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Stroke Alert May 2023 May 18, 2023

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On Episode 28 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the May 2023 issue of Stroke: "Decreased Estimated Glomerular Filtration Rate and Proteinuria and Long-Term Outcomes After Ischemic Stroke: A Longitudinal Observational Cohort Study" and "Stroke Prevention and Treatment in People With Type 2 Diabetes: Is There a Role for GLP-1 (Glucagon-Like Peptide-1) Analogues?" She also interviews Drs. Kanishk Kaushik and Marieke J.H. Wermer about their article "Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230501.274417

Stroke Alert April 2023 Apr 20, 2023

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On Episode 27 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the April 2023 issue of Stroke: "Association Between Hospital-Documented Atrial Fibrillation and Central Retinal Artery Occlusion" and "Early Stroke and Mortality After Percutaneous Left Atrial Appendage Occlusion in Patients With Atrial Fibrillation." She also interviews Drs. Wenting Zhang and Jun Chen about their article "Poststroke Intravenous Transplantation of Human Mesenchymal Stem Cells Improves Brain Repair Dynamics and Functional Outcomes in Aged Mice."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230407.897078

Stroke Alert March 2023 Mar 16, 2023

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On Episode 26 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the March 2023 issue of Stroke: "Tenecteplase Treatment and Thrombus Characteristics Associated With Early Reperfusion" and "Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke." She also interviews Dr. Mitchell Elkind about the life and the legacy of Dr. Ralph L. Sacco, Stroke's Editor-in-Chief, who died January 17, 2023.

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230308.776720

Stroke Alert February 2023 Feb 16, 2023

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On Episode 25 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the February 2023 issue of Stroke: "Early Antiplatelet Resumption and the Risks of Major Bleeding After Intracerebral Hemorrhage" and "Using Noncontrast Computed Tomography to Improve Prediction of Intracerebral Hemorrhage Expansion." She also interviews Dr. Lauren H. Sansing about her article "Role of Inflammatory Processes in Hemorrhagic Stroke."

For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230203.583057.

Stroke Alert January 2023 Jan 19, 2023

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On Episode 24 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2023 issue of Stroke: "Covert Brain Infarction as a Risk Factor for Stroke Recurrence in Patients With Atrial Fibrillation" and "Subarachnoid Hemorrhage During Pregnancy and Puerperium." She also interviews Dr. Georgios Tsivgoulis about his article "Clinical, Neuroimaging, and Genetic Markers in Cerebral Amyloid Angiopathy-Related Inflammation: A Systematic Review and Meta-Analysis." Dr. Negar Asdaghi: Let's start with some questions. 1) When during pregnancy is an intracranial aneurysm at the highest risk of rupture? 2) What does the presence of covert brain infarcts mean in the setting of atrial fibrillation? 3) And, finally, how is the inflammatory form of cerebral amyloid angiopathy different from the classic CAA form, and why is it important to differentiate between the two? We'll be answering these questions and much more in today's podcast. We're covering the latest in cerebrovascular disorders, and 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. Together with my co-editors, Drs. Nastajjia Krementz and Eric Goldstein, here's our article selection for the month of January. Symptomatic intracerebral hemorrhage is a feared complication of reperfusion therapies in acute stroke, so there's a lot of interest in looking for predictors of development of this complication, especially when you're making decisions for pursuing endovascular therapy. For many years now, we've known about some of these predictors, such as presence of a large infarct core and high blood glucose levels. But in the recent years, other radiographic markers of tissue viability, such as a poor collateral status and unfavorable venous outflow profile, have been shown to be predictors of post-reperfusion hemorrhagic transformation. In this issue of the journal, we learn about another imaging marker that can potentially predict parenchymal hemorrhage occurrence post-endovascular therapy, which is high hypoperfusion intensity ratio, or HIR, as measured by perfusion imaging. What is HIR? It's a long name for a simple ratio that can easily be measured by dividing the volume of tissue with Tmax delay of over 10 seconds to the volume of tissue with Tmax delays of over 6 seconds. Simply put, Tmax 10 divided by Tmax 6. These volumes, as you know, are typically provided to us by almost all post-processing perfusion softwares, and so this ratio can be easily calculated in the acute setting. So, in this paper led by Dr. Tobias Faizy from University Medical Center in Hamburg and colleagues, we learned that higher hypoperfusion intensity ratios are strongly associated with parenchymal hemorrhage occurrence after endovascular therapy. So, in summary, HIR, that is a quantitative ratio, can be used as a marker to risk stratify patients that are undergoing endovascular therapy in terms of helping us predicting the risk of development of intracerebral hemorrhage after reperfusion therapies. In a separate study in this issue of the journal, we read a very interesting paper titled "Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk." How are intracranial aneurysms even related to anti-epileptic drugs? Well, first of all, it's been known for a long time based on genome-wide association studies that there are multiple common genes that are associated with increased risk of intracranial aneurysm development. Now, some of the largest genetic studies to date have shown pleiotropy between genetic causes of development of intracranial aneurysms and genes encoding targets for anti-epileptic drugs. Now that's a fascinating finding because finding commonalities between these genes may help find new treatment targets for intracranial aneurysms. So, in this paper in this issue of the journal, the investigators from the University Medical Center in Utrecht found an association in the expression of anti-epileptic drug target gene CNNM2 and intracranial aneurysm risk. They found that certain anti-epileptic drugs, such as phenytoin, valproic acid, and carbamazepine, that are expected to lower CNNM2 levels in the blood may subsequently lead to a lower risk of development of intracranial aneurysms. And, of course, a reasonable follow-up study to this would be to investigate whether persons exposed to these anti-epileptic drugs have indeed a lower risk of unruptured intracranial aneurysms and subarachnoid hemorrhage, and how variation in CNNM2 expression can lead to development of aneurysms. Bottom line, CNNM2 may be a relevant drug target for treatment of cerebral aneurysms. As always, I encourage you to review these papers in detail in addition to listening to our podcast today. My guest on the podcast today is the Chairman of Neurology at the University of Athens, Dr. Georgios Tsivgoulis. He joins me all the way from Greece to talk about cerebral amyloid angiopathy-related inflammation, or CAA-ri. He's a remarkable researcher, and I can say with absolute confidence that we cannot find a better summary of this very tough topic elsewhere. He ends the interview with an intriguing account of the early description of dementia in Greek mythology. But first, with these two articles. What are covert brain infarcts, or CBIs? Are these the John Wick or the James Bond of the stroke world? After all, they operate undercover. They're ominous and attack without warning. That's probably why they're also called silent infarcts. Now, whatever we call them, we need to know how prevalent they are and what does their presence actually mean. Let's dive into this topic. For at least two centuries, if not longer, we've known about covert brain infarcts. Early description of these lesions is credited to Amédée Dechambre, a medical intern at Salpêtrière Hospital in Paris who noted that there are strokes that can cause symptoms like hemiplegia, but also strokes that are asymptomatic, or so he thought at the time. In the modern times, while we agree with our pathology forefathers that CBIs are different from symptomatic strokes, we also know that they are not entirely asymptomatic. The symptoms can be subtle and tend to sneak up on the patient, but what is clear is that amassing of covert brain infarcts results in an overall decline in cerebrovascular reserve of the brain. With the advent of neuroimaging, we now know that CBIs are age-dependent and prevalent, seen in almost 10 to 30% of even healthy adults, but much more prevalent in those with vascular risk factors, and they can be caused by nearly the entire spectrum of neurovascular disease, including large vessel, small vessel disorders, cardioembolism, and others. Now, how do these covert infarcts catch up in those with atrial fibrillation? Neuroimaging studies have shown that patients with A-fib, especially those untreated, have a higher percentage of embolic-appearing CBIs, and conversely, those with embolic formed pattern of CBIs are more likely to have undiagnosed A-fib. So the question is, what's the significance of CBI in those with confirmed A-fib? In this issue of the journal, Dr. Do Yeon Kim from Seoul National University and colleagues help us answer this question using the EAST-AF, which stands for East Asian Ischemic Stroke Patients With Atrial Fibrillation Study. So, the paper included over 1300 patients with A-fib and first-ever stroke without a prior history of TIA or stroke. And then they categorized these patients into those who had evidence of CBI on neuroimaging and those who didn't. So, what did they find? Forty-two percent of patients with A-fib and first-ever stroke had evidence of covert brain infarcts on neuroimaging. Let's think about it for a moment. These patients presented with what was thought to be their first-ever stroke, not knowing they already had some in their brain. Now, what makes things really worse is that over a quarter of these subjects had more than just one covert infarct. Not surprisingly, those with CBI tended to be older, had higher blood pressure, and had worse white matter hyperintensity burden. This is kind of expected and also not expected was the fact that most of these covert infarcts were actually embolic in pattern. Over 60% of them were embolic. Another 14% of cases had combined embolic and non-embolic-appearing CBIs. Now, overall, the one-year incidence of ischemic stroke and all-cause mortality was higher in those that had CBIs at baseline. When they started looking at the specific patterns of CBIs, those embolic-appearing CBIs had a threefold higher risk of recurrent ischemic stroke, whereas those with non-embolic-appearing covert infarcts had oddly a higher all-cause mortality rate but not recurrent ischemic stroke. And finally, just briefly, the authors noted that the addition of CBIs to the classic CHA2DS2-VASc score didn't meaningfully otherwise statistically improve the scoring metrics, so they left it at that. So, the take-home message is that 42% of A-fib patients presenting with first-ever stroke actually had prior strokes without even knowing based on this study. And most of these strokes were embolic-appearing, and these covert brain infarcts can be used as predictors of future clinical strokes in this population. Strokes should be the last thing to worry about when we think of pregnancy. In the United States, around 30 in 100,000 women, unfortunately, experienced a stroke during pregnancy, and between 6 to 8 in 100,000 deliveries are complicated by subarachnoid hemorrhage. What's the most common cause of pregnancy-associated subarachnoid hemorrhage? In the general population, close to 80% of subarachnoid hemorrhage cases are aneurysmal. Is this true for the pregnant population as well? And importantly, what's the contemporary incidence trend, risk factors, and outcomes of pregnancy-related subarachnoid hemorrhage? In this issue of the journal, Dr. Korhonen and Petra [Ijäs] and their colleagues from the Departments of Neurology and Obstetrics and Gynecology at Helsinki University Hospital will give us the answers to some of these questions through a nationwide population-based study in Finland. So, they looked at over one and a half million pregnant women who gave birth during a 30-year time period between 1987 to 2016. Subarachnoid hemorrhage was identified through appropriate ICD codes and then further adjudicated based on confirmatory information, including neuroimaging and data from lumbar puncture. A total of 57 cases of pregnancy-related subarachnoid hemorrhage was identified in this paper. The mean age of women was 33, ranging from 23 to 45, and the clinical presentation was typical for subarachnoid hemorrhage, including thunderclap headache and mild neurological symptoms. So, what did they find? So, first off, in terms of general observations, the overall incidence rate of pregnancy-related subarachnoid hemorrhage in this study was 3 over 100,000 deliveries. This is almost half the incidence rate reported from the nationwide registries in the United States. Seventy-seven percent of pregnancy-related subarachnoid hemorrhage cases were aneurysmal, so very similar to the general population. The other 23% were non-aneurysmal cases, but it's important to note that 40% of those non-aneurysmal cases also had vascular etiologies, so etiologies such as moyamoya syndrome, postpartum angiopathy, AVM, to name a few. Like non-pregnant patients with subarachnoid hemorrhage, the aneurysmal cases were sicker patients in general. They had a lower GCS at presentation, higher Hunt and Hess scores, and required more ICU admissions. The next finding is very important because it actually shows that development of subarachnoid hemorrhage during pregnancy significantly impacted obstetrical care. A total of 66% of women with subarachnoid hemorrhage during pregnancy ended up having a C-section and a high percentage of these cesarean sections were actually elective. This is in contrast with subarachnoid hemorrhages in the postpartum period where 67% of women had spontaneous vaginal deliveries. The other important finding of the paper was really highlighting the differences between pregnancy-related aneurysmal versus non-aneurysmal subarachnoid hemorrhages. We already talked about how, in general, aneurysmal cases had more severe neurological presentations, so, not surprisingly, they also had worse outcomes with a mortality rate of 16% for the aneurysmal subarachnoid hemorrhage cases, and only 68% of women with pregnancy-related aneurysmal subarachnoid hemorrhage reached a favorable outcome, which was defined in this study as modified Rankin Scale of 0 to 2. Other important differences included the fact that the incidence of aneurysmal subarachnoid hemorrhage increased towards the end of pregnancy and was highest in the third trimester. This ties in with the findings from prior studies all indicating that rupture of an aneurysm is most common in the third trimester. By contrast, the incidence of non-aneurysmal subarachnoid hemorrhage peaked in the second trimester in this study. And finally, in terms of risk factors, first let's talk about age. The incidence rate of pregnancy-associated subarachnoid hemorrhage increased with age of the mother. So, in this study, there were no cases noted amongst women aged below 20 years of age to an incident rate of 12 per 100,000 deliveries among women aged 40 years or over. So that's a fourfold increase from the overall incidence rate of pregnancy-related subarachnoid hemorrhage, and very important point that we learned from this paper. Apart from age, smoking beyond 12 weeks of gestation and hypertension were also independent factors associated with pregnancy-related subarachnoid hemorrhage. So, overall, hypertension, smoking are bad and are significant risk factors for pregnancy-related subarachnoid hemorrhage. And if we have to remember just one thing from this paper, let it be this one: The rupture of an aneurysm is most common in the third trimester of pregnancy. Cerebral amyloid angiopathy, or CAA, is an important cause of intracranial hemorrhage and refers to deposition of β-amyloid fibrils in the wall of the small- and medium-sized cerebral blood vessels, mostly involving cortical and leptomeningeal arteries. It is believed that the deposition of β-amyloid results in architectural disruption of the blood vessels, which then leads to perivascular leakage. That's the pathophysiological mechanism behind the development of cerebral microbleeds. And this process, of course, can cause frank vascular rupture resulting in cortical intracerebral hemorrhage or development of high-convexity subarachnoid hemorrhages. It is important to note that varying amounts of perivascular inflammation, that is inflammation surrounding β-amyloid-laden blood vessels, may be present in some CAA cases, rendering them the designation of inflammation-related CAA. However, frank vasculitic destruction of the vessel wall, such as what is found in amyloid-β-related angiitis, or ABRA, and primary angiitis of the central nervous system, is usually absent in most CAA-related inflammation cases. How these entities are best defined, diagnosed, and treated is subject of intense research. In this issue of the journal, in the study titled "Clinical, Neuroimaging, and Genetic Markers in CAA-Related Inflammation," Dr. Georgios Tsivgoulis and colleagues take us through a systematic review and meta-analysis of published studies of patients with CAA-related inflammation. I am joined today by Dr. Tsivgoulis himself to discuss this paper. He's a Prof…

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Stroke Alert December 2022 Dec 15, 2022

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On Episode 23 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the December 2022 issue of Stroke: "Direct, Indirect, and Combined Extracranial-to-Intracranial Bypass for Adult Moyamoya Disease" and "Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States." She also interviews Drs. Koji Tanaka and Andrew Demchuk about article "Significance of Baseline Ischemic Core Volume on Stroke Outcome After EVT in Patients Age ≥75 Years." Dr. Negar Asdaghi: Let's start with some questions. 1) Is direct bypass better than indirect bypass in preventing the future risk of vascular events in adult patients with moyamoya disease? 2) What is the contemporary incidence of cerebral venous sinus thrombosis in the pediatric population? 3) And finally, is endovascular therapy beneficial for patients presenting with a large ischemic core? We have the answers and much more in today's podcast. You're listening to the Stroke Alert Podcast, and 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. In our final podcast for the year, I'm thrilled to announce that Drs. Nastajjia Krementz and Eric Goldstein have joined our podcast as assistant editors to help us cover the latest and the best in the field of cerebrovascular disorder. And together, here's our article selection to close the year. As part of our Advances in Stroke, in the article titled "Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation," we get an update on current evidence from randomized controlled trials on the use of direct oral anticoagulants or vitamin K antagonists in patients with valvular heart disease that are mechanical valves, moderate to severe mitral stenosis, or bioprosthetic valves from the perspective of stroke physicians. What that means is that data from randomized trials was analyzed based on whether the patient had a prior history of stroke or TIA. In this review, we learned that direct oral anticoagulants may be used in patients with bioprosthetic valves who have atrial fibrillation, although DOACs have never been shown to be superior over vitamin K antagonists. We also learned that vitamin K antagonists should be used in patients with rheumatic moderate to severe mitral valve stenosis or patients with mechanical valves with or without atrial fibrillation and, of course, sometimes during the first few months after either surgical or transcatheter aortic valve replacement in patients without atrial fibrillation. And finally, patients with bioprosthetic valves without AFib don't have any other indications to be treated with anticoagulants should be treated with antiplatelet monotherapy in the long run. In a separate article in this issue of the journal, from Dr. Yang and colleagues from China, we learn about the pathophysiology of radiation-induced brain injury with special attention to radiation-induced vasculopathy. These investigators show that hyperactivity of notch signaling pathway that in normal state is essential in vascular morphogenesis and maintenance of arterial identity actually results in abnormal accumulation and disturbance of vascular smooth muscle cells, resulting in arterial muscularization and arterial dysfunction seen in radiation-induced vasculopathy. What's interesting is that inhibition of the notch signaling pathway in their study resulted not only in a measurable reduction in radiation induced vasculopathy, but also an overall improvement in radiation-induced brain injury as measured by the cognitive function of the mice exposed to radiation in their study. This study takes us a step closer to possible therapeutic options for radiation-induced vasculopathy and radiation-induced brain injury using compounds that can potentially inhibit the notch signaling pathway. As always, I encourage you to review these articles in detail in addition to listening to our podcast. For our interview today, I have a special guest who's not only a prominent researcher and a pioneer in the field of acute stroke therapies, but also, he's an experienced educator who has trained many of the current leaders in the field of vascular neurology and has been influential in shaping the careers of many vascular neurology fellows over the years. Take a listen. Dr. Andrew Demchuk: I've had the privilege of training fellows. I've been the director since 2004, and we've trained close to 100 fellows in Calgary over 20-some years now. Really, it's frankly an honor and privilege to be able to do that. These individuals come from all over the world. They're here to dedicate themselves to learning a subspecialty really, really well, and it's just a fantastic experience to interact with them all and all their cultures to help them learn those things, and doing it in a fun, enjoyable, comprehensive way. Dr. Negar Asdaghi: And those are the words of Dr. Andrew Demchuk, who's incidentally my own vascular fellowship director as well. Andrew joins me all the way from Canada to talk about his latest paper on the very hot topic of outcomes of endovascular therapy in patients presenting with a large ischemic core. And true to form, he's accompanied by one of his current vascular fellows. The interview is definitely worth the wait after we review these two articles. Most of us have heard of the term "moyamoya." First described in Japan in 1950s, the term refers to occlusion or stenosis of the terminal portion of the internal carotid artery and is associated with dilated collateral vessels of the proximal middle cerebral artery. These collaterals have a hazy appearance on angiography resembling the puff of smoke, which is Japanese for "moyamoya." Moyamoya is categorized into two broad categories of moyamoya syndrome and moyamoya disease. Syndrome refers to the situations where the occlusion occurs due to another condition. Conditions such as Down syndrome, sickle cell disease, neurofibromatosis type one have all been recognized as associated with moyamoya syndrome. Of course, moyamoya syndrome can occur due to a secondary insult to the blood vessels, anything from radiation vasculopathy, as we reviewed earlier in the podcast, to autoimmune vasculitis, or even good old advanced intracranial atherosclerosis involving the distal ICA region can cause moyamoya syndrome. Now, in contrast to moyamoya syndrome, the term "moyamoya disease" is reserved for individuals with no vascular risk factors or known moyamoya predisposing conditions other than, of course, some potential genetic factors. The most recognized genetic association for moyamoya disease is polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17. But we also have to keep in mind that the majority of moyamoya disease patients have no identified genetic abnormalities. So, moyamoya is truly a complex condition, and the physicians have to navigate the many possible etiologies that may cause or be associated with this condition. But when it comes to treatment options, we're really limited here. Antiplatelets are generally used and have been shown to reduce mortality in both moyamoya disease and syndrome, and especially cilostazol, which is the favorite antiplatelet therapy of our own assistant editor, Eric, has been shown to be significantly associated with increased survival rate in patients with moyamoya disease. Eric really wanted me to talk about a recently published study out of Korea, which included over 9,000 patients, and that showed that patients treated with cilostazol had a better survival rate than any other antiplatelet therapies. Apart from antiplatelet therapies, medical treatment includes optimizing all other vascular risk factors, which, as we mentioned, are rarely present in this population. So, it all comes down to most cases, at some point, needing surgical treatment, with bypass surgery being the most commonly surgical intervention for this population. Three flavors of bypass are used: indirect, direct, or combination of the two. Indirect bypasses are kind of like long-term investments where the surgeon moves vascular tissue to the surface of the brain in hopes of promoting angiogenesis. Several procedures, such as performing multiple burr holes, pial synangiosis, dural inversion, or omental transposition, among other methods, are used. And broadly speaking, we can think of indirect procedures as angiogenesis-dependent methods, the effect of which takes months to recognize and, in general, are thought to be more efficacious in the pediatric population than the adult population. The direct bypass, in contrast, commonly referred to as extracranial-to-intracranial, or ECIC, bypass, is more of an immediate reward where the surgeon stitches a vessel directly from a donor extracranial branch, typically the superficial temporal artery, to a recipient artery, typically the middle cerebral artery, to provide a direct anastomosis between the two vessels. There are technical variations, of course, especially with regards to the number of donors and recipient arteries used, but essentially this method is an angiogenesis-independent method that results in a quicker revascularization, but it's unclear if this strategy is long lasting. A combination of direct and indirect bypass can also be used. So, the question is, which method is better, especially in the adult population? In this issue of the journal, in the study titled "Direct, Indirect, and Combined ECIC Bypass for Adult Moyamoya Disease," Dr. Nickalus Khan and colleagues report on a meta-analysis and systematic review of those with adult moyamoya disease who underwent either direct, indirect, or a combination bypass. The main study question was whether there's a difference in the rates of early ischemic or hemorrhagic strokes, defined as strokes occurring within 30 days of bypass, or late strokes, defined as strokes occurring after 30 days of bypass, in this population when comparing the different surgical techniques. They also compared the "favorable" outcome rate; however, this outcome was defined in each study between the various broad techniques of direct, indirect, and combined bypass. So, with that, let's take a very quick look at their methodology. They screened more than 4,000 articles and identified 143 articles for their pooled analysis, the majority of articles being from Eastern Asian-based regions, and they had close to 4,000 combined, 4,000 direct, and 4,000 indirect bypass procedures for this analysis. And they had an average follow-up of over three and a half years. So, this is a great sample size for this large, pooled analysis. But they also performed a smaller meta-analysis where they were much more stringent with article selection, excluding pediatric papers, excluding articles containing only one surgical modality, or articles with insufficient outcome data. So, for that meta-analysis, they only had 43 articles qualified and were included in that meta-analysis. So, what did they find? In the larger pooled analysis, a significant benefit in favor of both direct and combined bypass techniques were noted in reduction of early and late ischemic strokes and late intracerebral hemorrhage. Also, a higher rate of that sort of vague favorable outcome was noted with both the direct or combined methods as compared to when indirect bypass techniques were used alone. So, everything in the large, pooled analysis pointed towards the direct bypass or combined technique performing better than all indirect bypass techniques, with only one exception, which was a lower incidence of early intracerebral hemorrhage rate in indirect bypass cases. So, that's one point to keep in mind. The second point was when they compared combined techniques to direct bypass. Overall, these procedures had more or less the same outcomes with the exception that the rate of late ischemic stroke was lower in the combined group than the direct bypass group. So, this is sort of the overall summary of what they found in that large, pooled analysis. When they were much more stringent with their selection criteria, focusing on the smaller meta-analysis portion of the study, what they found was that in the short term, there were no differences in outcomes of any type of stroke between any of these methods. So, basically, people, regardless of the type of bypasses they received, did the same with regards to the risk of intracerebral hemorrhage and ischemic stroke recurrence within the first 30 days after the bypass. But for the late stroke outcomes, whether ischemic or hemorrhagic, those with indirect bypass were nearly twofold more likely to develop late stroke after 30 days compared to those who've undergone the direct bypass. A similar pattern was found comparing combined bypass versus indirect bypass, in general, beyond the 30 days, with combined bypass doing better. Comparing direct versus combined bypass showed no difference regardless of timeframe. So, in summary, overall, it appears that combined or direct bypasses may be the best surgical strategies for treatment of adult patients with moyamoya disease. This study, of course, has many limitations, as does any meta-analysis, but most importantly, the authors focused on moyamoya disease in their analysis. It is presumed, but really unclear if patients with moyamoya syndrome would respond similarly to these different techniques. So, the question is, what surgical procedure are you using at your institution for treatment of adult moyamoya disease patients? And, of course, Eric wanted me to ask if your antiplatelet of choice is cilostazol for this population, yes or no. Leave us your comments, and let us know. Venous sinus thrombosis, or CVST, is a less common form of stroke most commonly affecting women and young individuals. In our past podcast, we've covered many aspects of CVST, especially when it comes to therapy with anticoagulation, anticoagulant of choice, and duration of therapy. In the October podcast, we reviewed a systematic review and meta-analysis comparing direct oral anticoagulants to vitamin K antagonists in the adult patients with CVST. But there are many aspects of this disease that we have not yet covered. For instance, you may ask, how common is this relatively uncommon condition? In the adult population, the incidence of CVST varies depending on the age of individuals studied, and ranges between 1.3 to 2.7 per 100,000 in women between the ages of 31 to 50, which is the adult population at highest risk for this disease. But the incidence of CVST, for instance, in the pediatric population is largely unknown. Some studies suggested an incidence rate of 0.67 per 100,000 in the pediatric population. That's roughly less than half the incidence rate in young female adults, but these reports are from the 1990s and are likely very outdated. Nowadays, many of the pediatric conditions, especially infectious conditions, that can predispose children to CVST are more readily diagnosed and treated. On the other hand, we now perform a lot more imaging than 30 years ago. Our neuroimaging modalities are more accurate, so we are more likely to diagnose CVST than before. So, the question is, what is the contemporary incidence of pediatric cerebral venous sinus thrombosis? In this issue of the journal, in the study titled "Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States," Dr. Fadar Otite and colleagues conducted a retrospective analysis of the New York State Inpatient Database, or SID, from 2006…

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Stroke Alert November 2022 Nov 17, 2022

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On Episode 22 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the November 2022 issue of Stroke: "Estimating Perfusion Deficits in Acute Stroke Patients Without Perfusion Imaging" and "Five-Year Results of Coronary Artery Bypass Grafting With or Without Carotid Endarterectomy in Patients With Asymptomatic Carotid Artery Stenosis." She also interviews Dr. George Ntaios about his article "Incidence of Stroke in Randomized Trials of COVID-19 Therapeutics." Dr. Negar Asdaghi: Let's start with some questions. 1) What is the actual incidence of stroke after COVID-19? 2) In the setting of acute ischemic stroke, can the volume of ischemic penumbra be estimated with just a regular MRI study of the brain without any vascular or perfusion imaging? 3) And finally, can a patient with significant carotid stenosis go through coronary artery bypass graft surgery? We're back here to answer these questions and bring us up to date with the latest in the world of cerebrovascular disorders. You're listening to the Stroke Alert Podcast, and 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. The November issue of Stroke is packed with a range of really exciting and exceedingly timely articles. As part of our Original Contributions in this issue of the journal, we have a post hoc analysis of the Treat Stroke to Target, or the TST, randomized trial by Dr. Pierre Amarenco and colleagues. We've talked about this trial in our past podcast, and the main study results that were published in New England Journal of Medicine in January of 2020. TST randomized patients with a recent stroke or TIA to either a low target of LDL cholesterol of less than 70 milligram per deciliter or a target LDL of 90 to 110. The main study showed that the low LDL target group had a significantly lower risk of subsequent cardiovascular events without increasing the risk of hemorrhagic stroke. So, from this, we know that achieving a low target LDL is possible and is actually better than the LDL target of 90 to 110 post-stroke. But in the new paper, in this issue of the journal, in a post hoc analysis of the trial, the TST investigators showed that it's not just achieving that magic low target LDL of less than 70 that's important in a reduction of cerebrovascular disorders, but it's also how we achieve it that determines the future of vascular outcomes. So, in this analysis that compared patients on monostatin therapy to those treated with dual cholesterol-lowering agents, that would be a combination of statin and ezetimibe, and showed that in the low LDL target group, only those patients treated with dual therapy had a significant reduction of subsequent vascular events as compared to those in the higher LDL category. But the same was not true for patients on statin monotherapy, even though they had all achieved a low target LDL. Think about this for a moment. Both groups, whether on statin monotherapy or on dual anti-cholesterol treatments, achieved the same low target of LDL, but only those on dual therapy had a lower risk of subsequent vascular events as compared to those that were in the higher LDL target group. Very thought-provoking study. In a separate paper by Dr. Shin and colleagues out of Korea, we learned that survivors of tuberculosis, or TB, are at a significantly higher risk of ischemic stroke than their age- and risk factors–matched non-TB counterparts. The authors used data from the Korean National Health Insurance Services and studied over 200,000 cases diagnosed with TB between 2010 and 2017 and compared them to a pool of over one million non-TB cases for matching. And they found that the risk of ischemic stroke was 1.2 times greater among TB survivors compared to matched non-TB cases after adjusting for the usual confounders, health behavioral factors, and other comorbidities. Now, why would TB increase the risk of stroke? The authors talk about the pro-inflammatory state of this condition, thrombocytosis, that is a known complication of chronic TB amongst other putative and less clear mechanisms. But what is clear is that findings from a large-scale population-based cohort such as the current study support an independent association between TB and ischemic stroke. As always, I encourage you to review these papers in addition to listening to our podcast today. My guest on the podcast today, Dr. George Ntaios, joins me all the way from Greece to talk to us about the much discussed topic of the risk of stroke in the setting of COVID-19. Dr. Ntaios is the President of the Hellenic Stroke Organization and an experienced internist who has been fighting this pandemic in the front lines since the beginning. In an interview, he talks about his recently published paper, his experience, and the lessons learned on balancing scientific rigor against the urgency of COVID-19. But first, with these two articles. In the setting of a target vessel occlusion in patients presenting with an acute ischemic stroke, distinguishing the ischemic core from the ischemic penumbra is of outmost importance. The success of all of our reperfusion therapies heavily lies on our ability to differentiate between the tissue that is already dead, which would be the ischemic core, from the tissue that is not dead yet but is going to die unless revascularization is achieved. That is the ischemic penumbra. Over the past two to three decades, there's been lots of debate over how these entities of dead tissue versus going-to-die tissue are best defined, especially when we're making these distinctions under the pressure of time. We don't even agree on the best imaging modality to define them. Should we rely on CT-based imaging? Do we stop at CT, CT angiogram? Should we do single-phase CTA or multiphase CTA? When do we perform CT perfusion, and what perfusion parameters best define core and penumbra, or should we rely on MRI-based modalities altogether? These questions have all been asked and extensively studied, which is why, as a field, I think, we have at least some agreements today on the basics of core and penumbra definitions. And I also think that overall we are becoming better at doing less imaging to be able to predict tissue outcomes in real time. And there's definitely a growing interest in trying to estimate tissue fate based on a single-imaging modality. So, I think you're going to find an Original Contribution in this issue of the journal, titled "Estimating Perfusion Deficits in Acute Stroke Patients Without Perfusion Imaging," really interesting. In this paper, Dr. Richard Leigh from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, in Bethesda and colleagues evaluated patients with acute ischemic stroke enrolled between 2013 to 2014 in the NINDS Natural History of Stroke study. A little bit about the study: It enrolled stroke patients presenting to three hospitals in Washington, DC, and Maryland with serial MRI scans during the acute and subacute time period after ischemic stroke. For this particular paper, they included patients who received MRI and perfusion-weighted imaging and included only those who were thrombolized. That was their way of ensuring that all patients in their study were in the hyperacute stage of stroke. They then looked at their MR imaging, specifically the fluid-attenuated inversion recovery, or FLAIR, images, for a presence of something called hyperintense vessels in the ischemic territory. Now, this is an audio-only podcast, so unless you're Googling FLAIR hyperintense vessels on MRI, to follow along, I have to take a bit of time explaining this entity. What do we mean by FLAIR hyperintense vessels? We are not just talking about the T2 hyperintense signal that's sometimes noticeable at the site of proximal occlusion. For example, in the setting of an M1 occlusion, we may be able to detect a T2 hyperintense signal at the site of M1 on FLAIR. That's not the point of this paper. The point is to look throughout the area supplied by that said target occlusion, in this case all of the MCA, and see whether there is hyperintense signal in all arteries in that potentially ischemic tissue and how the area delineated by these FLAIR hyperintense vessels could potentially correspond to the area of perfusion deficit on conventional perfusion imaging. It turns out that these hyperintense vessels actually map a pretty large area. So, this is the point of this study. The investigators developed a FLAIR hyperintense vessel scoring system and called it NIH, obviously, because this was a National Institutes of Health study, FHV, which stands for FLAIR hyperintense vessel, scoring system. And the score is based on presence of these hyperintense vessels in three vascular territories: ACA, MCA, or PCA. Now, seeing that MCA is a larger territory, they had to further divide it into four sub-regions: frontal, insular, temporal, and parietal. So, in total, we have six regions now. Each of them would get a score of zero if there were no hyperintense vessels in them, and a score of two if there were three or more FLAIR hyperintense vessels in a single slice, or if there were three or more slices that contained FLAIR hyperintense vessels. And, of course, a score of one would be anything in between. So, we have six regions in total, each maximum getting two points, to give us a composite score of maximum 12 for this scoring system. So, they wanted to see whether there's a correlation between the FLAIR hyperintense vessel score and the volume of perfusion deficits that is detected by conventional perfusion imaging, which is their main study result. But before we go there, it does seem like a lot of work to learn all these regions and count all these hyperintense vessels in these six regions and come up with an actual score. So, they had to do an interrater reliability to see how easy it is to score and how reliable are these scores. So, they had two independent reviewers for their study. On average, the scores of these two independent reviewers differed by one point for a κ of 0.31, which is quite a low interrater reliability. But when they looked at a more liberal way of assessing interrater reliability, where partial credit was given, when the raters were at least close in their scoring, the κ improved to 0.65 for a moderate degree of agreement. So, what that means is that it's not easy to learn the score, and potentially I can give a score and another colleague can give a different score. So, we have to keep that in mind. But I want to emphasize that in the field of stroke neurology, we are kind of used to these poor interrater reliability agreements in general. For example, the interrater reliability of the ASPECTS score, a score that is commonly used in our day-to-day practice, and especially in the acute phase, we communicate the extent of early ischemic changes by using the ASPECTS score, has a pretty poor interrater reliability, especially in the first few hours after the ischemic stroke. So, we can make due with a κ of 0.65. Now on to the results of this study. They had a total of 101 patients. Their median age was 73. The median FHV, which is that FLAIR hyperintense vessel score, in their entire cohort was four. And close to 80% of patients enrolled in their study had some perfusion abnormalities on their concurrent perfusion-weighted imaging. Now, briefly, they defined perfusion deficits as areas with delay in the relative time to peak map, or TTP maps, after applying a six-second threshold to these TTP maps. Of note, half of those patients with a perfusion deficit had a significant perfusion deficit, which meant that they had 15 cc or more of perfusion deficit. OK, now on to the main study results. Number one, the score obtained by NIH FLAIR hyperintense score highly correlated with the volume of perfusion deficit. In fact, every one point increase on the NIH-FHV score was approximately equal to 12 cc of perfusion deficit. That's a really useful way of thinking about this score. Each score translated in 12 cc of perfusion deficit. Number two, when they looked at the predictive ability of this score in predicting the presence of significant perfusion deficit, that is 15 cc or more of perfusion delay, the area under the curve was 0.9, which is quite high. This is quite reassuring that the FHV score was sensitive and specific in predicting the presence of significant perfusion deficit. Next finding, how does this score do in predicting a significant mismatch? They calculated mismatch ratio by dividing the perfusion volume to that of ischemic core as measured by diffusion volume as it's done conventionally, and then did the same for the score with the exception that instead of using the perfusion volume, they actually used this score and divided it by diffusion volume. And it turns out that FLAIR hyperintense mismatch ratio had a strong predictive capability in predicting the mismatch ratio of 1.8. So, in summary, if this score is validated in larger studies, it can potentially be used as a quick and dirty way of calculating the amount of perfusion deficit in the setting of target vessel occlusion. And, of course, it can also be used as a predictive way of presence of significant perfusion deficit, which is perfusion deficit of over 15 cc. This is all without the need to do actual perfusion imaging. Now, all we've got to do is to get comfortable with this scoring system and, of course, be able to multiply it by 12 to give us a quick guesstimate of the perfusion volume. And one final word on this is that I think the future of stroke imaging is not in doing more images, but to be able to extract more information from less imaging in the acute setting. Stroke physicians were frequently consulted to see patients that are scheduled to undergo coronary artery bypass graft surgery, or CABG. The stroke consult would be for the optimal perioperative management of an often incidentally found carotid disease. Now, why do I say we were frequently consulted? Because at least anecdotally in my own practice, I feel that over the past decade, the number of these consults has substantially reduced. Why is that? Well, let's dive into this topic and review some of the literature. First off, around 40% of patients who have active coronary artery disease and are scheduled to undergo CABG have concurrent carotid disease, and about 10% of CABG patients have evidence of hemodynamically significant carotid disease. And seeing that the risk factors for coronary artery disease are similar to those causing carotid disease, these high percentages are not surprising at all. But the question to ask is, can we put a patient with significant carotid disease through cardiac surgery? What is the perioperative risk of stroke in this situation? And importantly, should the carotid disease be surgically treated during carotid surgery? This is referred to as synchronous carotid endarterectomy, or CEA plus CABG. Or the carotid disease should be treated either surgically or endovascularly before CABG? We refer to this as staged carotid surgery or post-CABG. This is known as reverse staged carotid surgery. All of these questions are asked from the stroke physicians in that consult, and, like many of you, I have struggled to find the evidence to answer some of them. So, let's briefly review some of the current literature on this topic. The CABACS trial, the acronym stands for the Coronary Artery Bypass Graft Surgery in Patients With Asymptomatic Carotid Stenosis, was a randomized controlled trial that included patients undergoing CABG who are found, exac…

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Stroke Alert October 2022 Oct 20, 2022

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On Episode 21 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2022 issue of Stroke: "Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk" and "Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage." She also interviews Dr. Shadi Yaghi about his article "Direct Oral Anticoagulants Versus Vitamin K Antagonists in Cerebral Venous Thrombosis." Dr. Negar Asdaghi: Let's start with some questions. 1) Do hormone replacement therapies or oral contraceptives increase the risk of stroke? And if yes, does the age of the individual or the duration of therapy modify this risk? 2) Should survivors of intracranial hemorrhage who have atrial fibrillation be treated with antithrombotic therapies for secondary prevention of stroke? 3) And finally, what is the anticoagulant of choice for treatment of cerebral venous sinus thrombosis? We have the answers and much more in today's podcast as we continue to bring you the latest in cerebrovascular disorders. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us. Welcome back to another amazing 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. The October issue of Stroke covers a number of timely topics. As part of our October Literature Synopsis, we have a nice paper by Dr. Farida Sohrabji and colleague, which summarizes three recently published animal studies to evaluate the association between small vessel ischemic injury and either development of Parkinsonism or the future risk of Parkinson's disease. These studies looked at how ischemia, specifically involving the lenticulostriate arteries, can modulate the nigrostriatal dopaminergic pathway and ultimately lead to Parkinsonism. As part of our Original Contributions, we have the results of a small randomized trial out of Korea, which was led by Dr. Yun-Hee Kim from Sungkyunkwan University School of Medicine in Seoul, where we learned that doing 20 sessions of transcranial direct current stimulation for about 30 minutes for each session at home can improve post-stroke cognition. This was found to be specifically effective in patients with post-stroke moderate cognitive decline. Now, transcranial current stimulation can be given using a handheld device at home, and if truly proven safe and efficacious in larger studies, can dramatically change the landscape of stroke recovery in cognitive rehabilitation. I encourage you to review these articles in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Shadi Yaghi from Brown University. Shadi will walk us through a systematic review and meta-analysis of published studies to compare the safety and efficacy of direct oral anticoagulants to that of vitamin K antagonists in patients with cerebral venous sinus thrombosis. Our devoted Stroke Alert Podcast listeners recall that we did cover this topic in our March podcast when we reviewed the results of ACTION-CVT, a multicenter international study that was led by none other than Shadi himself. I'm delighted to have him as a guest on my podcast today to talk more about the seminal study and all things cerebral venous sinus thrombosis. But first, with these two articles. Millions of women worldwide use exogenous hormones, most commonly in the form of oral contraceptives and hormone replacement therapies. Despite the many different formulations of these drugs that are now available on the market, the two therapies are similar in that both combined oral contraceptives and hormone replacement therapies, or HRTs, contain various dosage of estrogen and progestin. Now, the principal difference between them being that the hormone contents of oral contraceptives are at high enough dosage to prevent ovulation, whereas hormone replacement therapies are considered more physiological as their aim is to return post-menopausal hormone levels to what they were before menopause. Well, by now, you must wonder how is any of this even relevant to vascular neurology? Well, the answer lies in the close relationship between hormonal therapies and stroke. But before we get to that, we have to review a few things. First of all, it's long been known that the endogenous estrogen has strong and protective effects on the arteries. It promotes vasodilation and cell survival of the endothelial layer. It increases the endothelial mitochondrial efficiency and stimulates angiogenesis. In other words, endogenous estrogen is good for vascular health. And in fact, that's why we think that premenopausal women, in general, are at a lower risk of stroke as compared to their age and vascular risk factors–matched male counterparts. And to make things even better for estrogen, there's enough evidence to suggest that exogenous estrogen also does all of these good things for the endothelium. So, why are we even talking about an increased risk of stroke associated with use of hormonal therapies? The problem is, we have to remember that exogenous estrogen also does other things. It can increase the blood concentration of procoagulants, which, in turn, can increase the risk of thromboembolism, especially venous thrombosis. But there's still a lot of unknown on this topic. For instance, the majority of the prior research on the topic involves postmenopausal women using hormonal therapies. Some of that research has actually suggested that HRTs may be protective against vascular events, while others showed the opposite. Well, we know that a majority of oral contraceptive users are actually much younger and use these medications premenopausal. So, there seems to be a lot of gaps in our current knowledge on the simple question of whether or not oral contraceptives and hormonal replacement therapies do, in fact, increase the risk of stroke or not. In the current issue of the journal, a group of researchers led by Drs. Therese Johansson, Torgny Karlsson, and Åsa Johansson from the Department of Immunology, Genetics and Pathology at Uppsala University in Sweden set out to fill some of these gaps with their study titled, "Oral Contraceptives, Hormone Replacement Therapy, and Risk of Stroke," as part of a large UK Biobank population-based cohort. Just a bit about the UK Biobank. This was a large population-based cohort from 2006 to 2010 that included over 500,000 residents of the United Kingdom between the ages of 37 and 73. Participants at the time of enrollment would have extensive information collected from them through questionnaires, interviews, health records, physical measures, as well as some imaging and biological samples. Data on each participant was collected from the time of their birth all the way to the day of assessment, which is interesting, because the day of assessment would then count as the end of the follow-up for each participant. Now, for the current study, they included over 250,000 women of White race in whom information required for the study on whether or not they use hormonal therapies, duration of treatment, age at the time of exposure was available. And just a quick comment about their methodology. They analyzed their cohort once for oral contraceptive use and once for HRT use and compared each group to a reference group of either women who never used their set therapy or the number of years they contributed to the study prior to initiating that set treatment. So, for instance, if a person started using oral contraceptives at the age of 21, all of the years that she contributed to the study before that age would count as non-exposed user years and were included in the control cohort. So now, on to their findings. A total of 3007 stroke diagnosis of any type were identified prior to the initial visit to the assessment center, which, as we mentioned, was the end of the follow-up in the study. Of these, 578 were ischemic strokes, 177 intracerebral hemorrhage, and 478 were subarachnoid hemorrhages. But as expected for any large cohort, over half of total strokes were self-reported as stroke of any type and could not be classified into any of the above subtypes. Now, let's look at the effects of oral contraceptives on the outcome of stroke. Overall of the women included in the study, 81% were classified as oral contraceptive users, while 19% reported never having used oral contraceptives at any point during the study. On the association between oral contraceptive use and the risk of stroke, at first glance, things looked OK. The hazard rates of any stroke for any stroke subtypes were not different between women who had used oral contraceptives as compared to those in the reference group. That's great news. But when they looked deeper, they realized that the odds of development of any stroke was actually quite high during the first year after the initiation of oral contraceptives with hazard rate of 2.49 for any stroke, while there was no difference in hazard rates found during the remaining years of use and after discontinuation of oral contraceptive use. So, meaning that there was no lingering effects of oral contraceptives on increased risk of stroke after the first year or after discontinuing the medication. Now, on to HRTs. In total, 37% of women in the study had initiated HRTs at some point during the study, while 63% had never used this therapy. Here's the bad news. Overall, HRTs did increase the risk of stroke. An approximately 20% increase event rate of any stroke was noted among women who had initiated HRTs as compared to those who had not. When analyzing stroke subtypes, the use of HRTs was associated with increased risk of only the subarachnoid hemorrhage subtypes. We don't know why. Diving deeper, in considering timing of HRT initiation, very similar to what was observed for the oral contraceptives, during the first year after starting the HRTs, the treatment group was twice more likely to suffer from any type of stroke, and the hazard rate was also increased for all three stroke subtypes that were available in the study. But, unlike oral contraceptives, the hazard rate of any stroke remains significantly high even after the first year of use, not just for those who continued HRTs, but sadly, even for those who discontinued the therapy. Though the risk remained high, the hazard ratio declined over time as we went further away from the first year when treatment was initiated. So, bottom line, if women had initiated HRTs at some point in their life, the hazard risk of any stroke increased significantly in the first year. That hazard risk did decline over time, but it always remained significantly higher than non–HRT users. Now, what about timing of treatment in relation to the onset of menopause? Is the risk of stroke any different if women start on HRTs prior to or after their menopause? The answer is no. Initiation of HRTs was associated with an increased hazard rate of any stroke if it was started pre- or postmenopausal, but the risks were higher if the treatment was started prior to menopause. So, in summary, this large population-based cohort has truly given us some very important practical findings. We learned that both oral contraceptives and hormone replacement therapies do, in fact, increase the risk of stroke, an effect that was most notable in this study in the first year after initiation of both of these therapies, and in the case of oral contraceptives, was just actually limited to that one year alone. Why does this happen? I guess the easy answer is that these drugs, as we noted earlier, have an immediate prothrombotic effect, which gradually weakens over time. That's one plausible explanation, but for instance, why HRTs increase the risk of subarachnoid hemorrhage is something we can't explain based on the prothrombotic effects of HRTs. So, we have to come back to the vessels, the impact of hormone therapies and estrogen specifically on the blood vessels, on the endothelial cells, the potential increase in blood pressure, especially early on in the course of treatment with these medications. And also, we have to think about the role these drugs may play in increasing inflammatory markers, providing a more suitable milieu for accelerated atherosclerosis, as to why these associations were noted in this study. And it's fair to say that we need more research on this topic in the future. One challenging scenario that we commonly face in our daily practice is deciding whether or not we should resume antithrombotics in patients with atrial fibrillation who have survived an intracranial hemorrhage. The majority of intracranial hemorrhage survivors with atrial fibrillation actually have a very high CHA2DS2-VASc score, which means that they are actually at a very high risk of future ischemic stroke and systemic embolic events unless they're treated with anticoagulants. On the other hand, the risk of spontaneous intracranial bleeding is substantially higher in a person who has previously suffered from one, let alone if we treat them with anticoagulants. And to make matters worse, we have little evidence from the literature to guide us. So, in the current issue of the journal, in the study titled "Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage," a group of researchers from the UK led by Dr. Deirdre Lane, Professor of Medicine at the University of Liverpool, performed a much needed systematic review and meta-analysis of the available evidence on this subject. I have to say that lately, it seems that we've been covering a few of these reviews in our podcasts, and we are just getting started. In fact, my next paper in today's episode is also a systematic review and meta-analysis. These papers are packed with details, a testament to the work needed to complete them, but I have to say that even summarizing these papers for a podcast has been a bit challenging. So, feel free to put me on pause, go get some coffee, and let's power through this one together. For their methods, they used the usual search engines looking for papers that included adults over the age of 18 with atrial fibrillation who had survived a non-traumatic spontaneous intracranial hemorrhage of any size, any type, and any location, be it lobar, brain stem, deep, cerebellar, subdural, epidural, or subarachnoid hemorrhage. And very importantly, they included even those with evidence of microbleeds on neuroimaging. The intervention of interest was either long-term oral anticoagulation or antiplatelet therapy versus no antithrombotic use for the following three outcomes of interest: number one, recurrent thromboembolic events; number two, recurrent intracranial hemorrhage; and number three, all-cause mortality. Just a quick note that for this analysis, they excluded studies that looked at either short-term anticoagulation or non-oral anticoagulation use for any reason that was given to the patient other than for secondary prevention of stroke. For example, if a patient suffered from a pulmonary embolism and was treated with IV heparin or, for a short period of time after that, with oral anticoagulation, those patients or those studies were excluded from this meta-analysis. So, with this criteria, they pulled over 4,000 citations and abstracts, and finally included 20 papers that were published between 2015 and 2021 for a total of over 50,000 participants for this meta-analysis, very nice sample size. Most of the papers included were observational cohorts, but in addition, we had two small randomized trials, and I want to take a moment and review these trials for our listeners. The first one was…

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Stroke Alert September 2022 Sep 15, 2022

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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…

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Stroke Alert August 2022 Aug 18, 2022

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On Episode 19 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2022 issue of Stroke: "Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion" and "Recurrent Ischemic Stroke and Bleeding in Patients With AF Who Suffered an Acute Stroke While on Treatment With NOACs." She also interviews Dr. Alexander Nave about "Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events." Dr. Negar Asdaghi: Let's start with a few questions. 1) How much time do we actually save if we were to transfer all patients with suspected target vessel occlusion directly to the angiosuite and practically bypassing our current conventional imaging model? 2) What is the impact of an impaired metabolic state as measured by abnormal glucose and triglyceride tolerance tests on the risk of stroke recurrence in patients with ischemic stroke? 3) And finally, should we or should we not change the anticoagulant therapy of a patient with atrial fibrillation who suffered an ischemic stroke despite appropriate treatment with anticoagulation? We have the answers to these questions and much more in today's podcast because this is the best in Stroke. Stay with us. Dr. Negar Asdaghi: 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. The August 2022 issue of Stroke contains a range of really stimulating articles. We have an interesting study titled "Individual and Joint Effects of Influenza-Like Illness and Vaccinations on Stroke in the Young," led by Dr. Amelia Boehme and colleagues from Columbia University, with its accompanying editorial on how influenza-like illness is associated with increased risk of stroke in the young and middle-aged population while vaccinations of any type is protective of this risk. In a different paper, as part of a population-based study out of Scotland, Dr. Rustam Al-Shahi Salman from University of Edinburgh and colleagues report on a positive association between the use of beta-blockers, especially propranolol, and a lower risk of cerebral cavernous malformation, or CCM, associated intracranial hemorrhage. This study's findings are very interesting and quite important, and I encourage you to review the growing literature to suggest how beta-blockers may, in fact, reduce the risk of CCM-related hemorrhages through their anti-angiogenic properties. Dr. Negar Asdaghi: Later in the podcast, I have the great pleasure of interviewing Dr. Alexander Nave from Charité University Hospital in Berlin to discuss the relationship between having an impaired metabolic state in the setting of acute stroke and the risk of ischemic stroke recurrence, as we'll review the long-awaited results of the Berlin "Cream&Sugar" study, a very catchy title. But first, with these two articles. Dr. Negar Asdaghi: Time to successful endovascular reperfusion is an important predictor of clinical outcomes in patients with acute ischemic stroke related to a large vessel occlusion. And for years, we've known that the faster we're able to open the affected artery, the better the ischemic stroke outcomes are. Correspondingly, systems of care have adapted to various requirements of this so-called rapid workflow to ensure that all necessary pre-reperfusion steps are completed as fast as possible, preferably most in parallel to one another. And if any steps are unnecessary, they're bypassed altogether. Dr. Negar Asdaghi: Despite all these modifications to date, time from conventional imaging to angiosuite arrival remains both the longest and the most variable interval in the intra-hospital workflow prior to endovascular therapy. So, it's not surprising that many recent studies have evaluated whether the current model of hospital arrival, then transfer to the scanner for imaging, then transfer to the angiosuite for endovascular therapy, can be replaced by a simpler model where, based on clinical assessment, a patient with high likelihood of having a target vessel occlusion can directly be transferred to the angiosuite, where fast stroke imaging, including CT, CT angiogram, and CT perfusion, are completed on the angiotable using the flat panel imaging technology. Dr. Negar Asdaghi: If the patient is then found to be eligible to receive reperfusion therapies, including intravenous thrombolytics, they can receive the treatments and then proceed to endovascular thrombectomy without any further delays. So, in this issue of the journal, in the study titled "Direct to Angiosuite Versus Conventional Imaging in Suspected Large Vessel Occlusion," Dr. Raul Nogueira from Department of Neurology at Emory University and colleagues performed a systematic review and meta-analysis of published articles on this topic. So, they included seven articles for this analysis after pulling over 4000 articles using the common search engines for this meta-analysis. These articles included two single-centered European randomized controlled trials, one conducted in Germany, and the other one conducted in Spain, and five observational studies for a total of 1971 patients. The primary outcome was the odds of achieving favorable neurological recovery as defined by a modified Rankin Scale of zero to two at 90 days. Dr. Negar Asdaghi: Now, a few things to note: All studies reported door-to-puncture times, but not all reported door-to-reperfusion times or rate of successful reperfusion, and we know that these metrics are important in predicting the odds of safety and efficacy outcomes of endovascular therapy. And also it's important to note that not all details of the safety and efficacy outcome measures were reported in all of those seven studies. So, with that, here are the main findings of the meta-analysis. First off, amongst patients who were directly transferred to the angiosuite across these seven studies, the overall rate of false activation was 28%, meaning that after imaging assessment, 28% of those who were directly taken to the angiotable were not found to have a target occlusion, and as such, there was no need to further proceed to endovascular thrombectomy. And this is a practical finding of this meta-analysis as we deal with resource allocation and concerns of potentially overwhelming the neurointerventional teams. Dr. Negar Asdaghi: Now, moving on to the next finding of the study, the direct angio approach significantly reduced door-to-puncture times by a median of 30 minutes, and door-to-reperfusion times, when these metrics were available, by a median of 33 minutes as compared to the conventional imaging approach. So, bypassing conventional CT does translate into faster time metrics. These were, of course, expected findings of this meta-analysis, but nonetheless, important to quantify. But these faster time metrics did not improve the endovascular procedural outcomes, meaning that the direct to angio approach did not increase the odds of achieving a TICI 2b or better reperfusion, which is how successful reperfusion is defined, or the odds of achieving full reperfusion, meaning modified TICI 2c or greater reperfusion. Dr. Negar Asdaghi: So, it's great to get to the angiosuite fast, but that does not impact the procedural outcomes of endovascular therapy. Despite the above, the faster approach resulted in a significantly better functional independence outcome as measured by mRS Scale at 90 days, again emphasizing how important time is when it comes to endovascular outcomes. Now, the authors also performed a number of subgroup analysis in this meta-analysis, which I'd like to highlight some of them. We know that the impact of time on endovascular outcomes is more robust in the early time window. So, not surprisingly, when restricting the primary outcomes to those presenting within six hours from symptom onset, the favorable effect of direct to angio approach persisted in the early time window as well. Dr. Negar Asdaghi: Another important subgroup analysis was when restricting data to those patients who were transferred from a primary hospital to an endovascularly-capable center, the direct angio method didn't really have a significant impact on improving the primary outcome. Why is that? Let me repeat. So, when they restricted the analysis to those patients who were transferred from one hospital to an endovascularly-capable center, they did not find the same significant positive impact on endovascular outcomes in the direct to angio approach. I think the way we can explain this from a pathophysiological standpoint is that transferred patients are more likely to be slow progressors and, therefore, less likely to be impacted by delays in the workflow process as compared to the fast progressors. Dr. Negar Asdaghi: Take-home message: We've got to be fast in the fast progressors, and it's safe to assume that those who are within the first six hours after presentation are more likely to be fast progressors, and these workflow modifications are, therefore, much more robust and much more impactful in patients who present early on after their symptoms onset. And finally, in terms of safety outcomes, there were no significant differences in the rate of symptomatic intracerebral hemorrhage rate or the 90-day mortality rates either for the whole study population or when the analysis was restricted to those treated in the early time window. Dr. Negar Asdaghi: So, in summary, what we learned from this large meta-analysis is that as compared to the current conventional imaging model, the direct transfer to angio model is not only plausible and unlikely to overwhelm the interventional teams, as only less than 30% of patients in a direct method were not eligible for endovascular thrombectomy, but also this method is safe and results in significant improvements in workflow time metrics and functional outcomes. So, as the saying goes, select faster, select less, and treat more will likely be the future of endovascular therapy, particularly in the early time window. Dr. Negar Asdaghi: We know that oral anticoagulants reduce the risk of ischemic events in patients with atrial fibrillation. Nonvitamin K antagonist oral anticoagulants, or NOACs, also known as direct oral anticoagulants, or DOACs, are currently the standard of care for treatment of patients with non-valvular atrial fibrillation. Now, we have to keep in mind that although NOACs reduce the risk of ischemic stroke and systemic embolism in atrial fibrillation, they don't completely abolish the risk. So, they're not curative treatments for AFib, and patients can still experience embolic events despite appropriate treatment with these agents. In a meta-analysis of randomized trials, the residual risk of ischemic events in patients treated with NOACs was estimated at 1.4% per year, but this number is a lot lower than what is reported by real-life observational studies. Dr. Negar Asdaghi: In the large multicenter RENO study, which was published in this journal in 2019, we learned that in the setting of atrial fibrillation treated with a NOAC, a number of factors, including atrial enlargement, dyslipidemia, scoring high on the CHA2DS2-VASc score, and the use of low dose of NOACs, especially off-label low dose use of these medications, are significantly associated with increased risk of recurrent ischemic events despite treatment. But there's still a number of important questions that we routinely encounter in practice, most important of which is how to manage these patients with these so-called breakthrough ischemic events moving forward? Do we switch them to a different NOAC or go back to a vitamin K antagonist? Should we add an antiplatelet treatment to the regimen? And importantly, how do we counsel these patients and their families on their future risk of recurrent ischemic or hemorrhagic events? Dr. Negar Asdaghi: So, in the current issue of the journal, the RENO investigators, led by Dr. Maurizio Paciaroni and Valeria Caso, set out to answer some of these important questions as part of the RENO-EXTEND study, which basically followed the patients in the RENO cohort for at least 12 months, evaluating them for either recurrent ischemic or hemorrhagic events, whether occurring intra or extracranially. So, a bit about this cohort. The RENO study was a multicenter observational cohort across 43 centers in Europe and the United States, including consecutive patients with atrial fibrillation who presented to the hospital with an acute ischemic stroke despite being on a NOAC therapy. Patients were enrolled in the study only if they were compliant with their NOAC treatment and they had not missed their treatment for any reasons for greater than 24 hours prior to their index event. Dr. Negar Asdaghi: The patients were followed in the cohort and the choice of whether or not to start and timing, very importantly, for resumption of anticoagulation therapies were left to the discretion of the treating physicians. For the current paper, they analyzed 1240 patients. After the index event, 39.5%, so close to 40%, had their NOACs changed to another NOAC, mostly to a different class of NOAC. 42.5% continued with the same NOAC at the same dose. 6.7% continued with the same NOAC, but the dose was increased, and a small percentage were shifted to warfarin, that was only 4.7% of the patients. And 6.6% were shifted to low molecular weight heparin or were never prescribed oral anticoagulations after that index event for a variety of reasons, such as earlier ischemic recurrence, early hemorrhagic transformation, or early death or severe index stroke. And the overall median follow up in the study was 15 months. Dr. Negar Asdaghi: So, with that, here are the main study findings. The annual rate of the primary outcome of recurrent ischemic or hemorrhagic events, again, a reminder that these could have been intra or extracranial events, was 13.4%. The majority of these events were ischemic stroke, followed by major extracranial bleeding, then intracranial bleeding and systemic embolism. We have to note that this overall primary outcome rate is a lot higher than what was observed as part of the randomized trials of NOACs, as we noted earlier, which is an important finding of these real-life studies. Now, with regards to the factors predicting the primary outcome, having a higher CHA2DS2-VASc score and persistent hypertension were both predictive of recurrent ischemic events, whether ischemic stroke or systemic embolism. Next, the predictive factors for hemorrhagic events, either intracranial or major extracranial bleeding, included age, for each year increase in age, the odds increased by 1.1; history of major bleeding in the past; and, very importantly, a scenario that not uncommonly happens in routine practice, which is the addition of antiplatelet to a NOAC after the so-called NOAC failure. Dr. Negar Asdaghi: And finally, it turns out that changing that failed NOAC to a different agent didn't really seem to make a difference at all. As we mentioned earlier, close to 40% of patients were changed from one NOAC to another agent after the index ischemic event, and when they looked at the primary outcome, there was no difference in the rate of combined ischemic and hemorrhagic events, or the ischemic events alone, or bleeding outcomes alone, amongst patients who changed their NOAC to a different agent as compared to those who did not. The authors performed a number of subanalyses to see whether a particular strategy, for example, a switch from a particular class of NOACs to another class, or change in dosage, or NOAC to warfarin change, may be more or less beneficial in reducing the primary outcome, a…

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