Stroke Alert September 2022

Stroke Alert

On Episode 20 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the September 2022 issue of Stroke: “Transdural Revascularization by Multiple Burrhole After Erythropoietin in Stroke Patients With Cerebral Hypoperfusion” and “Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait.” She also interviews Dr. Timo Uphaus about his article “Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis.”

Dr. Negar Asdaghi: Let's start with some questions.

1) Can performing multiple burrholes improve misery perfusion in patients with moyamoya disease? And if yes, how do the results compare to that of a direct EC-IC bypass surgery?

2) The glycoprotein VI antagonist Revacept provides lesion-directed thromboinhibition at the site of atherosclerotic plaque rupture without causing systemic platelet inhibition. In other words, it works where it should work without causing the systemic side effects of antiplatelet therapies. Is Revacept the future of carotid-related stroke treatment?

3) And finally, how should we counsel the family members of a patient with sickle cell anemia who are found to have sickle trait carrier state? Is sickle cell trait a risk factor for development of ischemic stroke?

We're back here with the Stroke Alert Podcast to answer these questions and cover the latest in Stroke because, without a doubt, this is the best in Stroke. Stay with us.

Welcome back to another issue 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.

For the September 2022 issue of Stroke, we have a number of articles that I'd like to highlight. As part of our International Stroke Early Career and Training section, or the InterSECT series, we have an important article by Drs. Kathryn Hayward and Aaron Davis to discuss the importance of science visualization as a simple, but not a simplistic way to improve scientific communications with the public.

The authors stress that the ability to communicate complex scientific information in an easily understandable format to those unfamiliar with the subject is not an obligation on the part of the scientists, rather, an opportunity for the scientific community to elevate knowledge translation for all.

In a separate article in this issue of the journal, we learned that the presence of early venous filling, or EVF, post-endovascular thrombectomy, defined as presence of contrast opacification of any cerebral vein before the late arterial phase, is an important angiographic marker that has been associated with an increased risk of post-reperfusion hemorrhage and worse clinical outcomes.

In an original contribution, Dr. Wagih Ben Hassen from the Department of Neuroradiology at Université de Paris and colleagues looked at the predictive ability of TAGE score to determine the odds of development of symptomatic intracerebral hemorrhage after thrombectomy. TAGE score, "T "for time from onset to successful recanalization of over 270 minutes, "A" for ASPECTS score either equal or less than five or ASPECTS of six to seven, "G" for blood glucose level of higher than seven millimole per liter, and "E" for EVF, or presence of early venous filling.

The authors found that presence of each of these variables within the TAGE score were independently associated with increased odds of post-thrombectomy symptomatic intracerebral hemorrhage, and together, a higher TAGE score had a great prognostic value in predicting development of reperfusion hemorrhage.

I encourage you to review these articles in detail in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Timo Uphaus from Johannes Gutenberg University in Mainz, Germany, on the results of a phase II clinical trial of symptomatic carotid stenosis patients treated with a novel glycoprotein VI inhibitor, Revacept. But first, with these two articles.

Bypass surgery is often performed for treatment of cerebral hypoperfusion, typically in the setting of chronic cerebral arteriopathies, such as moyamoya disease, moyamoya syndrome, or non-moyamoya steno-occlusive disorders causing perfusion-dependent ischemia.

In the adult population, the direct extracranial to intracranial bypass surgery, also referred to as EC-IC bypass, is the preferred procedure to improve cerebral perfusion as compared to all other currently performed indirect procedures.

This is for many reasons, but one being that direct bypass can immediately improve cerebral blood flow, whereas the indirect methods rely on gradual collateralization and new angiogenesis, a process that's not only slow, but especially in the adult population, is often suboptimal, even if we can wait.

On the other hand, a direct EC-IC bypass requires subspecialized surgical expertise in tertiary levels of stroke, neurosurgical, and neurointensive care, and the procedure could be challenging, especially if it's done in the setting of acute stroke where the patient is neurologically unstable.

Cranial multiple burrhole surgery is a minimally invasive procedure that was actually incidentally discovered to improve transcranial angiogenesis in moyamoya disease.

In 1984, a group of investigators from Japan reported their findings on a pediatric moyamoya case that had bilateral frontal burrholes for a completely different indication, which was drainage of an intraventricular hemorrhage, and three months later, unexpectedly, was found to have marked neurovascularization via the burrholes on the follow-up angiogram. Further experience over the next 30 years, mostly in children, would show that multiple burrholes truly have the potential to provide vascular ingrowth over the entire brain convexity in the ipsilateral hemisphere.

Now, how does this even work? Well, performing burrholes can simply break the barrier, so to speak, between the intracranial space, where there is misery perfusion for whatever the etiology, be Moyamoya or atherosclerotic disease, and the extracranial vascular system that's already overactivated in this setting, and breaking the barrier and disruption of the meninges can stimulate transdural collateralization. But we have to keep in mind that this is not a secure and robust transdural anastomosis that, for example, a direct bypass provides.

So, what do we know about the safety and efficacy of multiple burrhole surgery in the adult population? In this issue of the journal, Dr. Ji Man Hong from the Department of Neurology, School of Medicine, in Ajou University in South Korea and colleagues studied whether performing multiple burrholes, combined with high-dose systemic erythropoietin that's also known to enhance the angiogenetic potential of endothelial cells, improves cerebral perfusion in adult patients with perfusion-dependent acute ischemic stroke.

So, let's look at their study. This was a single-center, prospective, randomized trial, which included 42 patients enrolled within two weeks from their acute ischemic stroke from an intracranial steno-occlusive disorder causing hypoperfusion. The median age of patients was 55 years of age, and median NIH Stroke Scale was under five at presentation. So, this is truly an adult population, obviously, median age was over 50, and a mild stroke population as expected for a bypass cohort. 26% of their cohort had a diagnosis of moyamoya disease, and over 70% had other steno-occlusive disorders, most likely occlusions related to atherosclerosis, although this we cannot know for sure because the exact etiology was not specified in the paper.

Patients were randomized one-to-one to either receive multiple burrholes alone over the area of hemodynamic insufficiency under local anesthesia, or in combination with high-dose systemic erythropoietin, which was administered intravenously at 33,000 units per day for a total of a hundred thousand units administered over three consecutive days. So, everybody got surgery. The treatment group also got erythropoietin, and the control did not receive that. The two groups of patients were similar with regards to demographics, risk factors, stroke severity, and baseline perfusion parameters, and all received comparable stroke care. The primary outcome of the study was the rate of successful revascularization, which was determined on follow-up angiogram at six months.

So, now, on to their findings. So, number one, on their follow-up angio at six months, the combined multiple burrhole and erythropoietin patients had a higher percentage of successful hemispheric and trans-burrhole revascularization rates as compared to those who just had received multiple burrholes. But we have to note that when we look at the details, the rate of excellent revascularization that was defined as improved angiographic reperfusion in greater than 66% of the affected area was only achieved in a third of patients, and only in 23% of multiple burrholes cases alone. Close to half of patients who received both multiple burrholes and erythropoietin had either poor or fair revascularization, which was defined as improvement in angiographic perfusion in less than 33% of the affected area. So, obviously, these are important numbers and percentages to keep in mind as we try to understand the results of the study.

Next finding: In terms of perfusion imaging outcomes, the perfusion parameters were only available in half of their study population. On six months follow-up, the combined group had significant improvement in time-based perfusion parameters in the ipsilateral hemisphere. So, that included improvement in the mean transit time and time-to-peak maps, but not in the cerebral blood flow and cerebral blood volume maps.

Next, in terms of adverse events, there were no significant differences between the two groups in terms of risk of hemorrhage or infarct recurrence and other adverse events. However, in general, a number of important complications were noted in their study, including procedure-related brain hemorrhage in 14% of patients in the combined group and 14% systemic complications in the erythropoietin treated group, which again deserves further assessment.

And finally, I think one of the most important findings of the study was to evaluate serological biomarkers of angiogenesis, including matrix metalloproteinases 2 and 9, vascular endothelial growth factor, granulocyte colony stimulating factor, and interleukin 6. They compared these biomarkers at baseline and then remeasured them again at six months, and the most important finding was that the levels of MMP-9 were significantly increased in patients in whom successful revascularization was achieved, whereas these levels were similar at baseline if we went back and retrospectively divided the group into two groups of patients who would or would not receive successful revascularization at six months. MMP-9 is an important angiographic factor, but whether it can be used as a serological marker of complete revascularization remains to be seen.

So, in summary, what we learned from the study is that the combination of multiple burrholes and erythropoietin therapy is potentially efficacious and possibly safe, though both of these outcomes need further confirmation in larger studies for patients with moyamoya disease and other steno-occlusive disorders causing perfusion dependence. And, in general, it's fair to say that combined approaches in revascularization therapies, be using two indirect approaches, such as the method we just reviewed today, or perhaps combining direct bypass with an indirect approach, may improve the overall revascularization success in this population and may be the way to move forward in the future.

Sickle cell disease refers to an inherited group of hemoglobin disorders characterized by the presence of hemoglobin S either from homozygosity for the sickle mutation resulting in hemoglobin SS or compound heterozygosity with another beta-globin variant, for example, sickle beta thalassemia or hemoglobin SC disease. Now, as we know, even though this is a genetic hemoglobin problem, sickle cell disease creates a multi-system condition, and it's a major risk factor for stroke, with vaso-occlusive events accounting for much of its morbidity and mortality. Now, the question is, if sickle cell disease is a major risk factor for stroke, how about the much more common sickle cell trait carrier state? Sickle cell trait is about 20 times more common than sickle cell disease, is generally considered a benign condition, but some clinical events such as exercise-related injury, renal complications, and venous thromboembolism have been reported to occur more commonly in sickle trait carriers.

If sickle trait is, in fact, a risk factor for ischemia, then it's conceivable that there would be similar, but perhaps to a milder extent, neuroimaging findings of sickle cell disease in individuals with this carrier state. In this issue of the journal, in the study titled "Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait," Drs. Yan Wang and Andria Ford from the Department of Neurology at Washington University School of Medicine and colleagues report on the results of a prospective multimodal MRI study to measure various cerebrovascular structures, hemodynamic, metabolic functions, and silent infarct burden in young adults with and without sickle cell trait.

So, the cohort composed of 49 healthy young adults without any known risk factors with either hemoglobin AA, which composed their control group with a total of 24 participants, or hemoglobin AS, which gave them their sickle trait cohort with 25 participants. The median age of their participants was 33 years of age, and the groups were matched in regards to age, sex, demographics, and baseline laboratory values, with the exception that the sickle trait group had a higher methemoglobin levels and creatinine concentration as compared to controls. All participants underwent various MR imaging, including ASL perfusion imaging with volumetric analysis and diffusion tensor imaging, and then they compared various values between control and sickle trait group.

Now, let's look at their findings. Number one, as compared to control, participants with the carrier state had similar normalized whole brain gray and white matter volumes. What does normalized volume mean? Well, volume normalization is done in volumetric analysis to adjust for differences in the head size between different participants. So, so far, so good. No differences in size of white or gray matter in those patients who are sickle cell trait carriers.

Next finding, using diffusion tensor imaging, they measured fractional anisotropy and mean diffusivity values for white matter tracts in both groups. Now, we've covered the meanings of fractional anisotropy and mean diffusivity in our podcast a number of times, but just a quick reminder. In general, when we have a structurally organized tissue, such as white matter tracts, the diffusion of hydrogen molecules is unidirectional in these tracts and, therefore, restricted in all other directions as white matter tract is intending to do so.

Now, if we have a disruption to these tracts, for whatever the etiology, we can simply think of this disruption, allowing hydrogen molecules to now freely diffuse in various directions. And this would result in an increase in mean diffusivity values that is determined by diffusion tensor imaging, and a decrease in fractional anisotropy values. And I really want to stress that this is a very simplified formula to understand the values of FA and mean diffusivity for just the white matter tracts. But the damages to the gray matter actually creates differences in FA and mean diffusivity that are a bit different than what I just mentioned for the white matter tracts. Now, we have to keep this in mind if we're reviewing articles that deal with damages to other structures in the brain than the white matter tracts. Now, coming back to our study, for this study, comparing the FA and mean diffusivity values for the white matter tracts, it turns out that these values were similar between those with sickle trait and controlled individuals. So, also good news.

Next, they examined regional white or gray matter or whole brain cerebral blood flow, oxygen extraction fraction, and cerebral metabolic oxygen demand, and similarly found no differences between control and healthy sickle trait carrier adults.

Next finding, in terms of intracranial vascular imaging, there were two asymptomatic aneurysms found in this study, one in each cohort, and they found no differences in the two groups in terms of the prevalence of significant cerebral vasculopathy, which means equal or greater than 50% intracranial stenosis in either groups. So, also very, very good news so far.

Finally, eight people in the control group and 11 people in the carrier group had evidence of silent cerebral ischemia. That is a high percentage. That means that the prevalence of silent ischemia was 33% in the control group versus 44% in the sickle trait group.

This was not statistically different. It's interesting that the authors mentioned that the prevalence of silent ischemia was low, but I think it's actually alarming if we have a cohort of patients with a median age of 33 and found that one in three of them actually have evidence of silent ischemia on neuroimaging. But the good news is that the volumes of these lesions were exceedingly small, under 0.2 mL on volumetric analysis, and not different in size between the two groups. But when they did the analysis restricted to those who had silent ischemia, it turns out that these silent, incidentally found ischemic lesions were ever so slightly larger in those with sickle trait, as compared to the control cohort. The median volume of incidental silent ischemic lesions was 0.29 mL in sickle trait individuals as compared to 0.07 mL in control. So, very small differences, which may or may not become meaningful in larger cohorts.

So, in summary, based on the best neuroimaging capabilities we have to date, we can conclude that unlike sickle cell disease, individuals with sickle trait do not seem to be at an accelerated risk of neurological injury if they are otherwise healthy. But we also have to keep in mind that somehow those incidental cerebral ischemic lesions were ever so slightly bigger in individuals with sickle trait than their control counterparts. And this finding also reminds us of other studies in the literature to suggest that sickle trait may not be a direct risk factor for ischemic stroke, but may be a modifier for increased ischemic risk. For example, in patients with diabetes, those with sickle trait have been found to be at a higher risk of ischemic events, or in the elderly population, individuals with APOE4 genotype have been shown to experience greater cognitive decline if they have sickle trait as compared to their age-matched individuals with the same genotype.

So, the take-home message is that sickle trait is a benign condition, but may be a modifier of brain injury if it's combined with something else or other risk factors. So, it's safe to say that, as always, prevention and treatment of these risk factors are paramount in all, but especially in sickle carrier individuals, to maintain brain health.

It's long been known that patients with carotid disease are at increased risk of first and recurrent ischemic events. The risk of carotid-associated ischemic stroke in each patient is dependent on a number of factors and traditionally predicted by two important pieces of information. Number one, the actual degree of carotid stenosis, and number two, whether or not that carotid artery has already caused an ischemic event, rendering them the designation of symptomatic as opposed to asymptomatic carotid disease. We've also known for some time now that in patients with symptomatic disease, the risk of recurrent stroke is up front. It's quite high, especially in the first two weeks after the index event. More recently, we've learned that there are other factors over and above the absolute degree of carotid stenosis that we should be paying attention to. Features such as plaque morphology, complex plaques with calcified segments of type of soft plaques, and the presence of intraluminal thrombi have all been associated with plaque instability. In these unstable or so-called "hot plaques," further embolization is thought to occur due to activation of circulating platelets by exposed collagen at the site of ruptured plaques.

The presence of microembolic signals, as detected by transcranial Doppler studies, can assist with identifying these active plaques. What is the best antithrombotic regimen in the very hyperacute stage after presentation with acute ischemic stroke? Some of these decisions will depend on the type of presenting symptoms and whether the patient had received acute reperfusion therapies or not, but in routine practice, some patients are treated with dual antiplatelet therapy. Some are on monotherapy alone, especially if there are plans for endarterectomy, and this, in part, is influenced by the surgeon's practice patterns and so on. And some patients are actually treated with anticoagulation either alone or in combination with concurrent antiplatelet therapies. And, of course, we also have the intravenously administered options, the glycoprotein IIb/IIIa inhibitors and the glycoprotein VI antagonists, with growing potentials for usage in the acute setting of ischemic stroke, which are likely more and more to be used in the hyperacute stage of stroke.

In this issue of the journal, in the study titled "Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis," we learn about the role of Revacept, a glycoprotein VI antagonist, in patients with symptomatic carotid disease as part of a multicenter phase II randomized trial. I'm joined today by the first author of this randomized study, Dr. Timo Uphaus, all the way from Germany to learn about this newer class of antithrombotic agents and discuss the results of the trial. Dr. Uphaus is an Assistant Professor of Translational Neurology at the Johannes Gutenberg University in Mainz. He's one of the principal investigators of the Revacept randomized trial and is involved in multiple ongoing studies, including the prospective multi-centered German Stroke Registry to evaluate the safety and efficacy of endovascular thrombectomy in clinical practice and the prospective Gutenberg Stroke Study to evaluate biomarkers in patients undergoing endovascular therapy. Welcome to our podcast, Timo. Thank you so much for joining us.

Dr. Timo Uphaus: Great to be with you. Thanks for the invitation.

Dr. Negar Asdaghi: So, we'd like to learn more about Revacept first. How's this agent different from our usual antiplatelet agents?

Dr. Timo Uphaus: Oh, the mechanism of action of Revacept is quite unique, as you already mentioned. In contrast to available agents mediating inhibition of platelet activation in the whole circulation, Revacept is solely inhibiting platelet function really at the site of the plaque rupture. And this is achieved by shielding the exposed collagen after plaque rupture to the bloodstream so that platelets aren't able to be activated at this subendothelial exposed collagen.

And to really go in more mechanistic detail, Revacept is a fragment crystallizable region, also called FC fragment, fused to the glycoprotein VI, short GPVI receptor, which is an endogenous platelet collagen receptor. And this construct binds to the exposed collagen of unstable carotid plaque and acts as a physical barrier, reducing platelet activation, subsequent platelet binding, and aggregation on the carotid plaque. And this collagen-dependent, really, site-specific inhibition of platelet function might be as effective as available agents without side effects due to impairment of systemic platelet function, such as intracerebral hemorrhage. Concerning the administration route, Revacept is administered as an intravenous infusion of about 20 minutes, and, to go in more pharmacological details, Revacept exhibits a half-life of seven to 14 days and can also be administered several times in a row.

Dr. Negar Asdaghi: So, Timo, that's a lot of information, and I'm going to try to summarize it for our listeners. This is a very interesting drug as it works differently than our usual antithrombotics. It's a site-specific antiplatelet agent. So, as you mentioned, it is administered intravenously, but even though it's systemically administered, it goes right where the action is, to the so-called unstable plaque, and prevents the adhesion of platelets to the underlying exposed collagen. So, now, this agent is a newer therapy for us in the field of stroke, but it's not so new for cardiologists. Can you please briefly tell us about the cardiac literature and the current applications of Revacept in patients with, say, acute myocardial infarction or coronary artery disease?

Dr. Timo Uphaus: Well, we all know and experience that coronary and also carotid artery disease are commonly also linked in patients and can also occur simultaneously. And concerning the cardiac literature on Revacept, collagen-dependent platelet inhibition was recently also evaluated in patients with stable coronary artery disease undergoing elective PCI in the ISAR-PLASTER trial. And this was a phase II randomized clinical trial, including more than 300 patients who were allocated to receive either placebo or Revacept. And at the end, Revacept failed to show efficacy for the primary endpoint, which was a composite of death and also myocardial injury. Nonetheless, and this is an important point to mention, is that there were only few bleeding events within this trial and that there were no signs for increased bleeding rates after treatment with Revacept, which is always an issue when you're evaluating a new thrombocyte inhibition.

Dr. Negar Asdaghi: So, just to recap, this agent has been recently studied and as part of a randomized trial in patients undergoing PCI with active coronary disease, and even though the primary results of the ISAR-PLASTER trial was neutral in terms of efficacy, did show us a signal towards safety in terms of bleeding, which is important. So, there seems to be a lot of action happening in the cardiology world. Now, moving from heart to brain, what did we know about the efficacy of Revacept in stroke prior to the current trial?

Dr. Timo Uphaus: So, Revacept was really intensively studied in preclinical animal models, and these are also the basis for this trial now, phase II. And just to give you an example, what was studied in animal models so far, in animal model of a vascular atherosclerosis, Revacept dose twice weekly, over four weeks, was able to improve endothelial dysfunction and also vascular morphology on histology analyses. And importantly, within this study, no influence of Revacept on bleeding time alone, or also in combination with various antiplatelet drugs, could be observed. And another example is a study which made use of middle cerebral artery occlusion, and within this model, treatment with Revacept improved functional outcome, cerebral infarct size, and also edema formation compared to vehicle treatment. And Revacept also showed an effect on immune cell infiltration, which was demonstrated by reduced infiltration of macrophages within the CNS.

Dr. Negar Asdaghi: So, just to recap, there seems to be a lot of positive signal for efficacy of Revacept in patients with an active plaque rupture, whether from the coronary literature or the preclinical studies in stroke, which brings us nicely now to your current study. Please tell us what kinds of patients were included in your trial and the inclusion criteria.

Dr. Timo Uphaus: So, the Revacept/CS/02 study is, as we already mentioned, the first randomized trial examining GPVI inhibition in patients with stroke or symptomatic carotid artery disease as we did. And it is an international, randomized, placebo-control, double-blind, exploratory phase II study with three arm randomization and the treatment groups were placebo, 40 milligram Revacept, and also 120 milligram Revacept. So, we examined two treatment dosages. And who was enrolled in the study, in brief? 148 patients with recent symptomatic carotid artery disease were randomized to receive either high or low dose Revacept or placebo before they underwent then afterwards treatment of this ICA stenosis. It is important to mention that patient characteristics were balanced between these three treatment groups, and also that the treatment regimen was at the discretion of the treating physician, meaning the treatment regimen of the ICA stenosis, which could have been carotid endarterectomy, carotid angioplasty and stenting, and also best medical treatment.

And moving on to inclusion criteria, the initial symptoms qualifying for symptomatic carotid artery disease had to be within the last 30 days prior to screening. And the grading of the ICA stenosis had to be at least 50% according to ECST criteria. And what is some of our pitfall of the study is that the initial study design only included those patients presenting with detection of microembolic signals, which were detected by transcranial Doppler examination at the screening examination. But due to the low percentage of patients who presented with MES at screening, this protocol had to be changed, and all patients in whom transcranial Doppler was possible were then, after this protocol changed, eligible for participation within the study.

And what is the consequence of this protocol change? Well, that the primary efficacy endpoint of the study, which was reduction of microembolic signals after treatment, was no longer accessible, so that it was somehow switched to a number of new ischemic lesions on diffusion-weighted imaging and, therefore, the number of new DWI lesions detectable on MRI performed after the revascularization procedure compared to the MRI at screening served as new, now exploratory efficacy endpoint. And last, with regard to exclusion criteria, patients under dual antiplatelets or anticoagulation, or who received intravenous thrombolysis within the last 48 hours before screening, were eligible.

Dr. Negar Asdaghi: Okay. So, a lot of information again, so I'm going to try to recap it. And also some changes that had to be done during the trial administration, as is always the case for practical reasons. So, we have a trial of symptomatic carotid artery patients. Symptomatic carotid artery defined as percentage of stenosis over 50% in patients that had a relevant TIA or stroke in the past 30 days prior to enrollment, where patients were enrolled into three arms of either placebo or receiving 40 milligram or 120 milligram of Revacept over 20 minutes infusion. And, as you mentioned, just a note that initially the trial only enrolled patients that had a positive microembolic signal as detected by transcranial Doppler, but over the course of the randomization in the trial, this was changed to anyone that had a TCD emboli detection studied prior to randomization. So, with that, I think we're ready to hear about the primary outcomes of the study.

Dr. Timo Uphaus: Concerning this new exploratory efficacy end point, we were able to report a numerical reduction of new diffusion-weighted imaging lesions after treatment with 120 milligram Revacept. This effect was found to be significant within the main statistical analysis, which was a Poisson regression, but was not validated by respective sensitivity analysis, so that these findings at the end needs to be judged with caution. Nonetheless, we see a clear trend that number of new diffusion-weighted imaging lesions is decreased after treatment with 120 milligram Revacept.

And concerning clinical outcomes, we assessed the combined safety and efficacy endpoint, which includes occurrence of ischemic stroke, transient ischemic attack, hemorrhagic stroke, as well as myocardial infarction or necessary coronary intervention deaths and any bleeding complications. And for this combined safety and efficacy endpoint, we observed a 45% risk reduction of the treatment with 120 milligram Revacept compared to placebo treatment over the course of the study. And with a 66% risk reduction, this effect was even more pronounced than the subgroup of patients with more than 70% ICA stenosis.

Dr. Negar Asdaghi: All right. So, just to summarize, on the outcome of reduction of DWI positive lesions, there was a numeric reduction of the number of positive DWI lesions in patients that were enrolled to a higher dose of Revacept. That was not statistically significant in the Poisson regression analysis that you mentioned in the paper. So, this numeric reduction should be judged and needs to be further reevaluated in future studies, but obviously a very positive signal towards efficacy for Revacept. And the high dose Revacept seemed to reduce the combined primary safety and efficacy end points of the study, and that needs statistical analysis. So, very, very, very positive results. If I should say one more time, a very positive results for high dose Revacept in this study.

So, now, moving on, you have discussed a number of subgroup analyses that were pre-specified in the trial. Can you please briefly tell us what we learned from the subgroup analysis? I guess you already alluded to it, over 70% stenosis carotid disease, but I'll let you take away the question.

Dr. Timo Uphaus: Yeah, for sure. So, as you already mentioned, we analyzed subgroups, such as degree of ICA stenosis, prior statin treatment, and also different carotid interventions. And with regard to new diffusion-weighted imaging lesions on follow-up MRI, there were no effect of subgroups on the percentage of patients who suffered from new DWI lesions. However, the combined clinical safety and efficacy end point showed fewer outcome events after treatment with 120 milligram Revacept in the following subgroups: first, degree of ICA stenosis above 70%; second, patients with prior statin therapy; and last, but not least, patients undergoing carotid endarterectomy.

Dr. Negar Asdaghi: So, again, a lot of signal for efficacy of high dose Revacept in these subgroup analyses, specifically for those with a higher grade of stenosis, which are truly the subgroup of patients with carotid disease that are at higher risk of imminent recurrent ischemic events, so, those people at a lower combined safety and efficacy end point, so combined risk of TIA, stroke, hemorrhagic events, as you mentioned. And also there seems to be an improvement or reduction in the total primary outcomes in patients that had plans for endarterectomy. And the way I read it was perhaps that in routine practice, these patients were less likely to be aggressively treated with, for instance, dual antiplatelet therapy, so they really needed that additional push to try to prevent the number of recurrent events until such time that they get their surgical treatment. So, I think we are going to see a lot more in the future on studies of these particular subgroups of patients. Now, just to end the interview, we have two more questions for you, Timo. What should be our top two take-away messages from your study?

Dr. Timo Uphaus: So, I would say, take-home messages are, first, collagen-specific inhibition of GPVI through Revacept in patients with recently symptomatic carotid artery disease, in addition to standard of care medical treatment, is safe without any signs of increased bleeding rates. And second, Revacept showed a trend towards reduction of new ischemic lesions on diffusion-weighted MRI imaging, and altogether, I guess this paves the way for future phase III trials, not only in carotid artery disease, but probably in diseases with underlying rupture plaque embolization pathologies. And maybe I, at the end, I would add that change your primary efficacy endpoint wisely when you're studying a randomized trial.

Dr. Negar Asdaghi: Right? So, a lot of important comments that you made. Very important comment on the site-specific therapies. We are used to giving drugs either intravenously or orally that affects just about everything systemically, has a systemic effect. And many of the adverse events of the drugs that we currently administer are because of those systemic side effects. Here, we have a new therapy that is very site-specific, so it goes right where the problem is. And I think the future of medicine, in general, will be the usage of therapies with such site-specific properties. So, more of that in the future, I'm sure. And you already answered the next question, which was whether there will be a phase III trial for Revacept. So, we look forward to the results of that future randomized trial. So, with that, Dr. Timo Uphaus, it was a pleasure interviewing you on the podcast today.

Dr. Timo Uphaus: Thanks again for the invitation. It's been great talking to you.

Dr. Negar Asdaghi: Thank you.

And this concludes our podcast for the September 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including our Literature Synopsis on the latest developments in reperfusion therapies, covering the results of the newly published AcT randomized trial with a head-to-head comparison of tenecteplase to alteplase in treatment of patients with acute ischemic stroke, to the results of the CHOICE trial on the effects of intra-arterial alteplase following successful thrombectomy. The synopsis is sure a great way to keep updated on the latest in the field.

And now, to end this podcast, I'd like to remind us that September 8 is the International Day of Literacy. Even today, though hard to believe, it's estimated that there are more than 750 million adults around the world who cannot read. Let's think about it for a second. Illiteracy impacts all aspects of life, but especially an individual's health. Studies have shown that people with inadequate literacy have less health-related knowledge, receive less preventative care, have poorer control of their chronic illnesses, and are hospitalized more frequently than others.

But most may not know that illiteracy can also be acquired. How can we lose our ability to read and write? This concept is, of course, far too familiar for stroke neurologists, as a variety of stroke syndromes can cause alexia with agraphia, the very literal acquired illiteracy. So, as the world of education gathers on September 8 to celebrate the basic human right to literacy, in the world of vascular neurology, we celebrate stroke prevention and the right to keep our ability to read and write. And, of course, there's no better way to do so than staying alert with Stroke Alert.

This program is copyright of the American Heart Association, 2022. 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.