Efficacy and Safety of Prasugrel vs Clopidogrel in Thrombotic Stroke Patients With Risk Factors for Ischemic Stroke Recurrence: A Double-blind, Phase III Study (PRASTRO-III).

AIM: To examine the efficacy and safety of prasugrel vs clopidogrel in thrombotic stroke patients at risk of ischemic stroke. METHODS: This multicenter, active-controlled, randomized, double-blind, double-dummy, parallel group study enrolled thrombotic stroke patients aged ≥ 50 years at risk of ischemic stroke. Patients received prasugrel (3.75 mg/day) or clopidogrel (75 or 50 mg/day) for 24-48 weeks; other antiplatelet drugs were prohibited. The primary efficacy endpoint was the composite incidence of ischemic stroke, myocardial infarction (MI), and death from other vascular causes from the start to 1 day after treatment completion or discontinuation. Secondary efficacy endpoints included the incidences of ischemic stroke, MI, death from other vascular causes, ischemic stroke and transient ischemic attack, and stroke. Safety endpoints included bleeding events and adverse events (AEs). RESULTS: In the prasugrel (N=118) and clopidogrel (N=112; all received 75 mg) groups, the primary efficacy endpoint composite incidence (95% confidence interval) was 6.8% (3.0%-12.9%) and 7.1% (3.1%-13.6%), respectively. The risk ratio (prasugrel/clopidogrel) was 0.949 (0.369-2.443). Secondary efficacy endpoints followed a similar trend. The combined incidences of life-threatening, major, and clinically relevant bleeding were 5.0% and 3.5% in the prasugrel and clopidogrel groups, respectively. The incidences of all bleeding events and AEs were 19.2% and 24.6% and 76.7% and 82.5% in the prasugrel and clopidogrel groups, respectively. No serious AEs were causally related to prasugrel. CONCLUSIONS: We observed a risk reduction of 5% with prasugrel vs clopidogrel, indicating comparable efficacy. There were no major safety issues for prasugrel.

Clinical safety and outcome of recombinant tissue plasminogen activator in patients with stroke attributable to small artery occlusion: A protocol for systematic review and meta-analysis.

BACKGROUND: Recent observations raised concern that the intravenous recombinant tissue plasminogen activator (rt-PA) may result in damage to stroke patients caused by small artery occlusion (SAO). Thus, we perform a protocol for meta-analysis to investigate the efficacy and safety of intravenous thrombolysis with rt-PA in SAO-patients. METHODS: The search-style electronic libraries, including Pubmed, Embase, the Cochrane Library, Web of Science, Wanfang Data, VIP Chinese Journals, and China Biomedical Literature Service System are used for document retrieval in June 2021 with no restrictions on language. The risk of bias in include articles will be assessed using the Cochrane Risk of Bias Tool. We perform the meta-analysis by Stata version 10.0 software and calculated the statistics using the inverse variance statistical method. Binary outcomes are presented as Mantel-Haenszel-style risk ratios with 95% confidence interval. Continuous outcomes are reported as mean differences. RESULTS: The results of the article will be shown in a peer-reviewed journal. CONCLUSION: Intravenous rt-PA may be effective and safe in SAO-patients.

Adrenergic inhibition facilitates normalization of extracellular potassium after cortical spreading depolarization.

Cortical spreading depolarization (CSD) is a propagating wave of tissue depolarization characterized by a large increase of extracellular potassium concentration and prolonged subsequent electrical silencing of neurons. Waves of CSD arise spontaneously in various acute neurological settings, including migraine aura and ischemic stroke. Recently, we have reported that pan-inhibition of adrenergic receptors (AdRs) facilitates the normalization of extracellular potassium after acute photothrombotic stroke in mice. Here, we have extended that mechanistic study to ask whether AdR antagonists also modify the dynamics of KCl-induced CSD and post-CSD recovery in vivo. Spontaneous neural activity and KCl-induced CSD were visualized by cortex-wide transcranial Ca2+ imaging in G-CaMP7 transgenic mice. AdR antagonism decreased the recurrence of CSD waves and accelerated the post-CSD recovery of neural activity. Two-photon imaging revealed that astrocytes exhibited aberrant Ca2+ signaling after passage of the CSD wave. This astrocytic Ca2+ activity was diminished by the AdR antagonists. Furthermore, AdR pan-antagonism facilitated the normalization of the extracellular potassium level after CSD, which paralleled the recovery of neural activity. These observations add support to the proposal that neuroprotective effects of AdR pan-antagonism arise from accelerated normalization of extracellular K+ levels in the setting of acute brain injury.

The prognosis prediction significance of Hounsfield unit value for stroke patients treated by intravenous thrombolysis.

BACKGROUND: Intravenous thrombolysis (IVT) is a rapid and effective treatment in the early stage of ischemic stroke patients and the purpose of this work is to explore the significance of Hounsfield unit (HU) value in Alberta Stroke Program Early CT Score (ASPECTS) for predicting the clinical prognosis of stroke patients with middle cerebral artery occlusion (MCAO) treated by IVT. METHODS: The 84 stroke patients with MCAO treated by IVT were divided into good prognosis group (48 cases) and poor prognosis group (36 cases). HU ratio and HU difference calculated from non-contrast computed tomography between groups were analyzed. RESULTS: The HU ratio of good prognosis group was higher than that in poor prognosis group and the HU difference of good prognosis group was lower than that in poor prognosis group (P < 0.05). The HU ratio and ASPECTS were negatively correlated with the infarct volume, and the HU difference was positively correlated with the infarct volume (P < 0.05). HU difference was an independent risk factor for prognosis of patients with MCAO treated by IVT. The area under the receiver operating characteristic curve of HU ratio and HU difference for prognosis was 0.743 and 0.833 respectively. CONCLUSION: The HU value changes are related to the clinical prognosis of stroke patients with MCAO treated by IVT, HU value may be a prognostic indicator for stroke patients with MCAO treated by IVT.

Lysis of arterial thrombi by perfusion of N,N'-Diacetyl-L-cystine (DiNAC).

The search persists for a safe and effective agent to lyse arterial thrombi in the event of acute heart attacks or strokes due to thrombotic occlusion. The culpable thrombi are composed either primarily of platelets and von Willebrand Factor (VWF), or polymerized fibrin, depending on the mechanism of formation. Current thrombolytics were designed to target red fibrin-rich clots, but may be not be efficacious on white VWF-platelet-rich arterial thrombi. We have developed an in vitro system to study the efficacy of known and proposed thrombolytic agents on white clots formed from whole blood in a stenosis with arterial conditions. The agents and adjuncts tested were tPA, ADAMTS-13, abciximab, N-acetyl cysteine, and N,N'-Diacetyl-L-cystine (DiNAC). Most of the agents, including tPA, had little thrombolytic effect on the white clots. In contrast, perfusion of DiNAC lysed thrombi as quickly as 1.5 min, which ranged up to 30 min at lower concentrations, and resulted in an average reduction in surface area of 71 ± 20%. The clot burden was significantly reduced compared to both tPA and a saline control (p<0.0001). We also tested the efficacy of all agents on red fibrinous clots formed in stagnant conditions. DiNAC did not lyse red clots, whereas tPA significantly lysed red clot over 48 h (p<0.01). These results lead to a novel use for DiNAC as a possible thrombolytic agent against acute arterial occlusions that could mitigate the risk of hyper-fibrinolytic bleeding.

Tenecteplase for thrombolysis in stroke patients: Systematic review with meta-analysis.

INTRODUCTION: Alteplase is an approved treatment for acute ischemic stroke. Tenecteplase is a genetically modified form of alteplase, with lower cost and a more favourable pharmacokinetic profile allowing bolus injection. The aim of this study was to compare both drugs in adult patients with acute ischemic stroke undergoing thrombolysis. MATERIAL AND METHODS: PubMed and CENTRAL were searched for observational and experimental studies comparing both drugs in the population of interest. Additional studies were sought in clinical trial registries and by means of reference check. The efficacy outcomes of interest were functional status at 3 months, recanalization and early neurological improvement (ENI). The safety outcomes of interest were cerebral haemorrhage (ICH), symptomatic ICH and mortality. The effect measure of interest was the absolute risk difference (ARD). Effect measures for each outcome were pooled across studies using random effect models. RESULTS: Eight studies were included, involving 2031 patients. Overall, there were no differences in terms of good or excellent functional outcome (ARR = 0.07 and 0.03 respectively, p > 0.05 for both comparisons) but tenecteplase patients showed higher rates of recanalization (ARD = 0.11, 95% CI [0.01;0.20]) and ENI (ARD = 0.10, 95% CI [0.02;0.17]). There were no differences between groups in terms of ICH (ARD = -0.02, 95% CI [-0.06;0.01]), symptomatic ICH (ARD = 0.00, 95% CI [-0.01;0.02]) or death (ARD = 0.00, 95% CI [-0.03;0.03]). CONCLUSION: Tenecteplase is an alternative to alteplase for stroke thrombolysis, with lower cost and a more favourable pharmacokinetic profile.

Bioinformatics Gene Analysis of Potential Biomarkers and Therapeutic Targets for Unstable Atherosclerotic Plaque-Related Stroke.

Atherosclerotic plaque instability is a major cause of ischemic stroke. Researchers must develop novel strategies for the detection and treatment of unstable atherosclerotic plaque (UAP)-related stroke. We aimed to identify potential biomarkers and therapeutic targets of UAP-related stroke. Differentially expressed genes (DEGs) of UAP, ischemic stroke and smoking were identified by microarray analyses from the Gene Expression Omnibus. Gene Ontology (GO) and pathway functional enrichment analyses of DEGs were performed to analyze plaque destabilization and ischemic stroke physiopathology. An integrative analysis of UAP, ischemic stroke and smoking DEGs and functional annotations was performed to identify the underlying physiopathology and hub genes in UAP-related stroke and the relationship with smoking. Online search databases were applied to confirm hub gene biofunctions and their relationships with atherosclerosis and cerebrovascular diseases. Following integrative analysis, 18 co-DEGs of UAP and ischemic stroke, including 17 upregulated and one downregulated, were identified. Inflammation, immunity, extracellular matrix degradation, blood coagulation, apoptosis and nerve degeneration were the primary physiopathological processes in UAP-related stroke. Hub genes included MMP9, ITGAM, CCR1, NCF2 and CD163, among which MMP9 and ITGAM were top 10 genes for both UAP and stroke. Smoking may upregulate MMP9, NCF2, C5AR1 and ANPEP to accelerate plaque destabilization and UAP-related stroke. MMP9, ITGAM, CCR1, NCF2, CD163, hsa-miR-3123 and hsa-miR-144-3p are potential diagnostic and prognostic biomarkers of UAP-related stroke. MMP9 and ITGAM are potential therapeutic targets of UAP-related stroke, which will contribute to the development of novel management strategies.

Early Ultrafast Ultrasound Imaging of Cerebral Perfusion correlates with Ischemic Stroke outcomes and responses to treatment in Mice.

In the field of ischemic cerebral injury, precise characterization of neurovascular hemodynamic is required to select candidates for reperfusion treatments. It is thus admitted that advanced imaging-based approaches would be able to better diagnose and prognose those patients and would contribute to better clinical care. Current imaging modalities like MRI allow a precise diagnostic of cerebral injury but suffer from limited availability and transportability. The recently developed ultrafast ultrasound could be a powerful tool to perform emergency imaging and long term follow-up of cerebral perfusion, which could, in combination with MRI, improve imaging solutions for neuroradiologists. Methods: In this study, in a model of in situ thromboembolic stroke in mice, we compared a control group of non-treated mice (N=10) with a group receiving the gold standard pharmacological stroke therapy (N=9). We combined the established tool of magnetic resonance imaging (7T MRI) with two innovative ultrafast ultrasound methods, ultrafast Doppler and Ultrasound Localization Microscopy, to image the cerebral blood volumes at early and late times after stroke onset and compare with the formation of ischemic lesions.Results: Our study shows that ultrafast ultrasound can be used through the mouse skull to monitor cerebral perfusion during ischemic stroke. In our data, the monitoring of the reperfusion following thrombolytic within the first 2 h post stroke onset matches ischemic lesions measured 24 h. Moreover, similar results can be made with Ultrasound Localization Microscopy which could make it applicable to human patients in the future. Conclusion: We thus provide the proof of concept that in a mouse model of thromboembolic stroke with an intact skull, early ultrafast ultrasound can be indicative of responses to treatment and cerebral tissue fates following stroke. It brings new tools to study ischemic stroke in preclinical models and is the first step prior translation to the clinical settings.

Epicortical Brevetoxin Treatment Promotes Neural Repair and Functional Recovery after Ischemic Stroke.

Emerging literature suggests that after a stroke, the peri-infarct region exhibits dynamic changes in excitability. In rodent stroke models, treatments that enhance excitability in the peri-infarct cerebral cortex promote motor recovery. This increase in cortical excitability and plasticity is opposed by increases in tonic GABAergic inhibition in the peri-infarct zone beginning three days after a stroke in a mouse model. Maintenance of a favorable excitatory-inhibitory balance promoting cerebrocortical excitability could potentially improve recovery. Brevetoxin-2 (PbTx-2) is a voltage-gated sodium channel (VGSC) gating modifier that increases intracellular sodium ([Na+]i), upregulates N-methyl-D-aspartate receptor (NMDAR) channel activity and engages downstream calcium (Ca2+) signaling pathways. In immature cerebrocortical neurons, PbTx-2 promoted neuronal structural plasticity by increasing neurite outgrowth, dendritogenesis and synaptogenesis. We hypothesized that PbTx-2 may promote excitability and structural remodeling in the peri-infarct region, leading to improved functional outcomes following a stroke. We tested this hypothesis using epicortical application of PbTx-2 after a photothrombotic stroke in mice. We show that PbTx-2 enhanced the dendritic arborization and synapse density of cortical layer V pyramidal neurons in the peri-infarct cortex. PbTx-2 also produced a robust improvement of motor recovery. These results suggest a novel pharmacologic approach to mimic activity-dependent recovery from stroke.