Intra-arterial rt-PA Research Articles

Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke.

Background Thrombolysis and endovascular thrombectomy are the primary treatment for ischemic stroke. However, due to the limited time window and the occurrence of adverse effects, only a small number of patients can genuinely benefit from recanalization. Intraarterial injection of rtPA (recombinant tissue plasminogen activator) based on arterial thrombectomy could improve the prognosis of patients with acute ischemic stroke, but it could not reduce the incidence of recanalization-related adverse effects. Recently, selective brain hypothermia has been shown to offer neuroprotection against stroke. To enhance the recanalization rate of ischemic stroke and reduce the adverse effects such as tiny thrombosis, brain edema, and hemorrhage, we described for the first time a combined approach of hypothermia and thrombolysis via intraarterial hypothermic rtPA. Methods and Results We initially established the optimal regimen of hypothermic rtPA in adult rats subjected to middle cerebral artery occlusion. Subsequently, we explored the mechanism of action mediating hypothermic rtPA by probing reduction of brain tissue temperature, attenuation of blood-brain barrier damage, and sequestration of inflammation coupled with untargeted metabolomics. Hypothermic rtPA improved neurological scores and reduced infarct volume, while limiting hemorrhagic transformation in middle cerebral artery occlusion rats. These therapeutic outcomes of hypothermic rtPA were accompanied by reduced brain temperature, glucose metabolism, and blood-brain barrier damage. A unique metabolomic profile emerged in hypothermic rtPA-treated middle cerebral artery occlusion rats characterized by downregulated markers for energy metabolism and inflammation. Conclusions The innovative use of hypothermic rtPA enhances their combined, as opposed to stand-alone, neuroprotective effects, while reducing hemorrhagic transformation in ischemic stroke.

Cerebral Venous Oxygen Saturation in Hypoperfusion Regions May Become a New Imaging Indicator to Predict the Clinical Outcome of Stroke.

To automatically and quantitatively evaluate the venous oxygen saturation (SvO2) in cerebral ischemic tissues and explore its value in predicting prognosis. A retrospective study was conducted on 48 AIS patients hospitalized in our hospital from 2015–2018. Based on quantitative susceptibility mapping and perfusion-weighted imaging, this paper measured the cerebral SvO2 in hypoperfusion tissues and its change after intraarterial rt-PA treatment. The cerebral SvO2 in different hypoperfusion regions between the favorable and unfavorable clinical outcome groups was analyzed using an independent t-test. Relationships between cerebral SvO2 and clinical scores were determined using the Pearson correlation coefficient. The receiver operating characteristic process was conducted to evaluate the accuracy of cerebral SvO2 in predicting unfavorable clinical outcomes. Cerebral SvO2 in hypoperfusion (Tmax > 4 and 6 s) was significantly different between the two groups at follow-up (p < 0.05). Cerebral SvO2 and its changes before and after treatment were negatively correlated with clinical scores. The positive predictive value, negative predictive value, accuracy, and area under the curve of the cerebral SvO2 were higher than those predicted by the ischemic core. Therefore, the cerebral SvO2 of hypoperfusion regions was a stronger imaging predictor of unfavorable clinical outcomes after stroke.

Safety and Outcome of Intravenous Recombinant Tissue Plasminogen Activator (rt-PA) in the Nursing Home Residents Following an Acute Ischemic Stroke

Background and Purpose: Intravenous recombinant tissue plasminogen activator (IV rt-PA) is an effective treatment of acute ischemic stroke. The safety and efficacy of IV rt-PA were extensively studied in adults, including both octogenarians and nonagenarians.This study provides safety outcome of exclusive nursing home (NH) residents (dependent on activities of daily living [ADLs]) , who received IV rt-PA. Not much literature or studies are available exclusively on the NH residents. Aim: To assess the safety and outcome of IV rt-PA in patients from NHs who were admitted to our university-based tertiary care hospital, using data from a prospective stroke registry. Methods: Our study is a retrospective review of patients living in nursing facilities, admitted to our neuroscience intensive care unit after receiving IV rt-PA, from January 2010 to June 2018. We reviewed the clinical symptoms, comorbid conditions, medications, diagnostic evaluation, complications, and functional outcomes. The functional outcome was assessed based on the modified Rankin Scale (mRS) at the time of discharge, and 1- and 3-month follow-up. Results: Twenty-eight NH residents (20 [71.4%] were female with a mean age of 80.96 +/− 12.43 years) were identified who had received IV rt-PA for symptoms of acute ischemic stroke. The median mRS on admission was 3, and all of them were dependent on ADL. Twenty-seven (96.5%) patients were treated within the window (≤3 h) for IV rt-PA. There were no IV rt-PA-related violations from both our hospital and outside hospital treatment protocols. The initial computed tomographic (CT) scan of 8 (28.5%) patients revealed evidence of infarction. CT angiogram of head and neck revealed an acute intracranial blood vessel occlusion in 13 (46.4%) patients, and asymptomatic stenosis of intracranial and extracranial blood vessels in 4 (14.2%) patients. Mechanical thrombectomy was attempted in 6 (21.4%) patients and among them, the procedure was unsuccessful in 2 (7.1%) patients due to severe stenosis. One (1/21; 16.6%) patient received an intra-arterial rt-PA, and 5 (5/6;83.3%) patients developed symptomatic intracranial hemorrhage within 24 h following the procedure. Families of 9/28 (32.1%) patients decided to withdraw care. The median mRS on 30 and 90 days follow-up was 4 (interquartile range: 3-6). Conclusion: In this population, mechanical thrombectomy has a high risk for hemorrhagic conversion. IV rt-PA treatment in the NH residents may not improve the outcome of ischemic stroke.

Intra-Arterial Thrombolysis after Unsuccessful Mechanical Thrombectomy in the STRATIS Registry.

Recent data suggest that intra-arterial thrombolytics may be a safe rescue therapy for patients with acute ischemic stroke after unsuccessful mechanical thrombectomy; however, safety and efficacy remain unclear. Here, we evaluate the use of intra-arterial rtPA as a rescue therapy in the Systematic Evaluation of Patients Treated with Neurothrombectomy Devices for Acute Ischemic Stroke (STRATIS) registry. STRATIS was a prospective, multicenter, observational study of patients with acute ischemic stroke with large-vessel occlusions treated with the Solitaire stent retriever as the first-line therapy within 8 hours from symptom onset. Clinical and angiographic outcomes were compared in patients having rescue therapy treated with and without intra-arterial rtPA. Unsuccessful mechanical thrombectomy was defined as any use of rescue therapy. A total of 212/984 (21.5%) patients received rescue therapy, of which 83 (39.2%) and 129 (60.8%) were in the no intra-arterial rtPA and intra-arterial rtPA groups, respectively. Most occlusions were M1, with 43.4% in the no intra-arterial rtPA group and 55.0% in the intra-arterial rtPA group (P = .12). The median intra-arterial rtPA dose was 4 mg (interquartile range = 2-12 mg). A trend toward higher rates of substantial reperfusion (modified TICI ≥ 2b) (84.7% versus 73.0%, P = .08), good functional outcome (59.2% versus 46.6%, P = .10), and lower rates of mortality (13.3% versus 23.3%, P = .08) was seen in the intra-arterial rtPA cohort. Rates of symptomatic intracranial hemorrhage did not differ (0% versus 1.6%, P = .54). Use of intra-arterial rtPA as a rescue therapy after unsuccessful mechanical thrombectomy was not associated with an increased risk of symptomatic intracranial hemorrhage or mortality. Randomized clinical trials are needed to understand the safety and efficacy of intra-arterial thrombolysis as a rescue therapy after mechanical thrombectomy.

Abstract WP392: Intravenous Thrombolysis in Therapeutically Anticoagulated and Thrombocytopenic Ischemic Stroke Patients Does Not Increase Hemorrhage Rates

Introduction: IV rt-PA guidelines exclude therapeutically anticoagulated or thrombocytopenic patients. These exclusion criteria may limit thrombolytic therapy to patients who might benefit, especially with the increased use of novel oral anticoagulants (NOACs). The objective of this study is to determine if IV rt-PA is safe, especially in this patient population. Methods: Retrospective analysis of IV rt-PA treated patients receiving oral anticoagulation (warfarin (INR &gt; 1.7)), novel oral anticoagulant (NOAC), therapeutic heparin, low-molecular weight heparin (LMWH), or with thrombocytopenia (platelets &lt; 100K). Patients were treated using SMART criteria (consent obtained for off label rt-PA use). Safety was evaluated by symptomatic intracerebral hemorrhage (sICH) rate ≤36hr after treatment. Results: 81 patients were identified. 35 patients received therapeutic warfarin and 1 had coagulopathy (unclear etiology); mean INR=2.2 (range 1.7-3). 5 received therapeutic IV heparin, 6 full dose (1 mg/kg BID) LMWH, and 22 therapeutic NOACs. 12 had thrombocytopenia (mean platelet count 77K). There was a consistent increase in NOAC use in this cohort; 25% of the patients were taking NOACs from 2012-14, increasing to 71% from 2015-17. Out of all patients, 7 received intra-arterial (IA) rt-PA, and 8 thrombectomy. There were 3 sICH (3.75%), none in patients taking NOACs; for all sICHs there were mitigating factors that contributed (undiagnosed malignancy, adjunctive IA rt-PA, incorrect time of onset). Two developed hematoma at the catheter site with no clinical effect. Conclusions: These data suggest that IV rt-PA can be safely administered in therapeutically anticoagulated and thrombocytopenic patients, and sICH rates were similar to the NINDS cohort. The use of IV rt-PA in these patients may increase eligibility for acute stroke therapy, particularly where IA therapy is unavailable. Furthermore, preliminary results for patients taking NOACs indicate a good safety profile in this growing subpopulation.

Trombectomía mecánica: técnica de primera elección en el tratamiento ictus isquémico agudo. Análisis de beneficios y resultados

Esta revisión tiene como objetivo el uso de la Trombectomía Mecánica como técnica de primera elección en el tratamiento de Ictus Isquémico Agudo. Materiales y Método: La revisión incluye 9 pacientes con diagnóstico de Ictus Isquémico a los que se le realizo Trombectomía Mecánica, se utilizó el dispositivo de recanalización tipo Solitaire asociado a rtPA intraarterial 10% de la dosis intravenosa, los criterios diagnósticos: edad, período de ventana, imagen de TC al ingreso. Resultados: 8 pacientes (89%) correspondieron a oclusión de la circulación Anterior, 1 (11%) a la oclusión de circulación posterior, la efectividad terapéutica se la evalúo según la Escala de Rankin Modificada, 5 (55%) obtuvieron recuperación completa de sus funciones, 3 (33%) presentaron secuelas leves, y 1(11%) no obtuvo mejoría alguna. Discusión: Los resultados de nuestra revisión son alentadores sobre todo al reducir la secuela discapacitante, deja una ventana abierta para posteriores revisiones sobre este tratamiento.

Intraarterial Thrombolysis as Rescue Therapy for Large Vessel Occlusions.

Background and Purpose- Mechanical thrombectomy (MT) devices have led to improved reperfusion and clinical outcomes in acute ischemic stroke patients with emergent large vessel occlusions; however, less than one-third of patients achieve complete reperfusion. Use of intraarterial thrombolysis in the context of MT may provide an opportunity to enhance these results. Here, we evaluate the use of intraarterial rtPA (recombinant tissue-type plasminogen activator) as rescue therapy (RT) after failed MT in the North American Solitaire Stent-Retriever Acute Stroke registry. Methods- The North American Solitaire Stent-Retriever Acute Stroke registry recruited sites within North America to submit data on acute ischemic stroke patients treated with the Solitaire device. After restricting the population of 354 patients to use of RT and anterior emergent large vessel occlusions, we compared patients who were treated with and without intraarterial rtPA after failed MT. Results- A total of 37 and 44 patients was in the intraarterial rtPA RT and the no intraarterial rtPA RT groups, respectively. Revascularization success (modified Thrombolysis in Cerebral Infarction ≥2b) was achieved in more intraarterial rtPA RT patients (61.2% versus 46.6%; P=0.13) with faster times to recanalization (100±85 versus 164±235 minutes; P=0.36) but was not statistically significant. The rate of symptomatic intracranial hemorrhage (13.9% versus 6.8%; P=0.29) and mortality (42.9% versus 44.7%; P=0.87) were similar between the groups. Good functional outcome (modified Rankin Scale score of ≤2) was numerically higher in intraarterial rtPA patients (22.9% versus 18.4%; P=0.64). Further restriction of the RT population to M1 occlusions only and time of onset to groin puncture ≤8 hours, resulted in significantly higher successful revascularization rates in the intraarterial rtPA RT cohort (77.8% versus 38.9%; P=0.02). Conclusions- Intraarterial rtPA as RT demonstrated a similar safety and clinical outcome profile, with higher reperfusion rates achieved in patients with M1 occlusions. Prospective studies are needed to delineate the role of intraarterial thrombolysis in MT.

Adjuvant intra-arterial rt-PA injection at the initially deployed solitaire stent enhances the efficacy of mechanical thrombectomy in acute ischemic stroke

BackgroundBoth intra-arterial recombinant tissue plasminogen activator (rt-PA) and stent retrieval are effective for treating acute ischemic stroke. The goal of this study was to evaluate the effectiveness of stent retrieval combined with intra-arterial rt-PA administration via micro-catheter (called the complex technique) in acute ischemic stroke. Material and methodsA retrospective analysis was performed of 93 consecutive patients treated between 2015 and 2017 for occlusions of the intracranial large artery using the complex technique (n=37) or stent retrieval alone (n=56) in our stroke center. Data on procedure duration, number of passes, and angiographic findings were collected. Successful recanalization was defined as the accomplishment of grade 3 or 2b modified Treatment in Cerebral Ischemia recanalization in 1 or 2 passes. ResultsCompared to the stent retrieval group, complex technique group had a higher successful revascularization rate with 1 or 2 passes with the stent retriever (81.1% versus 51.8%, P=0.004), a shorter procedure time (59±34min versus 94±56min, P<0.001), fewer passes of the stent retriever (1.8±1.1 versus 2.5±1.4, P=0.012), a better prognosis (70.3% versus 48.2%, P=0.035), a lower embolic complication rate (18.9% versus 39.3%, P=0.038), similar mortality (13.5% versus 21.4%, P=0.334) and similar intracranial hemorrhage symptoms (2.7% versus 12.5%, P=0.204). Intra-arterial rt-PA administration was an independent negative predictor of procedure time (OR=−0.292, P=0.003). ConclusionMechanical thrombectomy utilizing stent retrieval combined with intra-arterial rt-PA administration in the anterior circulation of acute ischemic stroke patients improved the angiographic results and shortened the procedure duration without increasing adverse events.

Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors

Based on preclinical studies suggesting that recombinant tissue plasminogen activator (rt-PA) may promote ischemic brain injuries, we investigated in patients the possible risk of worse clinical outcome after rt-PA treatment as a result of its inability to resolve cerebral ischemia. Here, we designed a cohort study using a retrospective analysis of patients who received treatment with intravenous (4.5-h window) or intraarterial rt-PA, without or with thrombectomy. Controls were consecutive patients who did not receive recanalization treatment, who met all inclusion criteria. As a marker of reperfusion, we defined the variable of early neurological improvement as the difference between the score of the National Institute of Health Stroke Scale (NIHSS) (at admission and 24 h). The main variable was worsening of the patient’s functional situation in the first 3 months. To compare quantitative variables, we used Student’s t test or the Mann-Whitney test. To estimate the odds ratios of each independent variable in the patient’s worsening in the first 3 months, we used a logistic regression model. We included 1154 patients; 577 received rt-PA, and 577 served as controls. In the group of patients treated with rt-PA, 39.4% who did not present clinical reperfusion data developed worsening within 3 months after stroke compared with 3.5% of patients with reperfusion (P < 0.0001). These differences were not significant in the control group. In summary, administration of rt-PA intravenously or intraarterially without reperfusion within the first 24 h may be associated with a higher risk of functional deterioration in the first 3 months.

Sonothrombolysis

It has been shown that the significant reduction in disability after acute ischemic stroke (AIS) depends on early recanalization. Recombinant tissue plasminogen activator given within 3 hours improves disability by 30% in 3 months. However, still there are a great number of stroke patients who remained signifcantly disabled with this acute intervention. Currently, numerous strategies are being tested to increase further the recanalization rate in AIS. Sonothrombolysis or adding microsphere, intra-arterial rTPA and mechanical thrombectomy have been tried to increase the recanalization rate hence significant improvement has been reported. The simultaneous ultrasound delivery while administering rTPA known as Sonothrombolysis will be discussed in this lecture. A recently concluded randomized, placebo controlled sonothrombolysis study, the CLOTBUST trial has shown significant recanalization rate as its primary outcome measure. However, long-term disability did not show significant difference against placebo. Another non-significant RCT was carried out utilizing “hands-free” TCD device to deliver ultrasound during thrombolysis. Following these results from several trials; a meta-analysis has shown some signals favoring sonothrombolysis in acute ischemic stroke.

A New Proposal for Management of Severe Frostbite in the Austere Environment

Despite advances in outdoor clothing and medical management of frostbite, individuals still experience catastrophic amputations. This is a particular risk for those in austere environments, due to resource limitations and delayed definitive treatment. The emerging best therapies for severe frostbite are thrombolytics and iloprost. However, they must be started within 24 hours after rewarming for recombinant tissue plasminogen activator (rt-PA) and within 48 hours for iloprost. Evacuation of individuals experiencing frostbite from remote environments within 24 to 48 hours is often impossible. To date, use of these agents has been confined to hospitals, thus depriving most individuals in the austere environment of the best treatment. We propose that thrombolytics and iloprost be considered for field treatment to maximize chances for recovery and reduce amputations. Given the small but potentially serious risk of complications, rt-PA should only be used for grade 4 frostbite where amputation is inevitable, and within 24 hours of rewarming. Prostacyclin has less risk and can be used for grades 2 to 4 frostbite within 48 hours of rewarming. Until more field experience is reported with these agents, their use should probably be restricted to experienced physicians. Other modalities, such as local nerve blocks and improving oxygenation at high altitude may also be considered. We submit that it remains possible to improve frostbite outcomes despite delayed evacuation using resource-limited treatment strategies. We present 2 cases of frostbite treated with rt-PA at K2 basecamp to illustrate feasibility and important considerations.

Abstract WP437: Shear-activated Nanoparticle Aggregate Lysis Combined With Temporary Stent-bypass to Treat Emergent Large Vessel Occlusions (ELVO)

Introduction: Despite the high effectiveness of stent-retrievers in ELVO, half of the patients remained functionally dependent (mRS≥3) after 90-days. Beyond futile recanalizations, variable endoluminal damage caused by stent-retrievers may contribute to reperfusion injury, and recruit iniflammatory cell infiltration. The goal of this study was to assess a less traumatic endovascular approach in combination with a novel shear activated-nanotherapeutic (SA-NT) that releases r-tPA when exposed to high levels of hemodynamic stress. Hypothesis: SA-NT treatment coupled with temporary endovascular bypass provides high recanalization rates while reducing vascular injury. Methods: a rabbit carotid vessel occlusion model was used. We evaluated angiographic recanalization with stent-bypass alone, intra-arterial delivery of soluble r-tPA alone, or stent-bypass combined with two doses (2 and 20 mg r-tPA) of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy by assessing the level of damage on histology. Results: Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared to controls (p=0.0011). SA-NT (20mg) had a higher likelihood of obtaining complete recanalization (mTICI:3) as compared to stent-bypass alone (OR: 65.019,95%CI:[1.77,&gt;1000], p=0.0231), intra-arterial r-tPA alone (OR: 65.019, 95% CI [1.77,&gt;1000], p=0.0231), or stent-bypass with soluble r-tPA (2 mg) (OR: 18.78, 95%CI [1.28,275.05], p=0.0322) (Figure). Histologically, there was significantly less vascular injury using a stent-bypass as compared to stent-retriever procedure (OR 12.97, 95%CI [8.01,21.02], p&lt;0.0001). Conclusion: Nanoparticle-based thrombolytic therapy combined with stent-bypass achieves high rates of complete (mTICI:3) recanalization. This technology reduces vascular trauma as compared to stent-retriever thrombectomy

Abstract WP21: Primary Thrombectomy Within 3 Hours of Onset in Acute Ischemic Stroke From Large Artery Occlusion (PAST3-LAO)- A Pilot Study

Background: Based on recent trials, AIS due to large artery occlusion (LAO) is resistant to IV thrombolysis and adjunctive stent retriever thrombectomy (SRT) is associated with better recanalization rates and outcomes.Despite the benefit with endovascular therapy 39% to 68% of patients were either disabled or dead.Thrombectomy in AIS with LAO within 3 hours (IV t-PA window) is performed as secondary therapy after IV thrombolysis, which may be associated with delay in enrollment and recanalization. Objective: Primary objective is to evaluate the safety, feasibility and recanalization rate of primary SRT (without IV tPA) within 3 hours in AIS with NIHSS &gt;10 from LAO.Secondary objective is to determine the functional outcome in 30-days and 90-days. Methods: Based on institutionally approved protocol patients with LAO with LCB within 3 hours were offered primary SRT alone as an alternative to IV rtPA, after informed consent.Consecutive patients who underwent primary SRT for LAO within 3 hours from 2012 to 2014 were enrolled.Outcomes were measured using modified Rankin Scale. Results: 18 patients with LAO; mean age 62.8±15.3 years and mean NIHSS 16±5; chose primary SRT after informed consent.Thrombectomy was performed using new generation stent-retriever device in addition to small intra-arterial rtPA (2-10 mg).Number of passes was 1.6±0.9.Near complete (TICI2b in 1) and complete (TICI3 in 17) recanalization was observed in all (100%) patients.Mean time to recanalization from symptoms onset was 188.5±82.7 and from groin puncture was 64.61±40.14 minutes.Immediate post-thrombectomy, 24 hour and 30 day NIHSS score was 4.4±3.7, 1.9±3.2 and 0.3±0.9 respectively.There was no procedure related complication.Asymptomatic perfusion related hemorrhage developed in 6 patients (33%).30 days good outcome was observed in all cases (mRS0= 38.9%, mRS1=44.4%, mRS2=16.7%). 90 days good outcome was observed as follows (mRS0= 50.0%, mRS1=44.4%, mRS2=5.6%). Conclusion: Our pilot study demonstrates that primary SRT in AIS due LAO occlusion with LCB is not only safe and feasible, but associated with complete recanalization and good functional outcome.Larger randomized controlled studies are needed.

Shear-Activated Nanoparticle Aggregates Combined With Temporary Endovascular Bypass to Treat Large Vessel Occlusion.

The goal of this study is to combine temporary endovascular bypass (TEB) with a novel shear-activated nanotherapeutic (SA-NT) that releases recombinant tissue-type plasminogen activator (r-tPA) when exposed to high levels of hemodynamic stress and to determine if this approach can be used to concentrate r-tPA at occlusion sites based on high shear stresses created by stent placement. A rabbit model of carotid vessel occlusion was used to test the hypothesis that SA-NT treatment coupled with TEB provides high recanalization rates while reducing vascular injury. We evaluated angiographic recanalization with TEB alone, intra-arterial delivery of soluble r-tPA alone, or TEB combined with 2 doses of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy. Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared with controls (P=0.0011). SA-NT (20 mg) had a higher likelihood of obtaining complete recanalization as compared with TEB alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), intra-arterial r-tPA alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), or TEB with soluble r-tPA (2 mg; odds ratio 18.78, 95% confidence interval 1.28, 275.05; P=0.0322). Histological analysis showed circumferential loss of endothelium restricted to the area where the TEB was deployed; however, there was significantly less vascular injury using a TEB as compared with stent-retriever procedure (odds ratio 12.97, 95% confidence interval 8.01, 21.02; P<0.0001). A novel intra-arterial, nanoparticle-based thrombolytic therapy combined with TEB achieves high rates of complete recanalization. Moreover, this approach reduces vascular trauma as compared with stent-retriever thrombectomy.

Endovascular treatment of Stroke: Historical Perspective

Page e4 Effective acute ischemic stroke therapy hinges on rapid restoration of blood flow to the ischemic tissue. Since the National Institute of Neurological Diseases and Stroke r-tPA study,1 intravenous fibrinolytic therapy in appropriately selected patients has been the primary method used to open the vessels and improve neurological outcome from stroke. The intravenous administration allowed for widespread dissemination of the technique, since therapy could be started very rapidly after the diagnosis is made. However, successful treatment with r-tPA requires careful patient selection and adherence to strict inclusion and exclusion criteria. As a result, there is a significant number of patients who could not receive the therapy. Even though significantly better than placebo for most stroke patients, some still suffered a poor outcome in spite of therapy. This raised the question whether there could be a way to directly apply the fibrinolytic agent to the occlusive thrombus with catheter-based techniques in an effort to more effectively treat large vessel occlusions. Intra-arterial thrombolysis was reported helpful in restoring flow in relatively small series of patients, especially situations like basilar thrombosis, with a dire natural history.2 However, only one study, the PROACT study showed a positive impact on neurological outcome compared to placebo.3 Results of this study were often used to justify endovascular treatment of patients ineligible or unresponsive to intravenous r-tPA but intra-arterial administration of the fibrinolytic was often unsuccessful restoring flow in the occluded vessel, and not infrequently was associated with hemorrhagic transformation of the stroke. The endovascular armamentarium increased in the early years of the 21st century with the development of the MERCI device (Stryker, Fremont, CA, USA), a cork-screw-like device designed to mechanically retrieve thrombus.4,5 This resulted in a higher success rate in opening occluded vessels compared to pharmacological methods and could be used in patients in whom r-tPA is contraindicated. In the years that followed, additional mechanical thrombectomy devices were introduced including stent-like retrievers like the Solitaire (ev3-Medtronic, Irvine, CA, USA), and the Trevo (Stryker, Fremont, CA, USA), and the Penumbra aspiration system (Penumbra, San Leandro, CA, USA) which all appeared to be far more effective than Merci in opening occluded vessels. The IMS III study sought to provide evidence of the effectiveness of endovascular techniques plus intravenous r-tPA versus intravenous r-tPA alone, but it enrolled patients when these newer devices were just becoming available. Most endovascular patients were only treated with intra-arterial r-tPA and, not surprisingly, the study showed no benefit in outcome.6 This prompted some to predict the death of endovascular stroke therapy. A short time later, results of well-designed studies beginning with the MR CLEAN study7 appeared in rapid succession showing significantly improved outcome with endovascular treatment of large vessel occlusions using the modern stent-like retrievers.8-11 Within a short period of time, endovascular therapy went from being on the verge of extinction to being an integral part of comprehensive stroke care. The future will no doubt see investigations refining patient selection criteria, evaluating the role of advanced imaging techniques, evolving and improving the devices and techniques and improving infrastructure to allow all appropriate patients have access to these devices and the trained physicians that can use them safely and effectively.

Determinants of Intracranial Hemorrhage Occurrence and Outcome after Neurothrombectomy Therapy: Insights from the Solitaire FR With Intention For Thrombectomy Randomized Trial.

Intracranial hemorrhage is the most dreaded complication of neurothrombectomy therapy for acute ischemic stroke. The determinants of intracranial hemorrhage and its impact on clinical course remain incompletely delineated. The purpose of this study is to further investigate the clinical and procedural factors leading to intracranial hemorrhage and to define the clinical impact of different hemorrhagic subtypes. We analyzed data prospectively collected in the Solitaire FR With Intention for Thrombectomy randomized clinical trial. A multivariable logistic regression model was used to identify independent clinical, imaging, and procedural predictors of any intracranial hemorrhage and of 7 intracranial hemorrhage subtypes. Univariate analysis was used to determine the impact of each of the intracranial hemorrhage subtypes on clinical outcome. Among the 144 enrolled patients, any radiologic intracranial hemorrhage (21.3% versus 38.2%, P = .035), symptomatic intracranial hemorrhage (1.1% versus 10.9%, P = .012), and subarachnoid hemorrhage (2.2% versus 12.7%, P = .027) occurred less frequently in the Solitaire FR than in the Merci retriever arms. The most common independent determinant of hemorrhage occurrence was rescue therapy with intra-arterial rtPA, which was associated with any intracranial hemorrhage and 4 subtypes and tended to be used more frequently in the Merci group (10.9% versus 3.4%; P = .09). Among the hemorrhage subtypes, basal ganglionic hemorrhage had the strongest impact on good clinical outcome at 90 days (OR, 0.30; P = .025) and was associated with higher reperfusion, prolonged time to treatment, and rescue therapy with intra-arterial rtPA. Intracranial hemorrhage, especially subarachnoid and symptomatic intracerebral hemorrhage, occurs less frequently with the Solitaire FR than the Merci retriever, in part due to less frequent use of rescue therapy with intra-arterial rtPA. Basal ganglionic hemorrhage strongly affects clinical outcome and is distinctively related to late reperfusion.

Abstract T MP9: Primary Thrombectomy Within 3 Hours Of Onset In Acute Ischemic Stroke From Occlusion Of Middle Cerebral Artery- A Pilot Study

Background: Acute ischemic stroke (AIS) due to large artery occlusion (LAO) with high NIHSS (&gt;10), especially in internal carotid artery terminus (ICA-T) are resistant to IV thrombolysis and endovascular thrombectomy is associated with better recanalization rates. IV thrombolysis in large clot burden (&gt;8mm) (LCB) in the middle cerebral artery (MCA) is associated with poor recanalization and may impact outcome. However, thrombectomy in AIS with LAO within 3 hours is performed as secondary therapy after IV thrombolysis. Objectives: To evaluate the feasibility, safety and recanalization rate of primary thrombectomy within 3 hours in AIS with NIHSS &gt;10 from occlusion of MCA with LCB. Additionally, we like to report the functional outcome. Methods: Based on institutionally approved protocol patients with LAO (ICA-T, MCA, vertebral-basilar artery) with LCB within 3 hours were offered primary thrombectomy as an alternative to IV rtPA. They were entered into a stroke database. Patients who underwent primary MCA thrombectomy within 3 hours from 2012 to 2014 were retrospectively analyzed using SAS software. Outcomes were measured using modified Rankin Scale (mRS).Results: 10 patients with MCA occlusion ;mean age 65±15.87 years and mean NIHSS 16±; chose primary thrombectomy after informed consent. Thrombectomy was performed using stent-retriever device in addition to intra-arterial rtPA (2-4 mg). Mean number of passes was 1.4±.7. Near complete (TICI2b) and complete (TICI3) recanalization was observed in all patients. Mean time to recanalization from symptoms onset was 160±37 minutes. Immediate post-thrombectomy, 24 hour and 30 day NIHSS score was 2.6±1.4, 1.9±3.7 and 0 respectively. There was no procedure related complication. Asymptomatic perfusion related hemorrhage developed in 3 patients. 30 day good outcome was observed in all cases (mRS0= 30%, mRS1=50%, mRS2=20%).Conclusion: Our pilot study demonstrates that primary thrombectomy in AIS due to MCA occlusion with LCB is not only feasible and safe, but associated with complete recanalization and good functional outcome. Larger randomized controlled studies are needed.

Experience of mechanical thrombectomy for paediatric arterial ischaemic stroke

BackgroundPaediatric arterial ischaemic stroke (AIS) is an important cause of acute neurological symptoms in children, it causes significant morbidity and is one of the top ten causes of childhood deaths. Consensus papers have suggested guidelines for the management of AIS in childhood, although none recommend thrombectomy. Despite this, children within our institution have undergone mechanical thrombectomy for large vessel occlusion. This is the first series of mechanical thrombectomy and outcomes performed in children in the UK. MethodsWe describe the endovascular management of paediatric arterial ischaemic stroke (AIS) in four children (5–15 years) with PedNIHSS > 17. ResultsThree had basilar artery (BA) occlusion and one left middle cerebral artery (MCA) occlusion. All underwent uncomplicated thrombectomy followed by intravenous heparin. One had a successful second attempt. The BA cases underwent thrombectomy 17–36 h after symptom onset; the left MCA case <6 h after symptom onset. Modified Rankin Scale (MRS) was 0–3, 50% had MRS 0. DiscussionAdult AIS guidelines recommend IV recombinant tissue plasminogen activator (r-tPA) within 4.5 h of onset and intra-arterial r-tPA within 6 h; thrombectomy being reserved for carefully selected patients. Paediatric AIS recognition is problematic, often with delayed imaging. There is little evidence regarding efficacy of thrombectomy for paediatric AIS. Our experience suggests there may be a role for endovascular clot retrieval in selected patients managed by an experienced multidisciplinary team. Careful data collection is mandatory.

The Smoking Paradox: Impact of Smoking on Recanalization in the Setting of Intra-Arterial Thrombolysis

Background: The smoking paradox refers to a better outcome in smokers eligible for thrombolytic treatment in myocardial infarction or ischemic stroke. Recent findings suggest that current smokers may present higher recanalization rates after intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rt-PA). We evaluated the impact of smoking in a consecutive series of patients treated with intra-arterial (IA) rt-PA. Methods: We analyzed data collected between April 2007 and December 2012 in our prospective registry. All acute ischemic stroke patients with an arterial occlusion treated by IA rt-PA (± IV, ± thrombectomy) were included. Arterial status was monitored with conventional angiography during the IA procedure. The primary study outcome was a complete recanalization achieved immediately after termination of IA rt-PA infusion. Secondary outcomes included complete recanalization after the end of the endovascular therapy (including complete recanalization achieved after adjunctive thrombectomy), favorable outcome (90-day modified Rankin Score ≤2), 90-day all-cause mortality, and any intracerebral hemorrhage. Results: Among the 227 included patients, 18.5% (n = 42) were current smokers and 16.7% (n = 38) former smokers. Compared with nonsmokers, current smokers were younger, more often men, had less frequently hypertension, and cardioembolic etiology, whereas former smokers were more often men and had more frequently hypercholesterolemia. The rate of complete recanalization was 30% (n = 68) after IA rt-PA infusion and 49% after adjunctive thrombectomy. A higher complete recanalization rate was found both in current smokers (45.2%) and former smokers (42.1%) compared to nonsmokers (22.5%). After adjustment for potential confounders, the adjusted odds ratio (OR) for complete recanalization associated with ever-smokers was 2.51 [95% confidence interval (CI) 1.26-4.99; p = 0.009]. A similar adjusted OR was found when the complete recanalization achieved after thrombectomy was included (OR 2.18, 95% CI 1.13-4.19; p = 0.019). However, smoking status was not independently associated with favorable outcome (adjusted OR 1.41, 95% CI 0.62-3.22 for former smokers, and adjusted OR 1.35, 95% CI 0.59-3.05 for current smokers), 90-day all-cause mortality (adjusted OR 0.68, 95% CI 0.25-1.81 for former smokers, and adjusted OR 1.55, 95% CI 0.54-4.48 for current smokers) or intracerebral hemorrhage (adjusted OR 0.72, 95% CI 0.29-1.76 for former smokers, and adjusted OR 0.80, 95% CI 0.32-1.96 for current smokers). Conclusions: IA rt-PA administration was more effective to achieve complete arterial recanalization in current as well as former smokers. The characterization of the smoking paradox pathophysiology may lead to the identification of a patient-target population with a favorable response to rt-PA therapy. However, the smoking paradox should not be misinterpreted and not be used to promote smoking.

Fibrinolytic agents for peripheral arterial occlusion

Peripheral arterial thrombolysis is used in the management of peripheral arterial ischaemia. Streptokinase was originally used but safety concerns led to a search for other agents. Urokinase and recombinant tissue plasminogen activator (rt-PA) have increasingly become established as first line agents for peripheral arterial thrombolysis. Potential advantages of these agents include improved safety, greater efficacy and a more rapid response. Recently drugs such as pro-urokinase, recombinant staphylokinase and alfimperase have been introduced. This is an update of a review first published in 2010. To determine which fibrinolytic agents are most effective in peripheral arterial ischaemia. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched March 2013) and CENTRAL (2013, Issue 3) for randomised controlled trials (RCTs) comparing fibrinolytic agents to treat peripheral arterial ischaemia. RCTs comparing fibrinolytic agents to treat peripheral arterial occlusion. Data were analysed for the outcomes vessel patency, time to lysis, limb salvage, amputation, death, complications including major haemorrhage, stroke, and distal embolization. Five RCTs involving a total of 687 participants with a range of clinical indications were included. No new studies were included in this update. In one three-pronged study, vessel patency was greater with intra-arterial recombinant tissue plasminogen activator (rt-PA) than with intra-arterial streptokinase (P < 0.04) or intravenous rt-PA (P < 0.01). In participants with peripheral arterial occlusion there was no statistically significant difference in limb salvage at 30 days with either urokinase or rt-PA, though this may reflect the small numbers in the studies. Incidences of haemorrhagic complications varied with fibrinolytic regime but there was no statistically significant difference between intra-arterial urokinase and intra-arterial rt-PA. In the three-pronged study intravenous rt-PA and intra-arterial streptokinase were associated with a significantly higher risk of haemorrhagic complications than with intra-arterial rt-PA (P < 0.05). There is some evidence to suggest that intra-arterial rt-PA is more effective than intra-arterial streptokinase or intravenous rt-PA in improving vessel patency in people with peripheral arterial occlusion. There was no evidence that rt-PA was more effective than urokinase for patients with peripheral arterial occlusion and some evidence that initial lysis may be more rapid with rt-PA, depending on the regime. Incidences of haemorrhagic complications were not statistically significantly greater with rt-PA than with other regimes. However, all of the findings come from small studies and a general paucity of results means that it is not possible to draw clear conclusions.