Clinical Pharmacokinetics and Pharmacodynamics of Desmoteplase.

Desmoteplase is a bat (Desmodus rotundus) saliva-derived fibrinolytic enzyme resembling a urokinase and tissue plasminogen activator. It is highly dependent on fibrin and has some neuroprotective attributes. Intravenous administration of desmoteplase is safe and well tolerated in healthy subjects. Plasma fibrinolytic activity is linearly related to its blood concentration, its terminal elimination half-life ranges from 3.8 to 4.92 h (50 vs. 90 µg/kg dose). Administration of desmoteplase leads to transitory derangement of fibrinogen, D-dimer, alpha2-antiplasmin, and plasmin and antiplasmin complex which normalize within 4-12 h. It does not alter a prothrombin test, international normalized ratio, activated partial thromboplastin time, and prothrombin fragment 1.2. Desmoteplase was tested in myocardial infarction and pulmonary embolism and showed promising results versus alteplase. In ischemic stroke trials, desmoteplase was linked to increased rates of symptomatic intracranial hemorrhages and case fatality. However, data from "The desmoteplase in Acute Ischemic Stroke" Trials, DIAS-3 and DIAS-J, suggest that the drug is well tolerated and its safety profile is comparable to placebo. Desmoteplase is theoretically a superior thrombolytic because of high fibrin specificity, no activation of beta-amyloid, and lack of neurotoxicity. It was associated with better outcomes in patients with significant stenosis or occlusion of a proximal precerebral vessels. However, DIAS-4 was stopped as it might have not reached its primary endpoint. Due to its promising properties, desmoteplase may be added into treatment of ischemic stroke with extension of the time window and special emphasis on patients presenting outside the 4.5-h thrombolysis window, with wake-up strokes and strokes of unknown onset.

Low dosis of alteplase, for ischemic stroke after Enchanted and its determinants, a single center experience / Dosis reducida de alteplase en el accidente cerebrovascular isquémico después del estudio Enchanted y sus determinantes, una experiencia de un solo centro

Abstract Background: Low-dose alteplase (LrtPA) has been shown not to be inferior to the standard-dose (SrtPA) with respect to death/disability. Objective: We aim to evaluate the percentage of patients treated with LrtPA at our center after the ENCHANTED trial and the factors associated with the use of this dosage. Methods: Prospective study in consecutive patients with an acute stroke admitted between June 2016 and November 2018. Results: 160 patients were treated with intravenous thrombolysis, 50% female; mean age 65.4±18.5 years. Of these, 48 patients (30%) received LrtPA. In univariate analysis, LrtPA was associated with patient's age (p=0.000), previous modified Rankin scale scores (mRS) (p<0.000), hypertension (p=0.076), diabetes mellitus (p=0.021), hypercholesterolemia (p=0.19), smoking (p=0.06), atrial fibrillation (p=0.10), history of coronary artery disease (p=0.06), previous treatment with antiplatelet agents (p<0.000), admission International Normalized Ratio-INR (p=0.18), platelet count (p=0.045), leukoaraiosis on neuroimaging (p<0.003), contraindications for thrombolytic treatment (p=0.000) and endovascular treatment (p=0.027). Previous relevant bleedings were determinants for treatment with LrtPA. Final diagnosis on discharge of stroke mimic was significant (p=0.02) for treatment with SrtPA. In multivariate analysis, mRS (OR: 2.21; 95%CI 1.37‒14.19), previous antiplatelet therapy (OR: 11.41; 95%CI 3.98‒32.70), contraindications for thrombolysis (OR: 56.10; 95%CI 8.81‒357.80), leukoaraiosis (OR: 4.41; 95%CI 1.37‒14.10) and diagnosis of SM (OR: 0.22; 95%CI 0.10‒0.40) remained independently associated. Conclusions: Following the ENCHANTED trial, LrtPA was restricted to 30% of our patients. The criteria that clinicians apply are based mostly on clinical variables that may increase the risk of brain or systemic hemorrhage or exclude the patient from treatment with lytic drugs.

RESUMEN Introducción: Dosis reducidas de trombolitico (LrtPA) podrían no ser inferiores en muerte/discapacidad. Objetivo: Evaluar el porcentaje de pacientes tratados con LrtPA en nuestro centro después del ensayo ENCHANTED, y los factores asociados con el uso de esta dosis. Métodos: Estudio prospectivo de pacientes consecutivos con infarto cerebral ingresados ​entre junio de 2016 y noviembre de 2018. Resultados: 160 pacientes fueron tratados con trombólisis intravenosa, 50% mujeres; edad media 65,4±18,5 años. 48 casos (30%) recibieron LrtPA. En el análisis univariado, LrtPA se asoció con la edad del paciente (p=0,000), escala de Rankin modificadas (mRS) (p<0,000), hipertensión arterial (p=0,076), diabetes mellitus (p=0,021), hipercolesterolemia (p=0,19), tabaquismo (p=0,06), fibrilación auricular (p=0,10), antecedentes de enfermedad coronaria (p=0,06), tratamiento previo con antiplaquetarios (p<0,000), International Normalized Ratio-INR (p=0,18), recuento de plaquetario (p=0,045), leucoaraiosis en neuroimagen (p<0,003), contraindicaciones para el tratamiento trombolítico (p=0,000) y tratamiento endovascular (p=0,027). Las hemorragias previas relevantes fueron determinantes para el tratamiento con LrtPA. El diagnóstico al alta de imitador de accidente cerebrovascular fue significativo (p=0,02) para el tratamiento con dosis estándar. El análisis multivariado demostró que mRS (OR: 2,21; IC95% 1,37‒14,19), tratamiento antiplaquetario previo (OR: 11,41; IC95% 3,98‒32,7), contraindicaciones para trombólisis (OR: 56,1; IC95% 8,81‒357,8), leucoaraiosis (OR: 4,41; IC95% 1,37‒14,1) y un diagnóstico de imitador de accidente cerebrovascular (OR: 0,22; IC95% 0,1‒0,40) fueron asociados con la dosis recibida. Conclusiones: LrtPA está restringido al 30% de nuestros pacientes. Los criterios para tomar esta decisión se basan en variables que podrían aumentar el riesgo de hemorragia cerebral/sistémica o excluir al paciente del tratamiento con fármacos líticos.

Mechanical cardiopulmonary resuscitation for venoarterial ECMO implantation in pulmonary embolism complicated by type B aortic dissection and retroperitoneal hemorrhage.

A patient with acute pulmonary embolism suffered cardiac arrest, received manual and mechanical cardiopulmonary resuscitation and tissue plasminogen activator before extracorporeal cardiopulmonary resuscitation was initiated. She suffered a type B aortic dissection and retroperitoneal hemorrhage secondary to resuscitation measures. This case report describes high-risk anticoagulation management for contradicting treatment goals in preparation for pulmonary embolectomy on cardiopulmonary bypass.

Rosiglitazone ameliorates tissue plasminogen activator-induced brain hemorrhage after stroke.

OBJECTIVE: Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator-activated receptor-γ (PPAR-γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti-inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA-induced HT after stroke. METHODS AND RESULTS: We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA-induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA-treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA-treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA-alone-treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down-regulated in microglia of the RSG-treated mice. We further found that the expression of Arg-1 was also upregulated in those tPA and RSG-treated stroke mice and the protection against tPA-induced HT and BBB disruption in these mice were abolished in the presence of PPAR-γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). CONCLUSIONS: RSG treatment protects against BBB damage and ameliorates HT in delayed tPA-treated stroke mice by activating PPAR-γ and favoring microglial polarization toward anti-inflammatory phenotype.

Is Direct Endovascular Treatment as an Alternative of Bridging Therapy in Acute Stroke Patients with Large Vessel Occlusion?

BACKGROUND: Although endovascular treatment (EVT) is very effective for acute ischemia stroke (AIS) patients with proximal large vessels occlusion (LVO), whether bridging rPA before EVT in stroke patients of LVO is of any benefit and is currently one of the most urgent unanswered questions. We aim to comprehensively determine the efficacy and safety of direct EVT (DEVT) in AIS patients with LVO versus bridging therapy (BT). METHODS: Clinical researches published in the Embase, PubMed, and Cochrane Library electronic databases up to May 2017 were identified for analysis. Two reviewers extracted data and conducted quality assessment independently. Statistical tests were performed to check for heterogeneity and publication bias. Subgroup and sensitivity analysis were also conducted to evaluate the robustness of the conclusions. RESULTS: Overall, 13 studies involving 3302 patients met the inclusion criteria. The AIS patients with DEVT had a similar likelihood to achieve good functional outcome at 3 months (risk ratio [RR] = .93, 95% confidence interval [CI] = .85-1.01, P = .094), mortality at 3 months (RR = 1.10, 95% CI = .91-1.33, P = .33), and symptomatic intracranial hemorrhage (RR = 1.06, 95% CI = .74-1.51, P = .75) versus BT; furthermore, the risk of intracranial hemorrhage was lower in DEVT group (RR = .76, 95% CI = .60-.95, P = .02). No significant difference in recanalization rate existed between the 2 groups (RR = .97, 95% CI = .92-1.02, P = .22); however, in the subgroup analysis, it had a rise trend after DEVT than BT in IVT-eligible group (RR = 1.45, 95% CI = .95-2.22, P = .09). CONCLUSIONS: DEVT appears to have equally effectiveness to BT with a low risk of intracranial hemorrhage in AIS patients with LVO, especially for anterior circulation, which offered a practical information to select appropriate therapeutic strategies for patients with LVO, though the level of evidence seems to be quite shaky.

Efficacy and safety of desmoteplase in acute ischemic stroke patients: A systematic review and meta-analysis.

BACKGROUND: Pending results from double-blind, multicenter, parallel-group, randomized trials, the benefit and safety of the novel plasminogen activator, desmoteplase remain undetermined. The aim of this meta-analysis was to help evaluate desmoteplase's efficacy and safety. METHODS: A thorough search was performed of the Cochrane Library, PubMed, and Embase from the inception of electronic data to March 2017, and double-blind, multicenter, parallel-group, randomized trials were chosen. We conducted a meta-analysis of studies investigating intravenous desmoteplase treatment of acute ischemic stroke patients 3 to 9 hours after symptom onset. Asymptomatic intracerebral hemorrhage, good clinical outcome at 90 days, and reperfusion 4 to 8 hours posttreatment were variables assessing efficacy; symptomatic intracerebral hemorrhage and death rates were measures of safety. RESULTS: Six trials involving 1071 patients thrombolyzed >3 hours postonset were included (600 received intravenous desmoteplase, 471 placebo). Desmoteplase was associated with increased reperfusion (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.10-2.24; P = .01 vs control) and showed a tendency to increase asymptomatic intracerebral hemorrhage (OR 1.25; 95% CI, 0.97-1.62; P = .09 vs control), whereas there was no increase in symptomatic intracerebral hemorrhage and death rate with desmoteplase. However, there was no difference in the clinical response at 90 days (OR 1.14; 95% CI, 0.88-1.49; P = .31 vs control). Subgroup analysis showed that desmoteplase 90 µg/kg (OR 1.53; 95% CI, 1.07-2.21; P = .02 vs control) and 125 µg/kg (OR 4.07; 95% CI, 1.16-14.24; P = .03 vs control) were associated with an increase in reperfusion. Also, we found desmoteplase 90 µg/kg showed a tendency to increase asymptomatic intracerebral hemorrhage (OR 1.25; 95% CI, 0.95-1.63; P = .11 vs control). CONCLUSION: Intravenous desmoteplase is associated with a favorable reperfusion efficacy and acceptable safety in ischemic stroke treatment >3 hours after symptom onset. Well-designed randomized controlled trials with larger patient cohorts and a moderate dose of drugs are needed to further evaluate the true efficacy of desmoteplase in stroke patients. TRIAL REGISTRATION: URL: http://www.crd.york.ac.uk/PROSPERO; PROSPERO registration number: CRD42016037667).

Desmoteplase for Acute Ischemic Stroke: A Systematic Review and Metaanalysis of Randomized Controlled Trials.

INTRODUCTION: There is an unmet need to develop better treatments for acute ischemic stroke (AIS). Desmoteplase is a vampire bat saliva-derived analogue of human tissue plasminogen activator. It has higher fibrin selectivity and a longer half-life, compared to alteplase. We performed this metaanalysis to investigate the safety and efficacy of desmoteplase in AIS. METHOD: A computer literature search (PubMed, EMBASE, CENTRAL, Scopus, Web of science, and clinicaltrials.gov) was carried out. Data were extracted from eligible records and analyzed using RevMan software (version 5.3 for windows). Safety and efficacy endpoints were pooled as odds ratios (ORs) for the two groups. RESULT: Five randomized trials (n=821 patients) were pooled in the final analysis. The overall effect size favored desmoteplase over placebo in terms of reperfusion 4 to 24 hours posttreatment (OR 1.49, 95% CI [1.02, 2.19]). However, the pooled effect size did not favor either of the two groups in terms of good clinical outcome at 90 days (OR 1.16, 95% CI [0.86, 1.55]). Neither of the primary safety outcomes differed significantly between the two groups (symptomatic intracranial hemorrhage: OR 1.29, 95% CI [0.53, 3.16] and mortality within 90 days: OR 1.20, 95% CI [0.73, 1.97]). CONCLUSION: Current evidence suggests a favorable reperfusion effect for desmoteplase within 3 to 9 hours after AIS. Further large randomized trials, using a moderate dose between 90 µg/kg and 125 µg/kg, are required to translate this successful reperfusion into better clinical and quality of life outcomes for AIS patients.

Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke).

BACKGROUND AND PURPOSE: The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window. METHODS: Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 µg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08-2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0-2) at day 90 in both the treatment arms. CONCLUSIONS: Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661.

Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: This study investigated the safety and tolerability of desmoteplase administered within 3 to 9 hours after stroke symptoms onset in Japanese patients with acute ischemic stroke. METHODS: Patients were randomized to treatment with either desmoteplase or placebo in a 2:1 ratio in 2 consecutive cohorts (70 µg/kg and then 90 µg/kg). Included patients had a baseline National Institutes of Health Stroke Scale score of 4 to 24 and occlusion or high-grade stenosis in the middle cerebral artery segment M1 or M2 on magnetic resonance angiography. The incidence of symptomatic intracranial hemorrhage (≤72 hours) was defined as the primary end point. The occurrence of asymptomatic ICH, symptomatic cerebral edemas, and adverse events were other safety outcomes of special interest. RESULTS: Symptomatic intracranial hemorrhage was observed within 72 hours in 2 patients treated with placebo and in 1 patient treated with 70 µg/kg desmoteplase. Any ICH (symptomatic or asymptomatic ICH) within 72 hours were observed in 7 (43.8%) patients treated with placebo, in 8 (50%) patients treated with 70 µg/kg desmoteplase, and in 9 (56.3%) patients treated with 90 µg/kg desmoteplase. Desmoteplase treatment with 70 or 90 µg/kg was not associated with an increased risk of symptomatic cerebral edema compared with placebo. There were no other serious safety concerns associated with desmoteplase. CONCLUSIONS: Desmoteplase in both 70 and 90 µg/kg doses had a favorable safety profile and was well tolerated in Japanese patients with acute ischemic stroke when administered 3 to 9 hours after stroke symptoms onset. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01104467.

Safety and efficacy of desmoteplase given 3-9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Current treatment of ischaemic stroke with thrombolytic therapy is restricted to 3-4·5 h after symptom onset. We aimed to assess the safety and efficacy of desmoteplase, a fibrin-dependent plasminogen activator, given between 3 h and 9 h after symptom onset in patients with occlusion or high-grade stenosis in major cerebral arteries. METHODS: In a prospective, double-blind, multicentre, parallel-group, randomised trial, we enrolled patients from 77 hospitals in 17 countries who had ischaemic stroke and occlusion or high-grade stenosis in major cerebral arteries. We randomly assigned patients in a 1:1 ratio, using computer-generated randomisation lists with stratification for baseline National Institutes of Health Stroke Scale and age, to treatment with desmoteplase (90 µg/kg) given 3-9 h after symptom onset or to placebo. Patients, investigators, staff, and the funder were masked to treatment assignment. The primary outcome was a favourable modified Rankin Scale score (0-2) at day 90 in all treated patients who had at least one postbaseline measurement of the modified Rankin Scale. Safety was assessed in all randomly assigned patients who received study drugs. This trial is registered with ClinicalTrials.gov, number NCT00790920. FINDINGS: Between Feb 6, 2009, and Nov 27, 2013, we enrolled 492 patients and randomly assigned 247 to desmoteplase and 245 to placebo (236 in the desmoteplase group and 237 in the placebo group were included in the analysis of the primary endpoint). Median time from stroke onset to treatment was 6·9 h (IQR 5·7-8·0) for placebo and 7·0 h (6·0-7·9) for desmoteplase. Modified Rankin Scale score (0-2) at day 90 occurred in 121 (51%) patients given desmoteplase and 118 (50%) patients given placebo (adjusted odds ratio 1·20, 95% CI 0·79-1·81, p=0·40). 24 (10%) of 240 patients given desmoteplase died compared with 23 (10%) of 238 patients given placebo. Serious adverse events occurred in 64 (27%) of 240 patients receiving desmoteplase compared with 69 (29%) of 238 patients receiving placebo; frequency of symptomatic intracranial haemorrhage (six [3%] patients in the desmoteplase group vs five [2%] in the placebo group), symptomatic cerebral oedema (five [2%] vs four [2%]), and major haemorrhage (ten [4%] vs 15 [6%]) was much the same between treatment groups. INTERPRETATION: Treatment with desmoteplase did not cause safety concerns and did not improve functional outcome when given to patients who had ischaemic stroke and major cerebral artery occlusion beyond 3 h of symptom onset. FUNDING: H Lundbeck A/S.

What causes intracerebral bleeding after thrombolysis for acute ischaemic stroke? Recent insights into mechanisms and potential biomarkers.

The overall population benefit of intravascular recombinant tissue plasminogen activator (rtPA) on functional outcome in ischaemic stroke is clear, but there are some treated patients who are harmed by early symptomatic intracranial haemorrhage (ICH). Although several clinical and radiological factors increase the risk of rtPA-related ICH, none of the currently available risk prediction tools are yet useful for practical clinical decision-making, probably reflecting our limited understanding of the underlying mechanisms. Finding new methods to identify patients at highest risk of rtPA-related ICH, or new measures to limit risk, are urgent challenges in acute stroke therapy research. In this article, we focus on the potential underlying mechanisms of rtPA-related ICH, highlight promising candidate risk biomarkers and suggest future research directions.

Safety and Effectiveness of Intravenous Thrombolysis with Recombinant Tissue Plasminogen Activator in 80 Years and Older Acute Ischemic Stroke Patients.

This study aims to explore the safety and efficacy of intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) in elderly (≥80 years old) acute ischemic stroke (AIS) patients. The clinical data of patients who were treated in Tianjin Huanhu Hospital from June 2012 to November 2013 were retrospectively analyzed; among them, 404 patients had received IVT with rt-PA and 200 patients had not received IVT. Among ≥80-year-old patients, 204 had received IVT and 200 had not. And the 404 patients who had received IVT were divided into two subgroups: elderly (≥80 years of age; n = 204) and controls (<80 years old; n = 200). The incidence of intracranial hemorrhage (ICH) and symptomatic intracranial hemorrhage, case fatality rate, and other prognostic indicators were compared. Among all ≥80-year-old patients, the IVT subgroup had significantly superior good outcome rates than the non-IVT subgroup at 24-h and 3-month along with significantly lower case fatality rate. But for the patients those who had received IVT, the incidence of ICH and the 7-day case fatality rate were not significantly increased in both the elderly and control subgroups. The 24-h and 3-month good outcome rates were not significantly different between these two subgroups as well. IVT with rt-PA is a safe and effective treatment for ≥80-year-old AIS patients.

The intensive care management of acute ischemic stroke: an overview.

PURPOSE: Acute ischemic stroke (AIS) is a leading cause of morbidity and mortality worldwide. In part due to the availability of more aggressive treatments, increasing numbers of patients with AIS are being admitted to the intensive care unit (ICU). Despite the availability of consensus guidance for the general management of AIS, there is little evidence to support its ICU management. The purpose of this article is to provide a contemporary perspective, and our recommendations, on the ICU management of AIS. METHODS: We reviewed the current general AIS guidelines provided by the European Stroke Organisation, the American Stroke Association, and the U.K. National Institute for Health and Care Excellence, as well as the wider literature, for the data most relevant to the ICU management of AIS. RESULTS: There are four interventions in AIS supported by class I evidence: care on a stroke unit, intravenous tissue plasminogen activator within 4.5 h of stroke onset, aspirin within 48 h of stroke onset, and decompressive craniectomy for supratentorial malignant hemispheric cerebral infarction. However, robust evidence for specific AIS management principles in the ICU setting is weak. Management principles currently focus on airway and ventilation management, hemodynamic and fluid optimization, fever and glycemic control, management of anticoagulation, antiplatelet and thromboprophylaxis therapy, control of seizures and surgical interventions for malignant middle cerebral artery and cerebellar infarctions. CONCLUSIONS: We have provided our recommendations for the principles of ICU management of AIS, based on the best available current evidence. Encouragement of large-scale recruitment of patients with AIS into clinical trials should aid the development of robust evidence for the benefit of different interventions in the ICU on outcome.

Treatment of acute ischaemic stroke with thrombolysis or thrombectomy in patients receiving anti-thrombotic treatment.

Systemic thrombolysis with alteplase is the only approved medical treatment for patients with acute ischaemic stroke. Thrombectomy is also increasingly used to treat proximal occlusions of the cerebral arteries, but has not shown superiority over systemic thrombolysis with alteplase. Many patients with acute ischaemic stroke are pretreated with antiplatelet or anticoagulant drugs, which can increase the bleeding risk of thrombolysis or thrombectomy. Pretreatment with aspirin monotherapy increases the bleeding risk of alteplase in both observational and randomised trials with no effect on clinical outcome, and the risk of intracerebral haemorrhage is increased with the combination of aspirin and clopidogrel. Antiplatelet drugs should not be given in the first 24 h after alteplase treatment. Data from pooled randomised trials and a large observational study show that thrombolysis can probably be done safely in patients given vitamin-K antagonists if the international normalised ratio is less than 1·7, although bleeding risk is slightly raised. Almost no data are available for the safety of alteplase in patients with atrial fibrillation who have been given novel oral anticoagulants (NOAC) for stroke prevention. Some coagulation parameters could help to identify patients treated with NOAC who might be eligible for thrombolysis. Thrombectomy can be done in patients given antiplatelets and probably in those given anticoagulants; however, conclusions about anticoagulants are based on findings from observational studies with small patient numbers.

CT angiography in an acute stroke protocol: correlation between occlusion site and outcome of intravenous thrombolysis.

Thrombolysis with intravenous rt-PA is the current therapy for acute ischemic stroke. Unlike other outcome factors, relatively little is known about the prognostic value of the occlusion site on treatment outcome. We compared the effectiveness and safety of intravenous thrombolysis in patients with different levels of occlusion identified by CT angiography (CTA) in anterior circulation stroke, and analyzed the influence of the occlusion site on treatment outcome in relation to other outcome factors. We selected 71 patients from a stroke database collected between June 2007 and December 2011 at our hospital. All of the studied patients had anterior circulation stroke with intracranial occlusion detected by CTA and were treated with intravenous rt-PA. They were divided into two groups according to the site of occlusion along the middle cerebral artery course: proximal (carotid "T", complete M1 and mild M1 occlusions) and distal (M2/M3 occlusions). Treatment effectiveness was assessed by modified Rankin Scale (mRS) at three months, considering a positive outcome a mRS value ≤ 2. Treatment safety was assessed by evaluating the rate of hemorrhagic complications seen on unenhanced CT at 24 hours. Binary logistic regression was performed to evaluate the interaction between occlusion site and other variables such as sex, age, ASPECT score on admission and baseline NIHSS value in determining treatment outcome. The degree of effectiveness and safety differed when considering patients with proximal and distal occlusions. The percentage of successfully treated cases was 28.6% in the first group compared to 72% in the second, and the rate of hemorrhagic complications was 28.6% and 6% respectively. After adjustment for sex, age, ASPECT score on admission and baseline NIHSS value, occlusion site was the only variable significantly influencing treatment safety and, together with baseline NIHSS value, the only valid predictor of treatment effectiveness. We demonstrated a correlation between the site of arterial occlusion and outcome of intravenous thrombolysis. By helping the choice of the best therapeutic strategy depending on the identified occlusion site, CTA could be usefully added to the examinations included in the Stroke Protocol for the baseline evaluation of patients with suspected acute stroke.

Observational investigation of thrombolysis with the tissue-type plasminogen activator monteplase for acute pulmonary embolism in Japan.

BACKGROUND: In Japan, the safety and efficacy of thrombolytic therapy using tissue-type plasminogen activator for acute pulmonary embolism (PE) in the real world remain unclear. METHODS AND RESULTS: A total of 1,254 patients with acute PE covered by the post-marketing surveillance of thrombolytic therapy using monteplase were divided into 3 groups: cardiopulmonary arrest (CPA)/collapse group (n=85); massive group, patients with unstable hemodynamics without CPA/collapse (n=217); and submassive group, patients with stable hemodynamics and right ventricular dysfunction (RVD) (n=465). In the efficacy analysis of 767 cases, the response rate to monteplase was 94.6% according to pulmonary circulation assessment and 93.3% according to clinical efficacy judged by symptoms and signs. Overall survival rates at 30 days after monteplase administration were 89.2% overall, 41.2% for the CPA/collapse group, 93.0% for the massive group, and 96.3% for the submassive group. When the safety of monteplase was analyzed in 1,241 cases, severe bleeding complications occurred in 100 patients (8.1%). Intracranial hemorrhage (ICH) occurred in 21 patients (1.7%), but no significant independent predictors were found in multivariate analysis. CONCLUSIONS: Thrombolytic therapy is highly effective in Japanese acute PE patients and offers acceptable safety, but attention is needed regarding severe bleeding complications, including ICH.

Vascular occlusion enables selecting acute ischemic stroke patients for treatment with desmoteplase.

BACKGROUND AND PURPOSE: Desmoteplase is a novel and highly fibrin-specific thrombolytic agent. Evidence of safety and efficacy was obtained in 2 phase II trials (Desmoteplase In Acute Ischemic Stroke [DIAS] and Desmoteplase for Acute Ischemic Stroke [DEDAS]). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post hoc analyses were performed with the aim of predicting treatment responders based on CTA and MRA. METHODS: Patients were grouped according to vessel status (Thrombolysis In Myocardial Infarction [TIMI] grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2. RESULTS: In DIAS-2, a substantial number of mismatch-selected patients (126/179; 70%) presented with a normal flow/low-grade stenosis (TIMI 2-3) at screening, with the majority having a favorable outcome at day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0-1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 µg/kg, respectively. The clinical effect based on the pooled data from DIAS, DEDAS, and DIAS-2 was favorable for desmoteplase-treated patients presenting with TIMI 0 to 1 at baseline (OR, 4.144; 95% CI, 1.40-12.23; P=0.010). There was no desmoteplase treatment benefit in patients presenting with TIMI 2 to 3 (OR, 1.109). CONCLUSIONS: In this sample of patients with a mismatch diagnosed, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CTA or MRA in clinical trials of thrombolytic therapy is justifiable.

Development of a kit to treat subarachnoid hemorrhage by intrathecal simple urokinase infusion (ITSUKI) therapy: preliminary results in patients with World Federation of Neurological Surgery (WFNS) grade V subarachnoid hemorrhage.

OBJECTIVE: To report the effectiveness of intrathecal selective administration of urokinase infusion (ITSUKI) therapy delivered via a special kit (ITSUKit), developed to prevent vasospasm in patients with ruptured aneurysms who had undergone Guglielmi detachable coil (GDC) placement, in patients with World Federation of Neurological Surgery (WFNS) grade V subarachnoid hemorrhage (SAH). METHODS: A study of ITSUKI therapy with or without ventricular drainage enrolled 6 patients with WFNS grade V SAH owing to ruptured intracranial aneurysms who were eligible for coil embolization. The procedures were performed within 48 hours of the occurrence of aneurysmal SAH. The incidence of symptomatic vasospasm and the clinical outcomes based on the Glasgow Outcome Scale (GOS) were assessed at 6 months after SAH onset. RESULTS: All patients underwent complete coil embolization. There were no side effects or adverse reactions attributable to ITSUKI therapy. Symptomatic vasospasm occurred in one patient (16.7%). There were no patients with hydrocephalus. Based on the GOS, one patient had a good outcome, two manifested moderate disability, and three manifested severe disability. CONCLUSIONS: The results showed that the ITSUKit was useful for ITSUKI therapy. Although the combination of coil embolization and ITSUKI therapy did not completely eliminate WFNS grade V SAH, it significantly improved the treatment outcome in some patients.

SYNTHESIS expansion: design of a nonprofit, pragmatic, randomized, controlled trial on the best fast-track endovascular treatment vs. standard intravenous alteplase for acute ischemic stroke.

Rationale Reperfusion in ischemic stroke can be pursued by either systemic intravenous thrombolysis or endovascular treatment. However, systemic intravenous thrombolysis with alteplase within 4·5 h of symptom onset in selected patients is the only medication of proven efficacy. No randomized-controlled trials have so far compared the two modalities. To explore this, after a pilot phase, we started the SYNTHESIS Expansion trial. Aims To determine whether endovascular treatment (i.e., intra-arterial thrombolysis with alteplase - if necessary, associated to or substituted by mechanical clot disruption and/or retrieval) compared with systemic intravenous thrombolysis with alteplase, administered according to European labelling, increases the proportion of independent survivors at three-months. Design SYNTHESIS Expansion is an open-label, multicenter randomized-controlled trial, with blinded follow-up. Eligibility applies to; patients with symptomatic ischemic stroke, seen within 4·5 h of onset; being able to initiate intravenous alteplase immediately, and endovascular treatment as soon as possible (not later than six-hours of stroke onset). The study is pragmatically based on the 'uncertainty principle' between endovascular treatment and systemic intravenous thrombolysis for patients eligible for intravenous alteplase. There are no prespecified clinical or instrumental criteria to further select a patient, although investigators are left free to use them. Enrollment will be completed with 350 randomized patients. Primary analysis is on an intent-to-treat basis. Study outcomes Primary: modified Rankin scale score of 0 or 1 at three-months. Secondary: neurological deficit seven-days after thrombolysis and the safety of the procedure on the basis of events reported within seven-days following thrombolysis - symptomatic cerebral hemorrhage, fatal and nonfatal stroke, death from any cause, neurological deterioration.