle hypodensity all the way to areas with severe hypodensity on non-CORN CT.

Importantly, side-by-side voxels can have different degrees of schemic intensity. So the question is whether presence of voxels with severe hypodensity could impact the thrombectomy treatment effect in this large core population. Well, that's the question they intended to answer. How did they define severe hypodensity? They measured voxels with handsful units that would fall below the handsful unit of normal grey matter.

For the normal gray matter, they chose the contralateral thalamic region for each scan, and it turns out that on average, The ninety nine percent lower boundary of confidence interval for normal grey matter was the value of twenty six handsful units, which is the threshold they chose for the for defining severe hypodensity on non-contrast CT. Approximately 17% of total ischemic core volume across all scans.

had severe hypodensity, but the median volume of severe hypodens voxels being around 15 cc. Now, remember the average core size was just under 90cc, and now we have 15 cc on average with severe hypodensity.

So, what does this all mean? It turns out that the volume of severe hypodensity is independently associated with endovascular treatment outcomes. For each one C C increase in the volume of this tissue under twenty six Hansville unit density, the odds of achieving functional independence, that's MRS of zero to two, or independent ambulation, that's MRS of zero to three, decreased by four percent. only in the endovascularly treated arm, but not in the medically managed arm.

Very interesting. What was their tipping point? Now you really like this one. The tipping volume was 26cc. The beneficial effect of endovascular therapy was lost in those large schemic core patients that had greater than 26 cc of severe hypodensed tissue on baseline non-contrast CT. And importantly, things started looking better in the medically managed arm with regards to the favorable clinical outcomes. And unfortunately, things start looking worse in terms of complication rates.

in these population with greater than twenty six C C of Severe hypertensive tissue. the odds of having significant midline shift increased with endovascular therapy. Endovascularly treated patients with these characteristics that are over twenty six TC of severe hypodensed tissue were three times more likely to require hemicroniactomy for malignant cerebral edema. over medically banished arms.

None of these associations, either in terms of association with favorable outcomes or association with complications, were noted in patients with more than twenty six C C of severe hypodensed tissue. who did not undergo thrombectomy. And importantly, these results persisted irrespective of the median volume of schematic core. In other words, The issue is not the size of schemicore, rather the intensity of hypoperfusion as measured by severe hypodensity on non-contrast CT.

which could suggest a rule of twenty sixes of sorts. Large core patients with more than twenty-six cc volume of severe hypodensity measuring less than twenty-six ounces per unit, not only may not benefit from mechanical thrombectomy, but also run a higher risk for development of complications Specifically, it's development of significant midline shift and a need for hemicraniactomy as compared to those large group patients that are only medically managed. If these findings are validated.

We can imagine severe hypodensity volume measurements being incorporated into our existing automated imaging AI models to help us make better decisions about which large corporations to take to throw them back to me and which to defer. Can't get enough of large core data, no worries.

In our next issue of the podcast, we'll have a review of all six large core trial randomized studies when the principal investigator of SELECT II, Dr. Amru Saraj, joins me on the podcast to discuss many more nuances. from concurrent utilization of intravenous thrombolysis to clinical and neuroimaging details of large core patients. And he gives us an update on the ongoing patient-level data meta-analysis of these six trials, and even gives us its name, the much anticipated Atlas Collaboration.

In the context of acute ischemic stroke, it's increasingly recognized that achieving successful recanalization does not necessarily guarantee adequate cerebral reperfusion at microvascular levels. The no-reflow phenomenon, characterized by microvascular perfusion failure, despite a complete restoration of macrovascular circulation, has emerged as a significant predictor of poor stroke outcomes. Following endovascular thrombectomy.

A better understanding of the no-reflow phenomena and its clinical implications is essential for improving early prognostication, post-thrombectomy, and for guiding the development of novel therapies. beyond the currently available reperfusion treatment options. In this issue of the journal, we learn more about this topic in a paper titled Persistent Tissue Level Hypoperfusion Negates the Clinical Benefit of Successful Thrombectomy.

Joining me now all the way from Australia are the first and senior authors of this paper, doctors Samantha Rivid and Feelings Inc. doctor Rivet is a vascular neuralgy fellow at the Royal Melbourne Hospital, where she's pursuing a master's of medicine at the University of Melbourne, focusing on advanced imaging in stroke and pathophysiology of microvascular failure in schemic stroke.

Dr. Ng is an Australian National Health and Medical Research Council senior research fellow and a renowned investigator in the field of ischemic stroke. is a practicing stroke neurologist at the Royal Mapport Hospital and Austin Health. Dr. Ying is a principal investigator of the ongoing Extend Agnes TNK double blinded randomized control trial that tests the efficacy and safety of intraarterial tenectoplase following thrombectomy.

It's an absolute pleasure to welcome them both to our podcast. Good evening from Miami and good morning, Melbourne. Felix and Samantha, welcome to the podcast. Thank you for having us. Kinegar, it's a pleasure to be here. Great to have you both. Felix, let's start with you. What is the difference between futile recanalization and no reflow phenomena?

Yes, so futile road canalization and no flow are two related, but sometimes mistakenly interchangeably used terms, but I think they're in fact distinct entities. And futile recanalization described the general observation that up to half of previously well patients continues to do poorly in terms of functional outcome. despite receiving what we consider as very successful from Bectomy technically, and that is usually considered as angiographic result of T2B or Bub.

And in this sense, recanalizing the occluded artery seems to be ineffective or futile because the good radiological outcome hasn't translated into an acceptable or good outcome for the patient. But feed our recognisation is a broad entity that are due to many, many factors that can range from pre thrombectomy things as well as postfrombectomy events even in that post-acute period. And this may be related to an individual's physiological funability.

the res the physiological reserve to withstand cerebral ischemia, whether they can bounce back and recover even after the best and most successful treatment.

And some of the the factors that relate this components would be their age, uh their baseline degree of cerebral white matter change on CT, whether they have got atrophy on the brain, whether they've got a previous stroke or any other neurological conditions that can be decompensated just by a stroke and also their collateral status to withstand a period of ischemia before receiving the perfusion. And there's also the consideration of

Um how much brain injury has there already been and sustained before the perfusion, whether there's non-salvageable tissue, and how much is there already even before the successful treatment? And this is especially relevant in the fast progressive. And so some of the uh variables that look at this would be the aspect score at baseline, the core volume, but also about the degree of hypodensity within the core.

But also post-stroke complications can also contribute, and that means cerebral edema, um symptomatic integrate cranial hemorrhage, and also post-stroke pneumonia and acceration, all these. contribute to whether a patient will do well at 90 days. And in contrast, a normal flow is is a distinct entity a around the acute period, and it is one of the pathophysiological entities that contribute to futile reconalization, but they're not equal.

And conceptually uh d this is considered as the ongoing failure to reprofuse the distal microcirculation, despite recanalising the proximal macrovascular uh occlusion. So in contrast to the conventional thinking of cerebral ischemia, that there's a thrombus upstream, occluding blood flowing downstream to the capillary bed. The nova flow for monominine pathology is actually right down in the downstream at or just before the capillary bed. So blood flow is flowing to the capillary beds readily.

There's no delay from the proximal to the capillary beds, but blood just cannot get through at the final end through the microcirculation to reach the end organ, which is the brain parenchyma. And lessons learned from animal models of nerve flow in stroke and also um sort of analogous a condition of nerve flow in other human organs, in the hearts, in the kidneys.

We know that there are several mechanisms that can all end up causing mycrofissal occlusions. And this might be mycrofromboli from fragmentation of the proximal clot, showering into the distal capillary bed. There might be a red blood cell or white blood cell aggregation and and adhesions to the microcirculation vessels wall due to inflammatory changes locally, causing upregulation of adhesion molecules such as ICAM and VCAM.

Within the neurovascular unit, the parasite can constrict, and also the astrocyte feeds can swell up and compress the micro vessels mechanically. As opposed to other contributors to futile recanalization, there's increasing evidence to suggest Nova Flow may be an active and potentially reversible factor, which means it might be a therapeutic target to improve outcome after standard treatment.

And therefore it is not surprising that it is gaining more and more attraction and attention in the stroke research community.

Felix, uh amazing learning for me. Uh let me try to repeat and recap some of it just to make sure that I got it. So very important concept because futile recitalization, at least the terminology of it is kind of used interchangeably as you mentioned with the no reflow. But um you put it very nicely. We think about futile recanalization is sort of as a more overarching, a bigger umbrella, a variety of reasons.

why we think opening a macrocirculation will not necessarily result in an ultimate perfusion and good outcomes. You highlighted the many of the factors of futile recatalyzations actually exist even before we proceed to thrombacteriomy things such as age, advanced microvascular disease, advanced white matter disease in a person who has pre existing conditions prior stroke.

low aspect. So if you have already a large area of uh excuse me, core, these are all predictors that yes, technically we have the abilities to open that blood vessel. But ultimately we will not get a major efficacy from this procedure. Now, there are a number of factors post-trombactomy that can also result in futile recanalization. You highlighted development of

post-reperfusion edema, post-reperfusion syndrome, a number of other conditions even non relevant directly to stroke, but impacting stroke outcomes, development of post stroke infections, pneumonia, and all of those things. Sort of

a very large concept of many factors, from demographic to pre stroke conditions to post stroke events that could ultimately result in futile recanalization. In contrast, the no reflow phenomena, which is one of the components of futile recanalization, is this newly more and more defined acute process whereby

Prior to thrombectomy, all things are in a sense pointing out to a potentially successful outcome, in a sense that there is not much deficit in terms of aspect. In fact, many of the studies we're going to talk about had good aspect, not much deficit. Pre existing white matter disease or other insults in the brain, good aspect, good scan, a achievable target in terms of access that target, large vessel occlusion.

Successful revascularization posttrombectomy and yet microcirculation is still plugged despite a macrovascular recanalization. And this may have a number of ideologies. You highlighted presence of potentially small microthrombi within these microcirculation. or development of acute edema in other components of the neurovascular system, such as pericytes and astrocytes, that swelling is something that would prevent that ultimate

Cerebral reperfusion, despite the fact that upstream blood vessels angiographically are open. Did I get all of that? Yes, yeah, it was very well summarized. All right. So if that is a difference and now we're learning more about no reflow, can you please tell us about the best imaging markers of defining no reflow?

So yeah, present imaging is probably the only practical modality to detect neuroflow in a clinical setting. And commonly this is used using C T perfusion and MR perfusion following successful treatment as a follow up imaging. that is done around twenty-four hours as a standard care i in many centers. But in essence there are two components in identifying neuroflow radiologically. Firstly, there is there must be evidence that there was a proximal occlusion, which has now been recandalized.

And effectively that means patients with a large fissile occlusion with radiological evidence that there is angiographic recanalization of this occlusion. And at the moment there's still some ongoing debate whether that this should be defined as Tiki two B, two C or or even three.

But the second component of defining and identifying Nova Flow is to demonstrate that after satisfying the first condition of every canalized station, that there is still ongoing flow compromise or hyper perfusion in the brain tissue itself. And uh this is uh most easily done as a post follow up.

Post-frombectomy, a scan with MR perfusion and CT perfusion. And some of the metrics that that has been used to assess this includes reduced cerebral blood flow or cerebral blood volume within the infarctate tissue compared to a mirror hemorrhaging. on the contralateral side. And some other papers have also defined this as region of T max more than six seconds in accordance with the conventional thinking of critical ischemia in the baseline and pre-treatment presentation setting.

But we keep in mind that this definition is based on proximal upstream occlusion, which pathophysiologically is fundamentally different from the pathophysiology of Nova Flow. At the moment there's still again ongoing debates about what is the best definition to to use to define tissue hyperfusion. Besides CT and MR perfusion scan, there are some other ways that infer the presence of Nova flow. So transcranal Doppler.

to detect elevated uh cerebrovascular resistance in the territory of the recanalized MCA vessel. That is a one marker that has been used. And recently there has been an approach to look at DSA data to reprocess them and to assess the time delay from arterial contrast inflow to venous outflow to infer whether there has been any tissue or capillary bets delay. Okay. So we are talking about how can we identify Noary Flow. We need

to use advanced imaging. And what I hear is the best advanced imaging markers uh still profusion imaging. C T and MR profusion are both available. And essentially we need to satisfy a bunch of Criteria here. Number one, there must have been a initially a proximal occlusion that then recanalized with a tiki of to be or better. Of course you mentioned there's some debate over exactly which ticky is accepted. So angiographic macrovascular opening of that occluded vessel needs to be satisfied first.

And then post thrombac to me and I guess I what you mentioned is up to twenty four hours post thrombactomy. We have to show by way of perfusion imaging, evidence of ongoing hypoperfusion, and the markers I heard is just reduction if in relative cerebral blood flow or cerebral blood volume relative to the good side in the affected side within the territory of the ischemic bed.

or increase T max over six seconds. Again, some debates regarding which exact number to use, seeing that T max of six was conventionally developed in cases where there is an actual proximal occlusion. Here we have removed the proximal occlusion. And you highlighted other modalities now being studied like transcranial Doppler with evidence of increased strepovessel resistance and also a DSA showing time delays.

um between arterial inflow and venous outflow to sort of gauge again this phenomena of no reflex.

So this is great stuff. And now I think we're gonna take a pause, Felix. I'll come back to you'cause I have a number of questions to ask, but I wanna go to the current paper and the citizen of the journal. We know the data is coming from three seminal trials. Samantha, can you please first tell us about those large clinical trials? Yes, of course. So this paper, as you said, brings together data from three major multi-center clinical trials that were conducted across Australia and New Zealand.

And all of which really had a big impact on how we treat stroke both locally and also internally. So the first is Extin IA, which is one of the five landmark trombectomy trials that was published in 2015, which really transformed the acute stroke care. And it's a trial that enrolled patient within 4.5 hours of symptoms onset and randomized them to receive either alteplase alone or alteplased followed by trombectus.

And despite enrolling only 70 patients, it really showed that trombectomy dramatically improved outcomes, with a 4.5-fold increase in the odds of achieving significant reperfusion at 24 hours. Next, there is extend IATNK, which compared tenectoplase to altoplase in patients heading to trombectin. And connectoplase is a more trombin specific trombolytic that has been tried as a alternative to Alta Pl.

And it was really one of the first trials to do so. And for a long time, it provided really the strongest evidence suggesting that tenectoplase might actually be superior to altoplase and improving functional outcome. Something that's now supported by recent meta-analysis. And finally, there was Extend IATNK part two, which focused on determining the optimal dose of tinectoplase, and it's helping to guide the dosing strategies that we use today.

Beautiful Samantha. So just for our listeners, we are looking at data from three of the most seminal groundbreaking trials in acute reprovisional therapies. the extent IEA trial that effectively showed the beneficial effect of endovascular thrombectomy added to thrombolysis in patients arriving early.

within four and a half hours all within thrombolytic time window. This was, of course, one of the five original trial to basically put endovascular thrombectomy on the map for acute uh therapies and strokes.

And also we're gonna look at data from two of the subsequent Extend trials, Extend IATNK Part One, that effectively This time compared the efficacy of altoplase versus tenectoplase at lower dose, 0.25. and the extend IA T N K part two, but this time compared tenectoplase at point two five milligram to tenectoplase at point four milligram, effectively showing that that extra higher dose of tenectoplase

did not offer added benefits and may actually add a role in increasing the risk in the acute ischemic stroke population. These are really important trials as really They paved the way of how things are done in terms of acute reprovisional therapies today.

So very excited to have data from uh these trials. Can you now talk a little bit about the current paper on what kind of patients were included in your study and what did you set out to find? So from the overall pool cohort, we included 456 patients. And as we said before, all of them had both received thrombolysis and undergone trombectism. And our goal was to explore the impact of no reflow on functional outcomes.

So as we said earlier, but I'll repeat it a bit again, these no reflow patients are patient who On engiography, had achieved what we normally consider near-complete or complete recanalization of the large vessel occlusion. Which in our trial, we use a conservative Tiki score of 2C to 3. But these patients, on their follow up post-treatment perfusion imaging, they still had persistent ipoperfusion within the infarct lesion.

So what we set out to do was to compare outcomes in this no reflow group, not only to patients with similar TK score and a normal perfusion. but also to those with lower levels of angiographic success, meaning either partial recanalization, ETK of 2B, or even unsuccessful trombectomy, a ETK of zero to two A. And our primary outcome was functional independence at 90 days, and it was defined at a modified ranking scale of zero to two.

And one of the key strengths of our study, I think, is beyond being based on a large prospective multi-center data set, is that we used a practical and also reproducible definition of no ref. And it's a definition that had previously been shown to be the most predictive of outcome across different imaging criteria that we spoke a bit earlier.

And it's basically a two-step approach. First, there's a visual assessment of IPO perfusion, and that's really used to reduce the impact of image and artifacts. And this is followed by a quantitative threshold to provide objectivity. And basically by using it here. And also confirming its ability to differentiate outcomes. I'll have speak a bit later. We are proposing it as a reference definition.

And we hope that it can be used in future no reflow research to really improve consistency within the field and also make findings easier to compare across studies. All right, Samantha. So really important points. These three trials have patients in them, all of them receive thrombolysis. And with the exception of those randomized in the original trial of extend IA who uh were randomized to no thrombectomy, all of them also received thrombectomy.

And here we're looking at a subgroup of patients in whom perfusion imaging was available before and after thrombactomy. And looking and seeing how those patients that had biperfusion criteria, the definition of no reflow did in terms of outcomes. Now the catch here is that all of those patients must have had, as the no-reflow criteria demands, a complete recanalization by the end of angiography. And you use a very conservative approach.

Tiki to see or better. So that's as good as it comes in terms of reprofusional therapies, but despite this Seemingly complete recanalisation and despite having had thrombolysis on board prior to thrombectomy, they had still persistent hypoperfusion by the criteria you're about to tell us. And basically you looked and see how they're doing at 90 days in terms of outcomes.

and compared them to flat out those people who didn't achieve complete recatalyzation. Either a tiki worse than two C, so that's a two B, it's not that bad, or a tiki of zero to two A. So this is really exciting. I'm excited to learn what you found.

Yes, so first and foremost, in line to what's already been shown in the literature, we found that patient with no reflow, which in our study was defined as visible IPO perfusion. and median reduction of relative CBF or relative CBV, so cerebral blood volume or blood flow of more than 15% compared to their contralateral normal hemisphere. had a worse functional outcome than those who achieved successful trombectomy and had normal

So that was already been shown in the literature, but we did redemonstrate it in a large cohort. But what's really interesting. and quite actually unique to this study is that no reflow was associated with worse outcome, even when it was compared to patients who had partially recanalized. So had an ET key score of two B, which is about fifty percent recanalization of the large vessel occlusion that was there at the beginning.

And their outcomes were actually similar to those who had unsuccessful trombectomy, so an ETK of 0 to 2A, and basically less than 50% recanalizing. So that's really interesting because it's the first study that really shows that no reflow doesn't just predict the worst prognosis, but it may actually negate the benefit of clot retrieval altogether. So it's really a finding that reinforced the urgency of better understanding and addressing no reflow in research, but also in clinical practice.

Because as we know, currently a CT perfusion at 24 hour is not always a standard of care for most patients who had trombectomy. So we don't even always know if these patients had no reflow or. Samantha, let me ask you a follow-up question before I recap what you just mentioned. What percentage of your patient population who have achieved a perfect tiki score, that's a tiki of 2C or better, had evidence of no reflow by perfusion parameters?

Uh yeah, so it was about 20%. So 30 patient out of the 150 who had achieved the ETK2C23 had evidence of no reflow. And this is with using a definition that is quite conservative. Yeah, so it's still in a large proportion. Understood. So again for our listeners, we're looking at a group of patients who have all received thrombolysis. then proceeded to a successful trombectomy with a very good E Tiki score of two C or better.

And yet, despite all of these reperfusion therapies had evidence of persistent hypoperfusion at 24 hours by perfusion criteria you just mentioned, and that's 20% of this population have received everything, and these people did not only not good. but actually did worse than patients who had achieved an ETK score of two B and did exactly the same in terms of outcomes as those who had received no recandization. That's ETK of zero and two to A. So very important finding.

So Felix, I'm gonna come back to you. Can you please help us put this information into context? Now that we have thrown everything at these patients population, from IV thrombolysis to endovascular thrombactomy, and yet the outcomes are as bad as having received no recanalization at all. What are some of the current therapies that are happening and are specifically targeting microcirculation?

I think known flow as a entity has just is is now getting more attention and there's currently no evidence based treatment for No Reflow. There has been a lot of interest at improving the microcirculation for perfusion um using intra arteriolytics to address distal thrombi as one of the mechanisms of neuroflow. And there have been a number of trials especially in the last few years.

Uh firstly there's the there was the Choice Trial that was published in around 2022 in JAMA, and that was a phase two trial that tested IA alterplace infusion at a dose of at the quarter of the usual systemic dose. in patients in anterior circulation stroke within twenty four hours who had phombectomy and a successful outcome defined as Tiki to B to free.

Now the trial was terminated early um after recruiting about 121 patients because of COVID, but it was quite exciting because it met its primary endpoints of MLS0 to 1 at 90 days. And since then there has been four Chinese trials completed and presented within the last year that looked at adjunct intra arteriolytics in patients with anterior circulation LVO. Two were published as a twin trial at the start of the year. That was the post TNK and also the post UK trial.

And the post TNK trial was a randomized open label trial in China randomizing five hundred and thirty nine patients, anterior circulation, LVO, thrombectomy, but using a more narrow definition of thrombectomy success of Tiki 2C to 3. They're randomized into IATNK at 25% or a quarter dosage of the usual bridging systemic connected place dose. And then the primary endpoint was MO zero to one.

And in a parallel study by the same group, identical design, they also tested the use of an alternative agent in IA urokinase in around 535 patients. And the rationale behind that was that Eurocone is maybe a more affordable and more accessible agent in low and middle income countries. Now, these trials were neutral, but they did show a numerically higher proportion of patients with excellent outcome.

But what was reassuring was that there was no difference in adverse events in both trials, although admittedly there was a statistical increase in uh general hemorrhagic transformation at forty eight hours in the technectic place group in the post TNK. But uh Sitch and Def were the same. In February, one month later, two more Chinese IA lithic trials were presented at ISC, and I understand that they have not yet been published.

But Angel TNK was an open label randomized trial that differed to the previous trials because it tested IATNK dose at 50% of the systemic dose. So that's double dose of the previous IA lytics trials. But it was highly selective. It had patients that did not have IV thrombolysis, and you can't have early use of antiplatelet. And they also included patients with an angiographic assist defined as Tiki 2B.

to three as well, so it's a is a broader range. Now the trial was positive. It made its primary endpoint, with the endpoint being proportion of patients with MIR0 to one at 90 days. And the stitch rate was also similar between two groups. And the second uh trial that was presented at INC was Pearl. This was an IA altoplase trial at 25% of the usual systemic dose.

again including patients with T two B to free, but this time bridging lysis and early antiplatis was allowed. And encouragingly, the trial also met its primary end point, was positive without any safety signal. So to put all these files five trials together, I I think collectively they provide evidence to suggest Ialytics in patients with angiographic reperfusion that frombectomy appears to be safe. and probably effective in improving functional outcome in some patients.

But there's still a a lot of unanswered question about what agents should be used, at what dose, what is really the target population that benefit from Iolytics. And what stands out among these trials is they included different patients by their definitions of what is successful riperfusion. The two positive trials included patients with Tiki 2B. But the two neutral trials, post-TNK and post-G, only included patients with TK2C and above.

And also in a subgroup analysis of Perl, the IE lytics improved patients who had Tiki 2B, but was neutral in the subgroup of patients with Tiki 2C to three. So it's possible that the treatment effect we see in angel T and K and Pearl and and also choice maybe from recanalizing the medium distal vessel in tick of the Tiki2B rather than the mycrovascular occlusion at the capillary tissue level that we think of in Nova Flow.

There's also a concern about giving Ialytics about the risk and benefit consideration, because these are patients with successful angiographic reperfusion. They would usually do relatively well, at least among the group of patients who have strombectomy already. And would it really be worth the risk of giving additional IA lytics in this group, especially in the Tiki Free?

But across the all the studies there were no safety signals of a high situation, which is good. And especially in A angel T N K which use fifty percent of their systemic dose. But Again, this was a highly selective population of patients that did not have IV lysis and you can't use early antiplatelets. So this is not truly representative of clinical practice in many places.

And also all of these trials so far were open label uh where the control group would finish from Bectomy immediately after randomization, but then the treatment group would have additional procedural time of 15 to 30 minutes. And by design, the proceduralist. wasn't blinded. They know what was going in. And it's interesting to think how that might have influenced the procedure itself in terms of retrieval attempts and efforts, knowing that they're getting a medication.

I should say, however, the initial choice trial was double-blinded. And finally, one interesting question is. So if Ialytics does work, then how far can we push this treatment? Because we know thrombolysis is increasingly used in the extended time window. And the recent positive large trial uh large core trials means from bictomy are being performed in patients presenting with exceptional infarcting clinical practice now. So is Ialytics safe in these patients too?

Uh because all our lytics trials so far have been quite conservative and they've included patients with small core and good aspect only. And there are ongoing trials and that would take. hopefully provide some answers to these questions and and that include the choice two trials in Spain that tests IA out of place and also the techno trial in Switzerland, Belgium, Germany, Finland, Austria. and also the extended acnes TNK trial in Australia that would test intra tyrotenic discipline.

All right. Felix, I feel like we need a separate podcast on uh post-thrombactomyalytics. A lot of data, but let me just briefly highlight some of the salient points you mentioned. As things stand, we have five trials. that have crossed the finish line. The original choice trial that was the first. Back in twenty twenty two. positive double blinded randomized control trial. It was ended prematurely and during COVID because of, I guess, administrative issues.

But nonetheless it showed a benefit of uh IA thrombolysis over nothing post thrombectomy. Achieving a good MRS of uh zero to one at 90 days. Um, so that was a very positive signal. We have since four Chinese trials and uh very briefly two have been published. Two was just recently presented at the ISC that you nicely went over all. But essentially the first two that are published were neutral trials. Some important issues for our listeners to keep in mind was

First, the definition of no reflow and who uh should receive post-IA thrombolysis is slightly different. The two post-UK and post-TNK trials. both used a very tight definition, to see or better. And those were neutral trials. The two recent one that had not been published yet, that Peril trial, as well as the Angel TNK, that were presented at the ISC, but not as of the date of this recording not published yet.

were positive trials, but as you mentioned, we have to keep in mind some differences in inclusion criteria. They enrolled patients that have achieved an e tiki to be or better by the end of thrombactomy. None of those trials were double blinded. There were open labeled trials. And the investigators, the interventionalists were actually unblinded

to the location. So those things need to be kept in mind as we interpret the data. But overall we have a signal towards safety at the very least. And obviously lots of activity in this Area, including a number of trials that are ongoing, including your own, Extend Agnes trial. So we're excited to

hear and learn more about where the role of IALITIC may be post-rombactomy in the future. I know we're running out of time, but I want to ask one more quick follow-up question. Felix, Is just thrombolysis what's being studied for a no reflow or other agents are being studied as well? Uh in humans no other uh agents are being used to primarily look at improving microcirculation. There have been some agents looked at in experimental small animal models.

So adenosine used as a vasodilator and parasite relaxant to reverse neuroflow. But there's also celesto to modulate vascular smooth muscle reduced platelet aggregation and also pineglosone to reduce inflammation in order to limit expression of adhesive molecules. And there are also some clinical trials that use agents that may be indirectly improving microcirculation too.

So we we know that Nov can also be due to neutrophils secreting extracellular fibers composed of DNA acting as a scaffold and holding onto platelets and red blood cells. And this can be addressed by maybe giving DNA's NAS and the extent IA DNA's trial in Australia is looking at the use of Dorne's alpha as in a drunk to intervener slices to dissolve NETs in the proximal clock.

But it may also have a secondary benefit on the microcirculation. But in summary, there's no there's no uh non-thrombolytic agent that specifically target the microcirculation yet. Perfect Felix. What should be our top takeaway from the topic of no reflow? So yeah, I think the key point to learn in this study and in general is that neuroflow does have a significant clinical impact. It is not uncommon and therefore it is an important phenomenon to recognize in acute ischemic stroke.

And this study focused on reinforced the idea that riperfusing the brain tissue is the ultimate aim. And that what we currently consider as perfect and geographic result does not necessarily guarantee that. And our result would actually suggest that if no reflow is unaddressed in in full blown the outcome may be as bad as not even trying thrombectomy at all. Doctors Felix Ng and Samantha Riebert, thank you so much for joining us on the podcast.

It is our pleasure. Greeting from Melbourne. Thank you so much, Nika.

And this concludes our podcast for the June twenty twenty-five issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including a special report from Arise II that summarizes the consensus roundtable discussion with industry and stroke experts. On current treatment strategies for patients with intracranial atherosclerotic disease or ICAP.

This report highlights the critical role of lifestyle changes, vascular risk factor modifications, and medical therapy as the cornerstone of ICAT management.

It also reviews developments in endovascular treatment, including consensus recommendations on when to consider submaximal angioplasty in ICAT, and provides the latest insights on the use of neurovascular Optical coherence tomography, a new era in treating this leading cause of stroke is emerging, and what better way to stay informed than by staying alert with stroke alert? This podcast is produced by Walters Kluver and Biomedia Communications and supported by the editorial team of Stroke.

Our Stroke Aloy Podcast and Production staff includes Nastasia Kremens, Aaron Shoskis, Louise Pasha, Aaron Kane, Rebecca Seestrong, and Nagar Azdagi. This program is copyright of the American Heart Association 2025. 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 ahjournals.org.