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Johns Hopkins Stroke Dept. Live Blogs About “Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke”

Burton J. Tabaac, MD
@burtontabaac

Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019; 380:1795-1803.

The following discussion is documented via “LIVE Blogging,” a Journal Club held at Johns Hopkins Hospital in Baltimore, Maryland, on May 14, 2019. The journal article presented is “Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke,” published in The New England Journal of Medicine on May 9, 2019. The Journal Club presentation and discussion was led by Dr. Rebecca Gottesman, a neurology professor, cerebrovascular specialist, and International Stroke Conference 2019 award recipient.

Current American Heart Association/American Stroke Association guidelines for ischemic stroke limit the time to initiate intravenous thrombolytic therapy to within 4.5 hours after the onset of stroke. Representatives from the EXTEND trial and collaborators from the University of Melbourne, Royal Melbourne Hospital, in Australia published an article that challenges this limit. By carefully selecting the appropriate patient population using advanced imaging, patients who have salvageable brain tissue beyond 4.5 hours may benefit from treatment via IV thrombolysis! The authors tested the hypothesis that “intravenous thrombolysis with alteplase initiated between 4.5 and 9.0 hours after stroke onset or on awakening with stroke symptoms (for which the time of onset was not known) would provide a benefit in patients who had a small core volume of cerebral infarction that was disproportionate to a larger area of hypoperfusion.”

This paradigm change to carefully select the appropriate patients who may benefit from therapy outside current guidelines parallels a similar historical trajectory to that of endovascular intervention in treating large vessel occlusion. For an epoch, the standard of care in approaching embolectomies relied on the patient presenting to clinical attention within 6 hours of onset and a favorable ASPECTS score on “dry” CT brain imaging. This limit was breached via conclusions drawn from the DAWN and DEFUSE 3 trials. By carefully selecting the appropriate patient population in concordance with advanced imaging (e.g., CTP, hyperacute MRI), offerable treatment was readily introduced to a much larger eligible patient population.

ESOC: Official Welcome & Large Clinical Trials

European Stroke Organisation Conference
May 22–24, 2019

Alan C. Cameron, MB ChB, BSc (Hons), MRCP

The 5th European Stroke Organisation Conference (ESOC 2019) has opened with a fantastic session in Milan on Wednesday! The conference was opened by ESO President Bart van der Worp, Conference Chair Jesse Dawson, and Chair of the Local Organising Committee Danilo Toni, who welcomed over 5,500 participants from 94 countries to the conference, which has doubled in size since inception over the last four years.

Ten landmark studies were presented at the official welcome. Key highlights include results from RESTART, which answers whether to start or avoid antiplatelet therapy after ICH in patients taking antiplatelets for the prevention of occlusive vascular disease. Remarkably, restarting antiplatelet therapy does not increase major haemorrhagic events. In contrast, restarting antiplatelet therapy may reduce recurrent ICH and protect against recurrent major vascular events. This provides reassuring evidence on restarting antiplatelet medication for secondary prevention of occlusive vascular disease in patients with ICH.

RESILIENT demonstrates the overwhelming efficacy of mechanical thrombectomy persists when implemented in the challenges of a developing country healthcare system such as Brazil. In this setting, thrombectomy decreases disability with a number needed to treat of only 6.6, has low complication rates and no increase in symptomatic ICH compared to medical therapy. We must now ensure the tremendous benefits of thrombectomy are available to more patients globally, including developing countries. 

Interview: Professor Dr. Hans-Christoph Diener on “Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source”

Professor Dr. Hans-Christoph Diener

Professor Dr. Hans-Christoph Diener

A conversation with Professor Dr. Hans-Christoph Diener, Faculty of Medicine at the University of Duisburg-Essen, on the recently published randomized clinical trials assessing the safety and efficacy of non-vitamin K oral anticoagulants (NOACs) in patients with embolic strokes of undetermined source (ESUS), and on the future of anticoagulation in the secondary prevention of cryptogenic cerebral ischemia.

Interviewed by Aristeidis H. Katsanos, Research Fellow at the Department of Neurology, Ruhr University of Bochum.

They will be discussing the paper “Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source,” published in the May 16, 2019 issue of the New England Journal of Medicine.

Dr. Katsanos: Can you please summarize for the readers of the blog the main hypothesis and findings of the RE-SPECT ESUS trial?

Prof. Diener: Patients with ESUS (embolic stroke of undetermined source) have high risk of recurrent stroke, and the risk of recurrent stroke per year is about 5%. We assume that the majority of these recurrent strokes have an embolic source. Therefore, oral anticoagulation should be superior to antiplatelet therapy in patients with ESUS.

Article Commentary: “Cerebral Ischemia in Patients on Direct Oral Anticoagulants”

Bahar M. Beaver, MD

Macha K, Marsch A, Siedler G, Breuer L, Strasser EF, Engelhorn T, et al. Cerebral Ischemia in Patients on Direct Oral Anticoagulants: Plasma Levels Are Associated With Stroke Severity. Stroke. 2019;50:873–879.

Although anticoagulation is standard of care for secondary prevention in patients with cardioembolic stroke and non-valvular atrial fibrillation (a-fib), we often see recurrent strokes in patients taking vitamin K antagonists (VKA) or direct oral anticoagulants (DOACs). This group of authors at the University Medical Center in Erlangen, Germany, performed an observational study using a patient registry in order to correlate oral anticoagulant activity and plasma levels with severity of ischemic stroke.

From the Erlangen Registry of Patients on Oral Anticoagulation (ER-NOAC), 460 patients with acute ischemic stroke while on oral anticoagulation for a-fib were selected from November 2014 to October 2017. Of these, 234 (50.9%) were on DOAC, and 226 (49.1%) were on VKA. Functional plasma levels were assessed in the patients on DOAC, and the results were broken down by low (<50 ng/ML), intermediate (50-100 ng/mL), and high (>100 ng/mL). For patients on VKA, the threshold INR was set at 1.7. From the 226 patients on VKA, 41.2% had an INR below 1.7. The investigators correlated the various lab findings to NIHSS at time of presentation.

Article Commentary: “Dual Antiplatelet Therapy Improves Functional Outcome in Patients With Progressive Lacunar Strokes”

Philip Chang, MD

Berberich A, Schneider C, Reiff T, Gumbinger C, Ringleb PA. Dual Antiplatelet Therapy Improves Functional Outcome in Patients With Progressive Lacunar Strokes. Stroke. 2019;50:1007–1009.

As neurologists, we have all encountered patients with mild lacunar stroke, confirmed on MRI to be a small subcortical lesion, especially if caught early on. However, some patients, despite a small stroke seen on early MRI having waxing and waning symptoms, for example going from complete plegia to a mild hemiparesis within the same hour. Why would this be the case? CHANCE and POINT enrolled patients of minor non-cardioembolic strokes, and proved that dual antiplatelet therapy was superior in reducing recurrent strokes in minor strokes with NIHSS<3. If one thinks about the enrollment criteria, this would likely leave small vessel disease, large vessel disease, and other/cryptogenic by TOAST criteria.

In my blog entries’ ongoing discussion on dual antiplatelet data, there has been a long story about likely success of dual antiplatelet therapy in stabilizing large artery atherosclerosis, both by transcranial doppler studies as well as a newly published study in Stroke, “Dual Versus Mono Antiplatelet Therapy in Large Atherosclerotic Stroke: A Retrospective Analysis of the Nationwide Multicenter Stroke Registry.” In my opinion, this likely drives a large portion of the effect size in CHANCE/POINT. However, early neurologic deterioration was not differentiated from early recurrent stroke in these trials, and a portion of the effect size may have been from dual antiplatelet treatment of lacunar strokes with early neurological deterioration, which likely includes entities such as “stuttering lacunar syndrome” or “capsular warning syndrome.”

Craniocervical Arterial Dissection: A Common Cause of Stroke in Childhood

Alejandro Fuerte, MD
@DrFuerte1

Nash M, Rafay MF. Craniocervical Arterial Dissection in Children: Pathophysiology and Management. Pediatric Neurology. 2019

Craniocervical arterial dissection (CCAD) is a crucial emergency state causing 7.5% to 20% of all childhood arterial ischemic stroke (AIS) cases, with an annual incidence of all AIS estimated at 2.5 to 8 per 100,000 children per year. Childhood CCAD cases are often spontaneous or in association with head and neck trauma, both blunt injuries and hyperextension or manipulation of the neck. With spontaneous CCAD, at least 5% to 20% of children have an underlying risk factor, such as connective tissue diseases, genetic disorders, anatomic vascular variations or familial segregation. The clinical presentation of CCAD is non-differentiating from other causes of AIS aside from a history of head and neck trauma or pain. Magnetic resonance imaging is the preferred neuroimaging method, followed by cerebral catheter angiography as a gold standard definitive neurovascular imaging modality when initial vascular imaging reveals non-diagnostic findings.

For this review, the authors searched MEDLINE (2000 to 2018) for articles that contained patients aged less than 18 years with craniocervical arterial dissection, with the aim of analyzing their characteristics. Sixteen articles met the study criteria and reported 182 cases of craniocervical arterial dissection. 68% were male individuals, with an average of 8.6 years of age. From the 182 cases reviewed, 102 (56%) cases experienced concurrent or preceding trauma as the risk factor for dissection; 25% of these were associated with some type of contact sport or physical activity, and skull or spine fracture(s) was listed as a risk factor in 14%. Several risk factors were identified among the spontaneous dissection cases (mainly aberrant vertebral arcuate foramina).

Author Interview: Dr. Diogo Haussen, MD, and Dr. Thomas Madaelil, MD, on “Multimodality Imaging in Carotid Web”

Dr. Diogo Haussen, left, and Dr. Thomas Madaelil

Dr. Diogo Haussen, left, and Dr. Thomas Madaelil

A conversation with Dr. Diogo Haussen, MD (Assistant Professor of Neurology, Emory School of Medicine/Grady Memorial Hospital), and Dr. Thomas Madaelil, MD (Neurointerventional Fellow, Emory School of Medicine), on imaging and clinical significance of carotid web.

Interviewed by Sami Al Kasab, MD (StrokeNet fellow, University of Iowa Hospitals and Clinics).

They will be discussing the paper “Multimodality Imaging in Carotid Web,” published in Frontiers in Neurology.

Dr. Al Kasab: I read with great enthusiasm your recent article comparing different imaging modalities to diagnose a carotid web. Can you please summarize the key findings of your study, and how your results can be applied to our clinical practice?

Drs. Haussen and Madaelil: Thank you for your interest in our manuscript. Acute ischemic stroke is commonly a devastating condition, especially when occurring in young adults. Occasionally, we can get tangled when we cast wide nets for the diagnostic work-up in patients with cryptogenic stroke. Carotid web is a condition that can be overlooked when neurovascular studies are reviewed during this diagnostic work-up period, and it may actually be more common that previously thought. Our study is aimed to help shed light on the performance of different imaging modalities in the diagnosis of carotid web, which is particularly important since there were no previously published comparative studies. We observed that computed tomographic angiogram (CTA) shared very high rates of inter-rater agreement with digital subtraction angiogram (DSA), while the CTA agreement with ultrasonography was much more limited. Therefore, non-invasive multiplanar imaging modalities, such as CTA, should be considered in the evaluation of young patients with otherwise no identified stroke cause considering the possibility of an underlying carotid web.

Author Interview: Drs. Thabele (Bay) Leslie-Mazwi, MD, and Gregory W. Albers, MD, on “DEFUSE 3 Non-DAWN Patients: A Closer Look at Late Window Thrombectomy Selection”

Dr. Thabele (Bay) Leslie-Mazwi, left, and Dr. Gregory W. Albers

Dr. Thabele (Bay) Leslie-Mazwi, left, and Dr. Gregory W. Albers

An interview with Dr. Thabele (Bay) Leslie-Mazwi, MD, Director of Endovascular Stroke Services, Massachusetts General Hospital; Assistant Professor of Neurology, Harvard University; and Dr. Gregory W. Albers, MD, Director, Stanford Stroke Center; Professor of Neurology, Stanford University.

Interviewed by Kristina Shkirkova, BSc, Doctoral Student in Neuroscience, Department of Neurosurgery, Zilkha Neurogenetic Institute, University of Southern California.

They will be discussing the article “DEFUSE 3 Non-DAWN Patients: A Closer Look at Late Window Thrombectomy Selection,” published in the March 2019 issue of Stroke.

Ms. Shkirkova: Please briefly summarize the design and findings of your study.

Drs. Leslie-Mazwi and Albers: We evaluated DEFUSE 3 patients who would have been excluded from the DAWN trial based on DAWN eligibility criteria, with the goal of assessing treatment effect in that DEFUSE 3 subgroup (DEFUSE 3 Non-DAWN). The main reasons for DEFUSE 3 Non-DAWN were NIHSS 6-9, core too large (based on age and volume of established infarct), and mRS of 2. Patients with mRS 2 were included with the NIH stroke scale 6-9 group, as detailed in our paper, and so we analyzed the DEFUSE 3 Non-DAWN patients NIHSS 6-9 and core-too-large patients to assess treatment effect in that subgroup.

Patients with pretreatment core infarct volumes <70ml but too large for inclusion by DAWN criteria demonstrated robust benefit from endovascular therapy. Data supporting a beneficial treatment effect across the full range of NIHSS scores was documented in the entire DEFUSE 3 population. In our small subgroup of patients with NIHSS 6-9, we found a trend towards benefit.

Prehospital Transfer Tool for Stroke Patients: Simplifying Complex Decisions

Elena Zapata-Arriaza, MD
@ElenaZaps

Venema E, Lingsma HF, Chalos V, Mulder MJHL, Lahr MMH, van der Lugt A, et al. Personalized Prehospital Triage in Acute Ischemic Stroke: A Decision-Analytic Model. Stroke. 2019;50:313–320.

Delay in the administration of required treatment in ischemic stroke can worsen the patient’s functional prognosis. Which patient needs direct transfer to a primary stroke center or to an intervention center is still a challenge in decision making.

To determine optimal prehospital transportation strategy, the authors performed a decision – analytic model. As described in Figure 1, this model starts with the initial decision of transportation to the primary stroke center or to the nearest endovascular-capable intervention center. The benefit of direct transportation to the intervention center was defined as the average amount of quality-adjusted life years (QALYs) gained by this strategy (difference of >0.02 QALYs (=1 week in full health) was considered clinically relevant). The short-run model calculates the probability of every possible pathway and the associated distribution of the modified Rankin Scale (mRS) score after 3 months. It takes into account driving times, in-hospital workflow characteristics, and time-dependent treatment effects. In each annual cycle of the following Markov model, patients can remain in the same health state or die. These probabilities are based on the age and sex-dependent annual mortality rates, adjusted for previously reported death hazard rate ratios of stroke patients.

Schematic overview of the model structure.

Figure 1. Schematic overview of the model structure. The decision node is represented with a square. The circles represent chance nodes, the circles marked with an M represent Markov models and the triangles represent terminal nodes. EVT indicates endovascular treatment; IVT, treatment with intravenous thrombolytics; and LVO, large vessel occlusion.

Dual Antiplatelet Therapy for Large Artery Atherosclerosis

Victor J. Del Brutto, MD

Kim D, Park JM, Kang K, Cho YJ, Hong KS, Lee KB, et al. Dual Versus Mono Antiplatelet Therapy in Large Atherosclerotic Stroke: A Retrospective Analysis of the Nationwide Multicenter Stroke Registry. Stroke. 2019;50:1184–1192.

Large artery atherosclerosis (LAA) is responsible for a fourth of all ischemic strokes and is the mechanism of cerebral ischemia with the highest risk of recurrence. Current evidence supports that aggressive platelet anti-aggregation is beneficial in the acute phase due to the high thrombogenicity caused by plaque rupture, while the use of statins and strict vascular risk factors control is more relevant chronically to assure plaque stability and to stop arterial disease progression. Current guidelines recommend long-term antiplatelet monotherapy for secondary stroke prevention. However, high-risk clinical settings such as coexistence of coronary artery disease, stroke recurrence despite taking one antiplatelet agent, high-degree stenosis, or presence of micorembolic signals on transcranial Doppler often lead physicians to prescribe dual antiplatelet therapy (DAPT) beyond the acute phase.

The current study used a large multicenter prospective stroke registry from Korea to compare the effectiveness of DAPT with clopidogrel plus aspirin versus aspirin monotherapy in preventing vascular events and death in patients who had an ischemic stroke or TIA attributed to LAA. At one-year follow up, combination therapy was associated with lower risk of having the composite outcome of any stroke, myocardial infarction, or all-cause death. Of notice, DAPT did not reduce the risk of stroke recurrence when compared to aspirin alone, thus results were mainly attributable to overall mortality reduction (Figure 4).

Kaplan-Meier curves for primary outcome ( A), stroke recurrence ( B), and all-cause death ( C) after stabilized inverse probability of treatment weighting in intention-to-treat, per-protocol, and as-treated populations. A indicates aspirin; and C+A, clopidogrel plus aspirin.

Figure 4. Kaplan-Meier curves for primary outcome (A), stroke recurrence (B), and all-cause death (C) after stabilized inverse probability of treatment weighting in intention-to-treat, per-protocol, and as-treated populations. A indicates aspirin; and C+A, clopidogrel plus aspirin.

By |April 30th, 2019|clinical|1 Comment