Emergency LP in a patient receiving dabigatran after antagonization with idarucizumab.

Idarucizumab is an antibody fragment which is used to reverse the anticoagulant effects of dabigatran. We report on the first successful use of idarucizumab before performing an emergency lumbar puncture in a patient on effective anticoagulation with dabigatran thought to have infective cerebral disease (such as temporal encephalitis).

Intravenous Thrombolysis With Recombinant Tissue-Type Plasminogen Activator in a Stroke Patient Receiving Dabigatran Anticoagulant After Antagonization With Idarucizumab.

BACKGROUND AND PURPOSE: Therapeutic options for acute ischemic stroke patients presenting on effective anticoagulation are limited. Idarucizumab, a humanized, monoclonal antibody fragment for immediate reversal of dabigatran, may allow this subgroup of orally anticoagulated patients to regain eligibility for thrombolysis. METHODS: We report the first successful acute antagonization of dabigatran by idarucizumab before intravenous thrombolysis with recombinant tissue-type plasminogen activator. RESULTS: Idarucizumab was given to a 76-year-old male patient on dabigatran ≈3.5 hours after his last dose. Neurological status on admission was NIHSS (National Institutes of Health Stroke Scale) 11. Recombinant tissue-type plasminogen activator was initiated immediately after dabigatran reversal. The patient was discharged with a favorable outcome of NHISS 1 on day 7. No complications were observed. CONCLUSIONS: This case represents a new therapeutic paradigm. It is further supported by in vitro data showing no nonspecific interactions of idarucizumab with recombinant tissue-type plasminogen activator-induced thrombolysis. Thus, patients effectively anticoagulated with dabigatran who were previously contraindicated for thrombolytic therapy in this situation may now receive treatment because of the ability to rapidly reverse the anticoagulant activity of dabigatran with idarucizumab.

Fluorescent molecular peroxidation products: a prognostic biomarker of early neurologic deterioration after thrombolysis.

BACKGROUND AND PURPOSE: Fluorescent molecular peroxidation products (FMPPs) are considered potential markers of molecular oxidative damage and may provoke increased permeability and disruption of the blood-brain barrier. This study aimed to determine the value of FMPPs as a biomarker to predict neurological worsening related to early hemorrhagic transformation. METHODS: Baseline FMPP levels were measured in 186 consecutive acute ischemic stroke patients before tissue plasminogen activator treatment was administered. A serial FMPP profile (baseline before tissue plasminogen activator treatment, and 1, 2, 12, and 24 hours from treatment) was determined in a subset of 100 patients. Computed tomographic scans were performed at admission and repeated at 24 to 48 hours or after neurological worsening occurred. Symptomatic intracranial hemorrhage was defined as blood at any site in the brain associated with neurological deterioration. RESULTS: Patients who worsened had higher median FMPP levels compared with those who did not (59.68 [48.63-85.73] versus 44.87 [36.37-58.90] Uf/mL; P=0.035) at baseline. After logistic regression multivariate analysis, FMPP >48.2 Uf/mL together with age, hypertension, and systolic blood pressure remained baseline predictors of worsening at 48 hours. Moreover, baseline FMPP determination helped to distinguish between patients who worsened and those who did not (Integrated Discrimination Improvement index, 5.7%; P=0.0004). Finally, within patients who had worsened at 48 hours, those with symptomatic intracranial hemorrhage had higher FMPP levels (P=0.038). CONCLUSIONS: FMPPs might be a valuable biomarker of poor early neurological outcome and be related to the appearance of symptomatic intracranial hemorrhage in tissue plasminogen activator-treated patients, one of the most feared neurological complications after thrombolytic treatment of acute ischemic stroke.

Efficacy and safety of oral factor Xa inhibitors versus vitamin-K antagonists in the early phase after acute ischemic stroke or TIA in the real-world setting: The PRODAST study.

INTRODUCTION: Factor Xa (FXa) inhibitors are superior to vitamin K antagonists (VKAs) in terms of avoiding hemorrhagic complications. However, no robust data are available to date as to whether this also applies to the early phase after stroke. In this prospective registry study, we aimed to investigate whether anticoagulation with FXa inhibitors in the early phase after acute ischemic stroke or transient ischemic attack (TIA) is associated with a lower risk of major bleeding events compared with VKAs. MATERIALS AND METHODS: The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study is a prospective, multicenter, observational, post-authorization safety study at 86 German stroke units between July 2015 and November 2020. Primary outcome was a major bleeding event during hospital stay. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death and the composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. RESULTS: In total, 10,039 patients have been recruited. 5,874 patients were treated with FXa inhibitors and 1,050 patients received VKAs and were eligible for this analysis. Overall, event rates were low. We observed 49 major bleeding complications during 33,297 treatment days with FXa-inhibitors (rate of 14.7 cases per 10,000 treatment days) and 16 cases during 7,714 treatment days with VKAs (rate of 20.7 events per 10,000 treatment days), translating into an adjusted hazard ratio (aHR) of 0.70 (95% confidence interval (95% CI): 0.37-1.32) in favor of FXa inhibitors. Hazards for ischemic endpoints (63 vs 17 strokes, aHR: 0.96 (95% CI: 0.53-1.74), mortality (33 vs 6 deaths, aHR: 0.87 (95% CI: 0.33-2.34)) and the combined endpoint (154 vs 39 events, aHR: 0.99 (95% CI: 0.65-1.41) were not substantially different. DISCUSSION AND CONCLUSION: This large real-world study shows that FXa inhibitors appear to be similarly effective in terms of bleeding events and ischemic endpoints compared to VKAs in the early post-stroke phase of hospitalization. However, the results need to be interpreted with caution due to the low precision of the estimates.

Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial.

RATIONALE: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question. AIMS: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO. METHODS: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. STUDY OUTCOMES: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. DISCUSSION: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.

Outcome after intracranial hemorrhage under dabigatran and reversal with idarucizumab versus under vitamin-K-antagonists - the RIC-ICH study.

Background: Intracranial hemorrhage (ICH) is a rare but serious side effect associated with the use of oral anticoagulants, such as dabigatran. The specific reversal agent for dabigatran, idarucizumab, is available for the management of individuals with ICH. The aim of this study was to provide real-world evidence on patients with ICH and effective treatment with dabigatran and reversal with idarucizumab in clinical routine compared to those under effective treatment with vitamin-K-antagonist (VKA). Methods: Registration of Idarucizumab for Patients with IntraCranial Hemorrhage (RIC-ICH) is a non-interventional study conducted in 22 German stroke units that prospectively enrolled dabigatran patients treated with idarucizumab. Retrospective data from VKA patients served as reference population. Main objective was in-hospital mortality. Further objectives included change in bleeding volume, stroke severity, and functional status. Result: In-hospital mortality was 26.7% in 15 dabigatran and 27.3% in 88 VKA patients (hazard ratio 1.00, 95% CI 0.29-2.60). In patients with bleeding volume > 60 ml, mortality was lower in the dabigatran group (N = 6, 33%) compared to the VKA group (N = 15, 67%; HR 0.24, 95% CI 0.04-0.96). No differences were observed in secondary endpoints between dabigatran and VKA patients. Conclusion: These results, based on data from routine clinical practice, suggest that in-hospital mortality after idarucizumab treatment is comparable to that in patients pretreated with VKA. Due to the low precision of estimates, the results must be interpreted with caution.

Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study.

BACKGROUND: The optimal timing of initiating or resuming anticoagulation after acute ischemic stroke (AIS) or transient ischemic attack (TIA) in patients with atrial fibrillation (AF) is debated. Dabigatran, a non-vitamin K oral anticoagulant (NOAC), has shown superiority against vitamin K antagonists (VKA) regarding hemorrhagic complications. AIMS: In this registry study, we investigated the initiation of dabigatran in the early phase after AIS or TIA. METHODS: PRODAST (Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA) is a prospective, multicenter, observational, post-authorization safety study. We recruited 10,039 patients at 86 German stroke units between July 2015 and November 2020. A total of 3,312 patients were treated with dabigatran or VKA and were eligible for the analysis that investigates risks for major hemorrhagic events within 3 months after early (⩽ 7 days) or late (> 7 days) initiation of dabigatran or VKA initiated at any time. Further endpoints were recurrent stroke, ischemic stroke, TIA, systemic embolism, myocardial infarction, death, and a composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. RESULTS: Major bleeding event rates per 10,000 treatment days ranged from 1.9 for late administered dabigatran to 4.9 for VKA. Early or late initiation of dabigatran was associated with a lower hazard for major hemorrhages as compared to VKA use. The difference was pronounced for intracranial hemorrhages with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval (CI): 0.10-2.21) for early dabigatran use versus VKA use and an adjusted HR of 0.09 (95% CI: 0.00-13.11) for late dabigatran use versus VKA use. No differences were found between early initiation of dabigatran versus VKA use regarding ischemic endpoints. CONCLUSIONS: The early application of dabigatran appears to be safer than VKA administered at any time point with regards to the risk of hemorrhagic complications and in particular for intracranial hemorrhage. This result, however, must be interpreted with caution in view of the low precision of the estimate.

Salivette® Cortisol versus oropharyngeal swabbing for the detection of SARS-CoV-2 infection.

BACKGROUND: Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by naso/oropharyngeal swabbing may expose health-care workers to the virus and is technically challenging. The Salivette® is an alternative saliva-collection device with an oral cotton swab containing citric acid to stimulate saliva production, which may have an unpleasant taste. We present a pilot study comparing the Salivette® Cortisol (SC), which uses a synthetic swab without citric acid, against oropharyngeal swabbing for the detection of SARS-CoV-2 by reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESEARCH DESIGN AND METHODS: Symptomatic SARS-CoV-2-positive patients were sampled at various timepoints. The number of patients positive/negative for SARS-CoV-2 in oropharyngeal swab and SC samples and the percentage of patients testing true positive/true negative for SARS-CoV-2 from SC samples were determined. Positivity was defined by RT-qPCR amplification of 2/3 target SARS-CoV-2 N, ORF1, and S gene sequences. RESULTS: SC demonstrated 100% specificity, 52.2% sensitivity, and positive correlation with oropharyngeal swabbing for the detection of the SARS-CoV-2 S gene. In later-stage disease, lower viral load was observed in SC samples compared with oropharyngeal swabs. CONCLUSIONS: The SC may be an alternative for SARS-CoV-2 detection where naso/oropharyngeal swabbing is not feasible/available. This technique also confirms observations that the detection of SARS-CoV-2 in the upper airway may vary due to viral load over the disease course. TRIAL REGISTRATION: NCT04599959.

Transient filament occlusion of the middle cerebral artery in rats: does the reperfusion method matter 24 hours after perfusion?

BACKGROUND: There are two widely used transient middle cerebral artery occlusion (MCAO) methods, which differ in the use of unilateral or bilateral carotid artery reperfusion (UNICAR and BICAR). Of the two methods, UNICAR is easier to perform. This study was designed to comprehensively compare the two reperfusion methods to determine if there are any differences in outcomes. RESULTS: The UNICAR and BICAR groups each included 9 rats. At baseline, the average pO(2) was 20.54 ± 9.35 and 26.43 ± 7.39, for the UNICAR and BICAR groups, respectively (P = 0.519). Changes in pO(2), as well as other physiological parameters measured within the ischemic lesion, were similar between the UNICAR and BICAR groups during 90 min of MCAO and the first 30 min of reperfusion (all P > 0.05). Furthermore, both the Bederson score and Garcia score, which are used for neurological assessment, were also similar (both P > 0.05). There were also no significant differences in T2WI lesion volume, DWI lesion volume, PWI lesion volume, or TTC staining infarct volume between the two groups (all P > 0.05). CONCLUSION: UNICAR and BICAR have similar capability for inducing acute brain ischemic injury and can be considered interchangeable up to 24 hours after reperfusion.

Rationale, Design and Methods of the Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) Study.

Background: The optimal timing of anticoagulation following acute ischaemic stroke or TIA in patients with atrial fibrillation (AF) is a frequent challenge. Early initiation of anticoagulation can reduce the risk for recurrent ischaemic events, but may lead to an increased risk for intracerebral haemorrhage. Aim: The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study was initiated to investigate outcome events under antithrombotic therapy after ischaemic stroke or TIA in patients with AF. The main objective is to compare the three-month rates of major haemorrhagic events between early (≤ 7 days) versus late (> 7 days) administration of dabigatran or treatment with vitamin-K antagonists started at any time. Occurrences of ischaemic and major haemorrhagic events will be evaluated to determine the optimal time point for initiation or resumption of anticoagulation. Design and Methods: PRODAST is a prospective, multicenter, observational, non-interventional post-authorization safety study. 10,000 patients with recent (≤ 1 week from index event) ischaemic stroke or TIA and non-valvular AF were recruited at 86 German sites starting in July 2015. The observational plan includes a baseline visit, documentation of data during hospitalization and a telephone-based, central follow-up at three months after the index event. The primary endpoint is the major bleeding rate within three months. Secondary endpoints include rates of recurrent ischaemic or haemorrhagic stroke, TIA, systemic embolism, myocardial infarction and death. Summary: PRODAST will provide important real-world data on safety and efficacy of antithrombotic therapy after acute stroke and TIA in patients with AF.

Pilot study of an occupational healthcare program to assess the SARS-CoV-2 infection and immune status of employees in a large pharmaceutical company.

OBJECTIVE: To safeguard key workers involved in development and production of medicines and ensure business continuity, we developed an occupational healthcare program, performed by our company's occupational healthcare services, to assess the infection and immune status for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pilot program, conducted at our company facilities, evaluated the suitability of diagnostic tools in our setting for program upscaling. METHODS: We used different marketed in vitro diagnostics (including tests for antibodies against spike protein subunits S1 and S2 and nucleocapsid [N] protein) combined with medical history, symptoms and likelihood of infection. We evaluated the testing strategy over four visits in 141 employees (known positive COVID-19 history, n = 20; unknown status, n = 121) between April and June 2020 at four company locations in Germany. Digital self-monitoring over the pilot program duration was also included. RESULTS: No incident infections were detected. Based on immune status, medical history and likelihood of infection, 10 participants (8.3%) with previously unknown history of COVID-19 were identified to have been infected before entering the program. These participants, who recalled no or mild symptoms in the preceding months, were primarily identified using an assay that detected both S1 and S2 immunoglobulin (Ig) G. The frequency of positive lateral flow assay (LFA) results (IgM or IgG directed against the N-protein) in this cohort was lower compared with participants with a known history of COVID-19 (0‒10.8% vs. 33.8‒75.7%, respectively). CONCLUSIONS: Data from this pilot program suggest that LFA for antibodies may not always reliably detect current, recent or past infections; consequently, these have not been included in our upscaled occupational healthcare program. Regular testing strategies for viral RNA and antibodies directed against different SARS-CoV-2 proteins, combined with hygiene rules and a comprehensive baseline assessment, are recommended to ensure avoidance of infections at workplace as reliably as possible.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. AIMS: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. METHODS: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. RESULTS: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. CONCLUSION: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

The correlation between quantitative T2' and regional cerebral blood flow after acute brain ischemia in early reperfusion as demonstrated in a middle cerebral artery occlusion/reperfusion model of the rat.

INTRODUCTION: qT2'-maps are calculated by subtracting T2- from T2*-relaxation rates. They are oxygen-sensitive and depict oxygen extraction. In several studies they have been used to describe the penumbra in patients with acute ischemic stroke. No correlation between rCBF and qT2' has been performed to date. In this study a correlation between rCBF and qT2' was performed in a temporary middle cerebral occlusion-reperfusion model of the rat. MATERIALS AND METHODS: Temporary middle cerebral artery occlusion was performed on seven Sprague-Dawley rats. After 60 min of occlusion and 90 min of reperfusion MRI was performed including DWI, dynamic susceptibility contrast-weighted MR imaging (DSC-MRI) and qT2'. ROIs were placed inside the DWI lesion and transferred to rCBF- and qT2'-maps. rCBF and qT2' were compared to corresponding tissue in the contralateral hemisphere. RESULTS: qT2' was lower in the infarcted areas when compared to the contralateral hemisphere. Correlation between rCBF and qT2' was r = 0.41, p = 0.14 (Pearson's correlation coefficient), when corrected for outliers it was r = 0.58, p = 0.04. CONCLUSION: Our results show that there is a moderate correlation between rCBF and qT2'. qT2'-maps could be used to explore cerebral perfusion without the application of contrast agent or radiation.

Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection.

BACKGROUND: Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5-9 h after symptom onset benefit from intravenous thrombolysis compared to placebo. METHODS: Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0-6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63-2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53). CONCLUSIONS: Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo. (Supported by Boehringer Ingelheim, Germany; ISRCTN 71616222).

Circulating Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 predict Three-months Outcome after Ischemic Stroke.

Reports on neuroprotective effects of Insulin-like growth factor-1 (IGF-1) and Insulin-like growth factor binding protein-3 (IGFBP-3) in ischemic brain tissue are inconsistent. The aim of this study was to determine if plasma levels of IGF-1 and IGFBP-3 in acute stroke patients are indicative of 3 months functional outcome. Plasma levels were measured via chemiluminescence immunoassay in heparin blood samples of patients included in the EARLY trial (NCT00562588). Plasma samples were drawn on admission and 8 days post-stroke. Neurological deficits were assessed via modified Rankin Scale (mRS) 3 months post-stroke, resulting in favorable (mRS=0-2) or unfavorable (mRS=3-6) outcome. A multiple binary logistic regression including IGF-1 and IGFBP-3 levels and confounders was conducted. Out of 404 included patients, 89 patients had an unfavorable outcome. Mean mRS on admission as well as 3 months post-stroke was 2 (±1). Low IGF-1 levels (day 8) were independently associated with a decreased risk of an unfavorable outcome (OR 0.61; 95%CI 0.37-0.99; p=0.044). Low IGFBP-3 levels (day 8) were independently associated with an unfavorable outcome (OR 2.75; 95%CI 1.56-4.84; p<0.001). Low IGFBP-3 levels and high IGF-1 levels in the subacute phase are predictive of unfavorable outcome 3 months after stroke.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany - A national case collection.

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0-3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.

Involvement of the mitochondrial ATP-sensitive potassium channel in the neuroprotective effect of hyperbaric oxygenation after cerebral ischemia.

In the present study, we investigated whether activation of mitochondrial ATP-sensitive potassium channel is involved in the neuroprotective effect offered by early hyperbaric oxygenation after cerebral ischemia. The selective mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoate was infused intracerebroventricularly before hyperbaric oxygenation treatment initiated 3 h after middle cerebral artery occlusion for 90 min. Neurological status was evaluated and brains were removed for the measurement of infarct size and immunohistochemical evaluation of apoptosis 24 h after middle cerebral artery occlusion. Early hyperbaric oxygenation treatment improved neurologic deficits and reduced infarct volume, while these effects were reversed by the administration of 5-hydroxydecanoate. Furthermore, early hyperbaric oxygenation significantly decreased the number of apoptotic cells in the peri-infarct cortex 24 h after ischemic insult and this effect was also blocked by 5-hydroxydecanoate. The present findings suggest that early hyperbaric oxygenation therapy prevents apoptosis and promotes neurologic functional recovery after focal cerebral ischemia, and the opening of mitochondrial ATP-sensitive potassium channel plays a role in this antiapoptotic effect of early hyperbaric oxygenation.

Idarucizumab as Antidote to Intracerebral Hemorrhage under Treatment with Dabigatran.

BACKGROUND AND PURPOSE: Non-vitamin K anticoagulants (NOAC) such as dabigatran have become important therapeutic options for the prevention of stroke. Until recently, there were only nonspecific agents to reverse their anticoagulant effects in a case of emergency. Idarucizumab, an antibody fragment targeting dabigatran, is the first specific antidote for a NOAC to be approved, but real-world experience is limited. METHODS: We report two cases of patients on dabigatran with acute intracerebral hemorrhage who received idarucizumab. RESULTS: In both cases, idarucizumab promptly reversed the anticoagulant effect of dabigatran and there was no hematoma expansion in follow-up imaging. CONCLUSIONS: In addition to clinical and preclinical studies, our cases add to the experience regarding the safety and efficacy of idarucizumab. They show that idarucizumab may be an important safety option for patients on dabigatran in emergency situations.

European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND.

RATIONALE AND HYPOTHESIS: Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is an effective and approved therapy for acute ischemic stroke within 4.5 h of onset except for USA, Canada, Croatia, and Moldovia with a current 3 h label. We hypothesized that ischemic stroke patients selected with significant penumbral mismatch on magnetic resonance imaging (MRI) at 4.5-9 h after onset of stroke will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo. STUDY DESIGN: ECASS-4: ExTEND is an investigator driven, phase 3, randomized, multi-center, double-blind, placebo-controlled study. Ischemic stroke patients presenting within 4.5 and 9 h of stroke onset, who fulfil clinical requirements (National Institutes of Health Stroke Score (NIHSS) 4-26 and pre-stroke modified Rankin Scale (mRS) 0-1) will undergo MRI. Patients who meet imaging criteria (infarct core volume <100 ml, perfusion lesion: infarct core mismatch ratio >1.2 and perfusion lesion minimum volume of 20 ml) additionally will be randomized to either rt-PA or placebo. STUDY OUTCOME: The primary outcome measure will be the categorical shift in the mRS at day 90. Clinical secondary outcomes will be disability at day 90 dichotomized as favorable outcome mRS 0-1 at day 90. Tertiary endpoints include reduction in the NIHSS by 11 or more points or reaching 0-1 at day 90, reperfusion and recanalization at 24 h post stroke as well as depression, life quality, and cognitive impairment at day 90. Safety endpoints will include symptomatic intracranial hemorrhage (ICH) and death.

Therapeutic window for use of hyperbaric oxygenation in focal transient ischemia in rats.

BACKGROUND AND PURPOSE: Hyperbaric oxygenation (HBO) is an attractive procedure that has been used frequently in cerebral ischemia. However, depending on the model of cerebral ischemia and HBO protocol, different and conflicting results were obtained in the past. This study was undertaken to reevaluate the effects of single administration of HBO in 2 models of acute cerebral ischemia: transient or permanent focal ischemia in rats. A comparison of the 2 ischemia models was undertaken to search for a putative therapeutic window. METHODS: The intraluminal middle cerebral artery occlusion model (MCAO) was used. The effect of single HBO therapy (3 atm absolute, 60 minutes) on transient or permanent focal ischemia, when applied at different times (3, 6, or 12 hours) after MCAO, was investigated; infarct volume and neurological deficits were assessed at 24 hours and up to 7 days. RESULTS: HBO had neuroprotective effects on transient MCAO when HBO was initiated within the first 6 hours, while it aggravated the ischemic injury histologically and clinically when initiated 12 hours after MCAO. In permanent MCAO, HBO did not reduce tissue damage regardless of the timing of therapy. CONCLUSIONS: HBO is highly efficient in reducing infarct volume and improving neurobehavioral outcome in transient MCAO within the first 6 hours. HBO at later time points (>or=12 hours) is harmful by increasing infarct volume. In permanent MCAO, HBO failed to improve infarct volume and clinical outcome.