rt-PA Group Research Articles

HTUPA as a new thrombolytic agent for acute myocardial infarction: A multicenter, randomized study

BackgroundIt is necessary to develop a new thrombolytic agent which can be used by a single bolus at first aid sites to decrease the time to reperfusion in clinical practice. HTUPA, a genetically engineered new thrombolytic with a longer half-life, is well qualified. We aim to compare the thrombolytic efficacy and safety of human tissue urokinase type plasminogen activator (HTUPA) to recombinant tissue plasminogen activator (rt-PA) in Chinese patients with acute myocardial infarction (AMI). MethodsAMI patients (n=221) were randomized to rt-PA (a standard protocol) or HTUPA (25mg bolus) treatment groups. All patients also received oral aspirin and intravenous heparin. Coronary angiography was performed 90min after therapy initiation to determine infarct-related coronary artery (IRA) patency. Clinical outcomes and changes of clotting variables, heart rate, blood pressure, left ventricular ejection fraction (LVEF), and electrocardiogram were evaluated. ResultsPatent IRA [thrombolysis in myocardial infarction (TIMI) grade 2 or 3] was observed in 77% of HTUPA-treated patients, compared to 76% of rt-PA-treated patients (P=0.76). TIMI grade 3 patency rates were 52% and 44% in the HTUPA and rt-PA groups, respectively (P=0.37). The total patency rate was 77% (86/111 patients) in the HTUPA group and 73% (80/110 patients) in the rt-PA group (P=0.41). Adverse events were infrequent in both groups, and no significant differences were detected in mortality, re-occlusion rate, revascularization rate, adverse effects, clotting index, LVEF, or electrocardiogram between the two groups. ConclusionsIntravenous HTUPA had a safe and efficacious profile as good as rt-PA in patients with AMI.

Coadministration of FTY720 and rt-PA in an experimental model of large hemispheric stroke–no influence on functional outcome and blood–brain barrier disruption

BackgroundSystemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the standard of acute stroke care. Its potential to increase the risk of secondary intracerebral hemorrhage, especially if administered late, has been ascribed to its proteolytic activity that has detrimental effects on blood–brain barrier (BBB) integrity after stroke. FTY720 has been shown to protect endothelial barriers in several disease models such as endotoxin-induced pulmonary edema and therefore is a promising candidate to counteract the deleterious effects of rt-PA. Besides that, every putative neuroprotectant that will be eventually forwarded into clinical trials should be tested in conjunction with rt-PA.MethodsWe subjected C57Bl/6 mice to 3 h filament-induced tMCAO and postoperatively randomized them into four groups (n = 18/group) who received the following treatments directly prior to reperfusion: 1) vehicle-treatment, 2) FTY720 1 mg/kg i.p., 3) rt-PA 10 mg/kg i.v. or 4) FTY720 and rt-PA as a combination therapy. We measured functional neurological outcome, BBB disruption by quantification of EB extravasation and MMP-9 activity by gelatin zymography.ResultsWe observed a noticeable increase in mortality in the rt-PA/FTY720 cotreatment group (61%) as compared to the vehicle (33%), the FTY720 (39%) and the rt-PA group (44%). Overall, functional neurological outcome did not differ significantly between groups and FTY720 had no effect on rt-PA- and stroke-induced BBB disruption and MMP-9 activation.ConclusionsOur data show that FTY720 does not improve functional outcome and BBB integrity in large hemispheric infarctions, neither alone nor in conjunction with rt-PA. These findings stand in contrast to a recently published study that showed beneficial effects of FTY720 in combination with thrombolysis in a thrombotic model of MCAO leading to circumscript cortical infarctions. They might therefore represent a caveat that the coadministration of these two drugs might lead to excess mortality in the setting of a severe stroke.

The comparison of the effect of UK and rt-PA intravenous thrombolytic therapy for acute myocardial infarction

Objective To compare the clinical effect of UK and rt-PA intravenous thrombolytic therapy for acute myocardial infarction.Methods By SAS statistical analysis system,72 patients with acute myocardial infarction were randomly divided into rt-PA group and UK group,each group had 36 cases.The coronary artery recanalization rate,bleeding events,adverse cardiovascular events,mortality,and cardiac troponin T(cTnT) level were recorded.Results In rt-PA group,0.5h,1 h,2h after the start of thrombolytic therapy,the coronary artery recanalization rate was significantly higher than that in the control group,the difference was statistically significant (x2 =7.32,6.12,5.81,all P ＜ 0.05).In rt-PA group,3 cases had bleeding events,2 cases died,and in UK group,5 cases had bleeding events,3 cases died,,there was no statistically significant difference between the two groups (x2 =1.22,P ＞ 0.05).In rt-PA group,there were 6 cases with adverse cardiovascular events,14 cases in the control group,the difference was statistically significant (x2 =4.56,P＜0.05).2 cases died in rt-PA group,3 cases died in UK group,the mortality between the two groups had no statistically significant difference (P ＞ 0.05).The cTnT level in the hospital 6h,12h was significantly higher than admission in two groups (t =6.67,6.30,4.11,4.22,4.40,all P ＜ 0.05).In rt-PA group,cTnT level in the hospital 6h,12h was significantly lower than that in UK group (t =5.92,6.61,all P ＜0.05).Conclusion Compared with UK,rt-PA in the treatment of acute myocardial infarction can increase recanalization rate,decrease adverse events and myocardial injury,it is worthy of clinical application. Key words: Myocardial infarction; Urinary plasminogen activator; Recombinases ; Thrombolytic therapy

Intraventricular fibrinolysis for severe aneurysmal intraventricular hemorrhage: a randomized controlled trial and meta-analysis

The aim of this study was to assess the safety and efficacy of intraventricular fibrinolysis (IVF) for aneurysmal subarachnoid hemorrhage (aSAH) with severe intraventricular hemorrhage (IVH). In this randomized controlled trial, between 2005 and 2009, patients with aSAH and severe IVH were randomly assigned into two groups: one treated with external ventricular drainage (EVD) combined with intraventricular recombinant tissue plasminogen activator (rt-PA) and the second with EVD alone. The primary end-point was mortality rate within the first 30 days. We performed meta-analysis including all published articles that compared IVF + EVD to EVD alone in patients with aSAH IVH. Eleven patients were included in the rt-PA group, eight in the control group. At 30 days, mortality rate was lower in the rt-PA group (45.5 vs. 62.5%), but results were not statistically significant (p = 0.65). Clearance of third and fourth ventricles was obtained previously in the rt-PA group (4.25 days) compared to the control group (10.67 days) (p = 0.001). There was no statistically significant difference concerning the occurrence of complications. The meta-analysis showed a better survival rate with IVF without raised statistical significance (odds ratio = 0.32 [95% confidence interval, 0.10-1.03]). This study shows that IVF is as safe as EVD alone for aSAH with severe IVH. It accelerates blood clot resolution in the ventricular system. Mortality rate could be improved by IVF but without significant results. Because of the severity and rarity of this pathology, a multicenter study is required. www.clinicaltrials.gov (NCT00823485).

Can we extend thrombolysis indications for acute ischaemic stroke? The IST-3 study

BackgroundEach year, about 22 million people have a stroke world-wide, of whom 4 million reside in high-income countries.The burden of ischaemic stroke among the elderly is largeand increasing; it is estimated that annually ischaemicstroke affects about a million people older than 80 years inhigh-income countries and about 3 million in low-incomeand middle-income countries [1].So far intravenous thrombolysis is indicated for patientswith ischaemic stroke, aged less than 80, within 4.5 h fromthe occurence of neurologic signs, without any contrain-dications [2].Since many patients with acute ischaemic stroke,according to current guidelines, cannot be candidatedfor thrombolysis, it would be appealing to extend itsindications.Although thrombolysis has been proved to amelioratemorbidity in acute ischaemic stroke, it increases cerebralhaemorrhage; so, before extending thrombolysis indica-tions, strong evidence of benefits is needed [3].SummaryThe third international stroke trial (IST-3) is a multicentre,pragmatic, open-treatment study which randomised 3,035patients to 0.9 mg/kg intravenous recombinant tissueplasminogen activator (rt-PA) or to control [1].The primary endpoint was the proportion of patientsalive and independent at 6 months, as defined by an OxfordHandicap Score (OHS) of 0–2. The main secondary end-points were mortality and morbidity at 7 days. Initially,there was a pilot phase, double blinded and placebo con-trolled (\10 % pts), and then authors shifted to opentreatment. The eligibility criteria can be summarized interms of the uncertainty principle. Briefly, patients wereeligible according to the following criteria: they hadsymptoms and signs of clinically definite acute stroke; thetime of stroke onset was known; treatment could be startedwithin 6 h of onset; and CT or MRI had reliably excludedboth intracranial haemorrhage and structural brain lesions,which could mimic stroke. In addition, if the patient had aclear indication for intravenous thrombolysis with rt-PA,they were to be treated in accordance with local guidelines.Equally, if the patient had a clear contraindication totreatment, they were not to be entered in the trial. The datawere analysed following the intention-to-treat principles.Of notice that among 3,035 patients enrolled, 95 % didnot meet local European guidelines for thrombolysis, 72 %were treated more than 3 h after stroke onset, 53 % agedmore than 80 and 5 % had a NIHSS greater than 25.At 6 months, 554 (37 %) patients in the rt-PA groupversus 534 (35 %) in the control group were alive andindependent [OHS 0–2; adjusted odds ratio (OR) 1.13,95 % CI 0.95–1.35, p = 0.181). Fatal or non-fatal symp-tomatic intracranial haemorrhage within 7 days occurred in104 (7 %) patients in the rt-PA group versus 16 (1 %) inthe control group (adjusted OR 6.94, 95 % CI 4.07–11.8,p\0.001). More deaths occurred within 7 days in the rt-PA group [163 (11 %)] than in the control group [107(7 %), adjusted OR 1.60, 95 % CI 1.22–2.08, p = 0.001],

Intra-arterial Thrombectomy versus Standard Intravenous Thrombolysis in Patients with Anterior Circulation Stroke Caused by Intracranial Arterial Occlusions: A Single-center Experience

Severely impaired patients with persisting intracranial occlusion despite standard treatment with intravenous (IV) administration of recombinant tissue plasminogen activator (rtPA) or presenting beyond the therapeutic window for IV rtPA may be candidates for interventional neurothrombectomy (NT). The safety and efficacy of NT by the Penumbra System (PS) were compared with standard IV rtPA treatment in patients with severe acute ischemic stroke (AIS) caused by large intracranial vessel occlusion in the anterior circulation. Consecutive AIS patients underwent a predefined treatment algorithm based on arrival time, stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS) score, and site of arterial occlusion on computed tomographic angiography (CTA). NT was performed either after a standard dose of IV rtPA (bridging therapy [BT]) or as single treatment (stand-alone NT [SAT]). Rates of recanalization, symptomatic intracranial bleeding (SIB), mortality, and functional outcome in NT patients were compared with a historical cohort of IV rtPA treated patients (i.e., controls). Three-month favourable outcome was defined as a modified Rankin Scale (mRS) score ≤2. Forty-six AIS patients were treated with NT and 51 with IV rtPA. The 2 groups did not differ with regard to demographics, onset NIHSS score (18.5±4 v 17±5; P=.06), or site of intracranial occlusion. Onset-to-treatment time in the NT and IV rtPA groups was 230 minutes (±78) and 176.5 (±44) minutes, respectively (P=.001). NT patients had significantly higher percentages of major improvement (≥8 points NIHSS score change at 24 hours; 26% v 10%; P=.03) and partial/complete recanalization (93.5% v 45%; P<.0001) compared to controls. Treatment by either SAT or BT similarly improved the chance of early recanalization and early clinical improvement. No significant differences were observed in the rate of SIB (11% v 6%), 3-month mortality (24% v 25%), or favorable outcome (40% v 35%) between NT and IV rtPA patients. Despite significantly delayed time of intervention, NT patients had higher rates of recanalization and early major improvement, with no differences in symptomatic intracranial hemorrhages. Early NIHSS score improvement did not translate into better 3-month mortality or outcome. NT seems a safe and effective adjuvant treatment strategy for selected patients with severe AIS secondary to large intracranial vessel occlusion in the anterior circulation.

Thrombolysis on Ischemic Stroke Patients with Decreased Level of Consciousness within 4.5 h

Few reports concerned on recombinant tissue plasminogen activator (rt-PA) treatment in stroke patients with decreased consciousness. This study assesses the efficacy and safety of intravenous rt-PA administration within 4.5 h in stroke patients with decreased consciousness. A total of 136 stroke patients with decreased consciousness, who received or not rt-PA intravenously within 4.5 h after stroke onset from Jiangsu province of China from 2009 to 2012, were reviewed retrospectively. Glasgow Coma Scale (GCS), National Institute of Health Stroke Scale (NIHSS), intracranial hemorrhage rate, and mortality were used to determine patient outcome when discharged. A 3-month outcome was calculated by modified Rankin Scale (mRS) with score 0 to 1 considered favorable outcome. Baseline characteristics of two groups were similar. When discharged, no significant differences were observed regarding NIHSS score (P = 0.994) or GCS score (P = 0.591) between groups. After 3 months, 22.8% patients in rt-PA group had favorable outcome as compared with 7.5% patients in control group (P = 0.014). Treatment with rt-PA did not significantly increase incidence of hemorrhage (P = 0.494) or mortality (P = 0.169). Intravenous rt-PA administration within 4.5 h after onset of symptoms benefited stroke patients with abnormal consciousness.

Development of Endovascular Vibrating Polymer Actuator Probe for Mechanical Thrombolysis

In this study, we propose a new method for the enhancement of intraarterial thrombolysis by use of an endovascular vibrating polymer actuator probe (VPAP), which is fabricated from an ionic polymer metal composite (IPMC) actuator. The endovascular VPAP was fabricated by combining 0.8 × 0.8 × 10 mm3 IPMC samples, 0.22 mm × 50 cm copper wires, and 40 cm of Teflon tube. The purpose of this study was to evaluate the thrombolysis efficiency of an endovascular VPAP in a dog model. Both renal arteries of the enrolled dogs (n = 5) were used in the current study. A distal portion of the renal artery in a mongrel dog was occluded by a blood clot from autologous venous whole blood. Intraarterial thrombolysis was performed by use of a VPAP without the actuation force (control group), by a VPAP-only (VPAP-only group), or with a combination of recombinant tissue plasminogen activator (rtPA) and a VPAP (VPAP + rtPA group). The thrombolysis efficiency was evaluated by the modified Thrombolysis in Myocardial Infarction (TIMI) grading system based on the consensus between two radiologists. The grading scales were compared according to each intraarterial thrombolysis method. The VPAP + rtPA and VPAP-only groups showed a significantly higher thrombolysis efficiency than did the control group (p < 0.05). The VPAP-only group also showed a significantly higher thrombolysis efficiency than did the control group (p < 0.05). The VPAP+ rtPA group showed a significantly higher thrombolysis efficiency than did the VPAP-only group (p < 0.05). The use of an endovascular VPAP was a feasible and useful method for intraarterial thrombolysis, and it enhanced the thrombolysis efficiency when combined with the thrombolytic agent rtPA.

CDP-choline at high doses is as effective as i.v. thrombolysis in experimental animal stroke

Use of thrombolysis in acute ischaemic stroke may be limited by a narrow benefit/risk ratio. Pharmacological inhibition of the ischaemic cascade may constitute an effective and safer approach to stroke treatment. This study compared the effects of high doses of cytidine diphosphate-choline (CDP-choline; 1000 mg/kg) with recombinant tissue plasminogen activator (rt-PA; 5 mg/kg) in an experimental animal model of embolic stroke. Fifteen rats were embolized in the right internal carotid artery with an autologous clot and were divided into three groups: (1) infarct; (2) intravenous rt-PA 5 mg/kg 30 minutes post-embolization; and (3) CDP-choline 1000 mg/kg, intraperitoneal, three doses, 30 minutes, 24 hours, and 48 hours post-embolization. Functional evaluation scores were evaluated using Rogers test, lesion volume by haematoxylin and eosin staining, cell death with transferase-mediated dUTP nick-end labelling, and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha with enzyme-linked immunosorbent assay. In this study, CDP-choline and rt-PA produced a significant reduction in brain damage considering infarct volume, cell death, and inflammatory cytokines (tumour necrosis factor-alpha and IL-6) compared with the infarct group. Additionally, CDP-choline significantly decreased infarct volume, cell death, and IL-6 levels with respect to the rt-PA group. From these results, we conclude that high-dose CDP-choline may be an effective treatment for acute ischaemic stroke even in absence of thrombolysis.

Effect of Huatan Tongluo on the permeability of blood-brain barrier and ultrastructure of hippocampus endothelial cells after thrombolysis in acute cerebral infarction

Objective To observe the effects of Huatan Tongluo on the Bederson's scores , the permeability of blood-brain barrier and ultrastructure of hippocampus endothelial cells after thrombolysis in acute cerebral infarction. To provide experimental evidence for the prevention of bleeding after thrombolysis in acute cerebral infarction with Huatan Tongluo. Methods 120 SD male rats were randomly divided into sham group, model group, rt-PA group, Huatan Tongluo combined rt-PA low-dose group, Huatan Tongluo combined rt-PA medium-dose group and Huatan Tongluo combined rt-PA high-dose group(each group was divided in 6h, 24h, 3d, 7d four-phase). MCAO rats were prepared by self-embolus method. rt-PA group and Huatan Tongluo combined rt-PA groups were given rt-PA through tail vein injection and three doses of Huatan Tongluo to treat.To observe the Bederson's scores in rat on four-phase.To detect the permeability of blood-brain barrier(BBB) by the Evans Blue dye (EB dye) and watch the ultrastructure of hippocampus endothelial cells in ischemic region by electron microscopy. Results 1.Bederson's scores: Compared with model group, rt-PA group, Huatan Tongluo combined rt-PA low-dose group, Huatan Tongluo combined rt-PA medium-dose group and Huatan Tongluo combined rt-PA high-dose group significantly lower(P<0.01); Compared with rt-PA group, Huatan Tongluo combined rt-PA medium-dose groups and high-dose groups was significantly lower(P<0.05).2. EB dye: Compared with model group, rt-PA group, Huatan Tongluo combined rt-PA low-dose group, Huatan Tongluo combined rt-PA medium-dose group and Huatan Tongluo combined rt-PA high-dose group(P<0.01); Compared with rt-PA group(6h : (236.72±79.79)ng/g; 24h: (229.72±22.18)ng/g; 3d: (163.34±24.45)ng/g; 7d: (133.21±25.09)ng/g), Huatan Tongluo combined rt-PA medium-dose groups (6h: (121.63±33.27)ng/g; 24h: (153.78±60.67)ng/g; 3d: (76.05±27.11) ng/g; 7d: (72.97±25.81)ng/g)and high-dose groups (6h: (123.11±23.65)ng/g; 24h: (138.36±52.36)ng/g; 3d: (83.00±32.00)ng/g; 7d: (75.06±13.97)ng/g)was significantly lower(P<0.01).3. Electron microscopy: Compared with model group, treatment groups all protected the endothelial cells.In 24h, the Huatan Tongluo combined rt-PA high-dose group was best.At 3d and 7d, the Huatan Tongluo combined rt-PA medium-dose group was best. Conclusion Huatan Tongluo combined rt-PA to thrombolysis can protect the blood-brain barrier and endothelial cells of hippocampal's ischemic region. After thrombolytic, to adjust the medicine drug concentration at different time can play a better treatment results. Key words: Huatan Tongluo; Infarction; Thrombolysis; Blood-brain barrier; Endothelial cells; Morphology

The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial

SummaryBackgroundThrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset.MethodsIn this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0–2 at 6 months. The study is registered, ISRCTN25765518.Findings3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0–2; adjusted odds ratio [OR] 1·13, 95% CI 0·95–1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI −20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10–1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07–11·8; absolute excess 58/1000, 95% CI 44–72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22–2·08, p=0·001; absolute increase 37/1000, 95% CI 17–57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).InterpretationFor the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.FundingUK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.

Extracorporeal cardiopulmonary support may be an efficient rescue of patients after massive pulmonary embolism. An experimental porcine study

IntroductionTreatment of massive pulmonary embolism leading to cardiac arrest is controversial but restitution of circulation within a shorter time is crucial. Cardiopulmonary support and therapeutic hypothermia is an option for cardiac arrest and could be used to treat massive PE. However, hypothermia may influence the effect of the ongoing intrinsic fibrinolysis. ObjectivesTo establish a porcine model of massive pulmonary embolism, to show that cardiopulmonary support can rescue pigs with massive pulmonary embolism and to examine the effect of hypothermia on fibrinolysis. MethodsPigs ~80kg were anesthetised and prepared for cardiopulmonary support. Repetitive injections of preformed blood thrombi into the right atrium were done until cardiac arrest. Cardiopulmonary support was established and eighteen pigs were randomised into 3 groups: Normothermia (38-39°C); hypothermia (33-34°C); or medication with recombinant tissue plasminogen activator. After three hours the pigs were weaned from cardiopulmonary support, and after 15minutes with spontaneous circulation assassinated and autopsied. Remaining thrombi in the lungs were weighed. ResultsThe development of fatal pulmonary embolism was highly reproducible. All 18 pigs could be weaned from cardiopulmonary support and survived more than 15minutes. The amount of remaining thromboemboli was substantial in all groups and not significantly different between groups. Normothermic group 20.0±2.2g, Hypothermic group 17.0±3.7g, and rt-PA group 14.3±3.2g. ConclusionsCardiopulmonary support could rescue pigs with massive pulmonary embolism. Hypothermia did not reduce the emboli but may for other reasons be beneficial. The optimal additional treatment is still unknown but treatment modalities can be tested in this model.

Abstract 3797: Patients with Diabetes and Previous Ischemic Strokes in the National Institute of NINDS trial

Background and Purpose Ischemic stroke is the leading cause of morbidity in the United States. Intravenous recombinant tissue plasminogen activator (rt-PA) given within 4.5 hours from symptom onset has shown to improve outcomes. The ECASS III trial, which helped to extend the time window for thrombolysis, had specific exclusion criteria. One of these exclusions was patients who had a past medical history of both previous diabetes (DM) and an ischemic stroke. This retrospective study aims to evaluate the impact of a previous history of both DM and an ischemic stroke on outcome in patients in the NINDS trial. Methods A retrospective review was conducted of the NINDS database. Subjects with a previous history of both DM and an ischemic stroke were identified. Baseline characteristics were analyzed for any difference between the two groups. The outcome measures included symptomatic intracerebral hemorrhage (sICH) as defined by NINDS criteria, and 90 day NIHSS, mRS and death. The statistical analysis was performed using a two sample median test and a Fisher’s exact test. Results: Thirty four individuals were identified with a previous history of DM and ischemic stroke. Fifteen (4.8%) were in the treatment group and 19 (6.1%) were in the placebo group. The median age in those treated with rt-PA was 74.6 years compared to 61.9 years in those who received placebo (p=0.02). The median systolic blood pressure was 178mmHg in the treated group versus 150mmHg in the placebo group (p=0.02). There was no difference between the baseline NIHSS. The rt-PA treated patients had a sICH rate of 6.67% compared to 5.26% in the placebo group (p=0.70). The median NIHSS at 90 days was 5 in the treated group and 3.5 in the placebo group (p=0.26). The median 90 day mRS was 4 in the rt-PA group and 2 in the placebo group (p=0.29). Four (26.7%) of treated patients died compared to 3(15.8%) of patients in the placebo group (p=0.67). Conclusion: Subjects in the NINDS trial who had the past medical history of both DM and an ischemic stroke were older and had a higher blood pressure in the treatment arm. There was no difference in the sICH rate between both groups. There was no difference in the outcomes of both groups. This study is limited by its retrospective nature and the small sample size of the sub-group.

Tissue plasminogen activator versus heparin for locking dialysis catheters: A systematic review

Background and Objectives:Hemodialysis catheters are commonly used when renal replacement therapy is initiated. These catheters have significant complications. Among “locking” solutions used in an attempt to decrease these complications is recombinant tissue plasminogen activator (rt-PA). This systematic review is to determine the efficacy of rt-PA versus heparin, the standard of care.Materials and Methods:A systematic review of randomized controlled trials studying rt-PA alone or rt-PA plus heparin versus heparin alone as locking agents for hemodialysis catheters, which included patients needed a temporary hemodialysis catheter for hemodialysis. We identified relevant trials through electronic databases and correspondence with experts. Two investigators independently reviewed potentially eligible trials and extracted data.Results:Three trials met the inclusion criteria. One trial reported an improved catheter malfunctioning in patients using rt-PA plus heparin to lock catheters (20.0%) versus heparin alone (34.8%). Another trial reported higher blood flow rate in hemodialysis catheters in patients who received rt-PA (231.6 ± 12.4 mL/min) compared with those who received heparin (206.9 mL/min). The third trial reported formation and weight of clots which were decreased by half in rt-PA group versus heparin group.Conclusions:In the few randomized trials that met our inclusion criteria, the use of rt-PA as a locking solution for hemodialysis catheters seems to be associated with fewer adverse events and catheter malfunctioning as compared with heparin. Our systematic review is limited by the few randomized trials addressing our question and the wide variety of outcome measures. Further prospective randomized trials are needed to confirm this conclusion.

Serum uri acid: neuroprotection in thrombolysis. The Bergen NORSTROKE study

BackgroundA possible synergic role of serum uric acid (SUA) with thrombolytic therapies is controversial and needs further investigations. We therefore evaluated association of admission SUA with clinical improvement and clinical outcome in patients receiving rt-PA, early admitted patients not receiving rt-PA, and patients admitted after time window for rt-PA.MethodsSUA levels were obtained at admission and categorized as low, middle and high, based on 33° and 66° percentile values. Patients were categorized as patients admitted within 3 hours of symptom onset receiving rt-PA (rt-PA group), patients admitted within 3 hours of symptom onset not receiving rt-PA (non-rt-PA group), and patients admitted after time window for rt-PA (late group). Short-term clinical improvement was defined as the difference between NIHSS on admission minus NIHSS day 7. Favorable outcome was defined as mRS 0 - 3 and unfavorable outcome as mRS 4 - 6.ResultsSUA measurements were available in 1136 patients. Clinical improvement was significantly higher in patients with high SUA levels at admission. After adjustment for possible confounders, SUA level showed a positive correlation with clinical improvement (r = 0.012, 95% CI 0.002-0.022, p = 0.02) and was an independent predictor for favorable stroke outcome (OR 1.004; 95% CI 1.0002-1.009; p = 0.04) only in the rt-PA group.ConclusionsSUA may not be neuroprotective alone, but may provide a beneficial effect in patients receiving thrombolysis.

Efficacy and safety of recombinant tissue plasminogen activator and gas versus bevacizumab and gas for subretinal haemorrhage

To report the 12 months efficacy of initial intravitreal bevacizumab or intravitreal recombinant tissue plasminogen activator (rtPA) combined with expansile gas in patients with subretinal haemorrhage caused by neovascular age-related macular degeneration (AMD). Forty-five eyes of 45 patients with subretinal haemorrhage (1-5 disc diameters) involving the fovea secondary to neovascular AMD were evaluated retrospectively consecutively. Thirty-two eyes underwent treatment with rtPA (50 μg/0.05 ml) combined with intravitreal sulphur hexafluoride (SF6). The other 13 eyes were treated with bevacizumab (1.25 mg/0.05 ml) and SF6. Thereafter, all patients received Vascular Endothelial Growth Factor (anti-VEGF) treatment according to modified PrONTO criteria. Main outcome was change of best-corrected visual acuity (VA) at 12 months as determined by Early Treatment Diabetic Retinopathy (ETDRS). There was more improvement in patients initially treated with rtPA and gas (14 letters; bevacizumab and gas eight letters) and not suffering from adverse events. The incidence of vitreous haemorrhages was significantly higher in the rtPA group (nine of 32 versus one of 13, p < 0.01). In both groups, an average of 3.5 anti-VEGF injections were performed per patient during 12 months (no difference between both groups). Both initial treatment regimen lead to improved functional results after 1 year. However, patients, not suffering from adverse events, who underwent initial treatment with rtPA and gas showed better results. To maintain VA, controlling neovascular AMD by anti-VEGF treatment regime after initial treatment with rtPA+gas is important for all cases.

Local mild hypothermia with thrombolysis for acute ischemic stroke within a 6-h window

Objective To determine the safety and efficacy of combined local mild hypothermia and IV rtPA in treating acute ischemic stroke (AIS) patients with MRI perfusion- and diffusion-weighted imaging (PWI/DWI) mismatch within a 6-h stroke window. Methods AIS patients within 6 h of a minimum 20% PWI/DWI MRI mismatch were randomly assigned to 3 groups: local mild hypothermia with IV rtPA (Group A); IV rtPA (Group B); or conventional anti-platelet aggregation (Group C). Mortality and National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) score and Barthel Index (BI) were used in evaluation. Results There were significant differences in NIHSS 24 h after treatment among the three groups ( P < 0.001). Based on mRS and BI, more patients in Groups A and B showed favorable outcomes than patients in Group C ( P = 0.017 and P = 0.009, respectively); however, there were no significant efficacy differences between Groups A and B. The incidence of symptomatic ICH and the mortality rates within 90 days in the 3 groups were similar. In addition, there were no significant differences in NIHSS improvement at 24 h and favorable outcomes 90 days after IV rtPA treatment between patients within 3 h and 3–6 h from symptom onset. Conclusions There was no benefit of combined local hypothermia/IV rtPA treatment compared to IV rtPA alone. PWI/DWI mismatching on MRI can be a selection criteria for IV rtPA treatment within a 6-h window.

478 COLLAGEN MATRIX OF ATHEROSCLEROTIC PLAQUE AND LIPID SPECTRUM IN PATIENTS WITH MYOCARDIAL INFARCTION TREATED WITH ROZUVASTATIN DEPENDING ON REVASCULARIZATION METHOD

Objectives: Thrombolytic therapy in patients with acute myocardial infarction is hampered by bleeding complications and procoagulant effects favoring early reocclusion. TNK-tPA was shown in vitro to have considerable fibrin specificity. We investigated the effects of tenecteplase (TNK-tPA) and alteplase (rt-PA) on the haemostasis and fibrinolytic system. Methods and Results: We enrolled 30 patients with AMI into the study. Twenty patients received front-loaded rt-PA up to 100 mg; 10 patients were given TNK-tPA in a single bolus up to 50 mg. All patients received aspirin and intravenous heparin. During the first 2 days, the following parameters were repetitively determined: thrombin–antithrombin III complexes (TAT), antithrombin III (ATIII), prothrombin fragment F 1+2 (F 1+2), kallikrein-like activity (KK), activated factor XII (FXIIa), plasmin alpha 2–antiplasmin complexes (PAP), fibrinogen, D-dimers (DD), tissue-type plasminogen activator (t-PA). A total of 75 healthy persons served as control group. TAT increased significantly after rt-PA but not after TNK-tPA (3 h: 38.1±29.4 versus 10.5±4.2 μg/l; p<0.01), indicating paradoxical thrombin activation. F 1+2 increased transiently after rt-PA but not after TNK-tPA. Fibrinogen was significantly lower after rt-PA versus TNK-tPA (3 h: 163±27 versus 380±54 mg/dl; p<0.05). KK activities in the rt-PA group were significantly (p<0.01) increased over 48 h versus TNK-tPA. PAP and D-dimers were lower over the time course of 48 h in the tenecteplase group versus rt-PA. Conclusions: This study indicates that tenecteplase has higher fibrin specificity not only in vitro but also in vivo versus alteplase. TNK-tPA consecutively has no paradoxical systemic procoagulant effect due to the lower extent of activation of the kallikrein–factor XII system than alteplase.

Recombinant tissue plasminogen activator reduces incidence of catheter malfunction and bacteremia

Recombinant tissue plasminogen activator reduces incidence of catheter malfunction and bacteremia

E0632 A randomised comparison study of recombinant staphylokinase vs recombinant tissue-type tissue plasminogen activator for safety and coronary artery patency in patients with acute myocardial infarction

ObjectiveTo evaluate the efficacy and safety of r-SAK (recombinant staphylokinase) for acute ST-segment elevation myocardial infarction (STEMI).MethodsA total of 48 patients with acute STEMI randomised into r-SAK group and r-tPA...