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    Usefulness of postischemic thrombolysis with or without neuroprotection in a focal embolic model of cerebral ischemia. Yang Y,Li Q,Miyashita H,Howlett W,Siddiqui M,Shuaib A Journal of neurosurgery OBJECT:Recent studies have shown that the use of thrombolysis in the setting of acute stroke is associated with an increased risk of cerebral hemorrhage. The time of onset of symptoms to initiation of medication and the dose levels of the thrombolytic agents are important determinants for the risk of cerebral hemorrhage. The authors evaluated the time course of thrombolysis-related hemorrhages in experimental settings and tested whether the addition of neuroprotective medication augments the efficacy of thrombolysis and reduces the incidence of hemorrhages. METHODS:Male Wistar rats were subjected to right middle cerebral artery embolization with an autologous thrombus and were then randomly assigned to one of the following groups: Group 1, saline-treated (2 hours after ischemic insult) animals as controls; Groups 2 to 4, high-dose urokinase (5,000 U/kg) at 2, 3, and 6 hours after the insult; Group 5, low-dose urokinase (2,500 U/kg) at 2 hours after the insult; Group 6, 20 mg/kg topiramate (TPM) at 2 hours after the insult; Group 7, a combination of 20 mg/kg TPM at 2 hours and low-dose urokinase (2,500 U/kg) at 6 hours after the insult; and Group 8, 20 mg/kg TPM (20 mg/kg) at 2 hours and high-dose urokinase (5,000 U/kg) at 2 hours after the insult. Neurological behavior and the infarct volume in the brain were assessed following cerebral embolism and the various treatments. All animals in the single therapy and low-dose combination groups survived surgery. Three of eight animals treated with high-dose urokinase alone at 6 hours and three of six animals in the combined high-dose urokinase and TPM group developed fatal intracerebral hemorrhages. There was a significantly better neurological outcome at 24 hours in the animals treated with either medication compared with controls. The volume of the infarct in the saline-treated group was 54.2 +/- 9%. The use of TPM at 2 hours led to a decrease in the infarct to 20.1 +/- 11.2% (p < 0.01). Treatment with urokinase at 6 hours after the occlusion showed a trend toward protection; the infarct volume was 31.9 +/- 14.1% (p < 0.05). The addition of TPM to low- or high-dose urokinase achieved better neuroprotection (8.2 +/- 6% and 11.9 +/- 10.7%, respectively; both p < 0.01). CONCLUSIONS:In this study the authors show that the volume of the infarct can be significantly decreased with 2 to 6-hour delayed intraarterial thrombolysis with urokinase and that the efficacy of thrombolysis may be enhanced by combining neuroprotective agents like TPM. It is also shown that low-dose combination therapy may decrease the likelihood of cerebral hemorrhage. 10.3171/jns.2000.92.5.0841
    Reteplase: a review of its use in the management of thrombotic occlusive disorders. Simpson Dene,Siddiqui M Asif A,Scott Lesley J,Hilleman Daniel E American journal of cardiovascular drugs : drugs, devices, and other interventions Reteplase (Retavase) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific). Reteplase can be administered as a bolus dose (nonweight-based) rather than an infusion, which promotes rapid and safe administration. The ease of administration of this reteplase dosage regimen (two 10U bolus doses, each over 2 minutes, 30 minutes apart) is conducive to prehospital initiation of thrombolytic treatment in patients with ST-segment elevation myocardial infarction (STEMI), which reduces the time to treatment, a critical factor in improving long-term survival. In large randomized clinical trials of patients with STEMI, reteplase was superior to alteplase for coronary artery patency (according to TIMI [thrombolysis in myocardial infarction] flow) at 60 and 90 minutes, but there was no significant difference between agents for mortality rate and incidence of intracranial bleeding. The 35-day mortality rates were equivalent for reteplase and streptokinase recipients; there was reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic stroke. Reteplase has also shown thrombolytic efficacy (in nonapproved indications) as a catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions, as 5-minute bolus doses (in 1U increments) for acute ischemic stroke, as a low-dose solution for occluded catheters or grafts, and as an intravenous double bolus for massive pulmonary embolism. Across studies in these indications, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other thrombolytic agents. With its efficacy, and the ease of administration of the bolus doses potentially minimizing dosage errors when treatment is administered under time pressure, reteplase is a valuable option for pre- or in-hospital thrombolytic treatment in patients with STEMI, and is a useful thrombolytic for the treatment of the other thrombotic occlusive disorders described. 10.2165/00129784-200606040-00007
    PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. del Zoppo G J,Higashida R T,Furlan A J,Pessin M S,Rowley H A,Gent M Stroke BACKGROUND AND PURPOSE:To test the safety and recanalization efficacy of intra-arterial local delivery of plasminogen activators in acute ischemic stroke, a randomized trial of recombinant pro-urokinase (rpro-UK) versus placebo was undertaken in patients with angiographically documented proximal middle cerebral artery occlusion. METHODS:After exclusion of intracranial hemorrhage by CT scan, patients with abrupt onset of symptoms of focal ischemia likely to receive treatment within 6 hours who satisfied all clinical eligibility criteria underwent carotid angiography. Patients displaying Thrombolysis in Acute Myocardial Infarction grade 0 or 1 occlusion of the M1 or M2 middle cerebral artery were randomized 2:1 to receive rpro-UK (6 mg) or placebo over 120 minutes into the proximal thrombus face. All patients received intravenous heparin. Recanalization efficacy was assessed at the end of the 2-hour infusion, and intracerebral hemorrhage causing neurological deterioration was assessed at 24 hours. RESULTS:Of 105 patients who underwent angiography, 59 were excluded from randomization. Among the 46 patients randomized, 40 were treated with rpro-UK (n=26) or placebo (n=14) a median of 5.5 hours from symptom onset. Recanalization was significantly associated with rpro-UK (2P=.017). Hemorrhagic transformation causing neurological deterioration within 24 hours of treatment occurred in 15.4% of the rpro-UK-treated patients and 7.1% of the placebo-treated patients (2P=.64). Both recanalization and hemorrhage frequencies were influenced by heparin dose. CONCLUSIONS:Intra-arterial local rpro-UK infusion was associated with superior recanalization in acute thrombotic/ thromboembolic stroke compared with placebo. In this regimen, heparin dose influenced hemorrhage frequency and recanalization. Although symptomatic hemorrhage remains a concern, this study suggests that recanalization is enhanced with rpro-UK and heparin.
    The Interventional Management of Stroke (IMS) II Study. Stroke BACKGROUND AND PURPOSE:The purpose of this study was to further investigate the feasibility and safety of a combined intravenous and intra-arterial approach to recanalization for ischemic stroke. METHODS:Subjects, ages 18 to 80, with a baseline NIHSS > or =10 had intravenous recombinant tissue plasminogen activator (rt-PA) started (0.6 mg/kg over 30 minutes) within 3 hours of onset. For subjects with an arterial occlusion at angiography, additional rt-PA was administered via the EKOS micro-infusion catheter or a standard microcatheter at the site of the thrombus up to a total dose of 22 mg over 2 hours of infusion or until thrombolysis. RESULTS:The 81 subjects had a median baseline NIHSS score of 19. The median time to initiation of intravenous rt-PA was 142 minutes as compared with 108 minutes for placebo and 90 minutes for rt-PA-treated subjects in the NINDS rt-PA Stroke Trial (P<0.0001). The 3-month mortality in IMS II subjects was 16% as compared with the mortality of placebo (24%) and rt-PA-treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of symptomatic intracerebral hemorrhage in IMS II subjects (9.9%) was not significantly different than that for rt-PA treated subjects in the NINDS t-PA Stroke Trial (6.6%). IMS II subjects had significantly better outcomes at 3 months than NINDS placebo-treated subjects for all end points (OR > or =2.7) and better outcomes than NINDS rt-PA-treated subjects as measured by the Barthel Index and Global Test Statistic. CONCLUSIONS:A randomized trial of standard intravenous rt-PA as compared with a combined intravenous and intra-arterial approach is warranted and has begun. 10.1161/STROKEAHA.107.483131
    Intravenous administration of a GPIIb/IIIa receptor antagonist extends the therapeutic window of intra-arterial tenecteplase-tissue plasminogen activator in a rat stroke model. Zhang Li,Zhang Zheng Gang,Zhang Chunling,Zhang Rui Lan,Chopp Michael Stroke BACKGROUND AND PURPOSE:Occlusion of the middle cerebral artery triggers platelet accumulation at the site of occlusion and in downstream microvessels. The platelet-induced secondary thrombosis promotes the progressive development of ischemic brain damage and contributes to the resistance to thrombolysis and to the tight 3-hour therapeutic window. We tested the hypothesis that combination of intravenous (IV) administration of a GPIIb/IIIa receptor antagonist, 7E3 F(ab')2, with intra-arterial (IA) administration of tenecteplase-tissue plasminogen activator (TNK-tPA) increases the efficacy of thrombolysis and extends the therapeutic window of stroke. METHODS:Rats subjected to embolic stroke were treated with IV 7E3 F(ab')2 (6 mg/kg) in combination with IA or IV TNK-tPA (5 mg/kg) at 4 and 6 hours after onset of stroke, respectively; IA TNK-tPA (5 mg/kg) alone at 6 hours after onset of stroke; or saline at 6 hours after onset of stroke. RESULTS:The combination of IV 7E3 F(ab')2 (4 hours) and IA TNK-tPA (6 hours) significantly (P<0.05) reduced infarct volume and improved neurological functional deficits, which was associated with significant (P<0.05) reductions in the size of embolus at the origin of the occluded middle cerebral artery and in down-stream microvascular platelet and fibrin deposition, and enhanced microvascular patency compared with saline-treated rats. However, combination of IV 7E3 F(ab')2 (4 hours) and IV TNK-tPA (6 hours) or IA TNK-tPA (6 hours) alone failed to reduce infarct volume and improve neurological function compared with the saline-treated rats. No significant differences of the incidence of hemorrhage were detected among groups. CONCLUSIONS:These data suggest that the combination of IV 7E3 F(ab')2 (4 hours) and IA TNK-tPA (6 hours) extends the therapeutic window of thrombolysis to 6 hours after stroke. 10.1161/01.STR.0000147963.68238.da
    Adjunctive Intraarterial Thrombolysis in Endovascular Thrombectomy: A Systematic Review and Meta-analysis. Diprose William K,Wang Michael T M,Ghate Kaustubha,Brew Stefan,Caldwell James R,McGuinness Ben,Barber P Alan Neurology OBJECTIVE:To evaluate the safety and efficacy of intra-arterial thrombolysis (IAT) as an adjunct to endovascular thrombectomy (EVT) in ischemic stroke, we performed a systematic review and meta-analysis of the literature. METHODS:Searches were performed using Medline, Embase, and Cochrane databases for studies that compared EVT to EVT with adjunctive IAT (EVT+IAT). Safety outcomes included symptomatic intracerebral hemorrhage (sICH) and mortality at three months. Efficacy outcomes included successful reperfusion (Thrombolysis in Cerebral Infarction score of 2b to 3), and functional independence, defined as a modified Rankin Scale score of 0 to 2 at three months. RESULTS:Five studies were identified that compared combined EVT+IAT (IA alteplase or urokinase) to EVT-only, and were included in the random effects meta-analysis. There were 1693 EVT patients, including 269 patients treated with combined EVT+IAT and 1424 patients receiving EVT-only. Pooled analysis did not demonstrate any differences between EVT+IAT and EVT-only in rates of sICH (OR: 0.61, 95% CI: 0.20-1.85; P=0.78), mortality (OR: 0.77, 95% CI: 0.54-1.10; P=0.15), or successful reperfusion (OR: 1.05, 95% CI: 0.52-2.15; P=0.89). There was a higher rate of functional independence in patients treated with EVT+IAT, although this was not statistically significant (OR: 1.34, 95% CI: 1.00-1.80; P=0.053). CONCLUSIONS:Adjunctive IAT appears to be safe. In specific situations, neurointerventionists may be justified in administering small doses of intraarterial alteplase or urokinase as rescue therapy during EVT. 10.1212/WNL.0000000000012112
    Intra-arterial thrombolysis in acute stroke. Abou-Chebl A,Furlan A J Current opinion in neurology A relatively small number of studies were published on the intra-arterial therapy of stroke in the past year. Those reports, however, do offer strong evidence for the feasibility and safety of this therapeutic approach. Partly on the basis of these data it has become evident that the intra-arterial thrombolytic therapy of acute ischemic stroke is at least as effective as intravenous thrombolysis. There remain, however, many unresolved issues before such therapy can become a part of the standard of care. 10.1097/00019052-200002000-00010
    Intra-arterial thrombolysis. Saver J L Neurology Intra-arterial (IA) thrombolysis is an emerging treatment strategy for acute ischemic stroke. In IA thrombolysis, the cervicocephalic arterial tree is traversed with an endovascular microcatheter delivery system, the catheter port is positioned immediately within and adjacent to the offending thrombus, and fibrinolytic agents are infused directly into the clot. This delivery technique permits high concentrations of lytic agent to be applied to the clot while minimizing systemic exposure. Early open series suggested that IA thrombolysis achieves higher recanalization rates than i.v. thrombolysis. The first randomized Phase III trial of IA thrombolysis, the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial, confirmed this promise, showing that IA therapy begun up to 6 hours after symptom onset was associated with higher recanalization rates and better clinical outcomes, with acceptable hemorrhage rates. MRI studies have provided striking imaging evidence of the potential beneficial effects of IA therapy, showing not only rescue of regions of diffusion-perfusion mismatch but also normalization and salvage of some tissues with pretreatment bioenergetic failure evidenced by early diffusion abnormality. The Emergency Management of Stroke Bridging Trial demonstrated the feasibility of combined i.v. and intra-arterial thrombolysis. Intra-arterial thrombolysis is a promising treatment strategy for acute ischemic stroke. In coming years, IA thrombolysis, alone or in combination with endovascular mechanical reperfusion techniques, is likely to be increasingly refined and validated and to become a widely accepted therapy for acute ischemic stroke. 10.1212/wnl.57.suppl_2.s58
    Intraarterial recombinant tissue plasminogen activator for ischemic stroke: an accelerating dosing regimen. Qureshi A I,Suri M F,Shatla A A,Ringer A J,Fessler R D,Ali Z,Guterman L R,Hopkins L N Neurosurgery OBJECTIVE:Urokinase has been conventionally used for intraarterial thrombolysis in acute ischemic stroke. Recently, due to the withdrawal of urokinase from the market, attention has been focused on recombinant tissue plasminogen activator (r-tPA) for intraarterial administration. Data is limited regarding the intraarterial dose, efficacy, and safety profile of this agent. METHODS:We prospectively studied 8 consecutive patients with acute ischemic stroke who were referred for intraarterial lysis. Each patient was considered by the treating neurologist to be a poor candidate for intravenous therapy. We administered a maximum total dose of 40 mg of r-tPA intraarterially via superselective catheterization. Angiograms were obtained after each 10 mg of r-tPA, and responses were graded using modified Thrombolysis in Myocardial Infarction (TIMI) criteria for perfusion and degree of thrombus. RESULTS:Initial National Institutes of Health Stroke Scale (NIHSS) scores ranged from 16 to 21. Intervals from presentation to treatment initiation ranged from 1 to 8 hours. After administration of r-tPA, neurological improvement (decrease in NIHSS score > or =2) was observed in 4 patients. Mean perfusion grade improved from a pretreatment score of 0 with increasing doses of r-tPA to 1.1 +/- 1.0 with 10 mg, 1.5 +/- 1.4 with 20 mg, 2.0 +/- 0.8 with 30 mg, and 2.7 +/- 1.0 with 40 mg. Mean thrombus degree decreased from a pretreatment score of 4 with increasing doses of r-tPA to 2.8 +/- 1.2 after 10 mg, 2.6 +/- 1.4 after 20 mg, 1.9 +/- 1.5 after 30 mg, and 1.4 +/- 1.5 after 40 mg. Asymptomatic intraparenchymal hemorrhage was observed on CT scan in 2 patients at 24 hours. CONCLUSION:Our study suggests that intraarterial r-tPA in doses up to 40 mg is relatively safe. The dose appears to facilitate the recanalization process by lysis of local thrombus and improvement in distal flow.
    Long-term effect of intra-arterial thrombolysis in stroke. Nedeltchev Krassen,Fischer Urs,Arnold Marcel,Ballinari Pietro,Haefeli Tobias,Kappeler Liliane,Brekenfeld Caspar,Remonda Luca,Schroth Gerhard,Mattle Heinrich P Stroke BACKGROUND AND PURPOSE:Thrombolysis has been shown to improve the 3-month outcome of patients with ischemic stroke, but knowledge of the long-term effect of thrombolysis is limited. METHODS:The present study compares the long-term outcome of stroke patients who were treated with intra-arterial thrombolysis (IAT) using urokinase with the outcome of patients treated with aspirin. The modified Rankin Scale (mRS) was used to assess the outcome; 173 patients treated with IAT and 261 patients treated with aspirin from the Bernese Stroke Data Bank were eligible for the study. A matching algorithm taking into account patient age and stroke severity on admission (as measured by the National Institute of Health Stroke Scale [NIHSS]) was used to assemble an IAT and an aspirin group. RESULTS:One hundred and forty-four patients treated with IAT and 147 patients treated with aspirin could be matched and included in the comparative analysis. The median NIHSS score was 14 in each group. At 2 years, 56% of the patients treated with IAT and 42% of the patients treated with aspirin achieved functional independence (mRS, 0 to 2; P=0.037). Clinical outcome was excellent (mRS, 0 to 1) in 40% of the IAT and in 24% of the aspirin patients (P=0.008). Mortality was 23% and 24%, respectively. CONCLUSIONS:The present study provides evidence for a sustained effect of IAT when assessed 2 years after the stroke. 10.1161/01.STR.0000249417.24085.80
    Intra-arterial thrombolysis of occluded middle cerebral artery by use of collateral pathways in patients with tandem cervical carotid artery/middle cerebral artery occlusion. Ozdemir O,Bussière M,Leung A,Gulka I,Lee D,Chan R,Spence J D,Pelz D AJNR. American journal of neuroradiology BACKGROUND AND PURPOSE:Cervical internal carotid artery (ICA) occlusion with middle cerebral artery (MCA) embolic occlusion is associated with a low rate of recanalization and poor outcome after intravenous thrombolysis. Prompt revascularization is required to prevent disabling stroke. We report our experience on acute ischemic stroke patients with tandem ICA or MCA occlusions treated with microcathether navigation and intra-arterial thrombolysis by use of collateral pathways including the posterior or anterior communicating arteries, or both pathways. MATERIALS AND METHODS:We retrospectively identified 8 patients with proximal ICA occlusion associated with MCA embolic occlusions treated with intra-arterial thrombolysis (IA rtPA). Access to the occluded MCA was obtained via catheter navigation through intact collateral pathways, including posterior communicating (PcomA) or anterior communicating (AcomA) arteries, without passing a microcathether through the acutely occluded ICA. We assessed clinical outcomes using modified Rankin scale (mRS) and National Institutes of Health Stroke Scale (NIHSS). RESULTS:Eight patients with a mean age of 57 +/- 4 years and median NIHSS of 14 were identified. Mean time from stroke onset to intra-arterial thrombolysis was 292 +/- 44 minutes. The MCA was revascularized completely in 5 of the 8 patients via collateral intra-arterial rtPA administration. All of the patients had a favorable outcome defined as a mRS of < or =2 or more at 1 and 3 months' follow-up after thrombolytic therapy. One patient had an asymptomatic petechial hemorrhage. CONCLUSION:In this small number of patients with tandem occlusions of the ICA and MCA, intra-arterial thrombolysis and recanalization of the MCA by use of collateral pathways to bypass the occluded ICA is a safe and efficacious therapeutic option. 10.3174/ajnr.A1163
    Safety and Angiographic Efficacy of Intra-Arterial Fibrinolytics as Adjunct to Mechanical Thrombectomy: Results from the INFINITY Registry. Kaesmacher Johannes,Abdullayev Nuran,Maamari Basel,Dobrocky Tomas,Vynckier Jan,Piechowiak Eike I,Pop Raoul,Behme Daniel,Sporns Peter B,Styczen Hanna,Virtanen Pekka,Meyer Lukas,Meinel Thomas R,Cantré Daniel,Kabbasch Christoph,Maus Volker,Pekkola Johanna,Fischer Sebastian,Hasiu Anca,Schwarz Alexander,Wildgruber Moritz,Seiffge David J,Langner Sönke,Martinez-Majander Nicolas,Radbruch Alexander,Schlamann Marc,Mihoc Dan,Beaujeux Rémy,Strbian Daniel,Fiehler Jens,Mordasini Pasquale,Gralla Jan,Fischer Urs Journal of stroke BACKGROUND AND PURPOSE:Data on safety and efficacy of intra-arterial (IA) fibrinolytics as adjunct to mechanical thrombectomy (MT) are sparse. METHODS:INtra-arterial FIbriNolytics In ThrombectomY (INFINITY) is a retrospective multi-center observational registry of consecutive patients with anterior circulation large-vessel occlusion ischemic stroke treated with MT and adjunctive administration of IA fibrinolytics (alteplase [tissue plasminogen activator, tPA] or urokinase [UK]) at 10 European centers. Primary outcome was the occurrence of symptomatic intracranial hemorrhage (sICH) according to the European Cooperative Acute Stroke Study II definition. Secondary outcomes were mortality and modified Rankin Scale (mRS) scores at 3 months. RESULTS:Of 5,612 patients screened, 311 (median age, 74 years; 44.1% female) received additional IA after or during MT (194 MT+IA tPA, 117 MT+IA UK). IA fibrinolytics were mostly administered for rescue of thrombolysis in cerebral infarction (TICI) 0-2b after MT (80.4%, 250/311). sICH occurred in 27 of 308 patients (8.8%), with an increased risk in patients with initial TICI0/1 (adjusted odds ratio [aOR], 2.3; 95% confidence interval [CI], 1.1 to 5.0 per TICI grade decrease) or in those with intracranial internal carotid artery occlusions (aOR, 3.7; 95% CI, 1.2 to 12.5). In patients with attempted rescue of TICI0-2b and available angiographic follow-up, 116 of 228 patients (50.9%) showed any angiographic reperfusion improvement after IA fibrinolytics, which was associated with mRS ≤2 (aOR, 3.1; 95% CI, 1.4 to 6.9). CONCLUSIONS:Administration of IA fibrinolytics as adjunct to MT is performed rarely, but can improve reperfusion, which is associated with better outcomes. Despite a selection bias, an increased risk of sICH seems possible, which underlines the importance of careful patient selection. 10.5853/jos.2020.01788
    Intra-arterial vs intra-venous. Thrombolysis for anterior cerebral occlusion. Zhang Bin,Sun Xiaojiang,Li Minghua,Wang Feng,Xu Dan,Duan Hao,Fang Chun The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques BACKGROUND:The safety and effectiveness of intra-arterial thrombolysis (IAT) in comparison to intravenous thrombolysis (IVT) for the treatment of ischemic stroke is uncertain. Our study aims to assess and compare IAT to IVT for clinically relevant outcomes in patients with occlusion of the anterior cerebral circulation. METHODS:Patients with acute ischemic stroke were enrolled for either treatment; those whose symptoms occurred within 4.5 hrs after stroke were treated with IVT, whereas those who presented < 4.5 hrs but had contraindications to IVT or presented between 4.5 and 6 hrs were treated with IAT. Evaluated endpoints included: disability at 90 days as measured by the modified Rankin Scale (mRS), incidence of mortality, and incidence of symptomatic intracranial haemorrhage. RESULTS:78 patients with anterior cerebral circulation occlusion were included in the study (55 in IVT, 23 in IAT). After 90 days, 82.6% patients treated with IAT reached independence in comparison to 56.4% in the IVT group (P = 0.028, RR = 2.66, 95% CI: 1.10-7.04). The incidence of all intracranial haemorrhages in the IAT and IVT groups respectively were 30.4% and 12.7% (P = 0.103, RR = 2.391, 95% CI: 0.946-6.047); symptomatic intracranial haemorrhage occurred in 8.7% and 9.1% of patients (P = 1.00, RR = 0.957, 95% CI: 0.200-4.579), and mortality in 8.7% and 16.4% (P = 0.492, RR = 1.882, 95% CI: 0.440-8.045). CONCLUSION:Results suggest that IAT is more effective than IVT in allowing patients to achieve independence. While inconclusive, the safety of IAT within 6 hrs is comparable to IVT within 4.5 hrs.
    Selecting stroke patients for intra-arterial therapy. Balucani Clotilde,Grotta James C Neurology There is a great need for new treatments for acute ischemic stroke that will achieve greater rates of arterial recanalization and increase the population of patients who may benefit. Of several approaches under investigation, intra-arterial therapy (IAT) is the farthest along in clinical development, but experience has shown that the increased rates of recanalization achieved are not always translated to improved patient outcomes. Proper patient selection, allied to efficient strategies aiming at faster recanalization and reperfusion, may result in better clinical outcomes and more rational use of therapeutic resources. While high-tech multimodal imaging has the great promise of identifying hypoperfused but still viable brain tissue, a number of clues suggest that relatively low-tech approaches similar to those that were used to demonstrate the efficacy of systemic thrombolysis, and which have emphasized the key role of time and clinical factors such as age, glucose, stroke severity, and infarct on noncontrast CT scan, deserve greater study as an efficient way to optimize IAT. Eventually it will be a combination of predictors that will enable us to most precisely identify the best patients for IAT and any other new revascularization therapies. 10.1212/WNL.0b013e318248e558
    Pre- and in-hospital delays from stroke onset to intra-arterial thrombolysis. Nedeltchev Krassen,Arnold Marcel,Brekenfeld Caspar,Isenegger Jörg,Remonda Luca,Schroth Gerhard,Mattle Heinrich P Stroke BACKGROUND AND PURPOSE:Thrombolysis for treatment of acute ischemic stroke should be administered as fast as possible after symptom onset. The aim of this study was to examine, in our tertiary care center, the time intervals preceding intra-arterial thrombolysis in order to accelerate and optimize the management of acute strokes. METHODS:Between January 1, 2000, and April 30, 2002, 597 patients with acute stroke were admitted to our stroke center. One hundred forty-eight patients underwent diagnostic arteriography, and 100 (16.8%) received intra-arterial thrombolysis. For all patients, we prospectively recorded and analyzed the time of symptom onset, admission, CT and/or MRI scan, diagnostic arteriography, and, if performed, intra-arterial thrombolysis. RESULTS:The mean time to arrival in the emergency department was 99 minutes for patients who were admitted directly (Bern patients), 127 minutes for those who were referred from community hospitals without a CT scanner (non-Bern/-CT patients), and 210 minutes for patients from hospitals with imaging facilities (non-Bern/+CT patients). The mean delay from symptom onset to treatment was 234 minutes for Bern patients, 269 minutes for non-Bern/-CT patients, and 302 minutes for non-Bern/+CT patients. The patients from the last group needed longer to receive intra-arterial thrombolysis than did patients who were admitted directly (P=0.002) or who were transferred from a hospital without a CT scanner (P=0.03). CONCLUSIONS:This prospective study indicates that direct referral without prior imaging at community hospitals shortens the time until intra-arterial thrombolysis. In addition, our in-hospital delay preceding intra-arterial thrombolysis is longer than the delays reported for intravenous thrombolysis and indicates potential for improvement. 10.1161/01.STR.0000069164.91268.99
    Intra-arterial thrombolysis for acute ischemic stroke. Burnette W C,Nesbit G M European radiology Intra-arterial thrombolysis is a maturing treatment for acute thromboembolic stroke that shows promise in restoring cerebral blood supply. Reviewed evidence suggests that intra-arterial treatment has a longer window for treatment than intravenous t-PA and does improve outcome. A favorable outcome is dependent on careful patient selection aimed at avoiding intracranial hemorrhage. This article describes features to evaluate for patient selection and highlights factors along the treatment algorithm to maximize success. 10.1007/s003300000610
    A case-control analysis of intra-arterial urokinase thrombolysis in acute cardioembolic stroke. Inoue Takeshi,Kimura Kazumi,Minematsu Kazuo,Yamaguchi Takenori, Cerebrovascular diseases (Basel, Switzerland) BACKGROUND:Intra-arterial urokinase (IA-UK) thrombolysis is frequently given in Japan to selected patients with acute cerebral artery occlusion. However, it is not clear whether or not IA-UK thrombolysis has an efficacy for acute stroke patients. The purpose of this study was to assess the effects of IA-UK thrombolysis in acute cardioembolic stroke patients, by performing a case-control analysis using data from Japan's Multicenter Stroke Investigator's Collaboration (J-MUSIC). METHODS:16,922 acute ischemic stroke patients were enrolled into J-MUSIC. From these patients, we selected 91 patients (UK group) who met the following criteria: treatment with IA-UK; 20-75 years of age; cardioembolic stroke; presenting with a carotid stroke; admission within 4.5 h of symptom onset, and a National Institutes of Health Stroke Scale (NIHSS) score of 5-22 points on admission. A control group of 182 patients without IA-UK treatment and matched to the NIHSS score, gender, and age was chosen. We compared the modified Rankin scale (mRS) score at discharge and the mortality between the 2 groups. RESULTS:In both groups, the mean age was 65 +/- 8 years, and the median NIHSS score was 14. The mean interval between symptom onset and UK administration was 3.4 +/- 1.3 h, and the IA-UK dose was 392,000 +/- 200,000 units. The mRS score at discharge was lower in the UK group than in the control group (mean, SD, median; 2.8, 2.9, 2 in UK group vs. 3.3, 1.8, 4, in the control, respectively p = 0.031). A favorable outcome (mRS of 0-2) was more frequently observed in the UK group (50.5%) than in the control group (34.1%, p = 0.0124). No difference in the mortality rate was seen between the UK group (11.0%) and the control group (13.3%). As well, there was no difference in the length of hospital stay between the UK group (46 +/- 41 days, mean +/- SD) and the control group (42 +/- 42 days, mean +/- SD). CONCLUSIONS:IA-UK thrombolytic therapy may improve the outcome in hyperacute cardioembolic stroke patients. 10.1159/000083887
    Simple microwire and microcatheter mechanical thrombolysis with adjuvant intraarterial urokinase for treatment of hyperacute ischemic stroke patients. Kim Dong Joon,Kim Dong Ik,Byun Joon Soo,Jung Jin Young,Suh Sang Hyun,Kim Eung Yeop,Lee Kyung-Yul,Heo Ji Hoe Acta radiologica (Stockholm, Sweden : 1987) BACKGROUND:Mechanical thrombolysis may effectively enhance the efficacy of thrombolysis for hyperacute ischemic stroke patients. PURPOSE:To assess the feasibility and results of simple mechanical-based thrombolysis using microwire and microcatheter with adjuvant low-dose intraarterial (i.a.) urokinase (UK) for the treatment of hyperacute ischemic stroke. MATERIAL AND METHODS:Nineteen consecutive patients with hyperacute proximal middle cerebral artery (MCA) occlusions treated by a standardized protocol using microwire and microcatheter for mechanical thrombus disruption with adjuvant i.a. UK were reviewed. Simple to-and-fro passages through the clot with the microwire and microcatheter followed by disruptions by a J- or pigtail-shaped wire tip with alternating small-dose injections of UK distal, within, and proximal to the clot were performed. The recanalization rates, post-thrombolysis hemorrhage, and clinical outcome (baseline and discharge National Institute of Health Stroke Scale [NIHSS], mortality, 3-month modified Rankin scale [mRS]) were evaluated. RESULTS:Recanalization was achieved in 18 of 19 patients (94.7%). The mean UK dose was 375,789 IU (range 130,000-580,000 IU). Two patients (10.5%) developed symptomatic hemorrhage. One of the hemorrhages included a patient who developed subarachnoid hemorrhage. Mortality rate was 15.8% (n = 3). The median baseline NIHSS scores showed improvement from 17 to 10 at presentation and discharge, respectively. At three months, good outcome was noted in 11 of 19 patients (57.9%, mRS 0-2). CONCLUSION:Simple mechanical-based thrombolysis using microwire and microcatheter with adjuvant low-dose i.a. UK is safe and effective in achieving recanalization with good long-term outcome. 10.1080/02841850701819143
    Combined intravenous and intra-arterial recombinant tissue plasminogen activator in acute ischemic stroke. Ernst R,Pancioli A,Tomsick T,Kissela B,Woo D,Kanter D,Jauch E,Carrozzella J,Spilker J,Broderick J Stroke BACKGROUND AND PURPOSE:A retrospective analysis was performed on 20 consecutive patients who presented with severe acute ischemic stroke and were evaluated for a combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (rtPA) thrombolytic approach within 3 hours of onset. METHODS:Twenty consecutive patients with carotid artery distribution strokes were evaluated and treated using a combined IV and IA rtPA approach over a 14-month period (September 1998 to October 1999). rtPA (0.6 mg/kg) was given intravenously (maximum dose 60 mg); 15% of the IV dose was given as bolus, followed by a continuous infusion over 30 minutes. A maximal IA dose, up to 0.3 mg/kg or 24 mg, whichever was less, was given over a maximum of 2 hours. IV treatment was initiated within 3 hours in 19 of 20 patients. All 20 patients underwent angiography, and 16 of 20 patients received local IA rtPA. RESULTS:The median baseline National Institutes of Health Stroke Scale (NIHSS) score for the 20 patients was 21 (range 11 to 31). The median time from stroke onset to IV treatment was 2 hours and 2 minutes, and median time to initiation of IA treatment was 3 hours and 30 minutes. Ten patients (50%) recovered to a modified Rankin Scale (mRS) of 0 or 1; 3 patients (15%), to an mRS of 2; and 5 patients (25%), to an mRS of 4 or 5. One patient (5%) developed a symptomatic intracerebral hemorrhage and eventually died. One other patient (5%) expired because of complications from the stroke. CONCLUSIONS:We believe that the greater-than-expected proportion of favorable outcomes in these patients with severe ischemic stroke reflects the short time to initiation of both IV and IA thrombolysis. 10.1161/01.str.31.11.2552
    Effect of baseline Alberta Stroke Program Early CT Score on safety and efficacy of intra-arterial treatment: a subgroup analysis of a randomised phase 3 trial (MR CLEAN). Yoo Albert J,Berkhemer Olvert A,Fransen Puck S S,van den Berg Lucie A,Beumer Debbie,Lingsma Hester F,Schonewille Wouter J,Sprengers Marieke E S,van den Berg René,van Walderveen Marianne A A,Beenen Ludo F M,Wermer Marieke J H,Nijeholt Geert J Lycklama À,Boiten Jelis,Jenniskens Sjoerd F M,Bot Joseph C J,Boers Anna M M,Marquering Henk A,Roos Yvo B W E M,van Oostenbrugge Robert J,Dippel Diederik W J,van der Lugt Aad,van Zwam Wim H,Majoie Charles B L M, The Lancet. Neurology BACKGROUND:Whether infarct size modifies intra-arterial treatment effect is not certain, particularly in patients with large infarcts. We examined the effect of the baseline Alberta Stroke Program Early CT Score (ASPECTS) on the safety and efficacy of intra-arterial treatment in a subgroup analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). METHODS:MR CLEAN was a randomised, controlled, open-label, phase 3 trial of intra-arterial treatment in patients (aged ≥18 years from the Netherlands) with proximal arterial occlusion of the anterior circulation, given intra-arterial treatment within 6 h of stroke onset. The primary outcome was 90 day modified Rankin Scale (mRS) score. We estimated the intra-arterial treatment effect for all patients in MR CLEAN who had ASPECTS graded by using multivariable ordinal logistic regression analysis (a proportional odds model) to calculate the adjusted common odds ratio for a shift towards a better functional outcome according to the mRS for intra-arterial treatment and usual care than for usual care alone. We entered an interaction term into the model to test for interaction with prespecified ASPECTS subgroups: 0-4 (large infarct) versus 5-7 (moderate infarct) versus 8-10 (small infarct). MR CLEAN is registered with the Netherlands Trial Registry, number NTR1804, and the ISRCTN Registry, number ISRCTN10888758. FINDINGS:496 patients-232 (47%) in the intra-arterial treatment and usual care group and 264 (53%) in the usual care alone group-were included in the analysis. We noted no significant difference in intra-arterial treatment effect between the ASPECTS subgroups according to 90 day ordinal mRS (adjusted common odds ratio interaction term relative to ASPECTS 8-10: ASPECTS 0-4: 0·79 [95% CI 0·20-3·19], p=0·740; and ASPECTS 5-7: 1·02 [0·44-2·35], p=0·966). Intra-arterial treatment did not cause a significant increase in the proportion of patients with at least one serious adverse event in any of the ASPECTS subgroups (ASPECTS 0-4: eight [73%] of 11 patients in treatment and usual care group vs 11 [58%] of 19 in usual care alone group, p=0·42; ASPECTS 5-7: 32 [59%] of 54 vs 19 [49%] of 39, p=0·31; ASPECTS 8-10: 70 [42%] of 167 vs 82 [40%] of 206; p=0·68). For death within 7 days or within 30 days and hemicraniectomy, the differences between the intra-arterial treatment and usual care versus usual care alone groups were not significant by ASPECTS subgroups. A significantly higher proportion of patients had recurrent ischaemic stroke in the intra-arterial treatment plus usual care group than in the usual care alone group in the ASPECTS 8-10 subgroup (eight [5%] vs one [<1%]; p=0·007). INTERPRETATION:Contrary to findings from previous studies suggesting that only patients with non-contrast CT ASPECTS of more than 7 benefit from intra-arterial treatment, data from this study suggest that patients with ASPECTS 5-7 should be treated. Further evidence is needed for patients with ASPECTS 0-4, for whom treatment might yield only marginal absolute benefit. FUNDING:Dutch Heart Foundation, AngioCare, Medtronic/Covidien/EV3, Medac/Lamepro, Penumbra, Stryker, and Top Medical. 10.1016/S1474-4422(16)00124-1
    Intra-arterial thrombolysis using rt-PA in patients with acute stroke due to vessel occlusion of anterior and/or posterior cerebral circulation. Tountopoulou Argyro,Ahl Bjoern,Weissenborn Karin,Becker Hartmut,Goetz Friedrich Neuroradiology INTRODUCTION:The aim of our study was to evaluate the safety and efficacy of intra-arterial (IA) thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute stroke due to occlusion in the anterior or posterior circulation. METHODS:We retrospectively analyzed the clinical and radiological data of 88 consecutive patients with acute ischemic stroke who underwent emergency cerebral angiography for the purpose of subsequent IA thrombolysis. The neurological deficit on admission and discharge was graded using the National Institutes of Health Stroke Scale (NIHSS) score. Baseline computer tomography (CT) scans were examined for any signs indicative of cerebral ischemia. The angiographic findings were classified according to the Thrombolysis in Myocardial Infarction (TIMI) score for myocardial infarction. Follow-up CT scans were examined for hemorrhagic complication. RESULTS:Of the 88 patients who underwent IA thrombolysis, 63 presented with complete or partial arterial occlusion in the suspected perfusion area. In these 63 patients, the median NIHSS score dropped from 15 points on admission to 10 points at discharge. The recanalization rate was 52.6% for partial and complete reperfusion. In-hospital mortality was 20.6% (9.1% for carotid, 44.4% for basilar territory occlusion). Intracerebral bleeding (ICB) occurred in 38.6% of the patients with occlusion in the anterior circulation, resulting in these patients presenting a worse clinical outcome than those without ICB. Only minor extracranial bleedings occurred in 20.6% of patients. Patients with ICB had a significantly higher frequency of ischemic signs on the baseline CT scan. CONCLUSION:Occlusion of a cerebral artery is present in about 75% of the patients eligible for thrombolytic therapy. Intra-arterial thrombolysis using rt-PA in patients with acute ischemic stroke can achieve re-vascularization, although ICB remains the major risk factor affecting its efficacy. 10.1007/s00234-007-0306-1
    Intra-arterial thrombolysis for acute ischemic stroke. Jovin Tudor,Gebel James M,Wechsler Lawrence R Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Intra-arterial thrombolysis, administered within six hours of symptoms onset, has been shown in a randomized, prospective, multicenter trial and in several nonrandomized case series to be beneficial in acute ischemic stroke caused by occlusion of the middle cerebral artery or its major divisions. Benefit has been reported in a relatively small number of nonrandomized case series beyond the six-hour time window in basilar artery occlusion. Although intra-arterial thrombolysis appears to be an effective and relatively safe form of therapy for certain patients with acute ischemic stroke, better outcomes and fewer side effects than currently reported are to be desired. Whether this will be achieved in part by a better selection of patients based on physiologic rather than chronologic criteria, by achieving higher and faster recanalization rates (through combined use of intra-arterial and intravenous therapy or through use of mechanical clot-dissolution devices), or by combining thrombolysis with neuroprotectant strategies remains to be established by future trials. 10.1053/jscd.2002.129962
    Sequential combination of intravenous recombinant tissue plasminogen activator and intra-arterial urokinase in acute ischemic stroke. Lee Kyung Yul,Kim Dong Ik,Kim Seo Hyun,Lee Seung Ik,Chung Hae Woong,Shim Yong Woon,Kim Seung Min,Heo Ji Hoe AJNR. American journal of neuroradiology BACKGROUND AND PURPOSE:Combined intravenous (IV) and intra-arterial (IA) thrombolytic therapy may be faster and easier to initiate than monotherapy, and its recanalization rate may be better as well. The sequential combination of recombinant tissue plasminogen activator (rTPA) and urokinase (UK) has synergistic and complementary effects on clot lysis. We prospectively evaluated the effectiveness and safety of sequential combination of IV rTPA and IA UK in acute ischemic stroke. METHODS:IV rTPA was administered to patients with acute stroke within 3 hours of onset. Those whose condition had not improved at the end of rTPA infusion were further treated with selective IA UK. We evaluated baseline and 30-day National Institutes of Health Stroke Scale (NIHSS) scores and 90-day modified Rankin Scale scores. RESULTS:Thirty patients were initially treated with IV rTPA; 24 were further treated with IA UK. Four patients who had rapid reocclusion following initial successful IA therapy received IV abciximab. Fourteen of 24 patients who underwent angiography had an effective perfusion state of Thrombolysis in Myocardial Infarction grade 3 flow. Median baseline and 30-day NIHSS scores were 18 and 2, respectively. Eighteen patients improved to a modified Rankin scale score of 0 or 1 after 90 days. Symptomatic hemorrhage developed in two patients. CONCLUSION:The strategy of using conventional-dose IV rTPA and the sequential combination of IA UK in patients without an early clinical response to IV treatment was safe and feasible. This strategy achieved high complete arterial recanalization rates and good functional outcomes.
    Outcome in acute stroke with different intra-arterial infusion rate of urokinase on thrombolysis. Gan X,Luo Y,Ling F,Ji X,Chen J,Ding Y Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences Intra-arterial infusion of urokinase (UK) has been widely used. However, the optimal infusion rate of the reagent has never been determined. This was investigated in the acute stage of middle cerebral artery (MCA) embolism in the present study. Sprague Dawley male rats (n=43) were randomly divided into sham-operation and five ischemic groups with urokinase administration at different infusion rates or without urokinase administration. Ischemia was induced with MCA embolism. Two hours after embolism, total urokinase (urokinase, 170,000U/kg) was given in groups A,B,C and D (n=8 each) at different rates: 1,000 U (0.03 ml/min) per minute, 4,000U (0.12 ml/min), 10,000U (0.30 ml/min), and 16,000U (0.48 ml/min), respectively. Group E received normal saline at a rate of 0.48 ml/min. The sham-operation group (no embolism) received urokinase at (170,000U/kg, 1.5 ml, 16,000 U/min). During ischemia and thrombolysis, regional cerebral blood flow (CBF) was monitored by laser Doppler flowmetry. The neurological deficits, infarct volumes and mortalities in each group were determined. The CBF in ischemic hemisphere were significantly (p<0.05) decreased after embolism in groups A∼E at similar levels (27.32±8.20% to 34.71±6.84%). After different treatments, in group B 4,000U/min infusion of UK induced the best reperfusion, the least neurological deficits and infarct volume, as well as the least mortality and lowest incidence of hemorrhage. The effect of intra-artery thrombolysis of urokinase was related to the infusion rate. Our study demonstrated an optimal infusion rate at 4,000U/min, suggesting relatively low levels of infusion are better able to improve brain reperfusion and reduce brain injury after stroke. 10.1177/159101991001600311
    Local Intra-arterial Thrombolysis during Mechanical Thrombectomy for Refractory Large-Vessel Occlusion: Adjunctive Chemical Enhancer of Thrombectomy. Baik S H,Jung C,Kim J Y,Shin D-W,Kim B J,Kang J,Bae H-J,Kim J H AJNR. American journal of neuroradiology BACKGROUND AND PURPOSE:Data on adjunctive intra-arterial thrombolysis during mechanical thrombectomy for refractory thrombus are sparse. The aim of this study was to evaluate the efficacy and safety of local intra-arterial urokinase as an adjunct to mechanical thrombectomy for refractory large-vessel occlusion. MATERIALS AND METHODS:We retrospectively evaluated patients with acute ischemic stroke who underwent mechanical thrombectomy for anterior circulation large-vessel occlusion between January 2016 and December 2019. Patients were divided into 2 groups based on the use of intra-arterial urokinase as an adjunctive therapy during mechanical thrombectomy for refractory thrombus: the urokinase and nonurokinase groups. Herein, refractory thrombus was defined as the target occlusion with minimal reperfusion (TICI 0 or 1) despite >3 attempts with conventional mechanical thrombectomy. The baseline characteristics, procedural outcomes, and clinical outcome were compared between the 2 groups. RESULTS:One hundred fourteen cases of refractory thrombus were identified. A total of 45 and 69 patients were in the urokinase and the nonurokinase groups, respectively. The urokinase group compared with the nonurokinase group showed a higher rate of successful reperfusion (82.2% versus 63.8%, = .034), with lower procedural times (54 versus 69 minutes, = .137). The rates of good clinical outcome, distal embolism, and symptomatic intracranial hemorrhage were similar between the 2 groups. The use of intra-arterial urokinase (OR = 3.682; 95% CI, 1.156-11.730; = .027) was an independent predictor of successful reperfusion. CONCLUSIONS:The use of local intra-arterial urokinase as an adjunct to mechanical thrombectomy may be an effective and safe method that provides better recanalization than the conventional mechanical thrombectomy for refractory thrombus in patients with embolic large-vessel occlusion. 10.3174/ajnr.A7264
    Intra-arterial versus intra-venous thrombolysis within and after the first 3 hours of stroke onset. Padma Srivastava,Majaz Moonis Archives of medical science : AMS The NINDS trial demonstrated for the first time the effectiveness of intravenous thrombolysis in improving outcome after acute ischemic stroke. The absolute benefit of this intervention was 11-13% greater chance of being normal or near normal (MRS ≤ 1) at 3 months. However, if patients with severe stroke were considered (NIHSS ≥ 20), the absolute benefit dropped to 5-6%, indicating that IV thrombolysis may not be as effective for large vessel occlusion. This observation was further supported by TCD studies that clearly demonstrated that large artery occlusions had a recanalization rate of 13-18% with IV rt-PA. Intra-arterial thrombolysis achieves recanalization rates of 60-70%. Since tissue viability is clearly important, it is time to stop defining rigid time windows and if there is a large penumbra (20-50%) and the occlusion is in a large artery, there exists a logic and a growing evidence to consider either bridge therapy or direct intra-arterial therapy. 10.5114/aoms.2010.14248
    Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection. Lyden Patrick,Weymer Sara,Coffey Chris,Cudkowicz Merit,Berg Samantha,O'Brien Sarah,Fisher Marc,Haley E Clarke,Khatri Pooja,Saver Jeff,Levine Steven,Levy Howard,Rymer Marilyn,Wechsler Lawrence,Jadhav Ashutosh,McNeil Elizabeth,Waddy Salina,Pryor Kent Stroke BACKGROUND AND PURPOSE:The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. METHODS:The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. RESULTS:Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment. CONCLUSIONS:It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. 10.1161/STROKEAHA.116.013881
    Direct Intra-arterial thrombectomy in order to Revascularize AIS patients with large vessel occlusion Efficiently in Chinese Tertiary hospitals: A Multicenter randomized clinical Trial (DIRECT-MT)-Protocol. Yang Pengfei,Treurniet Kilian M,Zhang Lei,Zhang Yongwei,Li Zifu,Xing Pengfei,Zhang Yongxin,Zhang Ping,Wang Hao,Hong Bo,Dippel Diederik Wj,Roos Yvo Bwem,Majoie Charles Blm,Deng Benqiang,Liu Jianmin, International journal of stroke : official journal of the International Stroke Society RATIONALE:Intravenous thrombolysis combined with mechanical thrombectomy (MT) has been proven safe and clinical effective in patients with acute ischemic stroke of anterior circulation large vessel occlusion. However, despite reperfusion, a considerable proportion of patients do not recover. Incidence of symptomatic intracerebral hemorrhage was similar between patients treated with the combination of intravenous thrombolysis and MT, as compared to intravenous thrombolysis alone, suggesting that this complication should be attributed to pre-treatment with intravenous thrombolysis. Conversely, intravenous thrombolysis may be beneficial in patients with small clots occluding intracranial arteries with underlying intracranial atherosclerotic disease, not accessible for MT. AIM:To assess whether direct MT is non-inferior compared to combined intravenous thrombolysis plus MT in patients with AIS due to an anterior circulation large vessel occlusion, and to assess treatment effect modification by presence of intracranial atherosclerotic disease. SAMPLE SIZE:Aim to randomize 636 patients 1:1 to receive direct MT (intervention) or combined intravenous thrombolysis plus MT (control). DESIGN:This is a multicenter, prospective, open label parallel group trial with blinded outcome assessment (PROBE design) assessing non-inferiority of direct MT compared to combined intravenous thrombolysis plus MT. OUTCOMES:The primary outcome is the score on the modified Rankin Scale assessed blindly at 90 (±14) days. An common odds ratio, adjusted for the prognostic factors (age, NIHSS, collateral score), representing the shift on the 6-category mRS scale measured at three months, estimated with ordinal logistic regression, will be the primary effect parameter. Non-inferiority is established if the lower boundary of the 95% confidence interval does not cross 0.8. DISCUSSION:DIRECT-MT could result in improved therapeutic efficiency and cost reduction in treatment of anterior circulation large vessel occlusion stroke. 10.1177/1747493019882837
    Thrombolysis in acute ischemic stroke. Intra-arterial and intra-venous. Higashida T Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences Objectives for Presentation: 1. Review thrombolytic trials in acute ischemic stroke. 2. Discuss current recommendations for acute ischemic stroke therapy. 3. Discuss the role of intra-arterial thrombolysis in acute ischemic stroke. 4. Discuss the newest thrombolytic trials and recommendations for therapy in acute stroke prevention and management. 10.1177/15910199030090S204
    Intra-Arterial Treatment for Patients with Severe Acute Vertebrobasilar Occlusion: A Single-Center Retrospective Study. Cao Jie,Xuan Jinggang,Chen Ronghua,Zhu Xucheng,Shao Huaming,Chao Xiaofeng,Zhi Feng,Shao Naiyuan,Peng Ya Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:Recently, favorable outcomes from several randomized controlled trials of rapid endovascular treatment for acute ischemic stroke has emerged. OBJECTIVE:The aim of this retrospective study is to present our clinical experience in severe acute vertebrobasilar occlusion (AVBO) using intra-arterial treatment (IAT). METHODS:Twenty patients with ischemic stroke in the vertebrobasilar circulation treated by IAT between March 2011 and December 2014 were included. We retrospectively assessed National Institutes of Health Stroke Scale (NIHSS) score on admission and at discharge, Thrombolysis in Cerebral Infarction (TICI) scale, and clinical outcome using modified Rankin scale (mRs) at 90 days, and causes of stroke were prospectively assessed. RESULTS:The mean NIHSS score on admission was 26.4 ± 7.9 (range 9-33) points. The mean time from symptom onset to revascularization was 349.5 ± 124.0 (range 201-579) minutes. Successful recanalization (TICI ≥2b) was achieved in 19 (95.0%) patients. The mean NIHSS score at discharge was 5.7 ± 9.0 (range 0-30) points. A favorable clinical outcome (mRS ≤2) was observed in 12 (60.0%) patients at 90 days and mortality was 25.0% (n = 5). CONCLUSION:IAT for AVBO provides high rate of recanalization, favorable clinical outcome, and improved survival. 10.1016/j.jstrokecerebrovasdis.2017.05.028
    Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke BACKGROUND AND PURPOSE:To investigate the feasibility and safety of a combined intravenous (IV) and intra-arterial (IA) approach to recanalization in patients with ischemic stroke. MATERIALS AND METHODS:Subjects ages 18 to 80 with an NIH Stroke Scale (NIHSS) > or =10 at baseline had IV recombinant tissue plasminogen activator (rt-PA) started (0.6 mg/kg, 60 mg maximum over 30 minutes) within 3 hours of onset. Additional rt-PA was then administered via microcatheter at the site of the thrombus up to a total dose of 22 mg over 2 hours of infusion or until thrombolysis. Primary comparisons were with similar subsets of placebo and rt-PA-treated subjects from the NINDS rt-PA Stroke Trial. RESULTS:The 80 subjects had a median baseline NIHSS score of 18. The median time to initiation of IV rt-PA was 140 minutes as compared with 108 minutes for placebo and 90 minutes for rt-PA-treated subjects in the NINDS rt-PA Stroke Trial. The 3-month mortality in Interventional Management Study (IMS) subjects (16%) was numerically lower but not statistically different than the mortality of placebo (24%) and rt-PA-treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of symptomatic intracerebral hemorrhage (6.3%) in IMS subjects was similar to that of rt-PA-treated subjects (6.6%) but higher than the rate in placebo-treated subjects (1.0%, P=0.018) in the NINDS rt-PA Stroke Trial. IMS subjects had a significantly better outcome at 3 months than NINDS placebo-treated subjects for all outcome measures (odds ratios > or =2). CONCLUSIONS:A randomized trial of standard IV rt-PA as compared with a combined IV and IA approach is needed. 10.1161/01.STR.0000121641.77121.98
    Safety and Efficacy of Intra-arterial Urokinase After Failed, Unsuccessful, or Incomplete Mechanical Thrombectomy in Anterior Circulation Large-Vessel Occlusion Stroke. Kaesmacher Johannes,Bellwald Sebastian,Dobrocky Tomas,Meinel Thomas R,Piechowiak Eike I,Goeldlin Martina,Kurmann Christoph C,Heldner Mirjam R,Jung Simon,Mordasini Pasquale,Arnold Marcel,Mosimann Pascal J,Schroth Gerhard,Mattle Heinrich P,Gralla Jan,Fischer Urs JAMA neurology Importance:Achieving complete reperfusion is a key determinant of good outcome in patients treated with mechanical thrombectomy (MT). However, data on treatments geared toward improving reperfusion after incomplete MT are sparse. Objective:To determine whether administration of intra-arterial urokinase is safe and improves reperfusion after failed or incomplete MT. Design, Setting, and Participants:This observational cohort study included a consecutive sample of patients treated with second-generation MT from January 1, 2010, through August 4, 2017. Data were collected from the prospective registry of a tertiary care stroke center. Of 1274 patients screened, 69 refused to participate, and 993 met the observational studies inclusion criteria of a large vessel occlusion in the anterior circulation. Data were analyzed from September 1, 2017, through September 20, 2019. Intervention:One hundred patients received intra-arterial urokinase after failed or incomplete MT using manual microcatheter injections. Main Outcomes and Measures:Primary safety outcome was the occurrence of symptomatic intracranial hemorrhage (sICH) according to the Prolyse in Acute Cerebral Thromboembolism II criteria. Secondary end points included 90-day mortality and 90-day functional independence (defined as modified Rankin Scale score of ≤2). Efficacy was evaluated angiographically, applying the Thrombolysis in Cerebral Infarction (TICI) scale. Results:After exclusion of patients with posterior circulation strokes and those treated with intra-arterial thrombolytics only, 993 patients were included in the final analyses (median age, 74.6 [interquartile range, 62.6-82.2] years; 505 [50.9%] women). Additional intra-arterial urokinase was administered in 100 patients (10.1%). The most common reason for administering intra-arterial urokinase was incomplete reperfusion (TICI<3) after MT (53 [53.0%]). After adjusting for baseline characteristics underlying case selection, intra-arterial urokinase was not associated with an increased risk of sICH (adjusted odds ratio [aOR], 0.81; 95% CI, 0.31-2.13) or 90-day mortality (aOR, 0.78; 95% CI, 0.43-1.40). Among 53 cases of partial or near-complete reperfusion and treated with intra-arterial urokinase, 32 (60.4%) had early reperfusion improvement, and 18 of 53 (34.0%) had an improvement in TICI grade. Correspondingly, patients treated with intra-arterial urokinase had higher rates of functional independence after adjusting for the selection bias favoring a priori poor TICI grades in the intra-arterial urokinase group (aOR, 1.93; 95% CI, 1.11-3.37). Conclusions and Relevance:In selected patients, adjunctive treatment with intra-arterial urokinase during or after MT was safe and improved angiographic reperfusion. Systemic evaluation of this approach in a multicenter prospective registry or a randomized clinical trial seems warranted. 10.1001/jamaneurol.2019.4192
    Determining the optimal dose of tenecteplase before endovascular therapy for ischemic stroke (EXTEND-IA TNK Part 2): A multicenter, randomized, controlled study. Campbell Bruce Cv,Mitchell Peter J,Churilov Leonid,Yassi Nawaf,Kleinig Timothy J,Yan Bernard,Thijs Vincent,Desmond Patricia M,Parsons Mark W,Donnan Geoffrey A,Davis Stephen M International journal of stroke : official journal of the International Stroke Society BACKGROUND AND HYPOTHESIS:Intravenous thrombolysis with tenecteplase is more effective than alteplase in achieving substantial reperfusion at initial angiographic assessment and improves functional outcome. However, the optimal dose of tenecteplase remains uncertain. We hypothesized that 0.40 mg/kg tenecteplase is superior to 0.25 mg/kg tenecteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset, in patients planned to undergo endovascular therapy. STUDY DESIGN:EXTEND-IA TNK part 2 is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale (mRS)≤3 (no upper age limit), absence of contraindications to intravenous thrombolysis, and large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal CT. Patients are randomized to IV tenecteplase at either 0.40 mg/kg (max 40 mg) or 0.25 mg/kg (max 25 mg) prior to thrombectomy. STUDY OUTCOMES:The primary outcome measure is reperfusion on the initial catheter angiogram, assessed as modified Treatment In Cerebral Infarction (mTICI) 2b/3, or the absence of retrievable intracranial thrombus. Secondary outcomes include mRS at day 90 and early neurological improvement (reduction in National Institutes of Health Stroke Scale (NIHSS) by ≥8 points or reaching 0-1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration: ClinicalTrials.gov NCT03340493. 10.1177/1747493019879652
    Combined intravenous and intraarterial revascularization therapy using MRI perfusion/diffusion mismatch selection for acute ischemic stroke at 3-6 h after symptom onset. Han Moon-Ku,Kim Sung Hyun,Ko Sang-Bae,Paik Nam-Jong,Kwon O-Ki,Lee Yong-Seok,Oh Chang-Wan,Kim Jae Hyoung,Park Seong-Ho,Bae Hee-Joon Neurocritical care BACKGROUND AND PURPOSE:Intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rt-PA) has demonstrated favorable clinical outcomes in a 3-6 h window in patients selected with perfusion/diffusion mismatch. However, the advantages of combined IV and intraarterial (IA) thrombolysis after 3 h of stroke onset are unexplored. METHODS:Acute ischemic stroke patients with persistent occlusion of intracranial large arteries were screened prospectively for thrombolysis by evaluating perfusion/diffusion mismatch on MRI. The IV rt-PA was initiated within 3-6 h, and additional urokinase (UK) was then administered via the IA route after angiography. RESULTS:Four patients had middle cerebral artery occlusion and one patient had an internal carotid artery occlusion. The median time from the symptom onset to the initiation of IV therapy and to the initiation of IA treatment was 215 +/- 30 min and 292 +/- 41 min, respectively. The median National Institutes of Health Stroke Scale (NIHSS) scores were as follows: initial, 13; immediately after IA treatment, 8; at 24 h, 5; and at 7 days, 3. The Thrombolysis in Myocardial Infarction (TIMI) score after the completion of thrombolysis was 2-3. Four patients without intracerebral hemorrhage recovered completely or exhibited mild disability and one patient with hemorrhage also demonstrated a favorable outcome. CONCLUSION:This preliminary result suggests that if a significant perfusion/diffusion mismatch on MRI is identified, a sequential combination thrombolysis of IV rt-PA and IA UK is potentially beneficial in moderate to severe acute ischemic stroke patients who are treated within 3-6 h after symptom onset. 10.1007/s12028-007-9046-7
    Thrombolysis in acute stroke without angiographically documented occlusion. Shi M-C,Chu F-N,Li C,Wang S-C European review for medical and pharmacological sciences OBJECTIVE:The aim of this study was to evaluate the safety and efficacy of intra-arterial thrombolysis (IAT) using urokinase (UK) in acute stroke patients without angiographically-documented occlusion, and to define predictors of clinical outcome. PATIENTS AND METHODS:We analyzed clinical and radiological data of acute ischemic stroke patients whose angiography did not show an arterial occlusion within six hours of symptom onset and who were further treated with IAT using UK. The primary outcome was a modified Rankin Scale (mRS) score ≤ 2 at 90 days' post procedure. RESULTS:In a thrombolysis database of 263 patients, we identified 51 patients without angiographically-documented arterial occlusion who received IAT with UK within six hours of symptom onset. The median baseline NIH stroke scale measurement was 11 (range: 8-20). From symptom onset, the mean time to treatment was 4.1 ± 1.3 h (median: 4.5 h; range: 1.5-6.0 h). Immediate and dramatically clinical improvement was seen in 29/51 (56.9%) patients. One patient (2.0%) developed a symptomatic intracranial hemorrhage. At three months, 38/51 (74.5%) patients were independent (mRS ≤2), 13/51 (25.5%) patients were dependent (mRS > 3), and no patients died. No predictors of clinical outcome were identified. CONCLUSIONS:IAT using UK can be a safe and efficacious therapy for the treatment of acute ischemic stroke in patients without angiographic occlusion. Approximately 75% of these patients had a favorable clinical outcome and thrombolysis-related symptomatic hemorrhage was low.
    Intraarterial thrombolysis within the first three hours after acute ischemic stroke in selected patients. Moonis Majaz Stroke 10.1161/STROKEAHA.109.549568
    Intra-arterial reteplase compared to urokinase for thrombolytic recanalization in acute ischemic stroke. Sugg R M,Noser E A,Shaltoni H M,Gonzales N R,Campbell M S,Weir R,Cacayorin E D,Grotta J C AJNR. American journal of neuroradiology BACKGROUND AND PURPOSE:Reteplase (RP) and urokinase (UK) are being used "off-label" to treat acute ischemic stroke. The safety and efficacy of intra-arterial RP or UK in the treatment of acute ischemic stroke, however, has yet to be proved. We aim to evaluate the safety and efficacy of RP compared with UK in acute ischemic stroke patients with large vessel occlusion. METHODS:Retrospective analysis was conducted of cases from a prospectively collected stroke data base on consecutive acute ischemic stroke patients with large vessel occlusion by digital subtraction angiography treated with intra-arterial RP or UK. Thrombolytic dosage, recanalization rate, intracerebral hemorrhage (ICH), mortality, and outcome were determined. RESULTS:Thirty-three patients received RP and 22 received UK (mean doses, 2.5 +/- 1.4 mg and 690,000 +/- 562,000 U, respectively). Vascular occlusions included 9 basilar arteries (BAs), 7 internal carotid arteries (ICAs), and 17 middle cerebral arteries (MCAs) with RP and 9 BAs, 4 ICAs, and 9 MCAs with UK. Median baseline National Institutes of Health Stroke Scales were as follows: 16 (range, 5-25; 81% > or = 10) with RP and 17 (range, 6-38; 85% > or =10) with UK. Mean time from symptom onset to thrombolytic initiation: 333 +/- 230 minutes with RP and 343 +/- 169 minutes with UK. Recanalization rates were as follows: 82% with RP and 64% with UK (P = .13). Symptomatic ICH rates were as follows: 12% with RP and 4.5% with UK (P = .50). The mortality rate was 24% with RP and 27% with UK (P = .8). CONCLUSION:Although limited in statistical power, our study suggests that, although IA thrombolysis with RP shows a trend for higher recanalization rates and hemorrhage rates, IA thrombolysis with RP is not significantly different in recanalization, outcome, mortality, and ICH compared with that of UK or rates reported with IA pro-UK.
    Intra-Arterial Thrombolysis after Unsuccessful Mechanical Thrombectomy in the STRATIS Registry. Zaidi S F,Castonguay A C,Zaidat O O,Mueller-Kronast N,Liebeskind D S,Salahuddin H,Jumaa M A AJNR. American journal of neuroradiology BACKGROUND AND PURPOSE: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. MATERIALS AND METHODS: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. RESULTS: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 (= .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%, = .08), good functional outcome (59.2% versus 46.6%, = .10), and lower rates of mortality (13.3% versus 23.3%, = .08) was seen in the intra-arterial rtPA cohort. Rates of symptomatic intracranial hemorrhage did not differ (0% versus 1.6%, = .54). CONCLUSIONS: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. 10.3174/ajnr.A6962
    Comparison of combined venous and arterial thrombolysis with primary arterial therapy using recombinant tissue plasminogen activator in acute ischemic stroke. Wolfe Thomas,Suarez Jose I,Tarr Robert W,Welter Elisabeth,Landis Dennis,Sunshine Jeffrey L,Zaidat Osama O Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association OBJECTIVE:We sought to compare the safety and efficacy of combined intravenous (IV) and intra-arterial (IA) thrombolysis with primary IA therapy using tissue plasminogen activator for acute ischemic stroke presenting within 6 hours of symptom onset. METHODS:We performed quasirandomization of a single institution's prospectively collected stroke database, comparing IV/IA (0.6 mg/kg IV < or = 60 mg, followed by 0.3 mg/kg IA < or = 30 mg) versus primary IA. Outcome measures include 90-day modified Rankin scale score, mortality, symptomatic intracerebral hemorrhage, and recanalization rates. Statistical analysis was performed using bivariate and propensity score methods. RESULTS:Of 1057 patients, 41 patients were treated with IV/IA, and 55 with IA. There was significant difference in time to treatment (mean of 151 minutes for the combined group and 261 minutes for the IA, P < .0001) and arterial tissue plasminogen activator dose (17.5 mg for IV/IA v 22.8 mg for IA only, P = .05). Propensity score matching yielded 25 patients in each group. Symptomatic intracerebral hemorrhage rate was 12% in each group. Mortality was 20% in the IV/IA group versus 16% in the IA group (relative risk 1.3 [0.4-4.1], P = .7). More patients in IV/IA group had modified Rankin scale score less than or equal to 2 (odds ratio 1.6 [0.5-5.8], P = .3). Recanalization was 64% with IV/IA versus 48% with IA (odds ratio 1.9 [0.5-7.0], P = .3). CONCLUSION:This study demonstrates that both combined IV/IA and primary IA recombinant tissue plasminogen activator therapy is feasible and safe in the treatment of acute ischemic stroke. Combined IV/IA therapy may be associated with an improvement in clinical outcome without a significant increase in the risk of symptomatic intracerebral hemorrhage and mortality compared with IA therapy. 10.1016/j.jstrokecerebrovasdis.2007.12.004
    Bridging therapy in acute ischemic stroke: a systematic review and meta-analysis. Mazighi Mikael,Meseguer Elena,Labreuche Julien,Amarenco Pierre Stroke BACKGROUND AND PURPOSE:Pending the results of randomized controlled trials, the benefit and safety of bridging therapy (combined intravenous and intra-arterial thrombolysis) remain to be determined. The aim of this analysis was to give reliable estimates of efficacy and safety outcomes of bridging therapy. METHODS:We conducted a systematic review of all studies using bridging therapy published between January 1966 and March 2011. RESULTS:The literature search identified 15 studies. The pooled estimate for recanalization rate was 69.6% (95% CI, 63.9%-75.0%). Meta-analysis on clinical outcomes showed a pooled estimate of 48.9% (95% CI, 42.9%-54.9%) for favorable outcome, 17.9% (95% CI, 12.7%-23.7%) for mortality, and 8.6% (95% CI, 6.8%-10.6%) for symptomatic intracranial hemorrhage. In meta-regression analysis, the shorter mean time to intravenous treatment, the greater the recanalization rate (per 10-minute decrease: OR, 1.24; 95% CI, 1.02-1.51) and the lower mortality rate (per 10-minute decrease: OR, 0.75; 95% CI, 0.60-0.94). By using the control groups of intravenous alteplase-treated patients in 8 studies, bridging therapy was associated with a favorable outcome (OR, 2.26; 95% CI, 1.16-4.40), but no differences in mortality or symptomatic intracranial hemorrhage outcomes were found. CONCLUSIONS:Bridging therapy is associated with acceptable safety and efficacy in stroke patients. Time to intravenous treatment is critical to improve recanalization rates and favorable outcomes. 10.1161/STROKEAHA.111.635029
    Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Higashida Randall T,Furlan Anthony J,Roberts Heidi,Tomsick Thomas,Connors Buddy,Barr John,Dillon William,Warach Steven,Broderick Joseph,Tilley Barbara,Sacks David, , Stroke BACKGROUND AND PURPOSE:The National Institutes of Health (NIH) estimates that stroke costs now exceed 45 billion dollars per year. Stroke is the third leading cause of death and one of the leading causes of adult disability in North America, Europe, and Asia. A number of well-designed randomized stroke trials and case series have now been reported in the literature to evaluate the safety and efficacy of thrombolytic therapy for the treatment of acute ischemic stroke. These stroke trials have included intravenous studies, intra-arterial studies, and combinations of both, as well as use of mechanical devices for removal of thromboemboli and of neuroprotectant drugs, alone or in combination with thrombolytic therapy. At this time, the only therapy demonstrated to improve outcomes from an acute stroke is thrombolysis of the clot responsible for the ischemic event. There is room for improvement in stroke lysis studies. Divergent criteria, with disparate reporting standards and definitions, have made direct comparisons between stroke trials difficult to compare and contrast in terms of overall patient outcomes and efficacy of treatment. There is a need for more uniform definitions of multiple variables such as collateral flow, degree of recanalization, assessment of perfusion, and infarct size. In addition, there are multiple unanswered questions that require further investigation, in particular, questions as to which patients are best treated with thrombolysis. One of the most important predictors of clinical success is time to treatment, with early treatment of <3 hours for intravenous tissue plasminogen activator and <6 hours for intra-arterial thrombolysis demonstrating significant improvement in terms of 90-day clinical outcome and reduced cerebral hemorrhage. It is possible that improved imaging that identifies the ischemic penumbra and distinguishes it from irreversibly infarcted tissue will more accurately select patients for therapy than duration of symptoms. There are additional problems in the assessment of patients eligible for thrombolysis. These include being able to predict whether a particular site of occlusion can be successfully revascularized, predict an individual patient's prognosis and outcome after revascularization, and in particular, to predict the development of intracerebral hemorrhage, with and without clinical deterioration. It is not clear to assume that achieving immediate flow restoration due to thrombolytic therapy implies clinical success and improved outcome. There is no simple correlation between recanalization and observed clinical benefit in all ischemic stroke patients, because other interactive variables, such as collateral circulation, the ischemic penumbra, lesion location and extent, time to treatment, and hemorrhagic conversion, are all interrelated to outcome. METHODS:This article was written under the auspices of the Technology Assessment Committees for both the American Society of Interventional and Therapeutic Neuroradiology and the Society of Interventional Radiology. The purpose of this document is to provide guidance for the ongoing study design of trials of intra-arterial cerebral thrombolysis in acute ischemic stroke. It serves as a background for the intra-arterial thrombolytic trials in North America and Europe, discusses limitations of thrombolytic therapy, defines predictors for success, and offers the rationale for the different considerations that might be important during the design of a clinical trial for intra-arterial thrombolysis in acute stroke. Included in this guidance document are suggestions for uniform reporting standards for such trials. These definitions and standards are mainly intended for research trials; however, they should also be helpful in clinical practice and applicable to all publications. This article serves to standardize reporting terminology and includes pretreatment assessment, neurologic evaluation with the NIH Stroke Scale score, imaging evaluation, occlusion sites, perfusion grades, follow-up imaging studies, and neurologic assessments. Moreover, previously used and established definitions for patient selection, outcome assessment, and data analysis are provided, with some possible variations on specific end points. This document is therefore targeted to help an investigator to critically review the scales and scores used previously in stroke trials. This article also seeks to standardize patient selection for treatment based on neurologic condition at presentation, baseline imaging studies, and utilization of standardized inclusion/exclusion criteria. It defines outcomes from therapy in phase I, II, and III studies. Statistical approaches are presented for analyzing outcomes from prospective, randomized trials with both primary and secondary variable analysis. A discussion on techniques for angiography, intra-arterial thrombolysis, anticoagulation, adjuvant therapy, and patient management after therapy is given, as well as recommendations for posttreatment evaluation, duration of follow-up, and reporting of disability outcomes. Imaging assessment before and after treatment is given. In the past, noncontrast CT brain scans were used as the initial screening examination of choice to exclude cerebral hemorrhage. However, it is now possible to quantify the volume of early infarct by using contiguous, discrete (nonhelical) images of 5 mm. In addition, CT angiography by helical scanning and 100 mL of intravenous contrast agent can be used expeditiously to obtain excellent vascular anatomy, define the occlusion site, obtain 2D and 3D reformatted vascular images, grade collateral blood flow, and perform tissue-perfusion studies to define transit times of a contrast bolus through specific tissue beds and regions of interest in the brain. Dynamic CT perfusion scans to assess the whole dynamics of a contrast agent transit curve can now be routinely obtained at many hospitals involved in these studies. The rationale, current status of this technology, and potential use in future clinical trials are given. Many hospitals are also performing MR brain studies at baseline in addition to, or instead of, CT scans. MRI has a high sensitivity and specificity for the diagnosis of ischemic stroke in the first several hours from symptom onset, identifies arterial occlusions, and characterizes ischemic pathology noninvasively. Case series have demonstrated and characterized the early detection of intraparenchymal hemorrhage and subarachnoid hemorrhage by MRI. Echo planar images, used for diffusion MRI and, in particular, perfusion MRI are inherently sensitive for the susceptibility changes caused by intraparenchymal blood products. Consequently, MRI has replaced CT to rule out acute hemorrhage in some centers. The rationale and the potential uses of MR scanning are provided. In addition to established criteria, technology is continuously evolving, and imaging techniques have been introduced that offer new insights into the pathophysiology of acute ischemic stroke. For example, a better patient stratification might be possible if CT and/or MRI brain scans are used not only as exclusion criteria but also to provide individual inclusion and exclusion criteria based on tissue physiology. Imaging techniques might also be used as a surrogate outcome measure in future thrombolytic trials. The context of a controlled study is the best environment to validate emerging imaging and treatment techniques. The final section details reporting standards for complications and adverse outcomes; defines serious adverse events, adverse events, and unanticipated adverse events; and describes severity of complications and their relation to treatment groups. Recommendations are made regarding comparing treatment groups, randomization and blinding, intention-to-treat analysis, quality-of-life analysis, and efficacy analysis. This document concludes with an analysis of general costs associated with therapy, a discussion regarding entry criteria, outcome measures, and the variability of assessment of the different stroke scales currently used in the literature is also featured. CONCLUSIONS:In summary, this article serves to provide a more uniform set of criteria for clinical trials and reporting outcomes used in designing stroke trials involving intra-arterial thrombolytic agents, either alone or in combination with other therapies. It is anticipated that by having a more uniform set of reporting standards, more meaningful analysis of the data and the literature will be able to be achieved. 10.1161/01.STR.0000082721.62796.09
    Is intra-arterial thrombolysis safe after full-dose intravenous recombinant tissue plasminogen activator for acute ischemic stroke? Shaltoni Hashem M,Albright Karen C,Gonzales Nicole R,Weir Raymond U,Khaja Aslam M,Sugg Rebecca M,Campbell Morgan S,Cacayorin Edwin D,Grotta James C,Noser Elizabeth A Stroke BACKGROUND AND PURPOSE:The optimal approach for acute ischemic stroke patients who do not respond to intravenous recombinant tissue plasminogen activator (IV rt-PA) is uncertain. This study evaluated the safety and response to intra-arterial thrombolytics (IATs) in patients unresponsive to full-dose IV rt-PA. METHODS:A case series from a prospectively collected database on consecutive acute ischemic stroke patients treated with IATs after 0.9 mg/kg IV rt-PA during a 7-year interval was collected. Primary outcome measures included symptomatic intracranial hemorrhage and mortality. As indicators of response, secondary outcome measures were recanalization and discharge disposition. RESULTS:Sixty-nine patients (mean+/-SD age, 60+/-13 years; range, 26 to 85 years; 55% male) with a median pretreatment National Institutes of Health Stroke Scale score of 18 (range, 6 to 39) were included. IV rt-PA was started at 124+/-32 minutes (median, 120 minutes) and IAT, at 288+/-57 minutes (median, 285 minutes). IATs consisted of reteplase (n=56), alteplase (n=7), and urokinase (n=6), with an average total dosage of 2.8 U, 8.6 mg, and 700 000 U, respectively. Symptomatic intracranial hemorrhage occurred in 4 of 69 (5.8%) patients; 3 cases were fatal. Recanalization was achieved in 50 (72.5%) and a favorable outcome (home or inpatient rehabilitation) in 38 (55%). CONCLUSIONS:IAT therapy after full-dose IV rt-PA in patients with persisting occlusion and/or lack of clinical improvement appears safe compared with IV rt-PA alone or low-dose IV rt-PA followed by IAT. A high rate of recanalization and favorable outcome can be achieved. 10.1161/01.STR.0000251720.25337.b0
    [Endovascular treatment and intra-arterial thrombolysis in acute ischemic stroke]. Escudero D,Molina R,Viña L,Rodríguez P,Marqués L,Fernández E,Forcelledo L,Otero J,Taboada F,Vega P,Murias E,Gil A Medicina intensiva OBJECTIVE:Analysis of the safety and efficacy of intra-arterial thrombolysis therapy and endovascular treatment in acute ischemic stroke. DESIGN AND AREA: An observational prospective study in the Intensive Care Unit. PATIENTS AND METHODS:16 patients had endovascular treatment. Epidemiological data, arterial occlusion site, time between stroke onset and treatment, treatment indication, NIHSS scale at admission and discharge from hospital, complications and functional outcome measured by modified Rankin scale (obtained by telephone survey) were collected. RESULTS:Ten male patients with a mean age of 59 years (29-74) were included. The mean stay in the ICU was 6 days (1-33). Seven patients required mechanical ventilation. Treatment indications were: intravenous thrombolysis failure in 4 patients, major vessel occlusion in 5, outside of the therapeutic window in 2, posterior circulation occlusion in 3, outside of the therapeutic window plus major vessel occlusion in 1 and intravenous thrombolysis contraindication in 1. The occlusion site was on posterior circulation in 3 and on carotid territories and branches in 13. Thrombolytic treatment used was Urokinase at a dose of 100,000-600,000IU. Four patients required mechanical embolectomy and 10 stent implantation. Complete recanalization was observed in 11 (69%) and partial in 4 (25%). Three evolved to brain death. Six patients (46%) had a favorable outcome (modified Rankin scale score ≤ 2). Technical complication was 1 femoral artery pseudoaneurysm. CONCLUSIONS:With the intra-arterial treatment, high rates of recanalization and favorable outcome are obtained with few complications. It could be indicated in patients with severe neurological injury (NIHSS ≥ 10), evolution time between 3-6h, intravenous thrombolysis contraindication and proximal arterial occlusion. 10.1016/j.medin.2010.01.010
    Predictors of hemorrhage following intra-arterial thrombolysis for acute ischemic stroke: the role of pial collateral formation. Christoforidis G A,Karakasis C,Mohammad Y,Caragine L P,Yang M,Slivka A P AJNR. American journal of neuroradiology BACKGROUND AND PURPOSE:The extent of pial collateral formation during acute ischemic stroke has been shown to influence outcomes. This study examines whether angiographic assessment of pial collateral formation is predictive of hemorrhagic transformation following intra-arterial thrombolysis (IAT) for acute ischemic stroke. MATERIALS AND METHODS:Rates of any hemorrhage and significant hemorrhage (>25 mL) were reviewed in 104 consecutive patients who underwent IAT following acute ischemic stroke. The influence of the anatomic extent of pial collateral formation on the rates of hemorrhage and significant hemorrhage relative to known predictors for hemorrhagic transformation (presenting systolic blood pressure, blood glucose level, platelet level, and National Institutes of Health Stroke Scale [NIHSS] score, history of diabetes, time to treatment, age, sex, occlusion site, and extent of reperfusion) was analyzed by using logistic regression models. RESULTS:Rates of any hemorrhage and significant hemorrhage were 25.2% (26/104) and 9.7% (10/104), respectively. The rate of significant hemorrhage was 25.0% (8/32) in patients with poor pial collaterals and 2.78% (2/72) in those with good pial collaterals (P = .0004, Pearson correlation). The rate of any hemorrhage was also significantly higher in patients with poor pial collaterals (40.6% versus 18.1%; P = .0142, Pearson correlation). Logistic regression analyses revealed that pial collateral formation (odds ratio [OR] = 3.04), history of diabetes (OR = 4.83), platelets <200,000/microL (OR = 2.95), and time to treatment <3 hours (OR = 12.0) were statistically significant predictors of hemorrhage, whereas pial collateral formation (OR = 13.1) and platelets <200,000/microL (OR = 8.1) were statistically significant predictors of significant hemorrhage. CONCLUSIONS:Poor pial collateral formation is associated with higher incidence and larger size of hemorrhage following IAT. 10.3174/ajnr.A1276
    Hemorrhage rates and outcomes when using up to 100 mg intra-arterial t-PA for thrombolysis in acute ischemic stroke. Christoforidis G A,Slivka A P,Karakasis C,Mohammad Y,Avutu B,Yang M,Bourekas E C,Chakeres D W,Slone H W,Yuk W T Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences This work presents a unique single center experience with intra-arterial delivery of tissue plasminogen activator (t-PA) doses as high as 100mg for thrombolysis. Hemorrhage volumes, hemorrhage rates, clinical outcomes and radiographic outcomes were assessed. Prospectively collected angiographic, clinical and laboratory information on 67 consecutive patients with acute ischemic stroke involving either the m1 segment of the middle cerebral artery, the intracranial internal carotid artery or the basilar artery were retrospectively analyzed. Patients who received more than 50 mg t-PA were compared with those patients receiving 50 mg or less. Outcome measures included: symptomatic hemorrhage, significant hemorrhage volume (greater than 25 ml), hemorrhage rate, change in National Institutes of Health stroke scale score at 24 hours and at hospital discharge, modified Rankin score at 90 days, in-hospital deaths, death within 90 days, reperfusion rate, and infarct volume. Multivariate logistic regression analysis demonstrated that t-PA dose over 50 mg was associated with higher rates of hemorrhage and larger hemorrhages. Poor pial collateral formation, poor reperfusion (less than 50% of the territory involved), and platelet count below 200 K/μL influenced hemorrhage. Limiting t-PA dose to 100mg rather than 50mg improved documented reperfusion rates from 37% to 61%. Restricting intra-arterial t-PA administration to 100mg rather than 50mg, is associated with higher overall reperfusion rates and improves overall outcomes, however, the hemorrhage rate is also elevated. Poor pial collateral formation and platelet count less than 200 K/μL may be reasons to curtail the use of higher t-PA dose to reduce hemorrhage rate. 10.1177/159101991001600312
    Outcomes of intra-arterial thrombolytic treatment in acute ischemic stroke patients with a matched defect on diffusion and perfusion MR images. Sandhu Gurpreet S,Parikh Pankit T,Hsu Daniel P,Blackham Kristine A,Tarr Robert W,Sunshine Jeffrey L Journal of neurointerventional surgery BACKGROUND:For acute ischemic stroke patients with matched defects on diffusion-perfusion imaging, the effects of reperfusion therapy remain poorly documented. The outcomes in a rare series of patients who had a matched defect and then underwent intra-arterial thrombolytic treatment (IAT) are reported. METHODS:Medical record and MR image review between 1 January 1998 and 15 October 2008 revealed only eight acute ischemic stroke patients satisfying the atypical combination of both matched defect and IAT. Successful recanalization (SR), favorable clinical response (FCR) and symptomatic intracranial hemorrhage (SICH) were defined respectively as thrombolysis in cerebral infarction score ≥2 after IAT, discharge National Institutes of Health Stroke Scale (NIHSS) 0-1/≥8 point decrease from baseline and intracranial hemorrhage in infarct zone with ≥4 point increase in NIHSS Score within 24 h of IAT. RESULTS:Median (range) baseline NIHSS score was 16.5 (6-22). Median (range) time delays from symptom onset to MRI and to IAT initiation were 200 (83-240) and 267.5 (160-360) min, respectively. Median (range) values of diffusion and perfusion lesion volumes were 119.5 (24-205) and 118 (18-207) ml. Out of eight patients, one (12.5%) achieved FCR, four (50%) had SICH and five (62.5%) died. Out of six patients with SR, one achieved FCR and four had SICH and died, and of two patients without SR, none had FCR or SICH and one died. CONCLUSION:Our data on rare patients with matched defects who nevertheless had attempted rescue with IAT confirm a poor risk-benefit ratio generated by low favorable responses and high mortality rates, especially in large ischemic lesions. 10.1136/jnis.2010.004168
    MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial. Fransen Puck S S,Beumer Debbie,Berkhemer Olvert A,van den Berg Lucie A,Lingsma Hester,van der Lugt Aad,van Zwam Wim H,van Oostenbrugge Robert J,Roos Yvo B W E M,Majoie Charles B,Dippel Diederik W J, Trials BACKGROUND:Endovascular or intra-arterial treatment (IAT) increases the likelihood of recanalization in patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion. However, a beneficial effect of IAT on functional recovery in patients with acute ischemic stroke remains unproven. The aim of this study is to assess the effect of IAT on functional outcome in patients with acute ischemic stroke. Additionally, we aim to assess the safety of IAT, and the effect on recanalization of different mechanical treatment modalities. METHODS/DESIGN:A multicenter randomized clinical trial with blinded outcome assessment. The active comparison is IAT versus no IAT. IAT may consist of intra-arterial thrombolysis with alteplase or urokinase, mechanical treatment or both. Mechanical treatment refers to retraction, aspiration, sonolysis, or use of a retrievable stent (stent-retriever). Patients with a relevant intracranial proximal arterial occlusion of the anterior circulation, who can be treated within 6 hours after stroke onset, are eligible. Treatment effect will be estimated with ordinal logistic regression (shift analysis); 500 patients will be included in the trial for a power of 80% to detect a shift leading to a decrease in dependency in 10% of treated patients. The primary outcome is the score on the modified Rankin scale at 90 days. Secondary outcomes are the National Institutes of Health stroke scale score at 24 hours, vessel patency at 24 hours, infarct size on day 5, and the occurrence of major bleeding during the first 5 days. DISCUSSION:If IAT leads to a 10% absolute reduction in poor outcome after stroke, careful implementation of the intervention could save approximately 1% of all new stroke cases from death or disability annually. TRIAL REGISTRATION:NTR1804 (7 May 2009)/ISRCTN10888758 (24 July 2012). 10.1186/1745-6215-15-343
    Intra-arterial thrombolysis for acute ischemic stroke in octogenarians. Mono Marie-Luise,Romagna Lorenz,Jung Simon,Arnold Marcel,Galimanis Aekaterini,Fischer Urs,Kohler Adrian,Ballinari Pietro,Brekenfeld Caspar,Gralla Jan,Schroth Gerhard,Mattle Heinrich P,Nedeltchev Krassen Cerebrovascular diseases (Basel, Switzerland) BACKGROUND:It is unclear whether octogenarians benefit from intra-arterial thrombolysis (IAT) for the treatment of acute ischemic stroke (AIS). The aim of the present study was to compare baseline characteristics, clinical outcome and complications of patients aged ≥80 with those of patients aged <80 years. METHODS:Forty-three octogenarians and 524 younger patients with AIS were treated with IAT. The modified Rankin scale (mRS) score was used to assess 3-month outcome. RESULTS:There was a female preponderance among octogenarians (63 vs. 37%, p = 0.015). Stroke severity, occlusion site, and time from stroke onset to IAT did not differ between the groups. Good recanalization (TIMI 2-3) was achieved in 65% of older and in 71% of younger patients (p = 0.449). Rates of symptomatic intracranial hemorrhage (ICH) were 6% in patients <80 years and 2% in octogenarians (p = 0.292). Favorable outcome (mRS 0-2) was less frequent among octogenarians (28 vs. 46%, p = 0.019), while mortality was higher (40 vs. 22%, p = 0.008). Octogenarians died more often from extracerebral complications than younger patients (59 vs. 27%, p = 0.008). CONCLUSIONS:Compared with younger patients, octogenarians did not have a significantly increased risk of symptomatic ICH after IAT. Although favorable outcome was less frequent and mortality rates were higher, IAT appeared to be safe in octogenarians. It seems reasonable to include octogenarians in randomized clinical trials to assess the balance of risk and benefit of IAT in this patient group. 10.1159/000333429
    Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial. Ciccone A,Valvassori L,Ponzio M,Ballabio E,Gasparotti R,Sessa M,Scomazzoni F,Tiraboschi P,Sterzi R, Journal of neurointerventional surgery OBJECTIVE To assess the feasibility, safety and preliminary efficacy of intra-arterial thrombolysis (IAT) compared with standard intravenous thrombolysis (IVT) for acute ischemic stroke. METHODS Eligible patients with ischemic stroke, who were devoid of contraindications, started IVT within 3 h or IAT as soon as possible within 6 h. Patients were randomized within 3 h of onset to receive either intravenous alteplase, in accordance with the current European labeling, or up to 0.9 mg/kg intra-arterial alteplase (maximum 90 mg), over 60 min into the thrombus, if necessary with mechanical clot disruption and/or retrieval. The purpose of the study was to determine the proportion of favorable outcome at 90 days. Safety endpoints included symptomatic intracranial hemorrhage (SICH), death and other serious adverse events. RESULTS 54 patients (25 IAT) were enrolled. Median time from stroke onset to start to treatment was 3 h 15 min for IAT and 2 h 35 min for IVT (p<0.001). Almost twice as many patients on IAT as those on IVT survived without residual disability (12/25 vs 8/29; OR 3.2; 95% CI 0.9 to 11.4; p=0.067). SICH occurred in 2/25 patients on IAT and in 4/29 on IVT (OR 0.5; CI 0.1 to 3.3; p=0.675). Mortality at day 7 was 5/25 (IAT) compared with 4/29 (IVT) (OR 1.6; CI 0.4 to 6.7; p=0.718). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS Rapid initiation of IAT is a safe and feasible alternative to IVT in acute ischemic stroke. 10.1136/jnis.2009.001388
    Intravenous versus intra-arterial thrombolysis in ischemic stroke: a systematic review and meta-analysis. Ma Qing-feng,Chu Chang-biao,Song Hai-qing PloS one BACKGROUND:Reperfusion following ischemic stroke can be attained by either intravenous thrombolysis (IVT) or intra-arterial thrombolysis (IAT). Only a limited number of randomized prospective studies have compared the efficacy and safety of IVT and IAT. This meta-analysis investigated possible clinical benefits of IAT relative to IVT in patients with acute ischemic stroke. METHODS:We searched the PubMed, Cochrane, and Google Scholar databases through October 2013 for manuscripts that describe the findings of randomized controlled or prospective studies that evaluated the outcomes of patients with ischemic stroke who were treated with IVT or IAT. The clinical outcome measures were score on the modified Rankin scale (mRS) and mortality at 90 days. A favorable outcome was defined as an mRS score of 0 to 2. RESULTS:For the mRS, the combined odds ratio (OR) of 3.28 (95% confidence interval (CI), 1.91 to 5.65, P < 0.001) indicated that patients who received IAT had a significantly higher chance for a favorable outcome than did those who received IVT. For mortality, the OR indicated that IAT therapy significantly reduced the proportion of patients who died within 90 days of the procedure (combined OR, 0.40; 95%CI, 0.17 to 0.92; P = 0.032). CONCLUSION:This meta-analysis determined that IAT conferred a significantly greater probability of achieving a favorable outcome compared with IVT. There was also a significant difference in mortality rates between IAT and IVT. The studies included in this analysis were small and heterogeneous; therefore, larger randomized prospective clinical studies are necessary to further investigate this issue. 10.1371/journal.pone.0116120
    Systematic review of outcome after ischemic stroke due to anterior circulation occlusion treated with intravenous, intra-arterial, or combined intravenous+intra-arterial thrombolysis. Mullen Michael T,Pisapia Jared M,Tilwa Shiv,Messé Steven R,Stein Sherman C Stroke BACKGROUND AND PURPOSE:The optimal approach to recanalization in acute ischemic stroke is unknown. We performed a literature review and meta-analysis comparing the relative efficacy of 6 reperfusion strategies: (1) 0.9 mg/kg intravenous tissue-type plasminogen activator; (2) intra-arterial chemical thrombolysis; (3) intra-arterial mechanical thrombolysis; (4) intra-arterial combined chemical/mechanical thrombolysis; (5) 0.6 mg/kg intravenous tissue-type plasminogen activator and intra-arterial thrombolysis; and (6) 0.9 mg/kg intravenous tissue-type plasminogen activator and intra-arterial thrombolysis. METHODS:A literature search in Medline, Embase, and the Cochrane database identified case series, observational studies, and treatment arms of randomized trials of anterior circulation arterial occlusion treated with thrombolytic therapy. Included studies had ≥10 subjects, mean time to treatment <6 hours, and treatment specific reporting of disability, death, and intracerebral hemorrhage. Multivariable metaregression evaluated the effects of treatment group on outcome at the same time as accounting for differences in baseline covariates. RESULTS:A total of 2986 abstracts were identified from which 54 studies (5019 subjects) were included. There were significant differences across groups in age (P=0.0008), baseline National Institutes of Health Stroke Scale (P=0.0002), and time to treatment initiation (P<0.0001). There were also differences in mean modified Rankin Scale (P<0.0001), mortality (P=0.0024), and symptomatic intracerebral hemorrhage (P=0.0305). Differences in modified Rankin Scale were not significant in the metaregression and likely attributable to differences in baseline covariates between studies. CONCLUSIONS:This study found no evidence that one reperfusion strategy is superior with respect to efficacy or safety, supporting clinical equipoise between reperfusion strategies. Intravenous tissue-type plasminogen activator remains the standard of care for acute ischemic stroke. Randomized clinical trials are necessary to determine the efficacy of alternative reperfusion strategies. Participation in such trials is strongly recommended. 10.1161/STROKEAHA.111.639211
    Local intra-arterial thrombolysis with urokinase for acute ischemic stroke before and after the approval of intravenous tissue plasminogen activator treatment in Taiwan. Yang Fu-Chi,Lin Chun-Chieh,Hsueh Chun-Jen,Lee Jiunn-Tay,Hsu Chang-Hung,Lee Kwo-Whei,Peng Giia-Sheun Annals of vascular surgery BACKGROUND:Local intra-arterial thrombolysis (LIT) has been previously suggested as an effective therapy for acute ischemic stroke. In this study, we describe our experience of using LIT for the treatment of Taiwanese patients with ischemic stroke at different vascular locations, before and after Alteplase was approved as a first-line treatment in Taiwan. The criteria required for the initiation of LIT have become more stringent after the approval of Alteplase (AA). METHODS:A retrospective analysis of medical records was conducted for 20 ischemic stroke patients treated with LIT; including 10 patients treated before and 10 patients treated after AA (we did not treat any of the patients in this study with AA). Urokinase was used for LIT treatment. Outcome measures included patient demographics, clinical characteristics, and clinical outcomes before and after LIT. Clinical outcomes were evaluated using four different stroke scales. RESULTS:The median National Institutes of Health stroke scale score (NIHSS) before treatment was reported to be 19.2 (range: 8-30). After AA, only one patient who had an occluded internal carotid artery (ICA) was treated with LIT. Among the 20 patients, 11 (55%) (five before AA and six after AA) reported having favorable or good clinical outcomes within 3 months of treatment, whereas five reported having poor outcomes (three before AA and two after AA), and the rest four patients died following treatment (two before AA and two after AA). Arterial recanalization was reported as complete in 10 patients (50%; seven middle cerebral artery [MCA] and three basilar artery; six before AA and four after AA), as incomplete in four patients (20%; one MCA and three basilar artery; one before AA and three after AA), and it failed in the remaining six patients (30%; two MCA and four ICA; three before AA and three after AA). Five patients (one MCA and four ICA) in whom recanalization had failed reported having poor outcomes, including one ICA patient who subsequently succumbed to the illness. Intracranial hemorrhagic and intraventricular hemorrhage transformation occurred in three and two patients, respectively. A case of intraventricular hemorrhage transformation after AA was also reported. CONCLUSION:On the basis of our experience, we found that LIT was of limited value in patients with ICA occlusion before AA approval. After AA, the outcomes in acute stroke patients, who were receiving urokinase therapy and who were carefully selected on the basis of the site of occlusion, were improved. 10.1016/j.avsg.2010.07.003
    The short- and long-term efficacies of endovascular interventions for the treatment of acute ischemic stroke patients. Yang Xingxiu,Jia Xiaohui,Ren Hua,Zhang Hongxing American journal of translational research OBJECTIVE:We aimed to investigate the short- and long-term efficacies of endovascular interventional therapy in acute ischemic stroke (AIS) patients. METHODS:In this retrospective study, 94 patients with AIS were recruited and divided into a control group (n=51) that was administered intra-arterial thrombolysis and an observation group (n=43) that was administered Solitaire stent thrombectomies. The postoperative recanalization and overall response rates were recorded in both groups. The hemodynamic parameters (high shear viscosity, low shear viscosity, plasma viscosity, and hematocrit), and the C-reactive protein, interleukin 6, and fibrinogen levels were compared between the two groups before and after the treatment. In addition, the National Institutes of Health Stroke Scale and the modified Rankin Scale scores were analyzed before the treatment and at 1 and 3 months after the treatment in both groups. After a 3-year follow-up, a survival analysis was also performed using the Kaplan-Meier survival method. RESULTS:The overall response and recanalization rates were higher in the observation group than they were in the control group (P<0.05). Before the treatment, there were no significant differences in the hemodynamic parameter, C-reactive protein, interleukin, 6 and fibrinogen levels in the two groups (P>0.05). After the treatment, the above levels in both groups decreased compared to their levels before the treatment, and the observation group had significantly lower levels than the control group (P<0.05). Moreover, no significant differences were seen in National Institutes of Health Stroke Scale and modified Rankin Scale scores between the two groups before the treatment (P>0.05). After the treatment, the above scores were decreased in both groups at 1 and 3 months compared to their pre-treatment levels, and the scores were significantly lower in the observation group than they were in the control group at 1 month after the treatment (P<0.05). After a 3-year follow-up, the Kaplan-Meier survival curves demonstrated that the survival times were significantly longer in the observation group than they were in the control group (P<0.05). CONCLUSION:Solitaire stent thrombectomy markedly ameliorates neurological deficits in AIS patients, improves their recanalization rated, regulates the inflammatory response and hemodynamics in the lesion areas, thus exerting favorable short- and long-term clinical effects.
    Intra-arterial administration of cell-based biological agents for ischemic stroke therapy. Spiliopoulos Stavros,Festas Georgios,Reppas Lazaros,Brountzos Elias Expert opinion on biological therapy INTRODUCTION:Ischemic stroke is becoming a primary cause of disability and death worldwide. To date, therapeutic options remain limited focusing on mechanical thrombolysis or administration of thrombolytic agents. However, these therapies do not promote neuroprotection and neuro-restoration of the ischemic area of the brain. AREAS COVERED:This review highlights the option of minimal invasive, intra-arterial, administration of biological agents for stroke therapy. The authors provide an update of all available studies, discuss issues that influence outcomes and describe future perspectives which aim to improve clinical outcomes. New therapeutic options based on cellular and molecular interactions following an ischemic brain event, will be highlighted. EXPERT OPINION:Intra-arterial administration of biological agents during trans-catheter thrombolysis or thrombectomy could limit neuronal cell death and facilitate regeneration or neurogenesis following ischemic brain injury. Despite the initial progress, further meticulous studies are needed in order to establish the clinical use of stem cell-induced neuroprotection and neuroregeneration. 10.1080/14712598.2019.1566454
    Techniques for endovascular treatment of acute ischemic stroke. Pierot L,Gawlitza M,Soize S Revue neurologique Early recanalization of occluded vessels in patients with acute ischemic stroke (AIS) by either intravenous thrombolysis (IVT) or endovascular revascularization has been shown to be associated with improved clinical outcomes and reduced mortality. Since the initial report regarding endovascular treatment (EVT) of AIS in 1983, endovascular techniques have been tremendously improved, advancing from intra-arterial administration of thrombolytic drugs to stent retrievers. IVT has been evaluated in several large randomized trials and has been shown to improve clinical outcomes at 90 days if treatment was initiated within 3h of stroke onset, while its benefit at 3-4.5h was subsequently demonstrated in the European Cooperative Acute Stroke Study (ECASS) III. Thus, EVT had to be evaluated against IVT. The first randomized controlled trials (RCTs) were published in 2013, and demonstrated no major differences between IVT and EVT for AIS, although these trials had important limitations. The positive results of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke (MR CLEAN) in the Netherlands, followed by five other positive RCTs, finally established the efficacy of mechanical thrombectomy (MT) with stent retrievers (also called 'stentrievers') in AIS due to large vessel occlusion within 6h of stroke onset. Currently, the European and US guidelines recommend MT with stent retrievers as a first-line treatment in the management of AIS. The recent publication of the DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late-Presenting Strokes Undergoing Neurointervention (DAWN) trial is expected to lead to extension of the time window for patients carefully selected by imaging. Thus, optimizing the selection of patients as well as the EVT procedures and techniques used is still an important goal to be evaluated in further trials. 10.1016/j.neurol.2017.09.005
    Comprehensive analysis of intra-arterial treatment for acute ischemic stroke due to cervical artery dissection. Jensen Judd,Salottolo Kristin,Frei Donald,Loy David,McCarthy Kathryn,Wagner Jeffrey,Whaley Michelle,Bellon Richard,Bar-Or David Journal of neurointerventional surgery OBJECTIVE:The safety and efficacy of intra-arterial treatment (IAT) in patients with acute ischemic stroke (AIS) due to cervical artery dissection (CeAD) has not been formally studied. The purpose of this study was twofold: first, describe a large series with CeAD treated with IAT; second, analyze outcomes with CeAD receiving IAT versus (a) CeAD not treated with IAT, (b) CeAD receiving intravenous thrombolysis (IVT) alone, and (c) non-CeAD mechanism of AIS receiving IAT. DESIGN:Demographics, clinical characteristics, treatment, and outcomes were summarized for all CeAD patients treated with IAT from January 2010 to May 2015. Outcomes included favorable 90 day modified Rankin Scale (mRS) score of 0-2, symptomatic intracerebral hemorrhage (sICH), recanalization (Thrombolysis in Cerebral Infarction 2b-3), procedural complications, and mortality. Outcomes were analyzed with χ tests and multivariate logistic regression. RESULTS:There were 161 patients with CeAD: 24 were treated with IAT and comprised our target population. Dissections were more common in the internal carotid (n=18) than in the vertebral arteries (n=6). All but one patient had intracranial embolus. IAT techniques included thrombectomy (n=19), IA thrombolysis (n=17), stent (n=14), and angioplasty (n=7). Outcomes included favorable 90 day mRS score of 0-2 in 63%, 4 deaths, 1 sICH, and 3 procedural complications. After adjustment, favorable mRS in our target population was similar to comparison populations: (a) in CeAD, IAT versus no IAT (OR 0.62, p=0.56); (b) In CeAD, IAT versus IVT alone (OR 1.32, p=0.79); and (c) IAT in CeAD versus non-CeAD mechanism of AIS (OR 0.58, p=0.34). CONCLUSIONS:IAT is a valid alternative therapeutic option for AIS caused by CeAD due to the low complication rate and excellent outcomes observed in this study. 10.1136/neurintsurg-2016-012421
    Intra-arterial adjuvant tirofiban after unsuccessful intra-arterial thrombolysis of acute ischemic stroke: preliminary experience in 16 patients. Kwon Jee-Hyun,Shin Shang Hun,Weon Young Cheol,Hwang Jae Cheol,Baik Seung Kug Neuroradiology INTRODUCTION:Intra-arterial (IA) thrombolysis with plasminogen activator is well-known, but the use of IA tirofiban as an adjuvant for IA thrombolysis is not well-known. We investigated the feasibility of IA tirofiban as an adjuvant after unsuccessful IA recanalization with urokinase (UK) for acute ischemic stroke. METHODS:We retrospectively analyzed all 16 consecutive patients (11 men and five women; mean age, 61.3 years; range, 36-85 years) who were treated with IA tirofiban after isolated IA thrombolysis with UK or bridging therapy with systemic recombinant tissue plasminogen activator (rt-PA; 0.6 mg/Kg) and IA UK for acute ischemic stroke. Outcome measures included angiographic recanalization (thrombolysis in cerebral infarction, TICI), symptomatic and asymptomatic intracerebral hemorrhage (ICH), mortality, and functional independence at 3 months (modified Rankin Scale, 0-2). RESULTS:Among the 16 patients treated with IA tirofiban as an adjuvant, 10 patients had conventional dose (<25 ug/kg, bolus) and six patients had high dose (≥25 ug/kg, bolus) of IA tirofiban after unsuccessful IA thrombolysis whether systemic rt-PA used or not. Successful angiographic recanalization (TICI grade 2b or 3) was achieved in 13 patients (13/16) and a functional independence at 3 months in eight patients (8/16). Three months after therapy, three patients had died. There were two patients of symptomatic ICH and four asymptomatic ICH. CONCLUSION:Conventional dose of IA tirofiban as an adjuvant during IA thrombolysis for acute ischemic stroke seems feasible. However, further dose escalation studies should be performed regarding the IA use of tirofiban for acute ischemic stroke. 10.1007/s00234-011-0939-y
    Pharmacological recanalization therapy in acute ischemic stroke - evolution, current state and perspectives of intravenous and intra-arterial thrombolysis. Hlavica Martin,Diepers Michael,Garcia-Esperon Carlos,Ineichen Benjamin Victor,Nedeltchev Krassen,Kahles Timo,Remonda Luca Journal of neuroradiology. Journal de neuroradiologie Stroke ranges third in mortality in industrialized nations and is the leading cause of disability in older people. Ischemic stroke following thrombotic or embolic vessel occlusion accounts for more than 80% of cerebrovascular events. Immediate restoration of cerebral blood flow is crucial in order to salvage brain tissue. Experimental thrombolytic treatment was introduced into the clinical setting in the late 1950s and required more than 30 years of intense research till its breakthrough and subsequent routine clinical use by the presentation of the NINDS trial results in 1995. To date, intravenous thrombolysis with tissue plasminogen activator up to 4.5 h after symptom onset is the only proven reperfusion therapy for acute ischemic stroke. In this review, we summarize the evolution of intravenous and intra-arterial pharmacological recanalization therapies in acute ischemic stroke and present current clinical practice as well as its promising perspectives. 10.1016/j.neurad.2014.11.004
    Intra-arterial thrombolysis vs. standard treatment or intravenous thrombolysis in adults with acute ischemic stroke: a systematic review and meta-analysis. Nam Julian,Jing He,O'Reilly Daria International journal of stroke : official journal of the International Stroke Society BACKGROUND:Recent evidence has suggested that intra-arterial thrombolysis may provide benefit beyond intravenous thrombolysis in ischemic stroke patients. Previous meta-analyses have only compared intra-arterial thrombolysis with standard treatment without thrombolysis. The objective was to review the benefits and harms of intra-arterial thrombolysis in ischemic stroke patients. METHODS:We undertook a meta-analysis of randomized controlled trials comparing the efficacy and safety of intra-arterial thrombolysis with either standard treatment or intravenous thrombolysis following acute ischemic stroke. Primary outcomes included poor functional outcomes (modified Rankin Scale 3-6), mortality, and symptomatic intracranial hemorrhage. Study quality was assessed, and outcomes were stratified by comparison treatment received. RESULTS:Four trials (n = 351) comparing intra-arterial thrombolysis with standard treatment were identified. Intra-arterial thrombolysis reduced the risk of poor functional outcomes (modified Rankin Scale 3-6) [relative risk (RR) = 0·80; 95% confidence interval = 0·67-0·95; P = 0·01]. Mortality was not increased (RR = 0·82; 95% confidence interval = 0·56-1·21; P = 0·32); however, risk of symptomatic intracranial hemorrhage was nearly four times more likely (RR = 3·90; 95% confidence interval = 1·41-10·76; P = 0·006). Two trials (n = 81) comparing intra-arterial thrombolysis with intravenous thrombolysis were identified. Intra-arterial thrombolysis was not found to reduce poor functional outcomes (modified Rankin Scale 3-6) (RR = 0·68; 95% confidence interval = 0·46-1·00; P = 0·05). Mortality was not increased (RR = 1·12; 95% confidence interval = 0·47-2·68; P = 0·79); neither was symptomatic intracranial hemorrhage (RR = 1·13; 95% confidence interval = 0·32-3·99; P = 0·85). Differences in time from symptom onset-to-treatment and type of thrombolytic administered were found across the trials. CONCLUSIONS:This analysis finds a modest benefit of intra-arterial thrombolysis over standard treatment, although it does not find a clear benefit of intra-arterial thrombolysis over intravenous thrombolysis in acute ischemic stroke patients. However, few trials, small sample sizes, and indirectness limit the strength of evidence. 10.1111/j.1747-4949.2012.00914.x
    Intra-Arterial Alteplase Thrombolysis during Mechanical Thrombectomy for Acute Ischemic Stroke. Heiferman Daniel M,Li Daphne D,Pecoraro Nathan C,Smolenski Angela M,Tsimpas Asterios,Ashley William W Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:Intra-arterial alteplase (IA tPA) is commonly used during mechanical thrombectomy for acute ischemic stroke in patients with large-vessel occlusion, but specific indications and applications for its use remain undefined. METHODS:We analyzed 40 patients who underwent stent-retriever mechanical thrombectomy, 28 of whom received adjunctive IA tPA. To our knowledge, this is the largest cohort with this concomitant treatment reported in the literature in the post-mechanical thrombectomy trial era. RESULTS:Between patients with and without IA tPA, rates of hemorrhagic conversion, neurologic outcome, and mortality were equivalent, with a trend toward improved angiographic revascularization observed in the IA tPA group. CONCLUSIONS:IA tPA is a safe adjunct to mechanical thrombectomy, and more investigation is warranted to understand ideal indications and dosage methodologies. 10.1016/j.jstrokecerebrovasdis.2017.07.031
    Intra-Arterial Thrombolysis Improves the Prognosis of Acute Ischemic Stroke Patients without Large Vessel Occlusion. Shang Shuyi,Zhao Wenbo,Li Chuanhui,Dong Kai,Song Haiqing,Meng Ran,Ren Changhong,Duan Jiangang,Ji Xunming European neurology BACKGROUND AND PURPOSE:Intravenous thrombolysis is known as the only effective reperfusion therapy for acute ischemic stroke (AIS) caused by small branches occlusion. However, it is still unclear whether intra-arterial thrombolysis (IAT) is safe and effective for patients without detectable arterial occlusion. This study evaluated the safety and efficacy of IAT in these patients. METHODS:Data were collected on consecutive patients from December 2012 to February 2017 at the Xuanwu Hospital, Capital Medical University. AIS patients without large artery occlusion during digital subtraction angiography (DSA) were divided into 2 groups: (1) Intra-arterial urokinase thrombolysis group (UK group): received intra-arterial urokinase thrombolysis treatment; (2) Control group: cerebral angiography examination only. The primary outcome was 3-month favorable functional outcome (modified Rankin Scale 0-2). RESULTS:A total of 48 patients received urokinase thrombolysis, and 34 patients underwent DSA examination only. The UK group had more frequent favorable functional outcomes (70.8 vs. 50%, p = 0.032) at 3-month follow-up and higher score of National Institutes of Health Stroke Scale improvement on the second day (p = 0.007). One patient (2%) had symptomatic intracerebral hemorrhage and 3 patients (6.3%) had asymptomatic intracerebral hemorrhage (asICH) in the UK group. One patient (3.3%) had asICH in the control group. There were no significant differences about ICH. CONCLUSIONS:AIS caused by small branches occlusion could benefit from intra-arterial urokinase thrombolysis, and the risk of intracerebral hemorrhage was not significantly higher. 10.1159/000496936
    Adjuvant intra-arterial rt-PA injection at the initially deployed solitaire stent enhances the efficacy of mechanical thrombectomy in acute ischemic stroke. Yi Ting-Yu,Chen Wen-Huo,Wu Yan-Min,Zhang Mei-Fang,Lin Ding-Lai,Lin Xiao-Hui Journal of the neurological sciences BACKGROUND:Both 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 METHODS:A 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. RESULTS:Compared 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). CONCLUSION:Mechanical 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. 10.1016/j.jns.2018.01.012