Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000.

CONTEXT: Intravenous tissue-type plasminogen activator (tPA) therapy using the National Institute of Neurological Disorders and Stroke criteria has been given with variable safety to less than 5% of the patients who have ischemic strokes nationwide. Our center is experienced in treating large numbers of stroke patients with intravenous tPA. OBJECTIVE: To report our total 4-year experience in the treatment of consecutive patients who had an ischemic stroke. DESIGN: Prospective inception cohort registry of all patients seen by our stroke team and an additional retrospective medical record review of all patients treated between January 1, 1996, and June 1, 2000. SETTING: A veteran stroke team composed of fellows and stroke-specialty faculty servicing 1 university and 3 community hospitals in a large urban setting. PATIENTS: Consecutive patients with ischemic stroke treated within the first 3 hours of symptom onset. INTERVENTION: According to the National Institute of Neurological Disorders and Stroke protocol, 0.9 mg/kg of intravenous tissue-type plasminogen activator was administered. MAIN OUTCOME MEASURES: Number and proportion treated, patient demographics, time to treatment, hemorrhage rates, and clinical outcome. RESULTS: A total of 269 patients were treated between January 1, 1996, and June 1, 2000. Their mean age was 68 years (age range, 24-93 years); 48% were women. This represented 9% of all patients admitted with symptoms of cerebral ischemia at our most active hospital (over the final 6 months, 13% of all patients with symptoms of cerebral ischemia and 15% of all acute ischemic stroke patients). Before treatment the mean +/- SD National Institutes of Health Stroke Scale (NIHSS) score was 14.4 +/- 6.1 points (median, 14 points; range, 4-33 points). A tPA bolus was given at 137 minutes (range, 30-180 minutes); 28% of the patients were treated within 2 hours. The mean door-to-needle time was 70 minutes (range, 10-129 minutes). The symptomatic intracerebral hemorrhage rate was 5.6% of those patients with a second set of brain scans (4.5% of all patients), with a declining trend from 1996 to 2000. Protocol violations were found in 13% of all patients; the symptomatic intracerebral hemorrhage rate in these patients was 15%. At 24 hours, the NIHSS score was 10 +/- 8 points (median, 8 points; range, 0-36 points). In-hospital mortality was 15% and the patients' discharge NIHSS scores were 7 +/- 7 points (median, 3 points; range, 0-35 points). CONCLUSIONS: Intravenous tPA therapy can be given to up to 15% of the patients with acute ischemic stroke with a low risk of symptomatic intracerebral hemorrhage. Successful experience with intravenous tPA therapy depends on the experience and organization of the treating team and adherence to published guidelines.     

Thrombolysis for stroke caused by infective endocarditis: an illustrative case and review of the literature

Infective endocarditis represents a classical contra-indication to thrombolysis for acute ischemic stroke due to a potential increased risk of intracranial hemorrhage. However, some case reports have suggested safety and potential efficacy of intravenous or intra-arterial thrombolysis in stroke related to infective endocarditis. We present a case of ischemic stroke related to infective endocarditis who was treated with intravenous tissue plasminogen activator within the first 3 h of symptoms onset and subsequently developed symptomatic multifocal intracerebral hemorrhages, and summarize currently available data on this issue.     

Intravenous rtPA thrombolysis in acute ischemic stroke

Early intravenous thrombolysis within the first three hours has been considered in the United States as the first proven treatment in acute ischemic stroke. However, not all patients will respond to this therapy which is also associated with a risk of symptomatic, including fatal, intracranial hemorrhage. This overview addresses the issue of efficacy and safety of intravenous alteplase (tPA) in acute cerebral ischemia. The rationale for thrombolytic therapy and its limits are described. The controlled studies show that intravenous tPA is effective and safe when given under restrictive conditions within 3 hours after stroke onset, but the data for a larger therapeutic window between 3 and 6 hours remain controversial. The expected functional improvement and the risk of intracranial hemorrhage greatly depend on selective clinical and imaging criteria. For this purpose, MRI, using the diffusion- and perfusion-weighted sequences combined with MR- angiography, should be preferred to CT scan in the next future. Applicability of tPA thrombolysis in current neurological practice in Belgium is discussed. Before its generalization, this therapy should be restricted to specialized stroke centers and all treated patients should be recorded in a central data bank to guarantee continued surveillance.     

Acute anterior circulation stroke: recanalization using clot angioplasty

BACKGROUND AND PURPOSE: Different strategies have been employed to recanalize acutely occluded middle cerebral and internal carotid arteries (ICA) in the setting of acute stroke including intravenous and intra-arterial tPA. However, pharmaceutical thrombolysis alone, may not be effective in patients with a large amount of clot volume (complete M1, terminal internal carotid artery). We report our initial experience with endovascular clot disruption using a soft silicone balloon in addition to intravenous or intra-arterial thrombolysis with tPA. METHODS: This is a retrospective review of nine patients with symptoms of acute stroke from clot in the middle cerebral or internal carotid territories who were treated with intracranial balloon angioplasty. All patients presented with symptoms of acute anterior circulation stroke less than six hours from onset. Patients in whom computed tomography (CT) angiography confirmed the presence of large vessel clot (terminal ICA, M1 or proximal M2) were included in the study. A CT perfusion was performed providing maps of cerebral blood volume, flow and mean transit time. If the patient presented less than three hours from onset then intravenous tissue plasminogen activator (tPA) was also administered. Intra-arterial tPA was delivered into the clot. If the volume of clot was judged to be significant by the treating neurointerventionist, then a limited trial of tPA was administered intra-arterially followed by balloon angioplasty of persistant clot. The time from imaging to vessel recanalization was recorded. Clinical outcomes were assessed using the modified Rankin scale and Barthel Index. RESULTS: Diagnostic CT perfusion studies were performed in 7 (78%), all of which showed a significant amount of salvageable tissue as judged by the treating neurointerventionist and neurologist. Recanalization (TIMI 2 or 3) was possible in 8 (89%). There were no cases of symptomatic intracranial hemorrhage and 2 (22%) asymptomatic hemorrhages. The average time from performance of the initial emergency CT to vessel recanalization was 2.1 hours with mean time from symptom onset to vessel recanalization of 4.1 hours. Five (56%) patients had good outcomes, 1 (11%) had mild and 3 (33%) had moderate to severe disability. CONCLUSION: Clot angioplasty can potentially shorten recanalization times in well-selected patients and can be an effective complimentary procedure in patients with tPA resistant clot. Angioplasty can be performed with a very low complication rate using the technique described and may be associated with good outcomes.     

Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: the PROACT II trial.

OBJECTIVE: To analyze the frequency, clinical characteristics, and predictors of symptomatic intracerebral hemorrhage (ICH) after intraarterial (IA) thrombolysis with recombinant pro-urokinase (r-proUK) in acute ischemic stroke. METHOD: The authors conducted an exploratory analysis of symptomatic ICH from a randomized, controlled clinical trial of IA thrombolysis with r-proUK for patients with angiographically documented occlusion of the middle cerebral artery within 6 hours from stroke onset. Patients (n = 180) were randomized in a ratio of 2:1 to either 9 mg IA r-proUK over 120 minutes plus IV fixed-dose heparin or IV fixed-dose heparin alone. As opposed to intention to treat, this analysis was based on "treatment received" and includes 110 patients given r-proUK and 64 who did not receive any thrombolytic agent. The remaining six patients received out-of-protocol urokinase and were excluded from analysis. The authors analyzed centrally adjudicated ICH with associated neurologic deterioration (increase in NIH Stroke Scale [NIHSS] score of > or =4 points) within 36 hours of treatment initiation. RESULTS: Symptomatic ICH occurred in 12 of 110 patients (10.9%) treated with r-proUK and in two of 64 (3.1%) receiving heparin alone. ICH symptoms in r-proUK-treated patients occurred at a mean of 10.2 +/- 7.4 hours after the start of treatment. Mortality after symptomatic ICH was 83% (10/12 patients). Only blood glucose was significantly associated with symptomatic ICH in r-proUK-treated patients based on univariate analyses of 24 variables: patients with baseline glucose >200 mg/dL experienced a 36% risk of symptomatic ICH compared with 9% for those with < or =200 mg/dL (p = 0.022; relative risk, 4.2; 95% CI, 1.04 to 11.7). CONCLUSIONS: Symptomatic ICH after IA thrombolysis with r-proUK for acute ischemic stroke occurs early after treatment and has high mortality. The risk of symptomatic ICH may be increased in patients with a blood glucose >200 mg/dL at stroke onset.     

重组组织型纤溶酶原激活剂静脉溶栓治疗心源性脑栓塞的临床研究

目的 探讨重组组织型纤溶酶原激活剂(rt-PA)治疗急性心源性脑栓塞(CCE)的安全性及疗效.方法 符合入选标准的患者溶栓组19例,对照组21例,发病3h内给予rt-PA(0.9 mg/kg)静脉溶栓治疗,采用美国国立卫生院神经功能缺损评分及Barthel指数,评定溶栓前及溶栓后2、6 h、1、3、7、30、90 d的疗效及安全性.结果 溶栓后各时间点NIHSS评分均有显著改善(P＜0.05),溶栓组临床总有效率89.5%,对照组38.1%.溶栓组脑出血发生率为10.5%,其中症状性脑出血发生率5.26%.对照组脑出血发生率19%,其中症状性脑出血发生率4.76%.溶栓组病死率0,对照组病死率9.5%.结论 CCE患者3 h内给予rt-PA静脉溶栓治疗是安全有效的.     

Intravenous tPA in acute ischemic stroke related to internal carotid artery dissection

The authors describe the outcomes in 11 patients who had acute ischemic stroke related to internal carotid artery (ICA) dissection and were treated with IV tissue plasminogen activator (tPA). One symptomatic intracerebral hemorrhage occurred 36 hours after tPA was given. The mean day 90 modified Rankin Scale (m-RS) score was 2.4 (+/-1.6). No death was observed at 3 months. Four patients of 11 (36.4%) made an excellent recovery (day 90 m-RS score: 0 to 1). This study demonstrates the feasibility of IV thrombolysis with tPA (0.8 mg/kg) in ischemic stroke related to ICA dissection within the first 7 hours.     

The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators

BACKGROUND AND PURPOSE: The Thrombolytic Therapy in Acute Ischemic Stroke Study, which started in August of 1991, was designed to assess the efficacy and safety of intravenous rtPA (alteplase) in patients with acute (0 to 6 hours) ischemic stroke. In October 1993 enrollment was halted because of Safety Committee (DMSB) concerns. In December 1993 the time window was changed to 0 to 5 hours, and it was decided to restart enrollment as a separate study (part B). We report here the results of the original study (part A), focusing on evaluating the safety and efficacy of rtPA given between 0 and 6 hours after stroke onset. METHODS: This investigation was a phase II, placebo-controlled, double-blind, randomized study utilizing 0.9 mg/kg IV rtPA or placebo over 1 hour, which was conducted at university and community sites in North America. Except for time to treatment, enrollment criteria were very similar to those of the NINDS rtPA stroke study. Primary efficacy end points were the number of patients with a decrease of 4 or more points on the National Institutes of Health Stroke Scale (NIHSS) at 24 hours and day 30, along with infarct volume at day 30. Secondary end points included mortality and functional recoveries on the Barthel Index and Modified Rankin scale at days 30 and 90. RESULTS: A total of 142 patients were enrolled at 42 sites in North America, including 22 <3 hours (15%) and 46 between 5 and 6 hours (32%). The groups were well matched on baseline characteristics, including NIHSS (mean of 13 for both). For the primary end points, a higher percentage of rtPA patients had a 4-point improvement at 24 hours (placebo 21%, rtPA 40%; P=0.02); however, this early effect was reversed by 30 days, with more placebo patients having a 4-point improvement (75%) than patients treated with rtPA (60%, P=0.05). Treatment with rtPA significantly increased the rate of symptomatic intracerebral hemorrhage within 10 days (11% versus 0%, P<0.01) and mortality at 90 days (23% versus 7%, P<0.01). CONCLUSIONS: This study found no significant rtPA benefit on any of the planned efficacy end points at 30 and 90 days in patients treated between 0 and 6 hours after stroke onset. These negative results apply to patients treated after 3 hours, because only 15% of the patients were enrolled before 3 hours. The risk of symptomatic intracerebral hemorrhage was increased with rtPA treatment, particularly in patients treated between 5 and 6 hours after onset. These results do not support the use of intravenous rtPA for stroke treatment >3 hours after onset.     

经颅多普勒超声辅助动脉溶栓治疗急性缺血性卒中的临床研究

目的 观察应用经颅多普勒超声(TCD)辅助动脉接触性溶栓治疗急性缺血性卒中的临床疗效.方法 对北京军区总医院附属八一脑科医院自2010年8月至2011年4月收治的22例急性缺血性卒中患者(大脑中动脉闭塞13例,基底动脉闭塞9例)行动脉内超选择插管至闭塞动脉,注入重组人组织型纤溶酶原激活剂(rt-PA)20 mg进行接触性溶栓治疗,同时应用TCD对闭塞动脉进行低频(2 MHz)、低强度(0.25 W/cm2)超声辅助溶栓治疗.术后即刻及24h时复查头颅CT,观察动脉再通率、颅内出血率,并对术前术后美国国立卫生研究院卒中量表(NIHSS)评分及Barthel指数评分进行比较.结果 22例患者溶栓治疗后动脉再通率为77.27％(17/22),其中完全开通率为22.73％(5/22),部分开通率为54.55％(12/22);出现无症状性颅内出血3例(13.63％),均未发生症状性颅内出血;术后NIHSS评分及Barthel指数评分较术前明显提高,显示神经功能恢复良好.结论 对急性缺血性卒中患者在有效时间窗内应用低频TCD辅助小剂量rt-PA动脉接触性溶栓治疗,可显著提高闭塞动脉的再通率,明显减少颅内出血的发生,改善患者的预后,具有良好的临床疗效及安全性.     

Intravenous thrombolysis in proximal middle cerebral artery occlusion

Subgroup analyses of data from an open-label study of intravenous recombinant tissue plasminogen activator (rt-PA) administered to stroke patients were performed. Clinical outcome and incidence of intracranial hemorrhage were evaluated in 20 patients diagnosed by transcranial Doppler ultrasound as having proximal middle cerebral artery (MCA) occlusion. Additionally early infarct signs and size of final infarction were assessed. A favorable outcome (mRS 0-2) was seen in 30% of all patients. The incidence of symptomatic intracranial hematoma (10%) in patients with proximal MCA occlusion was higher than the overall hemorrhage rate of intravenous rt-PA treatment, but comparable to the data on intra-arterial thrombolysis in this stroke subgroup. All patients except 1 developed ischemic infarction in the MCA territory. Intravenous rt-PA treatment within 3 h may also be effective in patients with proximal MCA occlusion. The risk of intracerebral hematoma does not seem to be greater than in intra-arterial thrombolysis.     

Clinical and imaging predictors of intracerebral haemorrhage in stroke patients treated with intravenous tissue plasminogen activator

OBJECTIVE: To evaluate clinical, biological, and pretreatment imaging variables for predictors of tissue plasminogen activator (tPA) related intracerebral haemorrhage (ICH) in stroke patients. METHODS: 48 consecutive patients with hemispheric stroke were given intravenous tPA within seven hours of symptom onset, after computed tomography (CT) and magnetic resonance imaging (MRI) of the brain. Baseline diffusion weighted (DWI) and perfusion weighted (PWI) imaging volumes, time to peak, mean transit time, regional cerebral blood flow index, and regional cerebral blood volume were evaluated. The distribution of apparent diffusion coefficient (ADC) values was determined within each DWI lesion. RESULTS: The symptomatic ICH rate was 8.3% (four of 48); the rate for any ICH was 43.8% (21 of 48). Univariate analysis showed that age, weight, history of hyperlipidaemia, baseline NIHSS score, glucose level, red blood cell count, and lacunar state on MRI were associated with ICH. However, mean 24 hour systolic blood pressure and a hyperdense artery sign on pretreatment CT were the only independent predictors of ICH. Patients with a hyperdense artery sign had larger pretreatment PWI and DWI lesion volumes and a higher NIHSS score. Analysis of the distribution of ADC values within DWI lesions showed that a greater percentage of pixels had lower ADCs (< 400 x 10(-6) mm(2)/s) in patients who experienced ICH than in those who did not. CONCLUSION: Key clinical and biological variables, pretreatment CT signs, and MRI indices are associated with tPA related intracerebral haemorrhage.     

Strategy for circulatory disturbance]

A meta-analysis by the Cochrane Stroke Group (CSG) showed that thrombolytic therapy increased deaths as well as symptomatic and fatal intracranial hemorrhage within the first seven to 10 days and at final follow-up, although these risks are offset by a reduction in disability in survivors, so that there is overall a significant net reduction in the proportion of patients dead or dependent. Trials testing intravenous (i.v.) tPA suggest that it may be associated with less hazard and more benefit. A recent trial demonstrated that intra-arterial pro-urokinase improved long-term outcome in patients with M 1 or M 2 occlusion within 6 hours of onset. Trials of the third generation of thrombolytic agents are ongoing in patients with acute ischemic stroke. The latest CSG's meta-analysis showed that immediate anticoagulant therapy in patients with acute ischemic stroke was not associated with net short or long-term benefit because there was no evidence that anticoagulant therapy reduced deaths or non-fatal stroke during treatment or patients dead or dependent at the end of follow-up. However, an i.v. low-molecular-weight heparinoid showed a trend toward improving long-term outcome in subgroup of patients with atherothrombotic stroke. The thrombin inhibitor argatroban was proven to be comparable to the thromboxane A2 synthetase inhibitor ozagrel in the effect on the outcome at one month in patients with atherothrombotic stroke within 48 hours of onset in Japan, and a trial of the agent is ongoing in patients with ischemic stroke within 12 hours of onset in the United States. Two large trials of aspirin in patients with ischemic stroke within 48 hours of onset indicated that aspirin had a modest effect on reducing patients dead or dependent at the end of follow-up. An international trial of abciximab, a monoclonal antibody directed against platelet glycoprotein IIb/IIIa, is ongoing in patients with ischemic stroke within 6 hours of onset.     

急性脑梗死患者多模式CT指导下的静脉溶栓治疗

目的 对发病3～9 h内的急性脑梗死患者,应用多模式CT指导下静脉rt-PA溶栓治疗,研究其疗效.方法 2007年8月至2009年5月于我院就诊,经多模式CT筛选出符合溶栓的患者27例.分为＞3～6 h组及7～9 h组,记录溶栓前、后的NIHSS、mRS及BI评分,症状性出血率和病死率.结果 27例样本中20例(74.1%)患者溶栓治疗有效,11例(40.7%)临床结局良好,5例(18.5%)血管完全再通,症状性出血1例(3.7%).其中＞3～6 h组有效率为92.3%(12/13,χ~2=4.34,P=0.037),血管冉通率38.5%(5/13,χ~2=6.608,P=0.010).结论 多模式CT指导下＞3～9 h溶栓是超过常规溶栓时间窗患者的一种可选择的治疗方法.     

Post-licensed 1-year experience of systemic thrombolysis with tissue plasminogen activator for ischemic stroke in a Japanese neuro-unit

OBJECTIVE: In Japan, intravenous thrombolysis with tissue plasminogen activator (tPA) for ischemic stroke within 3h of onset was officially approved in October 2005. METHODS: We report initial 1-year clinical experience of intravenous alteplase at 0.6mg/kg in a Japanese neuro-unit. RESULTS: Twenty patients received intravenous tPA, corresponding to 12% of all ischemic strokes (n=166) and 38% of ischemic strokes within 3h of onset (n=52). The mean age was 68 years old and 15% had pre-morbid dependency with modified Rankin Scale (mRS) of 3 or 4. The median baseline National Institute of Health Stroke Scale score was 19 points (range; 5-37). Average time from stroke onset to tPA delivery was 136 min (range; 87-180). Of 18 (90%) patients receiving pretreatment vascular imaging, 16 (80%) patients had a large arterial occlusion. At 3 months, excellent outcome with mRS of 0 or 1 was 25%, and good outcome with mRS of 0-2 was 35%. One patient (5%) developed symptomatic intracranial hemorrhage within 36 h. Mortality rate was 15%. CONCLUSIONS: Intravenous tPA within 3h was safe and feasible, and possibly effective in clinical practice. The higher stroke severity in our cohort precluded to compare the sufficient effectiveness with clinical trials. In Japan, a post-licensed national surveillance is currently under way.     

Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations

BACKGROUND AND PURPOSE: Because of the risk of hemorrhage, especially in the brain, thrombolytic therapy with intravenous alteplase is restricted by guidelines, and only a small number of selected patients are being treated. Findings from metaanalyses, post hoc analyses of the randomized trials, and postlicensing experience suggest that more subjects, who otherwise have a poor predicted outcome without treatment, might benefit from intravenous alteplase. Summary of Review- There is a strong indication that treatment may still be beneficial beyond 3 hours up until 4.5 hours. The risk of symptomatic intracerebral hemorrhage is not increased in patients aged 80 years or older. Excluding patients with severe stroke or with early ischemic changes in more than one third of the middle cerebral artery territory on baseline CT scan is probably not necessary when treatment is started <3 hours of symptom onset. Patients with minor or improving symptoms can also benefit. Intravenous thrombolysis appears appropriate as first line therapy for posterior circulation stroke. Alteplase can be given to patients with cervical artery dissection, seizure at onset and evidence of acute ischemia on brain imaging, and after carefully weighing risk and benefit in pregnancy and during menstruation. There are anecdotal reports on its use in children, patients with recent myocardial infarction, cardiac embolus, intracranial aneurysm or arteriovenous malformation, prior stroke and recent surgery. There appears to be a substantially increased risk of symptomatic cerebral hemorrhage in hyperglycemic stroke patients. The combined intravenous and intraarterial approach to recanalization appears safe and is currently under investigation in a randomized trial. CONCLUSIONS: This document does not intend to change the guidelines but reviews the literature on the use of intravenous alteplase for stroke beyond guidelines and in particular conditions.     

Argatroban tPA stroke study: study design and results in the first treated cohort

BACKGROUND: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute stroke is linked to clot lysis and artery recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. There are no human data on this combination. DESIGN: We report the first phase of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose-escalation, safety and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 hours. After standard-dose intravenous rtPA administration, a 100-mug/kg bolus of argatroban followed by infusion of 1 mug/kg per minute for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times that of the control group. RESULTS: Fifteen patients (including 10 men) were enrolled, with a mean +/- SD age of 61 +/- 13 years. All patients had middle cerebral artery occlusions. Baseline median National Institute of Health Stroke Scale score was 14 (range, 4-25). The mean +/- SD time from symptom onset to argatroban bolus administration was 172 +/- 53 minutes. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 1 patient and there was 1 death. Recanalization was complete in 6 patients and partial in another 4, and reocclusion occurred in 3 within 2 hours of rtPA bolus administration. CONCLUSION: The safety of low-dose argatroban combined with intravenous rtPA may be within acceptable limits, and its efficacy for producing fast and complete recanalization is promising, but a larger cohort of patients is required to confirm these preliminary observations.     

Utilization of intravenous tissue plasminogen activator for acute ischemic stroke

BACKGROUND: Intravenous tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke, although only 2% of patients with stroke receive intravenous tPA nationally. OBJECTIVE: To determine the rate of tPA use for stroke in the Cleveland, Ohio, community and the reasons why patients were excluded from thrombolysis treatment. DESIGN: Retrospective cohort study. SETTING: Community.Subjects Patients admitted because of stroke to the 9 Cleveland Clinic Health System hospitals from June 15, 1999, to June 15, 2000. MAIN OUTCOME MEASURES: Utilization of intravenous tPA and reasons for ineligibility. RESULTS: There were 1923 admissions for ischemic stroke in the 1-year period. Of these, 288 (15.0%) arrived within the 3-hour time window, and approximately 6.9% were considered eligible for tPA. The most common reasons for exclusion among patients arriving within 3 hours were mild neurologic impairment and rapidly improving symptoms. The overall rate of tPA use among patients presenting within 3 hours was 19.4%, and the rate of use among eligible patients was 43.4% (n = 56). The use of tPA did not differ significantly according to race or sex. CONCLUSIONS: Only 15% of patients arrived within the 3-hour time window for intravenous tPA, making delay in presentation the most common reason patients were ineligible for i.v. thrombolysis. Neurologic criteria were the second most common group of exclusions. Overall tPA use was low, but it was used in nearly half of all patients with no documented contraindications. Intravenous tPA use in a community setting can compare favorably with the rate of use seen in academic medical settings.     

Effective acute stroke treatment beyond approval limitations: intravenous thrombolysis within an extended time window (3-6 h) and in old patients (aged 80 or older)

Intravenous thrombolysis with tPA is the only approved and effective treatment for acute ischemic stroke. The approval, however, is restricted to treatment within 3 hours of stroke onset, and it is not recommended to treat patients beyond 80 years of age. Due to these restrictions, thrombolysis is only given to a small number of acute stroke patients. At the same time there is growing evidence that patients can be treated with thrombolysis safely and effectively even beyond these restrictions. We give an overview over the published data regarding thrombolysis beyond the 3 hour time window and in patients aged 80 or over. Based on these data we conclude that (1.) intravenous thrombolysis in MRI selected patients is safe and effective within an extended time window of up to 6 hours, and (2.) there is no increase in mortality or symptomatic intracerebral bleeding complications in patients aged 80 or over treated with thrombolysis. A great number of acute stroke patients reaches the hospital beyond the 3 hour time window, and there is a growing number of old and very old stroke patients in the western world. Treating patients up to a 6 hour time window and beyond the age of 80 years would clearly increase the number of patients, which might benefit from this effective treatment. To summarize, we recommend experienced stroke centres to treat acute stroke patients with thrombolysis up to 6 hours using MRI criteria for patient selection, and to treat also patients aged 80 years or older.     

Comparison of intravenous and intra-arterial urokinase thrombolysis for acute ischaemic stroke

Intravenous fibrinolysis (IVF) with rt-PA (alteplase) provides significant benefits in acute ischaemic stroke when it is given within the first three hours following stroke onset. Intra-arterial fibrinolysis (IAF) with pro-urokinase in PROACT II study provides quite the same benefit in the first 6 hours. IVF and IAF have never been compared. To compare the efficacy and safety of IVF and IAF with urokinase given within the first 6 hours of acute ischaemic stroke. Patients fulfilling the selection criteria were randomly assigned to receive urokinase 900,000 units via intravenous or intra-arterial routes. This randomised monocentre study was done between December 1995 and August 1997. The primary outcome was defined as the number of patients with a modified Rankin score of 2 or less. Secondary outcomes included mortality, frequency of symptomatic intracranial haemorrhage (SIH), neurological and functional scores. Fourteen patients were given IVF and 13 IAF. The study was terminated by the National Health Authorities when 27 patients had been included because of the mortality rate. Seven patients (26%) died, 4 in the IV group (oedematous infarct in 3 and recurrence in 1), 3 in the IA group (SIH in 2, and oedematous infarct in 1). Patients given IVF were treated significantly earlier (4:16 h vs 5:24 h; p=.007). Although IA patients showed greater and earlier improvement there was no significant difference in primary and secondary outcomes. Because of premature termination, the trial was too small to provide any reliable and conclusive results. Intra-arterial fibrinolysis began significantly later than IV fibrinolysis but it gave non-significantly better results in this prematurely terminated study.     

Safety and efficacy of intravenous tissue plasminogen activator and heparin in acute middle cerebral artery stroke.

BACKGROUND AND PURPOSE: There is little reported of the safety and efficacy of high-dose intravenous recombinant tissue plasminogen activator (alteplase) in combination with heparin anticoagulation in patients presenting with acute ischemic stroke. METHODS: Thirty-two patients with severe hemispheric stroke syndrome caused by angiographically proven middle cerebral artery and/or intracranial internal carotid artery occlusion were treated with 100 mg alteplase by intravenous infusion over 90 minutes within a mean +/- SD of 226 +/- 68 minutes after symptom onset. Recanalization was assessed by digital subtraction angiography in all patients immediately after treatment and by transcranial Doppler monitoring (n = 30) and/or a third angiogram (n = 5) 12-24 hours later. RESULTS: Complete or partial reperfusion was observed in 11 patients (34%) 90 minutes after the initiation of alteplase infusion and in 17 patients (53%) within 12-24 hours. Hemorrhagic infarction without clinical deterioration was detected by follow-up computed tomography in nine patients (28%). Fatal parenchymal hemorrhage occurred in three patients (9%) with huge middle cerebral artery infarcts. Serious hemorrhage from the puncture site occurred in two patients (6%). Good clinical outcome correlated with reperfusion (p less than 0.05) and the presence of grade 2 collateral blood flow (p less than 0.01). CONCLUSIONS: When 100 mg of recombinant tissue plasminogen activator was given within the first 6 hours of acute stroke together with heparin the incidence of deleterious hemorrhage was less than 10%. Reperfusion and effective collateral blood flow seem to be two important factors associated with a small infarct volume and good clinical outcome.