Intravenous tPA Research Articles

Abstract P123: Comparing Process, Performance Measures and Clinical Outcome Between Mobile Stroke Unit and Usual Care in Underserved Areas

Background: The efficacy of mobile stroke units (MSU) in improving acute ischemic stroke (AIS) care in developing countries is unknown. We compared performance measures and treatment outcomes between MSU and usual care. Methods: We enrolled patients >18 years of age with a diagnosis of AIS who presented with onset to door < 4.5 hours and stroke code was alert either at the Siriraj MSU (SiMSU) or at the emergency department (ED). The same AIS treatment guideline for intravenous tPA or endovascular treatment (EVT) were applied in both groups. Demographic data, type(s) of reperfusion therapy (tPA and/ or EVT) were recorded. Stroke onset to door (OD), door to CT (DCT), door to needle (DN), and door to puncture (DP) time were collected. Stroke outcome was measured by the modified Rankin Score (mRS) at 3 months. Results: A total of 519 AIS patients (130 from SiMSU and 389 from ED) were enrolled between June 2018 and December 2019. The mean age ( + SD) was 66 ( + 13.9), 254 (48.9%) were male. AIS key process time measures were significantly shorter in the SiMSU with a mean + SD DCT time of 7 + 4.9 vs 16 + 13.7 minutes (p< 0.01), DN time of 21 + 7 vs 34 + 13.8 minutes (p< 0.01) and DP time of 71 + 20 vs 94 + 44.6 minutes, (p<0.01) in SiMSU and ED respectively. Although EVT rate was similar, intravenous tPA rate was significantly higher in SiMSU 59.2% vs 34.4% (p< 0.01). The mRS of 0-2 at 3 months was significantly higher in SiMSU than the ED (67.5% vs 57.9%, p=0.01). Conclusions: The SiMSU significantly shortened door to reperfusion treatment, increased access to IV t-PA and improved stroke outcomes by reducing disability at 3 months when compare to standard of care (i.e. ED arrival). This working paradigm could be implemented in other similar healthcare settings to improved AIS care.

Abstract P156: Impact of Covid-19 on Thrombolysis and Thrombectomy Time Metrics at Henry Ford Hospital’s Detroit and West Bloomfield Campuses

Background: We propose that social distancing policies during COVID-19 may have negatively impacted the timely administration of intravenous tPA and mechanical thrombectomy (MT) in acute ischemic strokes (AIS). Methods: In this retrospective study conducted at 2 large stroke centers serving Southeast Michigan, we included consecutive patients admitted to our stroke unit from 3/20/20 to 5/20/20 (COVID) and a similar epoch in 2019 (pre-COVID). We compared demographics and time metrics. Results: 247 patients with AIS were included in the tPA analysis, 167 (68%) in 2019 vs 80 (32%) in 2020. Overall mean age was 67.2, 60% male and 49% African Americans (AA). tPA was given in 13/80 in 2019 vs 17/167 patients in 2019 (16% vs 10%, p=0.143). There was no difference in tPA rates between AA and non-AA in 2020. There was a trend toward faster tPA administration in 2020 vs 2019 (median: 37.8 vs 51 min, p=0.051), significant among AA (37.8 vs 58.8 min, p=0.029). Mild/rapidly improving strokes was less frequently a tPA exclusion in 2020 vs 2019 (0% vs 10%). Delayed presentation was significantly less frequent among non-AA in 2020 vs 2019 (54% vs 66%, p=0.045) but there was a trend toward more frequent delayed presentations in AA vs non-AA in 2020 (76 vs 54%, P=0.073). 69 patients were eligible to receive MT, 42 (61%) in 2019 and 27 (39%) in 2020. Mean age was 67.9 and 36% were AA. No differences were detected between 2019 and 2020 in MT rates or time metrics. In 2020, there was a slight trend toward lower MT rates for AA vs non-AA patients (69% vs 30%, p=0.10). Conclusion: During the COVID-19 pandemic in Detroit there was a trend toward faster tPA administration compared to the same period pre-COVID, especially among AA. There was no significant difference in MT rates or time metrics. In our AA-majority city, there was a trend towards more delayed presentations and lower MT rates among AA during COVID. The reasons for these differences are yet to be determined and warrant further research.

Abstract 16: IV TPA in the 0-3 Hour Window: Quantitative Fragility-Robustness Assessment of the Strength of the RCT Evidence

Background: After 3 decades, the era of RCTs of IV tPA as a standalone therapy in acute ischemic stroke has now likely closed, with the completion of TESPI, PRISMS, and late, imaging-selection RCTs, and the advent of endovascular thrombectomy. Some non-expert contrarians questioned the accumulating evidence regarding tPA; the recently formulated fragility-robustness index (FRI) enables quantification of the actual rigor of evidence throughout the era of IV tPA investigation. Methods: The FRI summarizing the strength of the statistical evidence for clinical trial findings is the minimum nonevent to event changes needed to turn a statistically significant to non-significant result. The FRI was applied to disability-free (mRS 0-1) and independence (mRS 0-2) outcomes; cumulative meta-analyses delineated evidence strength after each successive RCT. FRI scores were classified: Not Robust (FRI 0-4), Somewhat Robust (5-12), Robust (13-33), and Highly Robust (>33). Results: Systematic search identified 8 RCTs (1960 patients) of IV tPA in the 0-3h window from 1995 - 2018. Study-level meta-analyses showed FRIs of 42 for mRS 0-1 and 40 for mRS 0-2; individual patient data meta-analyses showed FRIs of 40 for both mRS 0-1 and mRS 0-2, placing IV tPA in the highest quintile of FRIs among meta-analyses for all conditions. Evolution of RCT evidence over time is shown in Table 1. Strength of evidence for IV tPA superiority was already robust with publication of the initial 2 NINDS-tPA in 1995, remained robust through 2011 after 4 additional RCTs, increased to highly robust with the IST-3 mega-trial in 2012, and remains highly robust today after 1 additional trial. Conclusions: Intravenous tPA for acute ischemic stroke in 0-3h patients is one of the most robustly proven therapies in medicine. This therapy was already robustly supported with publication of the initial trials 25 years ago and advanced 9 years ago after additional trials to highly robust/non-fragile.

Abstract 3: Early Recanalization of Large Vessel Occlusions by tPA on the Mobile Stroke Unit

Introduction: The benefit of intravenous tPA in acute ischemic stroke patients with large vessel occlusions (LVOs) is limited but time dependent. We evaluated pre-hospital treatment with tPA on the Mobile Stroke Unit (MSU) to explore the recanalization rate in patients with LVOs and its effect on clinical improvement upon ED arrival. Methods: Prospectively derived data were analyzed from patients on the Houston MSU who were treated with tPA and had LVOs identified by hyperdense artery on MSU CT or arterial occlusion on MSU CTA. The primary outcome was early recanalization, categorized as resolution of LVO on repeat vascular imaging in the ED or on emergent angiography versus no recanalization. Secondary outcome was change in baseline NIHSS at 24 hours. Differences in NIHSS were evaluated using Wilcoxon rank sum test with continuity correction. Results: Seventy-one patients received tPA and had proximal LVOs both in the anterior and posterior circulation. Eleven had recanalization on CTA upon ED arrival (15.5%), while 7 had recanalization on emergent angiography (9.9%). The total early recanalization rate with tPA was 25.4%. Forty-seven patients with persistent LVOs on ED arrival (66.2%) underwent endovascular thrombectomy (EVT). Time from symptom onset (last known normal) to tPA bolus did not differ significantly between the early recanalization vs non-early recanalization groups (64.5 minutes [IQR 43.0-78.5] vs 64.0 minutes [52.5-92.0]; p = 0.41). Early recanalization resulted in greater improvement in baseline to ED arrival NIHSS (median NIHSS change 4.0 [0-11.8] vs 0 [0-3.5]; p = 0.01). There were no differences in ED arrival to 24 hour NIHSS between the early recanalization versus non-early recanalization groups irrespective of EVT. Conclusions: Recanalization by ED arrival occurs in 25% of LVO patients with tPA treatment on a MSU and was associated with early clinical improvement. Subsequent EVT did not “make up” for the clinical benefit of early recanalization.

Abstract P111: Ischemic Stroke Associated With Covid-19 and Racial Outcome Disparity in North America

Introduction: Underlying biological, genetic, or epigenetic characteristics may predispose to health differences and outcomes with COVID-19 associated stroke. Social determinants of health, access and geographical differences pertaining both to population density and other location-based factors may also be important. Methods: We report 69 cases of acute stroke in patients positive for SARS-CoV-2, in a dichotomized analysis of ischemic stroke outcomes between patients of African American background versus all other backgrounds. All patients presented to 14 major hospitals in the United States and Canada, from March 14-April 14, 2020. All patients had nasopharyngeal swab samples that were positive for SARS-CoV-2 on qualitative RT-PCR assays. Results: We found no significant difference in age (64.4 versus 62.9 years) or the proportion of females (51.9% versus 38.1%) (table 1). Diabetes mellitus was present significantly less in African American cases versus others (37% vs. 66.7%). The African American cohort had a similar mean NIHSS score of 16.3 compared with 14.9 in other races (p=0.63). The door-to-CT time was also similar (23 versus 19 minutes). The proportion of patients presenting with a large vessel occlusion was not significantly different (40.7% versus 47%). We noted 14.8% of African American cases received intravenous tPA compared to 31% in other races but was not significantly different. The proportion of thrombectomy cases mirrored this (14.8% versus 31%). Regarding stroke functional outcomes, there was no difference between African Americans and other races with respect to discharge mRS or proportion of favorable outcome (mRS 0-2). Symptomatic intracranial hemorrhage (sICH) was significantly higher for African Americans (11.1% versus 3%, p<0.001). Mortality was significantly higher in African Americans compared to other races (51.9% vs. 28.6%, p=0.03). Discussion: The reasons for increased mortality in African Americans with COVID-19-associated stroke are unknown. The finding in this study that mortality rate of COVID-19 positive stroke patients is greater than that previously reported in either COVID-19 respiratory infection alone or acute ischemic stroke alone, suggests an interaction that also warrants further study.

Safety and efficacy of intra-arterial fibrinolytics as adjunct to mechanical thrombectomy: a systematic review and meta-analysis of observational data

BackgroundAchieving the best possible reperfusion is a key determinant of clinical outcome after mechanical thrombectomy (MT). However, data on the safety and efficacy of intra-arterial (IA) fibrinolytics as an adjunct...

Response by Pfaff et al to Letter Regarding Article, “Direct Transfer to Angio-Suite Versus Computed Tomography-Transit in Patients Receiving Mechanical Thrombectomy: a Randomized Trial”

HomeStrokeVol. 52, No. 1Response by Pfaff et al to Letter Regarding Article, “Direct Transfer to Angio-Suite Versus Computed Tomography-Transit in Patients Receiving Mechanical Thrombectomy: a Randomized Trial” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBResponse by Pfaff et al to Letter Regarding Article, “Direct Transfer to Angio-Suite Versus Computed Tomography-Transit in Patients Receiving Mechanical Thrombectomy: a Randomized Trial” Johannes A.R. Pfaff, MD, Martin Bendszus, MD and Markus A. Möhlenbruch, MD Johannes A.R. PfaffJohannes A.R. Pfaff Department of Neuroradiology, Heidelberg University Hospital, Germany. Search for more papers by this author , Martin BendszusMartin Bendszus Department of Neuroradiology, Heidelberg University Hospital, Germany. Search for more papers by this author and Markus A. MöhlenbruchMarkus A. Möhlenbruch https://orcid.org/0000-0002-5075-704X Department of Neuroradiology, Heidelberg University Hospital, Germany. Search for more papers by this author Originally published28 Dec 2020https://doi.org/10.1161/STROKEAHA.120.032798Stroke. 2021;52:e28In Response:We thank Goyal et al for their interest in our trial.1 We agree that “direct” does not necessarily imply ”faster“ or even “better.”The distance between the hospital door and the angiosuite is given by the hospital’s floor plan. Having an angiography system directly in the emergency room might be desirable, but it is not common practice in most hospitals, unlike computed tomography scanners which are usually located close to the emergency room. Future trials comparing a computed tomography–transit workflow, and a direct-to-angiosuite workflow must describe the local conditions precisely in order to interpret findings correctly. A multicenter trial on this subject may indicate under which conditions patients benefit from a direct transfer to the angiosuite.With reference to Pfaff et al,1 the somewhat greater distance from the emergency room to the angiosuite and the positioning of the patient and monitoring devices contributed to a delay in stroke imaging when patients were transferred directly to the angiosuite.1 However, this delay was not the only reason to stop the trial prematurely. Enrollment to the trial was stopped also because early ischemic changes could not be adequately assessed in some patients randomized to directly to the angiosuite. However, administration of intravenous tPA (tissue-type plasminogen activator) as approved therapy requires a reliable imaging basis due to the potential harm. New imaging technologies in the angiosuite will probably contribute to an even faster and more reliable imaging, hopefully providing the same level of safety and reliability in stroke imaging as we already have today with computed tomography or magnetic resonance imaging.Sources of FundingNone.DisclosuresDr Pfaff reports personal fees from Stryker outside the submitted work. Dr Bendszus reports personal fees from Boehringer Ingelheim, B. Braun, Vascular Dynamics, Bayer, Merck, Teva, Grifols, Springer, grants and personal fees from Novartis and Guerbet, grants from Siemens, Hopp Foundation, from Deutsche Forschungsgemeinschaft (DFG), European Union, Stryker, outside the submitted work. Dr Möhlenbruch has received grants from Balt, Medtronic, MicroVention, and Stryker outside the submitted work.FootnotesFor Sources of Funding and Disclosures, see page e28.Reference1. Pfaff JAR, Schönenberger S, Herweh C, Ulfert C, Nagel S, Ringleb PA, Bendszus M, Möhlenbruch MA. Direct transfer to angio-suite versus computed tomography-transit in patients receiving mechanical thrombectomy: a randomized trial.Stroke. 2020; 51:2630–2638. doi: 10.1161/STROKEAHA.120.029905LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Potreck A, Falbesaner A, Seker F, Weyland C, Mundiyanapurath S, Heiland S, Bendszus M and Pfaff J (2021) Accuracy and reliability of PBV ASPECTS, CBV ASPECTS and NCCT ASPECTS in acute ischaemic stroke: a matched-pair analysis, The Neuroradiology Journal, 10.1177/19714009211015771, 34:6, (585-592), Online publication date: 1-Dec-2021. January 2021Vol 52, Issue 1Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.120.032798PMID: 33370179 Originally publishedDecember 28, 2020 PDF download Advertisement SubjectsIschemic Stroke

Who may benefit from lower dosages of intravenous tissue plasminogen activator? Results from a cluster data analysis

BackgroundThe risk of symptomatic intracranial haemorrhage (sICH) after thrombolysis is low but severe. Lower dose of alteplase may reduce the risk of sICH. We aim to identify subsets of patients...

SUDDEN CARDIAC DEATH AND THE PECULIAR COVID-19 CASE

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: The COVID-19 pandemic has left the medical community floundering for answers as patients present with a variety of symptoms, at different stages of the infection. As the outbreak spread, the public was made aware of the range of symptoms associated with SARS-COV-2. Respiratory symptoms of dry cough and shortness of breath, Gastrointestinal symptoms such as nausea, vomiting, and even more vague signs such as Anosmia have been observed. Our case further highlights the devastating outcomes and the multi systemic involvement, the difficulty of false-negative testing on these patients, the associated hyper-coagulability causing multi-organ dysfunction. CASE PRESENTATION: Healthy 32-year-old gentleman presented with nausea, non-bloody emesis, epigastric pain, and poor oral intake of 6 days duration. Patient also reported shortness of breath and cough productive of yellow sputum for the past 2 day. He denied any sick contacts and initial real-time PCR COVID testing in ED was negative. On admission, patient was comfortable on room air, with tachycardia. lab findings significant for elevated lactate, Procalcitonin, and LFTs. CT abdomen w/o contrast revealed bilateral pleural effusions and ground glass opacities. Upon transfer to medical floors, rapid response was called for hypotension. Initially, patient was alert, oriented, and in no acute distress. Shortly thereafter, he began to gasp for air and complain of chest pain. pulse-oximetry decreased to 75% and patient became unresponsive, without a pulse. Cardiopulmonary resuscitation was initiated promptly per ACLS protocol. reversible causes including tension pneumothorax, cardiac tamponade, and electrolyte/metabolic disturbances were ruled out. The course of illness and clinical features were highly suggestive of acute massive pulmonary embolism, and intravenous TPA was administered. Thrombectomy was considered, however it was determined that it would not change the outcome. After 64 minutes of resuscitation and 21 doses of epinephrine, the efforts came to a halt and patient was pronounced dead. A repeat swab for COVID-19 was taken and later reported as positive. DISCUSSION: This puzzling case displays a rapid deterioration of a COVID-19 related complication. The infection creates a diagnostic dilemma due to the myriad of associated symptoms and multi-system involvement as well as the False-negative testing which may alter the course of management and admission criteria. Hypercoagulability triad is seen with lack of mobility, systemic inflammatory response, and endothelial invasion by SARS-CoV-2 causing endothelial damage. This phenomena may be the underlying cause of the systemic involvement. CONCLUSIONS: Although COVID-19 infection is widely viewed as a respiratory infection, it's crucial to recognize the multi-systemic involvement and array of symptoms. Reliable testing may possibly alter medical management, improve outcome, and reduce exposure. Reference #1: Magro C. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Translational research : the journal of laboratory and clinical medicine. 04/2020. Doi 10.1016/j.trsl.2020.04.007. Reference #2: Panigada M. Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis. Journal of thrombosis and haemostasis. 04/2020. doi: 10.1111/jth.14850. DISCLOSURES: No relevant relationships by Padmini Giri, source=Web Response No relevant relationships by Verisha Khanam, source=Web Response No relevant relationships by Sarwan Kumar, source=Web Response No relevant relationships by DANYAL TAHERI ABKOUH, source=Web Response No relevant relationships by Jurgena Tusha, source=Web Response

Impact of Initial Imaging Protocol on Likelihood of Endovascular Stroke Therapy.

Noncontrast head CT and CT perfusion (CTP) are both used to screen for endovascular stroke therapy (EST), but the impact of imaging strategy on likelihood of EST is undetermined. Here, we examine the influence of CTP utilization on likelihood of EST in patients with large vessel occlusion (LVO). We identified patients with acute ischemic stroke at 4 comprehensive stroke centers. All 4 hospitals had 24/7 CTP and EST capability and were covered by a single physician group (Neurology, NeuroIntervention, NeuroICU). All centers performed noncontrast head CT and CT angiography in the initial evaluation. One center also performed CTP routinely with high CTP utilization (CTP-H), and the others performed CTP optionally with lower utilization (CTP-L). Primary outcome was likelihood of EST. Multivariable logistic regression was used to determine whether facility type (CTP-H versus CTP-L) was associated with EST adjusting for age, prestroke mRS, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, LVO location, time window, and intravenous tPA (tissue-type plasminogen activator). Among 3107 patients with acute ischemic stroke, 715 had LVO, of which 403 (56%) presented to CTP-H and 312 (44%) presented to CTP-L. CTP utilization among LVO patients was greater at CTP-H centers (72% versus 18%, CTP-H versus CTP-L, P<0.01). In univariable analysis, EST rates for patients with LVO were similar between CTP-H versus CTP-L (46% versus 49%). In multivariable analysis, patients with LVO were less likely to undergo EST at CTP-H (odds ratio, 0.59 [0.41-0.85]). This finding was maintained in multiple patient subsets including late time window, anterior circulation LVO, and direct presentation patients. Ninety-day functional independence (odds ratio, 1.04 [0.70-1.54]) was not different, nor were rates of post-EST PH-2 hemorrhage (1% versus 1%). We identified an increased likelihood for undergoing EST in centers with lower CTP utilization, which was not associated with worse clinical outcomes or increased hemorrhage. These findings suggest under-treatment bias with routine CTP.

Intravenous thrombolysis in the elderly is facilitated by a tele-stroke network: A cross-sectional study

BackgroundData suggest that elderly patients have less favorable outcomes after ischemic stroke. ObjectiveTo study the outcomes after intravenous tissue plasminogen activator (tPA) administration in elderly patients with acute ischemic stroke. MethodsCross-sectional study using prospective collected patient data maintained via our “tele-stroke” network, which provides acute care in 29 community hospitals within our region from 2013−2015. Exposure of interest was age divided into >80 years (octogenarian) or younger. Outcomes of interest were rate of intravenous tPA administration, hemorrhagic transformation (ICH), in-hospital neurological deterioration, and poor outcome defined as a composite of hospital discharge to long-term care facility or death. ResultsMean age 67 ± 16 years, 57 % (743/1317) were women, and median (Md) NIHSS was 4 (Interquartile Range [IQR] 8). The rate of tPA was 20 % (267/1317). Compared to reported rates of tPA administration in the nation, our tPA rate exceeded the one from the literature (20 % v 3%, z = 2.83, SE = 0.04, p = .005). There were no differences in ICH or neurological deterioration. The octogenarian group had a higher proportion of poor-outcome (61 % vs. 23 %, p < 0.001) than the younger group but similar in-hospital case-fatality (25 % v 14 %, p = 0.09). Predictors of poor-outcome were age >80 (OR 4.9; CI, 2.0–12, p < .001) and α−NIHSS>9. (OR 8.7; CI, 3.5–20, p < .001). ConclusionOur data suggest that in our “tele-stroke” network, rates of tPA administration are higher than those reported in the literature and that this rate was not different in octogenarians compared to younger patients. Octogenarians were not at risk for ICH or neurological deterioration after tPA administration. However, octogenarians had a higher risk of poor outcome.

Risk of Distal Embolization From tPA (Tissue-Type Plasminogen Activator) Administration Prior to Endovascular Stroke Treatment.

In large artery occlusion stroke, both intravenous (IV) tPA (tissue-type plasminogen activator) and endovascular stroke treatment (EST) are standard-of-care. It is unknown how often tPA causes distal embolization, in which a procedurally accessible large artery occlusion is converted to a more distal and potentially inaccessible occlusion. We analyzed data from a decentralized stroke telemedicine program in an integrated healthcare delivery system covering 21 hospitals, with 2 high-volume EST centers. We captured all cases sent for EST and examined the relationship between IV tPA administration and the rate of distal embolization, the rate of target recanalization (modified Treatment in Cerebral Infarction scale 2b/3), clinical improvement before EST, and short-term and long-term clinical outcomes. Distal embolization before EST was quite common (63/314 [20.1%]) and occurred more often after IV tPA before EST (57/229 [24.9%]) than among those not receiving IV tPA (6/85 [7.1%]; P<0.001). Distal embolization was associated with an inability to attempt EST: after distal embolization, 26/63 (41.3%) could not have attempted EST because of the new clot location, while in cases without distal embolization, only 8/249 (3.2%) were unable to have attempted EST (P<0.001). Among patients who received IV tPA, 13/242 (5.4%) had sufficient symptom improvement that a catheter angiogram was not performed; 6/342 (2.5%) had improvement to within 2 points of their baseline NIHSS. At catheter angiogram, 2/229 (0.9%) of patients who had received tPA had complete recanalization without distal embolization. Both IV tPA and EST recanalization were associated with improved long-term outcome. IV tPA administration before EST for large artery occlusion is associated with distal embolization, which in turn may reduce the chance that EST can be attempted and recanalization achieved. At the same time, some IV tPA-treated patients show symptomatic improvement and complete recanalization. Because IV tPA is associated with both distal embolization and improved long-term clinical outcome, there is a need for prospective clinical trials testing the net benefit or harm of IV tPA before EST.

In-Hospital Delays for Acute Stroke Treatment Delivery During the COVID-19 Pandemic.

We investigated the impact of regionally imposed social and healthcare restrictions due to coronavirus disease 2019 (COVID-19) to the time metrics in the management of acute ischemic stroke patients admitted at the regional stroke referral site for Central South Ontario, Canada. We compared relevant time metrics between patients with acute ischemic stroke receiving intravenous tissue plasminogen activator (tPA) and/or endovascular thrombectomy (EVT) before and after the declared restrictions and state of emergency imposed in our region (March 17, 2020). We identified a significant increase in the median door-to-CT times for patients receiving intravenous tPA (19 min, interquartile range (IQR): 14-27 min vs. 13 min, IQR: 9-17 min, p = 0.008) and/or EVT (20 min, IQR: 15-33 min vs. 11 min, IQR: 5-20 min, p = 0.035) after the start of social and healthcare restrictions in our region compared to the previous 12 months. For patients receiving intravenous tPA treatment, we also found a significant increase (p = 0.005) in the median door-to-needle time (61 min, IQR: 46-72 min vs. 37 min, IQR: 30-50 min). No delays in the time from symptom onset to hospital presentation were uncovered for patients receiving tPA and/or endovascular reperfusion treatments in the first 1.5 months after the establishment of regional and institutional restrictions due to the COVID-19 pandemic. We detected an increase in our institutional time to treatment metrics for acute ischemic stroke patients receiving tPA and/or endovascular reperfusion therapies, related to delays from hospital presentation to the acquisition of cranial CT imaging for both tPA- and EVT-treated patients, and an added delay to treatment with tPA.

Intravenous tPA for Acute Ischemic Stroke in Patients with COVID-19

Background/Purpose: Coronavirus disease 2019 (COVID-19) is associated with increased risk of acute ischemic stroke (AIS), however, there is a paucity of data regarding outcomes after administration of intravenous tissue plasminogen activator (IV tPA) for stroke in patients with COVID-19.Methods: We present a multicenter case series from 9 centers in the United States of patients with acute neurological deficits consistent with AIS and COVID-19 who were treated with IV tPA.Results: We identified 13 patients (mean age 62 (±9.8) years, 9 (69.2%) male). All received IV tPA and 3 cases also underwent mechanical thrombectomy. All patients had systemic symptoms consistent with COVID-19 at the time of admission: fever (5 patients), cough (7 patients), and dyspnea (8 patients). The median admission NIH stroke scale (NIHSS) score was 14.5 (range 3–26) and most patients (61.5%) improved at follow up (median NIHSS score 7.5, range 0–25). No systemic or symptomatic intracranial hemorrhages were seen. Stroke mechanisms included cardioembolic (3 patients), large artery atherosclerosis (2 patients), small vessel disease (1 patient), embolic stroke of undetermined source (3 patients), and cryptogenic with incomplete investigation (1 patient). Three patients were determined to have transient ischemic attacks or aborted strokes. Two out of 12 (16.6%) patients had elevated fibrinogen levels on admission (mean 262.2 ± 87.5 mg/dl), and 7 out of 11 (63.6%) patients had an elevated D-dimer level (mean 4284.6 ±3368.9 ng/ml).Conclusions: IV tPA may be safe and efficacious in COVID-19, but larger studies are needed to validate these results.

When Telestroke Programs Work, Hospital Size Really Does Not Matter.

Background There are still marked disparities in stroke care between rural and urban communities including difference in stroke-related mortality. We analyzed the efficiency of tissue plasminogen activator (tPA) delivery in the spoke sites in our telestroke network to assess impact of telecare in bridging these disparities. Methods We analyzed critical time targets in our telestroke network. These included door-to-needle (DTN) time, door-to-CT (D2CT) time, door-to-call center, door-to-neurocall, and total consult time. We compared these time targets between the larger and smaller spoke hospitals. Results Across all the 52 spokes sites, a total of 825 stroke consults received intravenous tPA. When compared with larger hospitals (>200 beds), the smaller hospital groups with 0 to 25 and 51 to 100 beds had significantly lower D2CT time ( p -value 0.01 and 0.005, respectively) and the ones with 26 to 50 and 151 to 200 beds had significantly lower consult time ( p -value 0.009 and 0.001, respectively). There was no significant difference in the overall DTN time when all the smaller hospital groups were compared with larger hospitals. Conclusion In our telestroke network, DTN times were not significantly affected by the hospital bed size. This shows that a protocol-driven telestroke network with frequent mock codes can ensure timely administration of tPA even in rural communities regardless of the hospital size and availability of local neurologists.

Association Between Thrombolytic Door-to-Needle Time and 1-Year Mortality and Readmission in Patients With Acute Ischemic Stroke

Earlier administration of intravenous tissue plasminogen activator (tPA) in acute ischemic stroke is associated with reduced mortality by the time of hospital discharge and better functional outcomes at 3 months. However, it remains unclear whether shorter door-to-needle times translate into better long-term outcomes. To examine whether shorter door-to-needle times with intravenous tPA for acute ischemic stroke are associated with improved long-term outcomes. This retrospective cohort study included Medicare beneficiaries aged 65 years or older who were treated for acute ischemic stroke with intravenous tPA within 4.5 hours from the time they were last known to be well at Get With The Guidelines-Stroke participating hospitals between January 1, 2006, and December 31, 2016, with 1-year follow-up through December 31, 2017. Door-to-needle times for intravenous tPA. The primary outcomes were 1-year all-cause mortality, all-cause readmission, and the composite of all-cause mortality or readmission. Among the 61 426 patients treated with tPA within 4.5 hours, the median age was 80 years and 43.5% were male. The median door-to-needle time was 65 minutes (interquartile range, 49-88 minutes). The 48 666 patients (79.2%) who were treated with tPA and had door-to-needle times of longer than 45 minutes, compared with those treated within 45 minutes, had significantly higher all-cause mortality (35.0% vs 30.8%, respectively; adjusted HR, 1.13 [95% CI, 1.09-1.18]), higher all-cause readmission (40.8% vs 38.4%; adjusted HR, 1.08 [95% CI, 1.05-1.12]), and higher all-cause mortality or readmission (56.0% vs 52.1%; adjusted HR, 1.09 [95% CI, 1.06-1.12]). The 34 367 patients (55.9%) who were treated with tPA and had door-to-needle times of longer than 60 minutes, compared with those treated within 60 minutes, had significantly higher all-cause mortality (35.8% vs 32.1%, respectively; adjusted hazard ratio [HR], 1.11 [95% CI, 1.07-1.14]), higher all-cause readmission (41.3% vs 39.1%; adjusted HR, 1.07 [95% CI, 1.04-1.10]), and higher all-cause mortality or readmission (56.8% vs 53.1%; adjusted HR, 1.08 [95% CI, 1.05-1.10]). Every 15-minute increase in door-to-needle times was significantly associated with higher all-cause mortality (adjusted HR, 1.04 [95% CI, 1.02-1.05]) within 90 minutes after hospital arrival, but not after 90 minutes (adjusted HR, 1.01 [95% CI, 0.99-1.03]), higher all-cause readmission (adjusted HR, 1.02; 95% CI, 1.01-1.03), and higher all-cause mortality or readmission (adjusted HR, 1.02 [95% CI, 1.01-1.03]). Among patients aged 65 years or older with acute ischemic stroke who were treated with tissue plasminogen activator, shorter door-to-needle times were associated with lower all-cause mortality and lower all-cause readmission at 1 year. These findings support efforts to shorten time to thrombolytic therapy.

A murine photothrombotic stroke model with an increased fibrin content and improved responses to tPA-lytic treatment

The Rose Bengal (RB) dye-based photothrombotic stroke (PTS) model has many methodological advantages including consistent location and size of infarct, low mortality, and relatively simple surgical procedures. However, the standard PTS has the caveat of poor responses to tissue-type plasminogen activator (tPA)-mediated lytic treatment, likely as a result of the platelet-rich, fibrin-poor content of the blood clots. Here we tested whether the admixture of thrombin (80 U/kg) and RB dye (50 mg/kg) in the proximal middle cerebral artery (MCA)-targeted PTS will modify the clot composition and elevate the responsiveness to tPA-lytic treatment (Alteplase, 10 mg/kg). Indeed, intravital imaging, immunostaining, and immunoblot analyses showed less-compacted platelet aggregates with a higher fibrin content in the modified thrombin (T) plus RB photothrombotic stroke (T+RB-PTS) model compared with the standard RB-PTS-induced clots. Both RB-PTS and T+RB-PTS showed steady recovery of cerebral blood flow (CBF) in the ischemic border from 1 day after infarction, but without recanalization of the proximal MCA branch. Intravital imaging showed high potency of restoring the blood flow by tPA after single vessel-targeted T+RB-PTS. Further, although intravenous tPA failed to restore CBF or attenuate infarction in RB-PTS, it conferred 25% recovery of CBF and 55% reduction of the infarct size in T+RB-PTS (P < .05) if tPA was administered within 2 hours postphotoactivation. These results suggest that T+RB-PTS produces mixed platelet:fibrin clots closer to the clinical thrombus composition and enhanced the sensitivity to tPA-lytic treatment. As such, the modified photothrombosis may be a useful tool to develop more effective thrombolytic therapies of cerebral ischemia.

Mobile stroke units: taking stroke care to the patient.

Since the development of intravenous tissue plasminogen activator (tPA) for acute ischemic stroke (AIS), functional outcome has improved when treatment occurs within 4.5 h of stroke onset and treatment benefits are greater with earlier treatment. Endovascular revascularization also is better the sooner it is delivered. The Get with the Guidelines Stroke registry found that less than one-third of treatment-eligible AIS patients receive intravenous tPA within 60 min of hospital arrival. Initiatives have tried to improve public education and awareness of stroke symptoms to decrease time to presentation. The mobile stroke unit (MSU) facilitates earlier computed tomography scans, delivery of tPA, proper triage and on-scene goal-directed care. MSUs reduce time from stroke alarm to treatment by 25-40 min and increase the rate of intravenous tPA use without an increase in hemorrhage risk. In addition, three-month favorable outcome is increased. MSUs likely will evolve further and be used for other acute neurologic disorders, help triage patients for endovascular therapy, and be incorporated into systems of care in remote areas. Further studies are awaited to fully understand the overall medical and health-economic benefit of MSUs.

Antiplatelet therapy within 24 hours of tPA: lessons learned from patients requiring combined thrombectomy and stenting for acute ischemic stroke

ObjectiveAlthough stroke guidelines recommend antiplatelets be started 24 hours after tissue plasminogen activator (tPA), select mechanical thrombectomy (MT) patients with luminal irregularities or underlying intracranial atherosclerotic disease may benefit from earlier antiplatelet administration.MethodsWe explore the safety of early (<24 hours) post-tPA antiplatelet use by retrospectively reviewing patients who underwent MT and stent placement for acute ischemic stroke from June 2015 to April 2018 at our institution.ResultsSix patients met inclusion criteria. Median presenting and pre-operative National Institutes of Health Stroke Scale scores were 14 (Interquartile Range [IQR] 5.5–17.3) and 16 (IQR 13.7–18.7), respectively. Five patients received standard intravenous (IV) tPA and one patient received intra-arterial tPA. Median time from symptom onset to IV tPA was 120 min (IQR 78–204 min). Median time between tPA and antiplatelet administration was 4.9 hours (IQR 3.0–6.7 hours). Clots were successfully removed from the internal carotid artery (ICA) or middle cerebral artery (MCA) in 5 patients, the anterior cerebral artery (ACA) in one patient, and the vertebrobasilar junction in one patient. All patients underwent MT before stenting and achieved thrombolysis in cerebral infarction 2B recanalization. Stents were placed in the ICA (n=4), common carotid artery (n=1), and basilar artery (n=1). The median time from stroke onset to endovascular access was 185 min (IQR 136–417 min). No patients experienced symptomatic post-procedure intracranial hemorrhage (ICH). Median modified Rankin Scale score on discharge was 3.5.ConclusionsAntiplatelets within 24 hours of tPA did not result in symptomatic ICH in this series. The safety and efficacy of early antiplatelet administration after tPA in select patients following mechanical thrombectomy warrants further study.

Tissue Plasminogen Activator Promotes TXNIP-NLRP3 Inflammasome Activation after Hyperglycemic Stroke in Mice

Hyperglycemia has been shown to counterbalance the beneficial effects of tissue plasminogen activator (tPA) and increase the risk of intracerebral hemorrhage in ischemic stroke. Thioredoxin interacting protein (TXNIP) mediates hyperglycemia-induced oxidative damage and inflammation in the brain and reduces cerebral glucose uptake/utilization. We have recently reported that TXNIP-induced NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation contributes to neuronal damage after ischemic stroke. Here, we tested the hypothesis that tPA induces TXNIP-NLRP3 inflammasome activation after ischemic stroke, in hyperglycemic mice. Acute hyperglycemia was induced in mice by intraperitoneal (IP) administration of a 20% glucose solution. This was followed by transient middle cerebral artery occlusion (t-MCAO), with or without intravenous (IV) tPA administered at reperfusion. The IV-tPA exacerbated hyperglycemia-induced neurological deficits, ipsilateral edema and hemorrhagic transformation, and accentuated peroxisome proliferator activated receptor-γ (PPAR-γ) upregulation and TXNIP/NLRP3 inflammasome activation after ischemic stroke. Higher expression of TXNIP in hyperglycemic t-MCAO animals augmented glucose transporter 1 (GLUT-1) downregulation and increased vascular endothelial growth factor-A (VEGF-A) expression/matrix metallopeptidase 9 (MMP-9) signaling, all of which result in blood brain barrier (BBB) disruption and increased permeability to endogenous immunoglobulin G (IgG). It was also associated with a discernible buildup of nitrotyrosine and accumulation of dysfunctional tight junction proteins: zonula occludens-1 (ZO-1), occludin and claudin-5. Moreover, tPA administration triggered activation of high mobility group box protein 1 (HMGB-1), nuclear factor kappa B (NF-κB), and tumor necrosis factor-α (TNF-α) expression in the ischemic penumbra of hyperglycemic animals. All of these observations suggest a powerful role for TXNIP-NLRP3 inflammasome activation in the tPA-induced toxicity seen with hyperglycemic stroke.