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On Episode 40 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the May 2024 issue of Stroke: “Incidence and Outcomes of Posterior Circulation Involvement in Moyamoya Disease” and “Glymphatic System Impairment Contributes to the Formation of Brain Edema After Ischemic Stroke.” She also interviews Dr. Susanne van Veluw about her American Heart Association Centennial Collection article on “Cerebral Amyloid Angiopathy.”
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240507.258307
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On Episode 39 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the April 2024 issue of Stroke: “Intravenous Tirofiban Versus Alteplase Before Endovascular Treatment in Acute Ischemic Stroke: A Pooled Analysis of the DEVT and RESCUE BT Trials” and “Radial Versus Femoral Access for Mechanical Thrombectomy in Stroke Patients: A Non-Inferiority Randomized Clinical Trial.” She also interviews Dr. Shadi Yaghi about his article “Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection: The STOP-CAD Study.”
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240401.480865
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On Episode 38 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the March 2024 issue of Stroke: “High-Serum Brain-Derived Neurotrophic Factor Levels Are Associated With Decreased Risk of Poststroke Cognitive Impairment” and “Long-Term Risk of Arterial Thrombosis After Intracerebral Hemorrhage: MUCH-Italy.” She also interviews Drs. Santosh Murthy and Wendy Ziai about their article “Association Between Hematoma Volume and Risk of Subsequent Ischemic Stroke: A MISTIE III and ATACH-2 Analysis."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240311.154039
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On Episode 37 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the February 2024 issue of Stroke: “Intravenous Thrombolysis Before Endovascular Treatment in Posterior Circulation Occlusions: A MR CLEAN Registry Study” and “Effect of the Factor XIa Inhibitor Asundexian According to Baseline Infarct Pattern and on MRI Covert Infarct Outcomes.” She also interviews Drs. Brian Hoh and Marc Chimowitz on the Focused Update series of articles in this issue on the topic of intracranial atherosclerosis.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240209.645497
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On Episode 36 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2024 issue of Stroke: “Time Window for Induced Hypertension in Acute Small Vessel Occlusive Stroke With Early Neurological Deterioration” and “Patent Foramen Ovale Management for Secondary Stroke Prevention: State-of-the-Art Appraisal of Current Evidence.” She also interviews Drs. Kelly Flemming and Issam Awad about their articles “Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage. Part I: Event Rates and Clinical Outcome” and “Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage. Part II: Biomarkers and Trial Modeling.”
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20240108.294731
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On Episode 35 of the Stroke Alert Podcast, host Dr. Negar Asdaghi is joined by Dr. Ashkan Shoamanesh, Associate Professor of Neurology at McMaster University, for the inaugural 2023 Ralph L. Sacco Review of Top Cerebrovascular Research of the Year. In honor of the late Dr. Ralph L. Sacco, former Editor-in-Chief of Stroke, who died in January 2023, Drs. Asdaghi and Shoamanesh review some of the top cerebrovascular science published in any journal or presented at any scientific forum throughout the past year.
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231206.234364
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On Episode 34 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the November 2023 issue of Stroke: “Identification of Clinically Relevant Brain Endothelial Cell Biomarkers in Plasma” and “Robot-Assisted Transcranial Doppler Versus Transthoracic Echocardiography for Right to Left Shunt Detection.” She also interviews Dr. Thalia Field about her article “Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis.”
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231027.572752
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On Episode 33 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2023 issue of Stroke: “Spreading Depolarizations Suppress Hematoma Growth in Hyperacute Intracerebral Hemorrhage in Mice” and “Comment on the 2023 Guidelines for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage.” She also interviews Dr. Rebecca Gottesman about her article “Cerebral Microbleed Patterns and Cortical Amyloid-β: The ARIC-PET Study.”
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20231004.445526
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On Episode 32 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the September 2023 issue of Stroke: “Prestroke and Poststroke Sulfonylurea Exposure and Functional Outcomes: A Post Hoc Analysis of the SHINE Trial” and “Sleep Duration Is Associated With Subclinical Carotid Plaque Burden.” She also interviews Dr. Alexandros Polymeris and Prof. Philippe Lyrer about their article “Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.”
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230829.123365
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On Episode 31 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2023 issue of Stroke: “Cancer Prediction With Machine Learning of Thrombi From Thrombectomy in Stroke: Multicenter Development and Validation” and “Differences in Stroke Recurrence Risk Between Atrial Fibrillation Detected on ECG and 14-Day Cardiac Monitoring.” She also interviews Dr. Robert Starke about the article “Outcome Evaluation of Repeat Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations.”
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230802.750121
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On Episode 30 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2023 issue of Stroke: “Temporal Trends and Determinants of Stroke Risk in Patients With Medically Treated Asymptomatic Carotid Stenosis” and “Diffusion-Weighted Imaging Lesion Reversal in Older Patients With Stroke Treated With Mechanical Thrombectomy.” She also interviews Drs. Thanh N. Nguyen and Simon Nagel about their article “Endovascular Versus Medical Management of Posterior Cerebral Artery Occlusion Stroke: The PLATO Study.”
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230629.275844
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On Episode 29 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2023 issue of Stroke: “Prevalence and Procedural Risk of Intracranial Atherosclerotic Stenosis Coexisting With Unruptured Intracranial Aneurysm” and “Adolescent Hypertension Is Associated With Stroke in Young Adulthood: A Nationwide Cohort of 1.9 Million Adolescents.” She also interviews Dr. Darren B. Orbach about his article "Transuterine Ultrasound-Guided Fetal Embolization of Vein of Galen Malformation, Eliminating Postnatal Pathophysiology."
For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230530.62217
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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
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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
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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
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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.
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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 Professor of Neurology and Chairman of the Second Department of Neurology at the University of Athens School of Medicine. Dr. Tsivgoulis is the residency program director and the director of cerebrovascular fellowship program with extensive research and expertise in the field of stroke. Good morning, Georgios, and welcome to our podcast.
Dr. Georgios Tsivgoulis: Good morning, Negar. I'm delighted to be here and delighted to present our findings, on behalf of all our co-authors.
Dr. Negar Asdaghi: Thank you very much for being here and congrats again on the paper. So, Georgios, let's start with this interest that's going on with using clinical and radiographic features to make the diagnosis of CAA-related inflammation in contrast to moving ahead and performing brain biopsy. Can you please start us off with a brief review of the newly proposed clinico-radiographic criteria for this condition, please?
Dr. Georgios Tsivgoulis: Yes. As you mentioned, Negar, CAA-ri is a distinct, however, rare subset of cerebral amyloid angiopathy. Firstly, Greenberg and the Boston group published in Neurology in 2007 a paper highlighting that a diagnosis of a probable CAA-ri patient could be made on the basis of characteristic clinical and neuroimaging findings without requiring a biopsy. Following this observation, Chung and colleagues in 2010, in a seminal paper in JNNP, proposed the first diagnostic criteria for probable and definite CAA-ri. For the definite diagnosis, besides the typical clinical presentation with headache, encephalopathy, focal neurological signs and seizures, and the characteristic neuroimaging findings with T2 or FLAIR hyperintense asymmetric white matter lesions complicated with microbleeds and leptomeningeal or parenchymal gadolinium enhancement, and histopathological confirmation with amyloid deposition within cortical leptomeningeal vessels associated with perivascular, transmural or intramural inflammation was also required. The latest criteria developed in 2015 by Auriel and colleagues that were published in JAMA Neurology using a validation study modified the current criteria for the diagnosis of CAA-ri.
In this paper, the author supported the use of empirical immunosuppressive therapy, avoiding brain biopsy, for patients meeting the criteria proposed for probable CAA-ri. They suggested that a brain biopsy should be considered in empirically treated patients who failed to respond to corticosteroid therapy within three weeks. The criteria by Auriel and colleagues are widely applicable in everyday clinical practice, and we also use this criteria for the inclusion of studies in our current meta-analysis. I would like to highlight for our audience that the latest criteria for CAA-ri were published in 2015 by Auriel and colleagues. However, these are different for the criteria for cerebral amyloid angiopathy than the latest criteria were published in 2022 in Lancet Neurology, OK?
Dr. Negar Asdaghi: Georgios, that was a great start for this interview. You had mentioned a lot of information here. I just want to highlight what you just said. So, we are using for this meta-analysis, the latest criteria in CAA-related inflammation published in JAMA by Auriel and colleagues. That's slightly different than, we're not referring to the 2022 criteria of cerebral amyloid angiopathy. It's an important distinction. We're going to talk about this a little more as we go through the interview, but I want to come back to your current paper and start from there. Can you please tell us about the importance of this paper, why doing a meta-analysis was important in your view, and tell us a little bit about the studies that were included in your paper?
Dr. Georgios Tsivgoulis: Yes, thank you for that question. CAA-ri is an increasingly recognized entity since the recent diagnostic criteria by Auriel and colleagues published in 2015. In collaboration with the greater availability of the high-resolution MR, we can have now a reliable non-invasive diagnosis of possible or probable CAA-ri, avoiding the risk of brain biopsy. However, I need to highlight that the early diagnosis remains a great challenge for the clinicians and neurologists. Searching the literature, we observe that there is scarce data regarding the prevalence of the distinct clinical, neuroimaging, and genetic markers among patients diagnosed with CAA-ri. We believe that pooling all this information in the current meta-analysis would be very helpful for every clinician, increasing a comprehensive understanding of this rare cerebrovascular disorder. Consequently, we conducted this meta-analysis including 21 studies that recruited a total of 378 patients with CAA-ri. Our study involved only 4 prospective and 17 retrospective hospital-based cohorts of patients diagnosed with CAA-ri based on autopsy or biopsy or on the recent Auriel diagnostic criteria that do not require autopsy or biopsy. Due to limited data in the literature regarding this entity, we had to include only small cohort studies with at least five patients in our meta-analysis. We excluded case reports and case series with less than five patients. This is, by far, the largest available sample of CAA-ri patients in the literature.
Dr. Negar Asdaghi: OK, great. So, let me just recap this, more so for myself. So, we have 21 studies, and you excluded studies that included less than 5 patients. So, practically speaking, case reports.
Dr. Georgios Tsivgoulis: Yes, and single-case reports.
Dr. Negar Asdaghi: Yes. And practically speaking, of the total number of patients that are included in this meta-analysis, you have 378 cases, and basically the diagnosis of CAA-related inflammation was either based on the newly proposed criteria or based on biopsy-confirmed or autopsy cases.
Dr. Georgios Tsivgoulis: Which is the standard criteria.
Dr. Negar Asdaghi: So, now, I'm dying to ask you about these clinical and radiographic characteristics of patients with CAA-related inflammation in this meta-analysis.
Dr. Georgios Tsivgoulis: The mean age of patients in the included studies was approximately 72 years old, and there was no obvious gender predominance. Fifty-two percent of the patients were of female sex. In our study, 70% of the included patients presented with cognitive decline, which was the most common neurological manifestation, while 50% of the total sample had focal neurological signs and 54% encephalopathy presentation. Symptoms such as headache and seizures were less common, 37 and 31% respectively. With regard to the radiological findings, hyperintense T2 FLAIR white matter lesions were very, very common in 98% of our patients, and they were also complicated with lobar cerebral microbleeds, with a prevalence of 96%, and these two were, by far, the most prevalent neuroimaging findings, that white matter hyperintensities coupled with a cerebral microbleed. The pooled prevalence rates of gadolinium-enhanced lesions was 54%, and also the prevalence of cortical superficial siderosis was 51%, which is also very high in this cohort of patients with CAA-ri.
Dr. Negar Asdaghi: OK. So many of the features Georgios said, you mentioned, from presence of white matter hyperintense lesions on T2 FLAIR to presence of cortical microbleeds or superficial siderosis, these features are also seen in patients with cerebral amyloid angiopathy. What are some of the important differentiating features between the two conditions?
Dr. Georgios Tsivgoulis: Yes, this is an excellent clinical question. First of all, the lower age threshold for CAA-ri is 40 years old, whereas in cerebral amyloid angiopathy, the lower age threshold is 50 years. So, patients who are younger than 50 years can be diagnosed with CAA-ri, but they cannot be diagnosed with CAA. Another issue is that comparing the result of this meta-analysis with another recent meta-analysis focusing on CAA, on cerebral amyloid angiopathy, that our international multi-collaborative group published in Stroke in 2002, we also evaluated the presence of clinical phenotypes and radiological markers among patients with cerebral amyloid angiopathy. We have documented that transient focal neurological episodes are much more common in patients with cerebral amyloid angiopathy in contrast to patients with CAA-ri. These episodes, which are called TFNEs, transient focal neurological episodes, are attributed to cortical subarachnoid hemorrhage or cortical superficial siderosis.
So, I think this is another important clinical distinction. The most important, however, differentiating features between the two entities are neuroimaging markers, in specific, in particular, T2 FLAIR hyperintense unifocal or multifocal lesions with mass effect. These are the most prevalent neuroimaging features among patients with CAA-ri, but they're very seldomly described in patients with cerebral amyloid angiopathy, in patients with CAA. Another characteristic neuroimaging finding very indicative of the inflammation is the leptomeningeal or parenchymal gadolinium enhancement. This finding has been very rarely described in patients with non-inflammatory cerebral amyloid angiopathy. So, the clinical distinction is not so solid. However, the neuroimaging distinction would provide us with very strong information that can help us differentiate these two conditions.
Dr. Negar Asdaghi: Excellent points, I have to say, golden points, not just excellent points. I'm going to try to recap this and see if I understood it correctly. So, for our listeners, we have two conditions that potentially have many common points. One is the cerebral amyloid angiopathy, and the second one, which is obviously the subject of this interview, is cerebral amyloid angiopathy-related inflammation. The most important differentiating factors between the two are actually the neuroimaging features, as Georgios mentioned. So, the first feature that was mentioned is presence of T2 FLAIR hyperintense lesions. Some of them are large and have actually mass effects. This feature is rarely seen in patients with CAA, and it's an important radiographic factor that is seen in patients with CAA-related inflammation. The second distinguishing feature was leptomeningeal enhancement, again, rarely seen in non-inflammatory CAA, but was seen in a significant proportion of patients with CAA-related inflammation. These were the neuroimaging features. You also mentioned two other factors. The median age of CAA-related inflammation was lower than CAA. That can be helpful. And also the entity of transient focal neurological episodes, or TFNE, is rarely seen in inflammatory cases of CAA, whereas it is described in cases with cerebral amyloid angiopathy and mostly related to development of either cortical subarachnoid hemorrhage or cortical superficial siderosis. I think I got this all, correct?
Dr. Georgios Tsivgoulis: Excellent.
Dr. Negar Asdaghi: All right, so let's come now to the genetics of CAA. The apolipoprotein E gene is associated with the presence of amyloid angiopathy and development of lobar intracerebral hemorrhage, and we've learned about this in cases with cerebral amyloid angiopathy. Is there an association with ApoE, and did you find anything in this meta-analysis?
Dr. Georgios Tsivgoulis: Another very exciting question. In 2007, there was a first report that the apolipoprotein ε4 homozygosity may be considered a risk factor for CAA-ri, and there was a strong correlation reporting a high prevalence of 77% of this apolipoprotein ε4 alleles among patients with CAA-ri. To justify this correlation, the hypothesis was that an underlying pathogenic mechanism, which increases the amyloid-β deposition and has a pro-inflammatory effect, may be suspected as the cause of this disorder. The largest, however, prospective cohort of CAA-ri patients conducted by Antolini and colleagues and was published in 2021 in Neurology, reported a much lower prevalence of apolipoprotein ε4 carriers accounting for 37%, 23% heterozygotes and 14% homozygotes. So, we also documented a pool prevalence of apolipoprotein ε4 homozygosity of 34%. So, we did not confirm the initial finding of 77%. However, in our meta-analysis, the homozygosity was 34%, and we need to have a cautious interpretation of these results because data is limited, and we need larger future population-based studies and in larger cohorts to evaluate the prevalence rate of these specific genetic markers. So, we can confirm an association between apolipoprotein ε4 homozygosity, however not as strong as originally reported in 2007.
Dr. Negar Asdaghi: OK. So, Georgios, thank you. And again, very important factor to keep in mind for our clinicians listening in. Unfortunately, based on what you mentioned, we don't have yet a genetic marker to, for sure, tell us if we're dealing with CAA-related inflammation, yes or no, as you mentioned. Just to recap, earlier on, there was studies to suggest a very strong association between apolipoprotein ε4 homozygosity and CAA-related inflammation. But later on, this was not confirmed by subsequent studies, and in your meta-analysis, you found 34% ApoE ε4 homozygosity amongst patients with CAA-related inflammation and could not confirm that original high association. OK, so with all of that, it's a lot of information. I have to go to the next question regarding controversies involving the levels of Aβ40, Aβ42, and P-tau proteins in CSF in the setting of CAA-related inflammation. Can you please tell us more about these biomarkers?
Dr. Georgios Tsivgoulis: Yes. The overlap of Alzheimer's disease and CAA can be attributed to the coexistence of some degree of cerebrovascular amyloid deposition and amyloid plaque pathology, which is very common. And, of course, the evaluation of amyloid and tau proteins in CSF is of high significance for the prognosis and the evolution of CAA patients. In our previous review, we have summarized the literature and noticed that CSF concentrations of Aβ40 and, secondarily, Aβ42 were much lower in patients with cerebral amyloid angiopathy compared with Alzheimer's disease. Total tau and phospho-tau CSF levels were comparable to healthy controls in CAA and lower than patients with Alzheimer's disease. Moving now to CAA-ri, there were scarce data about these biomarkers amongst CAA-ri patients. The majority of the relevant studies have found relatively low levels of Aβ42 and Aβ40 in the CSF and high levels of P-tau. In the present meta-analysis, the pooled means of biomarker levels were based on the findings of only two studies with heterogeneity, and these limit substantially the validity of our observations. However, they confirm the previous reports indicating, as I said before, but I would like to repeat, low levels of Aβ42 and Aβ40 in the CSF and high levels of P-tau.
Dr. Negar Asdaghi: Perfect. So, thank you, Georgios. I'm going to recap what you said. So, we're talking about CSF biomarkers, and first what you mentioned is going back to the original studies concentrated on using these biomarkers as ways of differentiating between cerebral amyloid angiopathy and Alzheimer's disease. And very briefly, to recap what you said, in general, the levels of Aβ40 and, secondarily, Aβ42 was found to be much lower than the Alzheimer's levels in patients with CAA. Now coming to the inflammatory form of CAA, what you mentioned and what you found in this meta-analysis, practically speaking, confirmed that the levels of Aβ40 and Aβ42 in CSF are low and the levels of P-tau are high in this condition as well. So, one thing I want to ask as a secondary question to that is, that it sounds like these biomarkers are more or less similar in CAA and CAA -related inflammation, not that different. Is that correct?
Dr. Georgios Tsivgoulis: It's absolutely correct. And I would also like to highlight a major limitation of the meta-analysis that we had available data from only two studies to pool the mean of these CSF biomarker levels. So, these results need to be acknowledged with caution, and we would love to repeat our meta-analysis after the publication of more studies and prospective cohorts measuring the CSF biomarkers in patients with CAA-ri.
Dr. Negar Asdaghi: OK. So, again, important to note, as you mentioned, that there's heterogeneity in data because of just paucity of information on this, but as we stand today, the biomarkers won't really help us in terms of differentiating between the two conditions that are CAA or CAA-related inflammation. And so, I think I've learned a lot from this interview myself, but I think we have to just talk briefly about the available therapies for CAA-related inflammation.
Dr. Georgios Tsivgoulis: Yes. In our meta-analysis, we sought to summarize the available information regarding different therapeutic strategies and outcomes among CAA-ri patients. Our results supported our clinical experience indicating that corticosteroids represent the first-line treatment in these patients' outlook. Steroids have been associated with clinical and radiological improvement of the primary disease episode and decreased risk of subsequent relapses in patients with CAA-ri. Additional immunosuppressive therapies, including cyclophosphamide, mycophenolate mofetil, azathioprine, IVIG, or rituximab, have been also reported as adjunct therapies in selected cases with a more severe course of the disease. However, this is another limitation that needs to be acknowledged. That data regarding the treatment and the outcomes are limited and heterogeneous, which prevented us from drawing robust conclusions using a meta-analytical approach. And we believe that we need future cohort studies with prospective data validation in order to generate a proposal for a therapeutic algorithm management in these cases.
Dr. Negar Asdaghi: Thank you, Georgios. So, we have a condition that is now being more and more recognized. We now have criteria based on clinical and radiographic presentation features of patients that might help us with this diagnosis to differentiate it from cerebral amyloid angiopathy. And in terms of therapies, the idea is that the most studied drug is really just first-line therapy, that's corticosteroids. And then there's positive data regarding use of all other forms of immunosuppression, including, as you mentioned, cyclophosphamide, rituximab, and oral agents such as mycophenolate mofetil or azathioprine. We have limited information about those, but I want to highlight something you actually mentioned earlier on in the interview, which is the field is moving towards making these diagnoses based on clinical features and radiographic features that you had highlighted and actually giving patients immunosuppression early on and only move on to a biopsy if the patient had failed these therapies for a period of time, which you mentioned three weeks. So, I think it's important for us as clinicians to keep this evolving criterion and recommendations in mind. And before we end, I want to ask you a hypothetical question, Georgios. In your opinion, what's an ideal randomized trial for CAA-related inflammation in the future?
Dr. Georgios Tsivgoulis: I think before going to the randomized, the ideal randomized trial for CAA-ri, and designing this trial, we need much more information regarding the underlying pathophysiological mechanisms. There are many unanswered questions. What is the diagnostic value of CSF biomarkers such as amyloid, we discussed earlier, and tau protein? And, of course, what is the value of CSF and the amyloid-β autoantibodies, if there is any? What is the value of genetic markers such as apolipoprotein E genotype and a correlation with the co-existing inflammation in CAA-ri? However, I don't want to defer this question. So, a typical answer would be that with regard to the ideal patients, we would want a young patient without comorbidities after the first manifestation of CAA-ri who has shown a good clinical and radiological response to corticosteroids in order to define the best second-line therapy. However, before answering all these questions in a clinical trial, if we can, I think that we need to understand the CSF and genetic biomarkers in order to uncover mechanisms regarding pathophysiology that can help us to design more targeted clinical trials studying novel disease-modifying treatments.
Dr. Negar Asdaghi: Thank you.
Dr. Georgios, it's been a pleasure having you on the podcast, and I can say we've learned a lot. We look forward to having you back here and talk about that hypothetical randomized trial, and I'm sure one day hopefully will happen in our lifetime. Thank you for being here.
Dr. Georgios Tsivgoulis: Thank you. Thank you for having me. It was a pleasure.
Dr. Negar Asdaghi: Thank you.
Homer, the legendary Greek poet, described a case of dementia in his seminal work, The Odyssey, in the late eighth century before Christ. He described the cognitive decline of Odysseus's father, King Laertes. The detailed account of the king's mental decline, loss of short-term memory with retention of long-term memory combined with his depression and despair over the loss of his son, is dramatically accurate for a nearly 3,000-year-old description of dementia. Before I ended the interview, I had to use this opportunity to ask Georgios about lessons learned from ancient Greeks and this seemingly timeless disease.
Dr. Georgios Tsivgoulis: Thank you for this question. King Laertes was indeed Odysseus's father, and it's a great paradigm describing dementia. However, the ancient history of dementia may be separated according to the Greek philosopher Posidonius in two periods. The first period is called dementia appearing due to old age, which is called in Greek, eros. And the second one is dementia appearing in other ages and mainly due to other reasons, called morosis. Posidonius of Rhodes was a Greek stoic philosopher of the second first century BC who strongly believed and suggested that morosis, which is that dementia appearing in younger ages due to other disorders, should be treated immediately after its onset. So, if I would like to end this podcast, I would just suggest that CAA-ri could be classified as morosis according to Posidonius. And what we could learn is that the early diagnosis is essential since the prompt initiation of corticosteroids should not be unreasonably delayed.
Dr. Negar Asdaghi: And this concludes our podcast for the January 2023 issue of Stroke. Please be sure to check this month's table of contents for the full list of publications, including a series of Focused Updates on post-stroke neurological recovery, from management of post-stroke attention deficit, neglect and apraxia to post-stroke memory decline. And with this, we end the start of our 2023 podcast series. Like all new things, a new beginning can come with new directions, and sometimes a new direction is all that we need. After all, as the legend has it, it was a direction of that falling apple back in the year 1666 that gave Isaac Newton the idea of the universal law of gravitation. Now, Isaac Newton has, without a doubt, given science some of its biggest discoveries in mathematics, physics, and astronomy. But most may not know that Newton had a pretty rough start in life.
A January-born premature baby, he was thought not to survive the first few days of life. Newton had a difficult childhood, and at the age of 16, he was pulled out of school by his family and forced to become a farmer, a job he didn't like and he was miserably bad at. So, as we start a new year, let's remember that even the smartest people are not good at everything, and it does take time to find one's passion in life. Now, while things may not always be clear, what is clear is that a great way to find that center of gravity is, as always, staying alert with Stroke Alert.
This podcast is produced by Wolters Kluwer and supported by the editorial team of Stroke. Our Stroke Alert podcast and production staff includes Danielle Cross, Eric Goldstein, Nastajjia Krementz, Ishara Ratnayaka, Erinn Cain, Rebecca Seastrong, and Negar Asdaghi. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.
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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 to 2018, and the National Kids Inpatient Database, referred to as KID, from 2006 to 2019, for all hospitalized CVST cases.
KID is the largest publicly-available pediatric inpatient care database in the United States, containing about 3 million pediatric discharges. They included over 700 hospitalized CVST cases from the SID database and 6,100 hospitalizations from the national KID database for the current analysis. And here's what they found. Number one, in terms of significant risk factors associated with CVST, congenital circulatory system anomalies, infections, head trauma, dehydration, and anemia were amongst the top CVST risk factors in the pediatric population. So that's very good to know. Number two, in terms of presentation, seizures were the most common presentation among all pediatric age groups, with close to half of infants with CVST presenting with seizures. Number three, in terms of outcomes, the rate of mortality was twice higher in the infants group as compared to all other age groups. And finally, the overall incidence of CVST, which was the main question of the paper, in this population was 1.1 per 100,000 per year, with a peak incidence during infancy of 6.4 per 100,000 per year.
Interestingly, incident admissions also increased annually by 3.8% throughout the study period, which was close to 15 years in this paper. And the national burden of hospitalization dramatically and exponentially grew during the study period. So, here are the top three points from this study. Point one: Girls included less than half of all admissions nationally and statewide, and the overall burden of CVST was higher in boys than girls. That's a dramatic difference between the pediatric and adult populations. Point two: Incidence of CVST in infants was higher than five times that of other age groups at 6.4 per 100,000 compared to overall incidence in children, which was 1.1 per 100,000 people per year. Mortality was also two times higher in infants than in any other age group. And finally, point 3, incident admissions and national burden of hospitalization have dramatically increased over time, but it remains unclear whether true incidence has been on the rise or if simply more cases are recognized nowadays due to heightened awareness of this condition and our advanced neuroimaging capabilities.
This study, of course, has some limitations. Data was only obtained on patients admitted, so many patients that may have had CVST but not admitted are not captured in this database. So, in summary, CVST can have catastrophic consequences in children and lead to long-term neurological deficits. Having a high clinical suspicion and early recognition remain crucial for prompt treatment and improved outcomes in this population.
Dr. Negar Asdaghi: Endovascular treatment, or EVT, is an effective method to achieve recanalization and to improve clinical outcomes in ischemic stroke patients with a target vessel occlusion. Both advanced age and having a large infarct volume at the time of presentation are negative predictors of beneficial outcomes post-EVT. Despite this, the neurological benefits of EVT seem to persist across the spectrum of age, and the same has been observed for a range of ischemic core volumes. But it's important to note that, in general, patients presenting with large ischemic core volumes were excluded from the original thrombectomy studies, and currently there's several ongoing trials to determine whether EVT is beneficial for the large core population.
Now, the question that everyone is interested in answering is whether there is an actual ischemic core volume beyond which endovascular therapy is either futile or potentially even harmful, and if this magic futile core volume is the same for all patients, or does it differ depending on the age and other factors.
In a previous podcast, in an interview with Dr. Osama Zaidat, we learned about that important interaction between the presenting ischemic core volume as measured by ASPECTS score and advanced age in an analysis of patients enrolled in the STRATIS registry. In that study, no one over the age of 75 achieved functional independence post-EVT if the presenting ASPECTS score was under 5 regardless of the angiographic outcomes. In that interview, we also discussed the limitations of STRATIS registry as a non-randomized, single-arm study, and the issues surrounding using ASPECTS score to define ischemic core. In today's podcast, we're going to revisit the important interaction between the presenting ischemic core volume and age while reviewing a pooled analysis of seven endovascular clinical trials in the paper titled "Significance of Baseline Ischemic Core Volume on Stroke Outcome After Endovascular Therapy in Patients Age 75 Years or Older."
I'm delighted to be joined today by the first and senior authors of this paper, Drs. Koji Tanaka and Andrew Demchuk. Dr. Tanaka is an Assistant Professor of Neurology at Kyushu University in Japan. With his experience working at the leading center for conducting stroke clinical trials in Osaka, he has now joined the Calgary Stroke Program as a research fellow. And he's accompanied today by his fellowship director, Dr. Demchuk. Dr. Demchuk, of course, needs no introduction to our Stroke readership and our podcast audience. He's a Professor of Neurology at the University of Calgary Cumming School of Medicine. He's a stroke neurologist and a leader in the field of cerebrovascular research who has been involved in multiple clinical studies and randomized trials, including the seminal studies that led to the approval of EVT as the standard of care for treatment of stroke. And, of course, he's a very special guest of this podcast this morning as he was my very own fellowship director. Top of the morning to you both, Andrew and Koji. Welcome to the podcast.
Dr. Andrew Demchuk: Thanks, Negar. It's great to be here.
Dr. Koji Tanaka: Thank you very much for your invitation. That is a great honor to be here.
Dr. Negar Asdaghi: Thank you both. Andrew, let's start with you. Can you please provide us some background on the pooled analysis and the HERMES collaboration, please?
Dr. Andrew Demchuk: Yeah, HERMES is a really, it's been a really fun journey. Years back, when these trials all came out roughly at the same time, right? There was a real quick succession of trials, the MR CLEAN trial was obviously first, and ESCAPE and others quickly followed it. It became very clear to us that it just made total sense to collaborate. And so we got together as a group and decided we will pool the data. We'll do it in a very careful scientific way with basically an independent statistical analysis, and develop a core imaging lab, and really actually share the workload amongst us.
I remember one of the really interesting tidbits about HERMES is when we got together, in order, I think, to really build trust in the group, one of the important things we decided early was we were going to have a snake draft. If you don't know what a snake draft is, Negar, it's essentially where you take turns selecting a topic through each of the trials. So, every trialist got an opportunity to pick a topic, and we just went down the list until everyone had their turn, and then we'd start over again and do it again. And I think that really worked very well to be as democratic as possible with this, and as fair. And it really allowed for a lot to get done because whoever was motivated in the collaboration was able to do an analysis.
Dr. Negar Asdaghi: So, what a great summary of this collaboration. So, it's true collaboration between the trialists that basically gave us those seven original randomized trials. Andrew, can I just stay with you, and can you tell us a little bit about the patient population that were enrolled in those trials?
Dr. Andrew Demchuk: Yeah, I think one of the important things to know, and I think a limitation for any kind of analysis like this, is the trials generally were small core trials, right? I mean there are some, MR CLEAN was certainly a more generalized population, but many other trials, including ESCAPE, I mean the "S" and the "C" in ESCAPE is "small core," right? And so a lot of these trials were small core. So, we don't have a lot of data in larger core patients. But, as you can imagine when you do core lab analysis, you realize that some of the stroke patients weren't as small core as we thought they were when we enrolled them. So, there is some sufficient data to hypothesize. I would consider this paper very much hypothesis-generating. So, yeah, it is a limitation to be considered here. I mean, our sample size isn't very large in the big core patients.
Dr. Negar Asdaghi: Perfect. Thank you, Andrew. So, again, a recap for our listeners, that we are looking at pooled analysis of seven original trials of thrombectomy, but keeping in mind that those patients that were enrolled in the trials had, generally speaking, small presenting ischemic core. So, now, Koji, on to you. Can you walk us please through the current study, and what was the premise of it, and who was actually included in this study?
Dr. Koji Tanaka: Yes. In this study, we aimed to evaluate association between baseline ischemic core volume and the benefit of endovascular therapy over the best medical treatment on functional outcomes. Patients were categorized age over 75 years, and less than 75 years old. The primary outcome of interest was a modified Rankin Scale of three or less, and we included 899 patients who underwent this baseline ischemic core volume measurement, which corresponds to 51% of our patients in the HERMES collaboration dataset.
Dr. Negar Asdaghi: All right. So, just a quick recap of what you said. Thank you for this. So, we have 899 patients. Those patients were all included in the HERMES collaboration, but, of course, these are patients in whom we had presenting ischemic core measurements. And that will get me, actually, Koji, to my second question. Can you please walk us through how you did analysis of ischemic core volume measurements in this study?
Dr. Koji Tanaka: In this study, ischemic core volume was measured by CT perfusion in 591 patients and by diffusion-weighted imaging in 309 patients. We defined the ischemic core volume as a relative cerebral blood flow of less than 30% in CT perfusion and diffusion coefficient of less than 620 square micrometers per second in diffusion-weighted imaging. Previous studies showed ASPECTS moderately correlate with ischemic core volume in both CT perfusion and diffusion-weighted imaging. For example, ASPECTS of eight can be considered as ischemic core volume of 20 milliliters. But underlying [inaudible 00:28:21] were different between CT perfusion and diffusion-weighted imaging, and previous studies suggested CT perfusion occasionally overestimates the ischemic core volume was on diffusion-weighted imaging. In this study, the results did not change when analyzing CT perfusion and diffusion-weighted imaging separately.
Dr. Andrew Demchuk: Yeah, that's a really important point Koji makes, is that because we had sort of a, not quite a 50/50 split, we had a 60/40 split of CTP and DWI, we did analyze them separately, and the odds ratios of treatment effect were pretty similar at different core thresholds. So, they're fairly similar when you separate them out, but obviously the methodology is a little different between a CTP and a diffusion. And to Koji's point, he's absolutely right, the CTP has a tendency to slightly overestimate core when you compare to diffusion.
Dr. Negar Asdaghi: Yeah, and thank you. I think you already sort of alluded to what I was going to ask you and Koji, because, in reality, we have different ways of measuring core. We have the ASPECTS score, which is just a quick and dirty way of estimating or guesstimating core, and then we have CT perfusion, and we also have diffusion that sometimes is available to us, but not always. And the question is, in the heat of it, how we're going to measure the volume. With post-processing softwares, with CT perfusion, we get a quick potential ischemic core volume, but we don't have that capability with diffusion even if we did get diffusion.
So, I think it's important to know that what Koji mentioned, an ASPECTS of eight can, more or less, in a quick fashion, be thought of as about 20 cc of core. And the other point that Koji raised was that CTP, again, this is sort of ballpark, can tend to overestimate ischemic core if you were to compare that with diffusion-weighted data. So, with that, now we have a study in which we have core volumes, and we're going to look at outcomes from endovascular thrombectomies compared to best medical management and see whether there is a correlation or interaction between ischemic core presentation, especially age. So, my next question would be to Andrew, can you walk us please through the main findings of the paper?
Dr. Andrew Demchuk: The whole goal of this paper was really to understand, are there thresholds in the older patients? When we looked at overall, and Bruce Campbell and the team wrote an important paper with HERMES and the CTP cohort overall, and the sort of message there was if you looked at shift analysis, there wasn't actually a core threshold found at all in HERMES for lack of benefit. There was a benefit across all the core volumes, but, of course, that's all ages. So, we were really interested in looking at the older patients because we felt there's more likelihood the core volume will matter in the elderly than in the younger patient. We know the younger population, it benefits overwhelmingly with EVT, it's hard to even find a core volume threshold. So, that was a premise.
Essentially, we had 247 patients over 75 in the overall cohort, of which 98 had EVT. So, it was a decent population, and not a huge sample, but a decent sample. And so we looked at various things. The first thing that was interesting we found was that infarct volumes, the average infarct volume to achieve an mRS three or less, was lower in the older patients, significantly lower, was 23.9 for younger patients under 75 and 10.7 for the older patients. You tend to have much smaller infarcts to achieve good outcome. And so that was kind of interesting, and I think that's been shown by others. Then we got into the weeds to try to figure out, OK, what are these thresholds? And if there's one figure that matters, Negar, you know me to always point out that there's always one figure or table in a paper that's kind of where the money is, where the real learning is, and that's Figure 2 on this paper in my opinion, beautiful figure with four figure A, B, C, and D. And it really sort of nicely highlights these issues and these cutoffs.
But what we saw is that in the older patients who received EVT, around 50 mils seemed to be a threshold to achieve zero three, you had to, to see treatment effect, you had to have a baseline infarct volume less than 50 mils for a zero three outcome advantage. For zero four, it was 85 mils. And then we looked at this issue of what we called futility, true futility. And that's a very controversial thing. What is futility, or how do you measure futility? And really, I think, we even had a debate about this as a HERMES group when we were designing the analysis, and we sort of landed on mRS five six. A 90% chance of mRS five six, right? That's quite the bar, right, to say true futility because some people argue mRS four is still not a horrible outcome. Culturally, that is an OK outcome in some situations.
But when we did use that five six 90% threshold, it was 132 mils. So, you're getting up to these really large volumes. But here's the catcher in the whole thing, and Koji will probably speak to this a bit more. I don't want to steal his thunder too much, but this issue of reperfusion seemed to matter in this. And we'll come back to that maybe with another question. Reperfusion matters a lot when you think about these thresholds.
Dr. Negar Asdaghi: OK, so, Andrew, a lot of information, I don't know if I need a recap myself to recap, but basically what you mentioned is that for the older patients who received EVT, if we keep our eyes on the outcome of mRS of zero to three, it seems to be the magic core volume for that outcome post-endovascular therapy that it lands on the magic volume of 50 cc core. Did I get that right?
Dr. Andrew Demchuk: That's correct.
Dr. Negar Asdaghi: Then if you're still a bit more lenient with the definitions of what is favorable outcome, what outcomes we're looking at and so on, so forth, for an mRS of five to six, then when we talk about futility of endovascular thrombectomy, the volume that you mentioned, and again I want to ask you this, this volume is for elderly over the age of 75, is 130 mil.
Dr. Andrew Demchuk: 132, but yeah, absolutely. But there's a real catcher here, and we need to really emphasize the catcher in this.
Dr. Negar Asdaghi: Okay. I will ask you one more question before I go to Koji, which I'm sure is going to tell us more about that catcher. Andrew, can you please tell us about the factor of time? I feel like that is something that we need to discuss, as well. Your study included patients early on in their stroke onset, but we're talking about an important interaction. The question is, do you think the results of this interaction would be different or impacted by the value of time?
Dr. Andrew Demchuk: Hypothetically? It must, right? I think that that must be the case. We don't have any data specific to this. That would be an interesting Aurora analysis to do. Now, of course, the challenge with late window analysis is, we are really small core in our late window trials, we probably have even a much smaller proportion of large cores. So, to be able to even tackle that question in the late window is, I don't know if we have the data yet, to be honest. But it makes sense that you would expect the thresholds to be a bit lower the later you are in the window. But that is a hypothetical opinion.
Dr. Negar Asdaghi: Right, so, I want to take that and come to Koji. I want to digress a little bit to Koji and see how we can understand the finding of this current analysis of this paper. So, small core patients early on into their onset, we're looking at the interaction between age and their core volume and coming up with numbers 50 cc for the elderly population. If you're looking at the outcome of zero to three or 132, as Andrew pointed out, for an MRS of much higher, four or five.
Dr. Andrew Demchuk: Actually five, six, 90% chance of five, six. So, it's there. It's like almost everybody got five, six, took 132 mils to get there. So, it's like this extreme outcome.
Dr. Negar Asdaghi: Right, so, exactly, and I have to correct it, again, mRS of five or six or dead or almost dead mRS basically.
Dr. Andrew Demchuk: In 90% of patients.
Dr. Negar Asdaghi: 90% of patients. So, we have these important numbers here, and I want us to basically understand these numbers in these volumes in the context of the recently published RESCUE-Japan LIMIT study. Can you tell us a little bit about that study and how we can make sense of these volumes in the setting of that paper?
Dr. Koji Tanaka: In the recent RESCUE-Japan LIMIT trial, the median ASPECTS was lower, and baseline ischemic core volume was greater than those in our study. And surprisingly, the median ischemic core volume in that trial was close to our threshold to predict less than 10% of patients achieve a modified Rankin Scale of four or less after endovascular therapy. We thought this is due to much higher complete reperfusion rate in HERMES patient. We have much interest in their additional analysis for outcomes in elderly patients by reperfusion status. This potential benefit of endovascular therapy in the area is promising for the future clinical trials.
Dr. Andrew Demchuk: I think just to add to that, it was actually really interesting, Negar, because when we were analyzing all of this and then the trial came up and it was actually really nice because we're like, OK, how does our data relate to their data? And that's where Table 2 comes in, and it would almost be worth putting on the pod, whatever, I don't know if you have on your podcast website, you have one figure that you can sit there with as you listen to the podcast, because that would be the figure.
Dr. Negar Asdaghi: We'll work on that Andrew, but tell us a little bit more because, really, when I read the trial results, the way I understand it is that people enrolled in RESCUE-Japan that were older than 75, and these are all large core patients, benefited more from endovascular therapy than their younger counterpart. How do I understand that? I don't know how to wrap my head around that finding.
Dr. Andrew Demchuk: You want to try to answer that, and then I'll add?
Dr. Koji Tanaka: As I mentioned previously, we want to know about the exact patient population just only for elderly patients, whether they have a exactly larger ischemic core volume or as well as their functional outcome. How many patients achieved modified Rankin Scale four or less or three or less, or more than five or six?
Dr. Andrew Demchuk: Koji's point's very important. We actually don't have the breakdown of the mRS, so we don't know if they created a lot of fours, or threes, or what. So, that's one issue. But I think that the key to this whole thing is to understand that this is a 2022 trial. HERMES data is essentially a 2015 equivalent where we're looking at a number of clinical trials who roughly ended between 2014, 2016. So, the technology, the technique, the operators, are just at a different level back then than now. And quite frankly, EVT is an improving treatment. We probably don't even fully understand how much, I mean, we're just getting better at it. And I think what's happened here is the reperfusion rates have improved. And our HERMES reperfusion rates, remind me, Koji, I think they're about half, we think, in HERMES, than like the TICI 2bs, threes, are half in HERMES what they got in RESCUE-Japan LIMIT.
So, when you achieve successful reperfusion, what were the numbers here? TICI 3 was 43% in the Japan RESCUE LIMIT, and 8.6% in HERMES. Okay, TICI 3s were not ... Now that may be slight differences in core lab interpretation, but we were just starting to get good at 3s. We were getting a lot of 2bs and some 2cs, but we weren't getting a massive number of 3s back in 2015. Well, voilà, now we are, right? We're hitting home runs when we didn't before. And I think that has really shifted the goalposts on the large core. If you open the vessel, they can still do well if they're elderly, but you've got to really open that vessel. And in HERMES, we only did that in a small portion of patients. So, these thresholds are sort of representative of 2015 skill.
Dr. Negar Asdaghi: Golden points, Andrew and Koji, both of you. I want to recap what you mentioned here. A note to all of our audience and listeners that we are looking at an analysis with RESCUE-Japan, an analysis of a 2022 study. And the patient population that were enrolled were also treated much later in terms of time than the patient population that was enrolled in the HERMES collaboration and in all of the trials that contributed to HERMES. So, we've got to remember that EVT is this fluid, ongoing, everyday-improving therapy, from our techniques to everything else, you know, how fast we get patients to the angiosuite. And the point that you raise, I want to repeat that, the percentage or the odds of achieving a perfect reperfusion was, in RESCUE-Japan, was 43% odds of TICI 3 reperfusion, whereas only 8.6%.
So, when we're talking about all of these predictive modeling or predictive factors that will tell us who's going to do well, who's not going to do well, it also is predicated on the angiographic success. And perhaps in the earlier trials or even the early study that we covered as part of the STRATIS registry, we put everybody, TICI 3s with TICI 2b or better, whereas nowadays we accept the best, TICI 3s, and maybe that improved percentage in the most recent trial, the RESCUE-Japan, really did what it had to be done for the elderly population to keep that in mind. And Andrew, before we end our interview, I want us to get your top two takeaway messages from this paper.
Dr. Andrew Demchuk: Clearly, elderly patients do better when their strokes are smaller, that we know, compared to younger patients. But it's all about hitting the home run. It's all about hitting the home run. Figure 2C and 2D, you can see that if you achieve that high TICI score, a significant proportion of elderly patients potentially could still benefit, 30–40% reasonable outcomes with bigger cores if you get those high TICI scores. So, it is about hitting the home run in reperfusion in the elderly. You need to go for it, and hopefully you're successful, because if reperfusion isn't successful, then generally the outcomes are not ideal and they certainly worsen as the core volumes become larger, bigger.
Dr. Negar Asdaghi: Before I ended the interview, given Andrew's tremendous experience as a longtime fellowship director and seeing that he was flanked by two of his fellows, one past, myself, and one present, Koji, I had to ask him one final question of what his philosophy is as an educator.
Dr. Andrew Demchuk: I have a sort of philosophy on life with fellows. I always look for the special power in a fellow. I realized a long time ago we’re all, we’re not perfect, nobody’s perfect, I’m not perfect, but there’s usually a special power in people, and if you spend the time to get to know them, you identify that special power, and you really help harness it because you know that if they can harness it when they go back to their faculty job, they’re going to really contribute something special to their team, right? You can imagine six special powers from six different people in a team. Now you’ve got a real team, right? If you know what your power is, you know your limitations, but you know where your strengths you can add to the group, and that’s what we try to do here when we can. It’s not always, you know, special powers, you have to kind of seek them out. But they’re there in most people, and that’s really important for career down the line.
Dr. Negar Asdaghi: And this concludes our podcast for the December 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including our very interesting Stroke Images series. In this month, we have a case of progressive cervical myelopathy secondary to a dural AV fistula supplied by the anterior inferior cerebellar artery. We also have a separate case of carotid rete mirabile imaged with a four-dimensional flow MRI study.
And with these cases, we bring our 2022 Stroke Alert Podcast series to an end. Over the past 12 months, we've ended our podcasts with various inspirational tales. From the moving account of the American runner Steve Prefontaine and the remarkable journey of the Syrian refugee and Olympian swimmer Yusra Mardini, to the discovery of positron and Commander Armstrong's landing on the moon, our podcast stories have but one thing in common, which is the story of human perseverance and consistency in the face of hardship. So, as we end 2022 to start 2023 anew, Andrew's comments on finding that special power in each of us resonate with our resolution to stay alert with Stroke Alert.
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.
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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, exactly like that consult, to have an asymptomatic carotid disease of equal or greater than 70% stenosis. The carotid disease for this trial had to be amenable to carotid endarterectomy, or CEA, and the patients were randomized to either receive synchronous CEA plus CABG or just go through with the CABG alone. The trial started in 2010 and planned to enroll over a thousand patients, but was stopped, unfortunately, prematurely in 2014 due to slow recruitment and withdrawal of funding after only 129 patients were enrolled from 17 centers in Germany and Czech Republic.
The original study was published in this journal in 2017. So, what did it find? In their intention-to-treat analysis, the primary outcome of any stroke or death at 30 days was 18% in patients receiving synchronous CEA plus CABG as compared to only 9% in patients receiving isolated CABG. Ouch, a double risk of stroke in those who had concurrent surgical treatment of their carotid disease in addition to CABG. Now, this was an underpowered study, and the results should be understood in that context, but it really didn't appear that synchronous CEA plus CABG would decrease the rate of stroke in the first 30 days.
Now, how about the long-term outcomes of these patients? We know that asymptomatic carotid disease carries a cumulative annual risk of stroke, and it's important to see if the risk of subsequent stroke was lower downstream if the carotid was already fixed early on. So, in the current issue of the journal, the CABACS trial investigators, led by Dr. Stephan Knipp from the Department of Thoracic and Cardiovascular Surgery in Essen, Germany, and colleagues are back with the five-year results of this trial. How did synchronous CABG plus CEA do as compared to CABG alone? Well, by five years, the rate of stroke or death was 40% in the combined group and 35% in the CABG-only group. This was not a statistically significant difference.
Now, when they broke down the primary outcomes, the rate of death from any cause was similar in the two groups. By five years, the mortality rate was 25% in the combined group and 23% in the CABG-only group. And the same was true for the rate of nonfatal strokes. And also the cumulative rate of nonfatal strokes from year one to year five was similar between the two groups, which meant that the higher stroke risk early on in the CABG plus CEA group was not counterbalanced by decreased rate of stroke later on during the long-term follow-up.
And finally, they looked at the rate of disability-producing stroke. First of all, after the first year, no new disabling strokes were observed in either group. That's great news. However, in the early period, unfortunately, close to half of strokes that had happened after the combined CEA and CABG were disability-producing, and about a third of strokes that happened after CABG alone were also disability-producing. So, in summary, even though this study is quite underpowered, it appears that performing synchronous CEA plus CABG increases the preoperative morbidity and mortality in patients with asymptomatic carotid disease without providing any long-term benefits to these patients.
Coronaviruses are important human and animal pathogens. By now, I think it's safe to say that most of the population of the world has heard of at least one of the members of the coronavirus's family, which was first identified in late 2019 as the cause of a cluster of cases of pneumonia in Wuhan, China. In the early months of 2020, COVID-19, the disease caused by this novel coronavirus, would rapidly spread to involve much of the world. And on March 11 of the same year, the World Health Organization declared COVID-19 a pandemic. Today, over two and a half years have passed since that day, and an avalanche of scientific papers have since been published about COVID-19, not just in medicine, but in each and every imaginable field of life. Neurology's, of course, no exception.
The clinical presentation of COVID-19 largely depends on the severity of the disease and may range from a simple asymptomatic infection to a severe, lethal, multi-organ disease. In the world of neurology, a myriad of neurological symptoms, from loss of sense of taste and smell to headache, all the way to encephalopathy and seizures, have been reported in association with this disease. Early in the pandemic, some studies suggested that COVID-19 is indeed a risk factor for stroke. Like many severe infections, COVID-19 can potentially cause a prothrombotic state and can be associated with thromboembolic events. But most of these earlier studies were smaller observational studies that were completed in an inpatient setting, including those with severe COVID.
In fact, to date, we still don't have an accurate and reliable estimate of stroke incidence among patients with COVID-19. On the other hand, stroke is the second leading cause of death globally and the fifth cause of death in the US. In the United States, every 40 seconds, someone has a stroke, and every four minutes, someone dies of a stroke. So, I think the question that everyone should be asking is, has COVID-19 changed this statistic?
In this issue of the journal, in the study titled "Incidence of Stroke in Randomized Trials of COVID-19 Therapeutics: A Systematic Review and Meta-Analysis," Dr. Ntaios and colleagues aim to get us a step closer to answering this very important question. Dr. Ntaios is an Associate Professor of Medicine at the University of Thessaly in central Greece, and he's the current President of the Hellenic Stroke Organization. It is my great honor to have Dr. Ntaios today in our podcast to discuss this paper and all things stroke-related COVID-19. Good afternoon, George, and welcome to our podcast.
Dr. George Ntaios: Thank you for the invitation, Negar, and for highlighting our work. It's a pleasure to be here with you today.
Dr. Negar Asdaghi: Thank you for being here, and congrats on the paper. George, can you start us off by discussing the pathophysiological mechanisms through which COVID can potentially cause a stroke?
Dr. George Ntaios: Well, one of the most attractive things about stroke, which makes it fascinating for all of us, is its complexity. So many different pathologies can cause stroke, and, quite frequently, identifying the actual cause of stroke can be really challenging. And in a similar way, the pathophysiological association between COVID and stroke seems to be, again, complex. Different pathways have been proposed. Internal, we talk about two broad mechanisms. One is the vascular inflammation and thrombosis, and the other is cardioembolism. And there are several pathways which are involved in vascular inflammation and thrombosis: activation of the complement, activation of the inflammasome, activation of thrombin, increased production of [inaudible 00:24:47] constriction, state of stress, platelet aggregation, vascular thrombosis.
So, collectively, this thromboinflammation could lead to damage of the neurovascular unit and consequently to stroke. And in a similar way, there are several cardiac pathologies which can cause stroke in a COVID patient, like acute left ventricular dysfunction, which can be caused, again, by several mechanisms, like coronary ischemia, stress-induced takotsubo cardiomyopathy, myocarditis inflammation, or also as a result of direct effect of the coronavirus at the myocardial cell. And, of course, we should not forget about atrial fibrillation, which seems to be more frequent in COVID patients.
So, we see that the proposed mechanisms behind the association between COVID and stroke, that is, vascular thromboinflammation on one hand, or cardioembolism on the other hand, are complex, but whether these derangements they have a clinically relevant effect or they are just biochemical derangements without any clinical effect is a debate. For example, the incidence of myocarditis in COVID is about 0.2%. That is, in every 500 COVID patients, you have one patient with myocarditis. But myocarditis has a very wide clinical spectrum ranging from subclinical elevation of myocardial enzymes to full and life-threatening disease. So, obviously, the incidence of severe myocarditis is even lower than 0.2%. And the same is true also for the incidence of myocarditis after COVID vaccination. The CDC estimates that one case of myocarditis occurs every 200,000 vaccinations, with the number being slightly higher in young men after the second dose. And this is extremely rare, and the huge majority of these myocarditis cases, they're mild.
So, this is about ischemic stroke. Now, with regard to hemorrhagic stroke and its association with COVID, again, it seems to be, again, very rare. The best estimate that we have comes from the Get With The Guidelines – Stroke Registry and is about 0.2% and involves mainly patients who are already on anticoagulants. So, they had already a risk factor for ICH. So, again, whether all these pathophysiologic derangements in COVID patients, they have a clinical meaningful association with stroke risk or not, I think it's a matter of debate.
Dr. Negar Asdaghi: Wow, George, it was a simple question, but it seems like the answer was not that straightforward. Let me just recap some of the things you mentioned. So, first of all, the answer is not straightforward and depends on whether we're talking about ischemic stroke or hemorrhagic stroke. There seems to be a lot of connecting points, at least, so to speak, between COVID and either forms of stroke. But you touched on two major sort of broad mechanisms. One is the idea of vascular thromboinflammation that goes along the lines of many sort of hyperacute, hyperinflammatory processes that can occur, especially in the setting of severe COVID. You touched on activation of thrombin, complement activation, platelet aggregation, sort of an activation of that microvascular or vascular unit in a sense.
And then a second mechanism you touched on is the impact of COVID on the myocardium on sort of many different pathways. Again, you talked about acute left ventricular dysfunction, stress-induced myocarditis, and the impact of COVID on perhaps increasing the rate of atrial fibrillation. Again, these are all very complex associations, and some could be already present in a patient who is perhaps of an older age, and COVID is just a modifier of that risk factor that was already present in that particular person. And you also touched on how COVID can potentially increase the risk of hemorrhagic stroke, but the study seems to suggest that those patients already had risk factors for the same. And perhaps, again, COVID is a modifier of that risk factor.
All right, so with that information, a number of studies early on, especially, in the pandemic and later, some meta-analyses, have aimed to estimate the incident rate of stroke post-COVID. Can you please briefly tell us what were their findings, and how is your current paper and current meta-analysis different in terms of methodology from those earlier studies?
Dr. George Ntaios: Yes. Well, it all started from this letter to the editor at the New England Journal of Medicine. It was published very early in the pandemic during the outbreak in New York. And in this letter, the authors had reported that within a period of two weeks, they had five young patients with COVID and large artery stroke, which they commented that it was much higher than their typical, actually their average, of 0.7 cases during a two-weeks period within the last year. And remember that back then, we knew literally nothing about COVID. So, this letter was really a huge, loud alert that something is going on here and that perhaps our hospitals would be flooded with COVID patients with stroke.
So, subsequently, several reports were published aiming to estimate the incidence of stroke in COVID. Rather contradictory with the incidence, estimates are ranging from as low as 0.5% to even 5%. However, these estimates could well be inaccurate. They were observational studies. Most of them were limited to the inpatient setting. Most of them were single-center studies. Most of them, if not all, were retrospective studies. So, there was really a high risk of registration and assessment bias, as well as reporting bias. And also remember that back then during the outbreak, people were really reluctant to visit the hospital, even if they had a serious condition like stroke, an urgent condition, which means that the real incidences could be even higher.
So, it was our feeling that these estimates were perhaps inaccurate. And there are also some meta-analyses of these studies which estimate that the incidence of stroke in COVID is about 1.5%. But, of course, any meta-analysis is as good as the studies it includes. So, we tried to find a way to have a more accurate estimate than these estimates. And we followed a different methodology. We studied randomized trials of COVID therapeutics, and we looked for strokes reported as adverse events or as outcome events. And the good thing about randomized trials is the rigorous assessment and reporting of outcomes in adverse events. So, we think, we believe, that this methodology provides a more reliable and a more robust estimate of stroke incidence in COVID patients.
Dr. Negar Asdaghi: OK. George, it's very important what you just mentioned, so I wanted to recap for our listeners some of the things you mentioned. It all started with a letter to the editor of New England Journal of Medicine on a report of five young patients that had large vessel occlusion in the setting of COVID. And then, basically, the floodgates opened in terms of all these observational studies that basically reported the same. And subsequent to that, meta-analyses that were completed containing those observational studies predominantly gave us an incident rate of 0.5 to 5%. That's much, much higher than basically the non-COVID–associated incidence rate of stroke in the population-based studies, and basically suggested that COVID-19 is indeed a major risk factor for all types of stroke.
So, that's where it all started. And, as you alluded to, these numbers had to be reverified in bigger settings, more controlled setting. And you already answered my next question, which is the difference between those studies and prior meta-analyses to the current meta-analysis is that you basically took the simple question and started looking at it in a controlled setting of randomized trials. And you already answered this question of the methodology, but I want to recap. You took basically patients included in randomized trials of therapeutics for COVID-19, various therapies for COVID-19, and you did a meta-analysis to see what were the incident rate of stroke as an outcome in these trials.
So, with that, could you please tell us a little more about the population that you had in this meta-analysis in terms of their age, the types of therapies that these randomized trials had looked at, and the duration of the follow-up, please?
Dr. George Ntaios: The follow-up included 77 randomized trials, which corresponds to more than 38,000 COVID patients. The mean age of these patients was about 55 years of age, and they were followed for an average of 23 days after study enrollment. With regard to the set strategy, I think it was not strict at all. I would rather say it was very liberal. We allowed trials of any drug in COVID patients of any age, of any severity, coming from any setting: outpatient, inpatient, either general ward or intensive care unit. And from any country. I don't think that we could achieve a wider inclusion than this strategy did. And the huge majority of patients, more than 95%, they were hospitalized patients. So, by definition, they had severe COVID disease. And the drugs studied in these trials included everything that was actually tried in COVID, including tocilizumab, IL-6R inhibitors, steroids, remdesivir, chloroquine, azithromycin, ritonavir, interferon, ivermectin, and many other drugs. So, I think we tried to include as many trials as possible.
Dr. Negar Asdaghi: OK. So, let me see if I got it. You basically included 77 randomized trials. It is a younger population of patients in these trials, median aged 55. You had a total of over 38,000 patients. It's a great sample size for this meta-analysis. And importantly, the duration of follow-up is median of 23 days. And it's just about any treatments we've heard that have been tried for COVID, from dexamethasone to remdesivir and ivermectin. And a rigorous methodology. So, I think we're ready to hear the primary results of this meta-analysis. How many strokes happened in these patients?
Dr. George Ntaios: In the overall population, that is both in the hospital and in the outpatient setting, there were totally 65 strokes in these 38,000 COVID patients, which corresponds to one stroke every 600 COVID patients or else an incident of only 0.16%, 0.16%. This is very low, much lower than the previous estimates. And, of note, all strokes occurred in hospitalized patients. There were no strokes at all in the ambulatory COVID patients. So, just to repeat the result, we just found that only one patient will have a stroke every 600 COVID patients who are either hospitalized or are ambulatory.
Dr. Negar Asdaghi: OK. So, I need to have these numbers, I think, committed to memory, especially when we speak to family members and patients in the hospital. Ninety-five percent of the patient population of this meta-analysis were inpatient COVID. So, by definition, they must be sicker in terms of the severity of their COVID disease. Out of 38,000 patients, you had 65 events of stroke. So, these are very, very important numbers, a lot basically lower than the incidence rate reported from prior studies. So, I wanted to ask you about the sensitivity analysis that was done in the meta-analysis.
Dr. George Ntaios: Yes. When we designed the analysis, we were expecting that we would find numbers was similar to those reported before. So, we thought that perhaps a sensitivity analysis would be able to increase the confidence and the robustness of the results. That's why we did this sensitivity analysis. However, it proved that the number of strokes, the number of outcome events was much lower than what expected. So, the power for those sensitivity analysis to show a meaningful conclusion was low. So, actually, that's why we don't comment at all on those sensitivity analysis because there were so few strokes to support such an analysis.
Dr. Negar Asdaghi: OK. So, basically, you had a priori design the meta-analysis based on the assumption that the incidence rate of stroke would be a lot higher, but then later on, when the incidence rates was lower, then the sensitivity analysis didn't really give any meaningful data to us. So, I mean, I think we already talked about this, but I want to ask you, why do you think that the incidence rates were so much lower in your analysis than the prior meta-analysis?
Dr. George Ntaios: I believe that our estimate is quite accurate. I think that the reports of stroke incidence published during the pandemic possibly overestimated the association. I think that the early concern that we all had in the beginning, that we would be flooded with strokes during the pandemic, was not confirmed. I think that we can support with decent confidence that stroke is a rare or perhaps very rare complication of COVID.
Dr. Negar Asdaghi: Right. That's great news. That really is great news, and we take every bit of good news in these trying times. George, something that was not touched on in the paper, but I want to ask you and basically get your opinion on this matter, is a much talked about concept in the COVID literature of how COVID could potentially modify certain risk factors. There are much talk about how people with pre-existing diabetes or obesity can potentially develop more severe COVID and, hence, have more complications of COVID, including stroke. What is your clinical experience on this matter, and do you think there are certain predictors of development of COVID-associated stroke?
Dr. George Ntaios: That's a very good point. For the last two years, I was involved in the hospitalization management of COVID patients. So, what we see is what is also described in the literature, that there are certain patient characteristics that predispose them to severe COVID. For example, obesity, for example, older age, pregnancy. Perhaps our analysis was not designed to respond to this question. The data available on the studies that were included, they could not support such an analysis. So, I cannot provide information from our study. But the fact that all strokes in our study, they occurred in hospitalized patients and none of them occurred in ambulatory patients, confirms what is known, that those strokes occurred in patients who, by definition, they have severe COVID disease. So, they confirm this putative association that perhaps severe COVID is associated with stroke rather than just mild COVID.
Dr. Negar Asdaghi: All right. Thank you. And I just want to end with this simple question that I get asked often, and I want to see how you respond to patients or their loved ones when you're asked this question: "Doctor, did COVID give me a stroke?" How should we answer that question?
Dr. George Ntaios: Yes. As we discussed, I think that stroke is a rather rare or perhaps very rare complication of stroke and certainly less frequent than we initially thought. And in those stroke patients who had already other pathologies which can cause stroke, I would be rather reluctant to attribute it to COVID. I would be perhaps more willing to do so in younger patients, but again, only after exhaustively looking for another cause, like PFO, dissection, etc.
I mean, the concern is that if we as the treating stroke physicians assume that the stroke is caused by COVID, then we might discourage patients from doing the necessary diagnostic workup to find the actual cause of stroke. And if it happens, then perhaps an underlying pathology may be missed, which means that the patient will remain vulnerable to stroke recurrence. So, in general, I'm rather very reluctant to say that the stroke is caused by COVID unless a really thorough diagnostic workup shows nothing else at all.
Dr. Negar Asdaghi: All right. Very important message now to all practicing clinicians is don't stop at COVID. Don't just say simply, "Oh, this is COVID. COVID gave you a stroke." Keep looking for potential causes of stroke. Still do put that patient in the category of potentially ESUS or cryptogenic stroke if no other causes are found. And keep in mind that stroke is rare or, as George said, a very rare complication of COVID. Dr. George Ntaios, this is an exceedingly timely topic and a very important contribution to the field. Congratulations again on your paper, and thanks for taking the time to chatting with us today.
Dr. George Ntaios: Thank you for the wonderful discussion, Negar, and for the focus of our work.
Dr. Negar Asdaghi: Thank you.
And this concludes our podcast for the November 2022 issue of Stroke. As always, please be sure to check out the table of contents for the full list of publications, as we can only cover a fraction of the incredible science published in this journal each month. And don't forget to check our fantastic Literature Synopsis. In this month's issue, we read a short summary of the ACST-2 trial published in Lancet on the results of a randomized comparison of stenting versus endarterectomy in asymptomatic carotid disease patients with over 60% of carotid stenosis.
We also have the results of the CASSISS randomized trial, which was published in JAMA earlier this year, and it studied the effect of stenting plus maximal medical therapy versus maximum medical therapy alone on the risk of subsequent stroke and death in patients with symptomatic intracranial stenosis, either in the anterior or in the posterior circulation. CASSISS did not show that stenting was superior to maximum medical therapy, and sadly, these patients remain at a substantial risk of recurrent stroke despite being on best medical therapy.
But I wouldn't be too despondent about the future of interventional therapy for intracranial atherosclerotic disease. After all, we've come a long way since Dr. Charles Thomas Stent, an English dentist, started experimenting with products to advance the field of denture making around 1865. The work that Dr. Stent had started would be continued by his two sons, both dentists, to eventually make its way to products to create surgical tools. But it would be another 100 years before the first percutaneous coronary procedure was completed in 1964. And in honor of Dr. Stent's pioneering work, the device used to keep the coronaries open was named, you guessed it, stents.
Today's stroke care cannot be imagined without the use of various stents, and there's no doubt the future is promising for ways in which we will be able to safely treat intracranial atherosclerotic disease amongst all other vascular disorders. And what better way to keep our enthusiasm than staying alert with Stroke Alert.
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.
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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 a small noninferiority pilot trial out of the UK, the SoSTART trial, that looked at any anticoagulant versus either antiplatelet therapy or no antithrombotics in this population, and the other trial was the Phase 2 trial, the APACHE-AF, that studied apixaban versus no anticoagulation after anticoagulant-associated intracerebral hemorrhage. A reminder that both of these trials were published in Lancet Neurology in 2021. And before we move on to the findings of the meta-analysis, it's worth noting that they had included a mix of patients, some were oral anticoagulant–naive, and some had developed their index intracranial hemorrhage while already on treatment with anticoagulants or antiplatelet therapies. OK, now on to their findings, as mentioned, we're going to review three outcomes of recurrent thromboembolism, recurrent intracranial hemorrhage, and all-cause death for the following three groups: group one, oral anticoagulant therapy versus no therapy; group two, oral anticoagulation therapy versus either antiplatelet treatment or no therapy; group three, comparing new oral anticoagulants versus warfarin.
So, for the first outcome of recurrent thromboembolic events in group one, when comparing oral anticoagulant therapy to no therapy, the study showed a significant reduction in thromboembolic events in favor of oral anticoagulation compared to no therapy. That's great news. Next, analysis of the studies that compared oral anticoagulation versus either antiplatelets or no therapy didn't show the same difference in prevention of embolic events in favor of either groups. Actually, no difference was noted between the two groups. Number three, now, in terms of comparing NOACs to warfarin, three studies had the information on this comparison, and they reported a significant reduction in the risk of thromboembolic events with NOAC as compared to warfarin. So, great news for oral anticoagulation overall, and especially for NOACs.
Now, on the next outcome. Our second outcome was a recurrent intracranial hemorrhage. Keeping in mind that they included some studies where the outcome was defined as any form of intracranial hemorrhage, meaning they included subdurals, epidurals, etc., and some studies only included the outcome of intracerebral hemorrhage. So, on to the first group, comparing oral anticoagulants to no therapy, the pooled estimate revealed no statistically significant difference between oral anticoagulant–treated patients to those who were not treated with any antithrombotics on the risk of recurrent intracranial hemorrhage. That's great news. Next, on our second group, for the same outcome of recurrent intracranial hemorrhage, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found that oral anticoagulation was associated with a higher risk of recurrent intracranial hemorrhage as compared to antiplatelets or no therapy. And finally, third group comparing new oral anticoagulants to warfarin for the same outcome, the risk of recurrent intracranial hemorrhage was significantly reduced in patients treated with NOACs as compared to warfarin. And now, we're finally on to our last outcome of the study, which is the outcome of all-cause mortality.
So, again back to group one, comparing oral anticoagulants to no therapy, this meta-analysis showed a significant reduction in all-cause mortality rate associated with oral anticoagulation. That's, again, great news. Next group, for the same outcome of mortality, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found no significant difference in the mortality rates between the two groups. And finally, comparing NOACs to warfarin, the pooled estimate showed that NOACs were associated with a significantly reduced risk of all-cause mortality. Amazing news for NOACs.
So, in summary, here's what we learned from this big study. Oral anticoagulation use after intracranial hemorrhage in patients with atrial fibrillation did significantly reduce the risk of thromboembolic events and all-cause mortality without significantly increasing the risk of recurrent intracranial hemorrhage. In general, new oral anticoagulants, or NOACs, are preferred to warfarin as they do prevent embolic events with a lower risk of recurrent intracranial hemorrhage. But, of course, we still have a lot more questions. For instance, would any of the outcomes mentioned above be different in patients with lobar intracerebral hemorrhage, a condition typically associated with amyloid angiopathy, which carries a high risk of development of intracerebral hemorrhage? Also, we have to keep in mind that the majority of the studies included in the meta-analysis were observational. So, there remains an urgent need for a larger randomized trial on this subject, and we have to stay tuned for more research.
Cerebral venous sinus thrombosis, or CVST, is an uncommon form of stroke resulting in headaches, seizure, or focal neurological symptoms due to either intracranial hemorrhage or venous ischemic infarcts. The rarity of the disease has made it difficult to study as part of randomized trials, so current treatment guidelines for CVST are consensus-based with much of the recommendations extrapolated from data on treatment of patients with systemic deep vein thrombosis. In general, based on the current evidence, the field agrees that a patient with CVST should be anticoagulated. The decision that is difficult and sometimes inappropriately delayed in the setting of acute hemorrhage in the brain. And not surprisingly, there's significant equipoise around the choice of anticoagulant, duration of therapy, and the role of heroic therapies, especially in the acute setting. Currently, there are a number of ongoing trials to address some of these issues. The direct oral anticoagulants present an attractive alternative to vitamin K antagonists for treatment of patients with CVST. This is partly because of their convenience of use.
But how do direct anticoagulants compare in safety and efficacy to the vitamin K antagonists in the setting of CVST is less known. In our March podcast, we reviewed the results of ACTION-CVT, which was a multicenter international study that compared the safety and efficacy profile of the direct oral anticoagulants to that of warfarin in routine practice. The study included over a thousand imaging-confirmed CVST patients from multiple centers in the US, Italy, Switzerland, and New Zealand. And if you missed it, no worries at all. We're here to review some of the results again, as in this issue of the journal, many of the ACTION-CVT investigators, led by Dr. Shadi Yaghi, present the results of a systematic review and meta-analysis comparing the safety and efficacy of DOACs, or direct oral anticoagulants, to that of vitamin K antagonists. I'm joined today by Dr. Yaghi himself to discuss ACTION-CVT and the current meta-analysis. Dr. Yaghi is a Director of Vascular Neurology at Lifespan and Co-Director of Comprehensive Stroke Center and a Director of Research at the Neurovascular Center at Rhode Island Hospital. Good afternoon, Shadi, and welcome to our podcast.
Dr. Shadi Yaghi: Good afternoon, Dr. Asdaghi. Thank you so much for having me.
Dr. Negar Asdaghi: Thank you. And please call me Negar. Congrats on the paper. Before we talk about the meta-analysis, can you please remind us of the results of ACTION-CVT and why the systematic review, in your opinion, was an important next step to that effort?
Dr. Shadi Yaghi: Thank you so much for having me and for bringing up ACTION-CVT. So ACTION-CVT is a real-world multicenter international study that used real-world observational data to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The reason why we did ACTION-CVT was, as you know, cerebral venous thrombosis is a rare disease, and it's hard to have large studies that would be powered enough to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists. So, most of the studies that were done are small, retrospective. There's one randomized controlled trial, but most of them are underpowered to detect the difference between the two groups. So, we decided to do a large-scale international multicenter study using real-world data to compare the safety and efficacy of both.
Dr. Negar Asdaghi: OK, so we're glad you did. Let's start with the methodology of the current meta-analysis. Can you please give us an overview of the inclusion criteria for selection of the papers and the intervention and outcomes that you were interested in?
Dr. Shadi Yaghi: Of course. So, this is a systematic review and meta-analysis that included studies comparing direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The studies needed to have the two groups included, the direct oral anticoagulants and vitamin K antagonists, and they need to include at least one of the outcomes in our study to compare this outcome between the two groups. In addition, we included articles published in English, and we also included papers that had five patients or more in each group.
Dr. Negar Asdaghi: Perfect. So just recap for our listeners, in order to have been included in the meta-analysis, the paper had to have a reasonable number of patients, and you put that reasonable at the number five, and also they had to have at least one of the outcomes of interest reported in their papers. And those outcomes were either recurrent venous thromboembolism or recanalization rates. Right?
Dr. Shadi Yaghi: Correct. Yes.
Dr. Negar Asdaghi: Perfect. So with that, how many papers did you have to go through to come up with the current number of papers included?
Dr. Shadi Yaghi: That's a great question. We had a little over 10,000 papers, and then we went through a screening process. We used this tool that was developed by Brown University. It's called Abstrackr, and what you do is, we did the search and using several databases like PubMed, Cochrane, and then we included all these studies. We uploaded them in Abstrackr, and Abstrackr was utilized to be able to review all these abstracts and select studies that may or will probably qualify and then go through the studies and details that would qualify. So, we had about 10,000 studies with the initial search, and we had two reviewers go through each abstract, and from these 10,665, we excluded 10,411, and that left us with 254 studies. And then we went through these 254 studies in details. And then finally, we had 19 studies included that met our inclusion/exclusion criteria. And these 19 studies included three randomized control trials and 16 observational studies.
Dr. Negar Asdaghi: Incredible effort. So, three randomized trials in this meta-analysis and 16 observational studies. I think we're very ready to hear the primary outcomes.
Dr. Shadi Yaghi: Yeah, so, the primary outcomes were recurrent venous thrombosis, and that included recurrent venous thromboembolism like peripheral DVTs or PEs, for example, and including recurrent cerebral venous thrombosis. And we know that most of the events are recurrent VTEs, not CVTs, like probably about two-thirds to three-quarters were VTEs, and a third to a quarter were CVT. And then the other efficacy outcome is venous recanalization on follow-up imaging. And we found that direct oral anticoagulants and warfarin were not significantly different in the primary efficacy outcomes.
Dr. Negar Asdaghi: Thank you. I just want to repeat this for our listeners. So, you mentioned some important information here. First one was the fact that about three-quarters of recurrent events were actually systemic thromboembolic events rather than cerebral thromboembolism. So, an important outcome to keep in mind for our practicing physicians. And the fact that DOACs did the same as compared to vitamin K antagonist. So, I think you can already guess my next question, and that is, was there any compromise on the safety profile when using DOACs as compared to vitamin K antagonists in this meta-analysis?
Dr. Shadi Yaghi: Thank you. That's a great question. In ACTION-CVT, we found that there was a lower risk of major hemorrhage with direct oral anticoagulants compared to vitamin K antagonists. In this systematic review and meta-analysis, we didn't find a significant difference, but there were fewer events in patients treated with direct oral anticoagulants versus vitamin K antagonists. This did not reach statistical significance, but if you look at the raw data, it's kind of along the same lines as ACTION-CVT, so the risk of major hemorrhage was about 3.5% with warfarin, and that was about 2% with direct oral anticoagulants.
Dr. Negar Asdaghi: So, again, very important finding, and I want to repeat this for our listeners. So, important finding number one was that there was a superiority in favor of DOACs that you found in terms of a reduced risk of intracerebral hemorrhage in ACTION-CVT. You didn't find this superiority in the meta-analysis, but there was sort of a hint to perhaps lower risk of intracerebral hemorrhage in patients that were treated with DOACs. Did I get that right?
Dr. Shadi Yaghi: Yes, that is correct, and in addition, also major hemorrhage in general, and that included also ICH.
Dr. Negar Asdaghi: Oh, OK, so not just intracranial, but systemic hemorrhages as well. All right. Very good. So, I think my next question would be, why do you think that DOACs have a lower chance of causing hemorrhage?
Dr. Shadi Yaghi: Yeah, that's a really good question. This is not unexpected with DOACs as opposed to vitamin K antagonists. We saw these same trends in patients with atrial fibrillation. We saw improved bleeding profiles with direct oral anticoagulants as compared to vitamin K antagonists. And the risks were along the same lines that we found in patients with cerebral venous thrombosis in ACTION-CVT. Also in the VTE trials as well, there was also reduced bleeding complications with direct oral anticoagulants as compared to vitamin K antagonists. So, it was kind of reassuring to see the same results in patients with cerebral venous thrombosis.
Dr. Negar Asdaghi: Perfect, so kind of expected based on what we know from treatment of systemic conditions with DOACs. The next question I have for you is that in routine practice, treatment of cerebral venous sinus thrombosis almost always starts parenterally with either unfractionated heparin or low molecular weight heparin and then we switch to an oral agent. In the observational studies, did you find any differences in terms of timing of this switch or characteristics of the patients in whom vitamin K antagonists were chosen over direct oral anticoagulants?
Dr. Shadi Yaghi: Thank you very much. Most of the studies did not report these details. I think the one study, off the top of my head, that does report the differences in characteristics between the two groups is RESPECT-CVT. That's the randomized controlled trial comparing dabigatran to vitamin K antagonists. In this study, there was a treatment with parenteral anticoagulation for several days, I think seven to 14 days, prior to transitioning to oral anticoagulation. And this is generally my practice. I typically would treat patients with at least seven days or so parenteral anticoagulation, and once they're clinically stable, then I would transition them to oral anticoagulation, either vitamin K antagonists or direct oral anticoagulant.
Dr. Negar Asdaghi: And I think my next question is along the lines of this question as well. We have several direct oral anticoagulants now available on the market. What was the most common DOACs used for treatment of CVST in these studies, and did you note a preference for the use of any particular agent over others?
Dr. Shadi Yaghi: Thank you so much for the question. Anti-Xa inhibitors were much more common than dabigatran, and the anti-Xa inhibitors most commonly used were apixaban and rivaroxaban. It's in line with what we saw in ACTION-CVT as well, although most of the randomized controlled trials or the largest randomized controlled trial, RESPECT-CVT, used dabigatran, but overall people have been using anti-Xa inhibitors, more particularly apixaban, which was also in line with what we saw in ACTION-CVT.
Dr. Negar Asdaghi: But I think it's fair to say that we don't really have data on superiority of one over others. Is that fair?
Dr. Shadi Yaghi: Yes, that is correct.
Dr. Negar Asdaghi: OK, and so now, where are we at in terms of the future of studies on this topic? We have one ongoing randomized trial now?
Dr. Shadi Yaghi: Yes, we have one randomized controlled trial ongoing, and this is the SECRET trial, and it's looking at rivaroxaban versus vitamin K antagonists in patients with cerebral venous thrombosis. There's another study, it's a prospective observational study that's called the DOAC-CVT study. It's an international study also looking at real-world data prospectively to see if there's a difference in outcomes between the two groups.
Dr. Negar Asdaghi: So, we look forward to the results of those studies. Shadi, a follow-up question I have on this topic is, how long should a duration of therapy be in idiopathic cases of cerebral venous sinus thrombosis?
Dr. Shadi Yaghi: Thank you so much for this question. So, it's unknown at this point for how long should we treat. The key things from the treatment are first achieving venous recanalization, and second is preventing another venous thromboembolic event from happening. So, regarding the venous recanalization, studies have shown that there's not a lot of recanalization beyond four months of treatment. So, a lot of the recanalization really happens early, and continuing anticoagulation beyond the six-months interval, for example, in order to achieve further venous recanalization probably has limited utility. And the second important reason why we treat patients with anticoagulation is also to reduce the risk of a recurrent venous thromboembolic event or cerebral venous thrombosis.
And for that, if it's a provoked CVT, then I think usually it's three to six months. If it's unprovoked, up to maybe six to 12 months or even longer, depending on the profile. And if there's a persistent provoking factor, such as cancer, antiphospholipid antibody syndrome, then the treatment is lifelong or until this condition subsides. There's a lot of controversy about the duration of treatment. The European guidelines were very helpful in identifying the duration of treatment. Hopefully, also, we have some guidelines or at least a scientific statement by the AHA that also doles details out and provides some guidance to practitioners.
Dr. Negar Asdaghi: Shadi, what should be our top two takeaways from the current meta-analysis and also ACTION-CVT?
Dr. Shadi Yaghi: So, really, the top two from ACTION-CVT and the meta-analysis are, first is direct oral anticoagulants have a comparable efficacy to vitamin K antagonists in terms of recurrent venous thrombosis and achieving venous recanalization on follow-up imaging. And then the second point is direct oral anticoagulants are probably safer than vitamin K antagonists. We have to keep in mind that this data is based mostly on observational studies. And, as we mentioned earlier, we need more randomized controlled trials to support these findings.
Dr. Negar Asdaghi: Dr. Shadi Yaghi, it was a pleasure interviewing you on the podcast. Thank you very much for joining us, and we look forward to having you back on the podcast and reviewing this topic again in the future.
Dr. Shadi Yaghi: Thank you so much. I appreciate you having me.
Dr. Negar Asdaghi: Thank you.
And this concludes our podcast for the October 2022 issue of Stroke Please be sure to check out this month's table of contents for the full list of publications, including an important update from the European Stroke Organisation by Prof. Martin Dichgans.
I also want to draw your attention to this month's InterSECT paper, which is our International Stroke Early Career and Training section, to discuss the key topic of burnout and mental health amongst physicians, especially amongst neurologists and stroke neurologists. It's alarming to read in this article that neurology is one of the specialties with the highest reported rates of burnout syndrome, and stroke neurologists are at particularly higher risk than other neurological subspecialties. The article tackles some tough subjects, such as the barriers for physicians to seek help and important strategies to mitigate burnout and how to improve mental health in general. I think it's also timely to know that October is the Mental Health Awareness Month, and the theme for October 2022 is "Back to Basics." The basics of recognizing the burden of stress, anxiety, the burden of isolation and depression, not only on those who we take care of, but also on those who give care to us.
So, whether you're a stroke physician, a stroke caregiver, or whether you've been touched by this disease in some way or shape, please know that you are part of the stroke community and a part of our Stroke podcast family. Thank you for listening to us, and, as always, stay alert with Stroke Alert.
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.
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