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Background and Purpose: The aim of this study is to investigate the efficacy and safety of preoperative versus intraoperative tirofiban in patients with large vessel occlusion (LVO) due to large artery atherosclerosis (LAA)., Methods: This is a retrospective multicenter cohort study based on the RESCUE-RE (Registration Study for Critical Care of Acute Ischemic Stroke After Recanalization) trial enrolling patients with anterior circulation LVO classified as LAA within 24 h of onset. Patients were divided into three groups: preoperative tirofiban (PT), intraoperative tirofiban (IT), and no tirofiban (NT). Propensity score matching (PSM) was used to balance baseline characteristics. The efficacy outcomes included 90-day functional independence (modified Rankin Scale score = 0-2) and early partial recanalization (EPR; defined as a modified Thrombolysis in Cerebral Infarction score = 1-2a). The safety outcomes included symptomatic intracranial hemorrhage (sICH)., Results: A total of 104 matched triplets were obtained through PSM. Compared with NT, PT increased 90-day functional independence (60.8% vs. 42.3%, p = 0.008) and EPR (42.7% vs. 18.3%, p < 0.001) rate, with a tendency to increase the asymptomatic intracranial hemorrhage (aICH) proportion (28.8% vs. 18.3%, p = 0.072). Compared with IT, PT had a higher 90-day functional independence (60.8% vs. 45.2%, p = 0.025) and EPR (42.7% vs. 20.2%, p = 0.001) rate, with no significant difference in sICH (14.4% vs. 7.7%, p = 0.122) and aICH (28.8% vs. 21.2%, p = 0.200). Compared with NT, IT had a lower 90-day mortality rate (9.6% vs. 24.0%, p = 0.005)., Conclusions: Tirofiban shows good adjuvant therapy potential in acute ischemic stroke-LVO due to LAA patients. PT is associated with higher rates of EPR and better therapeutic efficacy. In addition, EPR may be a potential way to improve prognosis., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: A mobile stroke unit (MSU) reduces delays in stroke treatment by allowing thrombolysis on board and avoiding secondary transports. Due to the beneficial effect in comparison to conventional emergency medical services, current guidelines recommend regional evaluation of MSU implementation., Methods: In a descriptive study, current pathways of patients requiring a secondary transport for mechanical thrombectomy were reconstructed from individual patient records within a Danish (n = 122) and an adjacent German region (n = 80). Relevant timestamps included arrival times (on site, primary hospital, thrombectomy centre) as well as the initiation of acute therapy. An optimal MSU location for each region was determined. The resulting time saving was translated into averted disability-adjusted life years (DALYs)., Results: For each region, the optimal MSU location required a median driving time of 35 min to a stroke patient. Time savings in the German region (median [Q1; Q3]) were 7 min (-15; 31) for thrombolysis and 35 min (15; 61) for thrombectomy. In the Danish region, the corresponding time savings were 20 min (8; 30) and 43 min (25; 66). Assuming 28 thrombectomy cases and 52 thrombolysis cases this would translate to 9.4 averted DALYs per year justifying an annual net MSU budget of $0.8M purchasing power parity dollars (PPP-$) in the German region. In the Danish region, the MSU would avert 17.7 DALYs, justifying an annual net budget of PPP-$1.7M., Conclusion: The effects of an MSU can be calculated from individual patient pathways and reflect differences in the hospital infrastructure between Denmark and Germany., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Thrombo-inflammation is a key feature of stroke pathophysiology and provides multiple candidate drug targets. Thrombin exerts coagulation-independent actions via protease-activated receptors (PAR), of which PAR1 has been implicated in stroke-associated neuroinflammation. The role of PAR4 in this context is less clear. This study examined if the selective PAR4 antagonist ML354 provides neuroprotection in experimental stroke and explored the underlying mechanisms., Experimental Approach: Mouse primary cortical neurons were exposed to oxygen-glucose deprivation (OGD) and simulated reperfusion ± ML354. For comparison, functional Ca 2+ -imaging was performed upon acute stimulation with a PAR4 activating peptide or glutamate. Male mice underwent sham operation or transient middle cerebral artery occlusion (tMCAO), with ML354 or vehicle treatment beginning at recanalization. A subset of mice received a platelet-depleting antibody. Stroke size and functional outcomes were assessed. Abundance of target genes, proteins, and cell markers was determined in cultured cells and tissues by qPCR, immunoblotting, and immunofluorescence., Key Results: Stroke up-regulated PAR4 expression in cortical neurons in vitro and in vivo. OGD augments spontaneous and PAR4-mediated neuronal activity; ML354 suppresses OGD-induced neuronal excitotoxicity and apoptosis. ML354 applied in vivo after tMCAO reduced infarct size, apoptotic markers, macrophage accumulation, and interleukin-1β expression. Platelet depletion did not affect infarct size in mice with tMCAO ± ML354., Conclusions and Implications: Selective PAR4 inhibition during reperfusion improves infarct size and neurological function after experimental stroke by blunting neuronal excitability, apoptosis, and local inflammation. PAR4 antagonists may provide additional neuroprotective benefits in patients with acute stroke beyond their canonical antiplatelet action., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The transplantation of bone marrow mesenchymal stem cells (MSCs) in stroke is hindered by the restricted rates of survival and differentiation. Ginsenoside compound K (CK), is reported to have a neuroprotective effect and regulate energy metabolism. We applied CK to investigate if CK could promote the survival of MSCs and differentiation into brain microvascular endothelial-like cells (BMECs), thereby alleviating stroke symptoms. Therefore, transwell and middle cerebral artery occlusion (MCAO) models were used to mimic oxygen and glucose deprivation (OGD) in vitro and in vivo, respectively. Our results demonstrated that CK had a good affinity for GLUT1, which increased the expression of GLUT1 and the production of ATP, facilitated the proliferation and migration of MSCs, and activated the HIF-1α/VEGF signaling pathway to promote MSC differentiation. Moreover, CK cooperated with MSCs to protect BMECs, promote angiogenesis and vascular density, enhance neuronal and astrocytic proliferation, thereby reducing infarct volume and consequently improving neurobehavioral outcomes. These results suggest that the synergistic effects of CK and MSCs could potentially be a promising strategy for stroke., (© 2024 John Wiley & Sons Ltd.)

Background and Purpose: This systematic review examines the effectiveness of motivational interviewing (MI) on medication adherence for preventing recurrent stroke and transient ischemic attack (TIA)., Methods: MEDLINE (via PubMed), CINAHL, PsycINFO, CENTRAL, and ClinicalTrials.gov were searched from inception to 12 June 2023. Randomized controlled trials comparing MI with usual care or interventions without MI in participants with any stroke type were identified and summarized descriptively. Primary outcome was medication adherence. Secondary outcomes were quality of life (QoL) and different clinical outcomes. We assessed risk of bias with RoB 2 (revised Cochrane risk-of-bias tool) and intervention complexity with the iCAT&#95;SR (intervention Complexity Assessment Tool for Systematic Reviews)., Results: We screened 691 records for eligibility and included four studies published in five articles. The studies included a total of 2751 participants, and three were multicentric. Three studies had a high risk of bias, and interventions varied in complexity. Two studies found significantly improved medication adherence, one at 9 (96.9% vs. 88.2%, risk ratio = 1.098, 95% confidence interval = 1.03-1.17) and one at 12 months (97.0% vs. 95.0%, p = 0.026), but not at other time points, whereas two other studies reported no significant changes. No significant differences were found in QoL or clinical outcomes., Conclusions: Evidence on MI appears inconclusive for improving medication adherence for recurrent stroke and TIA prevention, with no benefits on QoL and clinical outcomes. There is a need for robustly designed studies and process evaluations of MI as a complex intervention for people with stroke., Registration: PROSPERO (CRD42023433284)., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long-term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti-IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti-IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti-IS drugs/agents are briefly provided to move the field forward., (© 2023 Wiley Periodicals LLC.)

Background and Purpose: Orolingual angioedema (OA) represents a rare but life-threatening complication among patients with acute ischemic stroke treated with intravenous thrombolysis with alteplase. Novel agents, including icatibant, are recommended in resistant patients with alteplase-induced OA who have failed to respond to first-line therapies including corticosteroids, antihistamines, and/or adrenaline., Methods: We present a patient with alteplase-induced OA who showed substantial clinical improvement following the administration of icatibant., Results: We describe a 71-year-old woman with known arterial hypertension under treatment with angiotensin-converting enzyme inhibitor, who presented with acute ischemic stroke in the territory of the right middle cerebral artery and received intravenous alteplase. During intravenous thrombolysis, the case was complicated with OA without any response to standard anaphylactic treatment including corticosteroids, dimetindene, and adrenaline. Thirty minutes after symptom onset, icatibant, a synthetic selective bradykinin B2-receptor antagonist, was administered subcutaneously. Substantial symptomatic resolution was observed only following the icatibant administration., Conclusions: This case highlights the effectiveness of icatibant in the acute management of alteplase-induced OA. In particular, icatibant administration, following first-line therapies including corticosteroids, antihistamines, and/or adrenaline, may avert tracheostomy and intubation in resistant and refractory cases with OA following intravenous thrombolysis for acute ischemic stroke., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Adipocyte fatty acid-binding protein (A-FABP) exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier (BBB) through inducing expression of MMP-9. Circulating A-FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A-FABP by a neutralizing antibody would alleviate ischaemic stroke outcome., Experimental Approach: Monoclonal antibodies (mAbs) against A-FABP were generated using mouse hybridoma techniques. Binding affinities of a generated mAb named 6H2 towards various FABPs were determined using Biacore. Molecular docking studies were performed to characterize the 6H2-A-FABP complex structure and epitope. The therapeutic potential and safety of 6H2 were evaluated in mice with transient middle cerebral artery occlusion (MCAO) and healthy mice, respectively., Key Results: Replenishment of recombinant A-FABP exaggerated the stroke outcome in A-FABP-deficient mice. 6H2 exhibited nanomolar to picomolar affinities to human and mouse A-FABP, respectively, with minimal cross-reactivities with heart and epidermal FABPs. 6H2 effectively neutralized JNK/c-Jun activation elicited by A-FABP and reduced MMP-9 production in macrophages. Molecular docking suggested that 6H2 interacts with the "lid" of the fatty acid binding pocket of A-FABP, thus likely hindering the binding of its substrates. In mice with transient MCAO, 6H2 significantly attenuated BBB disruption, cerebral oedema, infarction, neurological deficits, and decreased mortality associated with reduced cytokine and MMP-9 production. Chronic 6H2 treatment showed no obvious adverse effects in healthy mice., Conclusion and Implications: These results establish circulating A-FABP as a viable therapeutic target for ischaemic stroke, and provide a highly promising antibody drug candidate with high affinity and specificity., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Hip and knee replacement surgery is a well-established means of improving quality of life, but is associated with a significant risk of bleeding. One-third of people are estimated to be anaemic before hip or knee replacement surgery; coupled with the blood lost during surgery, up to 90% of individuals are anaemic postoperatively. As a result, people undergoing orthopaedic surgery receive 3.9% of all packed red blood cell transfusions in the UK. Bleeding and the need for allogeneic blood transfusions has been shown to increase the risk of surgical site infection and mortality, and is associated with an increased duration of hospital stay and costs associated with surgery. Reducing blood loss during surgery may reduce the risk of allogeneic blood transfusion, reduce costs and improve outcomes following surgery. Several pharmacological interventions are available and currently employed as part of routine clinical care., Objectives: To determine the relative efficacy of pharmacological interventions for preventing blood loss in elective primary or revision hip or knee replacement, and to identify optimal administration of interventions regarding timing, dose and route, using network meta-analysis (NMA) methodology., Search Methods: We searched the following databases for randomised controlled trials (RCTs) and systematic reviews, from inception to 18 October 2022: CENTRAL (the Cochrane Library), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Transfusion Evidence Library (Evidentia), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP)., Selection Criteria: We included RCTs of people undergoing elective hip or knee surgery only. We excluded non-elective or emergency procedures, and studies published since 2010 that had not been prospectively registered (Cochrane Injuries policy). There were no restrictions on gender, ethnicity or age (adults only). We excluded studies that used standard of care as the comparator. Eligible interventions included: antifibrinolytics (tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid (EACA)), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants and non-fibrin sealants., Data Collection and Analysis: We performed the review according to standard Cochrane methodology. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using CINeMA. We presented direct (pairwise) results using RevMan Web and performed the NMA using BUGSnet. We were interested in the following primary outcomes: need for allogenic blood transfusion (up to 30 days) and all-cause mortality (deaths occurring up to 30 days after the operation), and the following secondary outcomes: mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), length of hospital stay and adverse events related to the intervention received., Main Results: We included a total of 102 studies. Twelve studies did not report the number of included participants; the other 90 studies included 8418 participants. Trials included more women (64%) than men (36%). In the NMA for allogeneic blood transfusion, we included 47 studies (4398 participants). Most studies examined TXA (58 arms, 56%). We found that TXA, given intra-articularly and orally at a total dose of greater than 3 g pre-incision, intraoperatively and postoperatively, ranked the highest, with an anticipated absolute effect of 147 fewer blood transfusions per 1000 people (150 fewer to 104 fewer) (53% chance of ranking 1st) within the NMA (risk ratio (RR) 0.02, 95% credible interval (CrI) 0 to 0.31; moderate-certainty evidence). This was followed by TXA given orally at a total dose of 3 g pre-incision and postoperatively (RR 0.06, 95% CrI 0.00 to 1.34; low-certainty evidence) and TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively (RR 0.10, 95% CrI 0.02 to 0.55; low-certainty evidence). Aprotinin (RR 0.59, 95% CrI 0.36 to 0.96; low-certainty evidence), topical fibrin (RR 0.86, CrI 0.25 to 2.93; very low-certainty evidence) and EACA (RR 0.60, 95% CrI 0.29 to 1.27; very low-certainty evidence) were not shown to be as effective compared with TXA at reducing the risk of blood transfusion. We were unable to perform an NMA for our primary outcome all-cause mortality within 30 days of surgery due to the large number of studies with zero events, or because the outcome was not reported. In the NMA for deep vein thrombosis (DVT), we included 19 studies (2395 participants). Most studies examined TXA (27 arms, 64%). No studies assessed desmopressin, EACA or topical fibrin. We found that TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively ranked the highest, with an anticipated absolute effect of 67 fewer DVTs per 1000 people (67 fewer to 34 more) (26% chance of ranking first) within the NMA (RR 0.16, 95% CrI 0.02 to 1.43; low-certainty evidence). This was followed by TXA given intravenously and intra-articularly at a total dose of 2 g pre-incision and intraoperatively (RR 0.21, 95% CrI 0.00 to 9.12; low-certainty evidence) and TXA given intravenously and intra-articularly, total dose greater than 3 g pre-incision, intraoperatively and postoperatively (RR 0.13, 95% CrI 0.01 to 3.11; low-certainty evidence). Aprotinin was not shown to be as effective compared with TXA (RR 0.67, 95% CrI 0.28 to 1.62; very low-certainty evidence). We were unable to perform an NMA for our secondary outcomes pulmonary embolism, myocardial infarction and CVA (stroke) within 30 days, mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), or length of hospital stay, due to the large number of studies with zero events, or because the outcome was not reported by enough studies to build a network. There are 30 ongoing trials planning to recruit 3776 participants, the majority examining TXA (26 trials)., Authors' Conclusions: We found that of all the interventions studied, TXA is probably the most effective intervention for preventing bleeding in people undergoing hip or knee replacement surgery. Aprotinin and EACA may not be as effective as TXA at preventing the need for allogeneic blood transfusion. We were not able to draw strong conclusions on the optimal dose, route and timing of administration of TXA. We found that TXA given at higher doses tended to rank higher in the treatment hierarchy, and we also found that it may be more beneficial to use a mixed route of administration (oral and intra-articular, oral and intravenous, or intravenous and intra-articular). Oral administration may be as effective as intravenous administration of TXA. We found little to no evidence of harm associated with higher doses of tranexamic acid in the risk of DVT. However, we are not able to definitively draw these conclusions based on the trials included within this review., (Copyright © 2024 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1-knockout (KO) mice and MT1-KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene-expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species-induced oxidative stress and activates the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1-KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Gabapentinoids (GABA) prescribing as a potential and conceivably safer substitute for opioids has substantially increased. Understanding all potential adverse drug events (ADEs) associated with GABA will guide clinical decision-making for pain management., Methods: A 20% sample of Medicare enrollees with new chronic pain diagnoses in 2017-2018 was selected. GABA users were those with >=30 consecutive days prescription in a year without opioid prescription. Opioid users were similarly defined. The control group used neither of these drugs. Propensity score match across three groups based on demographics and comorbidity was performed. We used proportional reporting ratio (PRR), Gamma Poisson Shrinker, and tree-based scan statistic (TBSS) to detect ADEs within 3, 6, and 12 months of follow-up., Results: Immunity disorder was detected within 3 months of follow-up by PRR compared to opioid use (PRR:2.33), and by all three methods compared to controls. Complications of transplanted organs/tissues and schizophrenia spectrum/other psychotic disorders were consistently detected by PRR and TBSS within 3 months. Skin disorders were detected by TBSS; and stroke was detected by PRR within 3 months compared to opioid use (PRR:4.74). Some malignancies were detected by PRR within 12 months. Other signals detected in GABA users were neuropathy and nerve disorders., Conclusions: Our study identified expected and unexpected ADE signals in GABA users. Neurological signals likely related to indications for GABA use. Signals for immunity, mental/behavior, and skin disorders were found in the FDA adverse event reporting system database. Unexpected signals of stroke and cancer require further confirmatory analyses to verify., (© 2023 John Wiley & Sons Ltd.)

Background: High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross-sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood-based proteins., Methods: We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel, ICAM-1 set and VCAM-1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio-Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in σ -standardized cytokine levels on the log 2 -scale., Results: Stromal-cell-derived-factor 1 alpha (SDF-1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (β = 0.48; 95% CI 0.22; 0.75; P adj  = 0.036). Significantly lower levels of interleukin-6 (IL-6) (β = -0.53; 95% CI -0.84; -0.23; P adj  = 0.036) and macrophage migration inhibitory factor (MIF) (β = -0.52; 95% CI -0.84; -0.21; P adj  = 0.043) were found in the small vessel versus large vessel stroke subtype., Conclusions: Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The pathogenesis of ischemic stroke is complex, and PI3K/Akt signaling is considered to play a crucial role in it. The PI3K/Akt pathway regulates inflammation, oxidative stress, apoptosis, autophagy, and vascular endothelial homeostasis after cerebral ischemia; therefore, drug research targeting the PI3K/Akt pathway has become the focus of scientists. In this review, we analyzed the research reports of antiischemic stroke drugs targeting the PI3K/Akt pathway in the past two decades. Because of the rich sources of natural products, increasing studies have explored the value of natural compounds, including Flavonoids, Quinones, Alkaloids, Phenylpropanoids, Phenols, Saponins, and Terpenoids, in alleviating neurological impairment and achieved satisfactory results. Herbal extracts and medicinal formulas have been applied in the treatment of ischemic stroke for thousands of years in East Asian countries. These precious clinical experiences provide a new avenue for research of antiischemic stroke drugs. Finally, we summarize and discuss the characteristics and shortcomings of the current research and put forward prospects for further in-depth exploration., (© 2023 John Wiley & Sons, Ltd.)

Background and Purpose: The best management of acute ischemic stroke patients with a minor stroke and large vessel occlusion is still uncertain. Specific clinical and radiological data may help to select patients who would benefit from endovascular therapy (EVT). We aimed to evaluate the relevance of National Institutes of Health Stroke Scale (NIHSS) subitems for predicting the potential benefit of providing EVT after intravenous thrombolysis (IVT; "bridging treatment") versus IVT alone., Methods: We extracted demographic, clinical, risk factor, radiological, revascularization and outcome data of consecutive patients with M1 or proximal M2 middle cerebral artery occlusion and admission NIHSS scores of 0-5 points, treated with IVT ± EVT between May 2005 and March 2021, from nine prospectively constructed stroke registries at seven French and two Swiss comprehensive stroke centers. Adjusted interaction analyses were performed between admission NIHSS subitems and revascularization modality for two primary outcomes at 3 months: non-excellent functional outcome (modified Rankin Scale score 2-6) and difference in NIHSS score between 3 months and admission., Results: Of the 533 patients included (median age 68.2 years, 46% women, median admission NIHSS score 3), 136 (25.5%) initially received bridging therapy and 397 (74.5%) received IVT alone. Adjusted interaction analysis revealed that only facial palsy on admission was more frequently associated with excellent outcome in patients treated by IVT alone versus bridging therapy (odds ratio 0.47, 95% confidence interval 0.24-0.91; p = 0.013). Regarding NIHSS difference at 3 months, no single NIHSS subitem interacted with type of revascularization., Conclusions: This retrospective multicenter analysis found that NIHSS subitems at admission had little value in predicting patients who might benefit from bridging therapy as opposed to IVT alone. Further research is needed to identify better markers for selecting EVT responders with minor strokes., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Cardiovascular disease is the most frequent cause of death in people with early stages of chronic kidney disease (CKD), and the absolute risk of cardiovascular events is similar to people with coronary artery disease. This is an update of a review first published in 2009 and updated in 2014, which included 50 studies (45,285 participants)., Objectives: To evaluate the benefits and harms of statins compared with placebo, no treatment, standard care or another statin in adults with CKD not requiring dialysis., Search Methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 4 October 2023. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. An updated search will be undertaken every three months., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of statins with placebo, no treatment, standard care, or other statins, on death, cardiovascular events, kidney function, toxicity, and lipid levels in adults with CKD (estimated glomerular filtration rate (eGFR) 90 to 15 mL/min/1.73 m 2 ) were included., Data Collection and Analysis: Two or more authors independently extracted data and assessed the study risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes and risk ratios (RR) for dichotomous benefits and harms with 95% confidence intervals (CI). The risk of bias was assessed using the Cochrane risk of bias tool, and the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Main Results: We included 63 studies (50,725 randomised participants); of these, 53 studies (42,752 participants) compared statins with placebo or no treatment. The median duration of follow-up was 12 months (range 2 to 64.8 months), the median dosage of statin was equivalent to 20 mg/day of simvastatin, and participants had a median eGFR of 55 mL/min/1.73 m 2 . Ten studies (7973 participants) compared two different statin regimens. We were able to meta-analyse 43 studies (41,273 participants). Most studies had limited reporting and hence exhibited unclear risk of bias in most domains. Compared with placebo or standard of care, statins prevent major cardiovascular events (14 studies, 36,156 participants: RR 0.72, 95% CI 0.66 to 0.79; I 2 = 39%; high certainty evidence), death (13 studies, 34,978 participants: RR 0.83, 95% CI 0.73 to 0.96; I² = 53%; high certainty evidence), cardiovascular death (8 studies, 19,112 participants: RR 0.77, 95% CI 0.69 to 0.87; I² = 0%; high certainty evidence) and myocardial infarction (10 studies, 9475 participants: RR 0.55, 95% CI 0.42 to 0.73; I² = 0%; moderate certainty evidence). There were too few events to determine if statins made a difference in hospitalisation due to heart failure. Statins probably make little or no difference to stroke (7 studies, 9115 participants: RR 0.64, 95% CI 0.37 to 1.08; I² = 39%; moderate certainty evidence) and kidney failure (3 studies, 6704 participants: RR 0.98, 95% CI 0.91 to 1.05; I² = 0%; moderate certainty evidence) in people with CKD not requiring dialysis. Potential harms from statins were limited by a lack of systematic reporting. Statins compared to placebo may have little or no effect on elevated liver enzymes (7 studies, 7991 participants: RR 0.76, 95% CI 0.39 to 1.50; I² = 0%; low certainty evidence), withdrawal due to adverse events (13 studies, 4219 participants: RR 1.16, 95% CI 0.84 to 1.60; I² = 37%; low certainty evidence), and cancer (2 studies, 5581 participants: RR 1.03, 95% CI 0.82 to 1.30; I² = 0%; low certainty evidence). However, few studies reported rhabdomyolysis or elevated creatinine kinase; hence, we are unable to determine the effect due to very low certainty evidence. Statins reduce the risk of death, major cardiovascular events, and myocardial infarction in people with CKD who did not have cardiovascular disease at baseline (primary prevention). There was insufficient data to determine the benefits and harms of the type of statin therapy., Authors' Conclusions: Statins reduce death and major cardiovascular events by about 20% and probably make no difference to stroke or kidney failure in people with CKD not requiring dialysis. However, due to limited reporting, the effect of statins on elevated creatinine kinase or rhabdomyolysis is unclear. Statins have an important role in the primary prevention of cardiovascular events and death in people who have CKD and do not require dialysis. Editorial note: This is a living systematic review. We will search for new evidence every three months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background and Aim: Our previous study has revealed that OEA promotes motor function recovery in the chronic stage of ischemic stroke. However, the neuroprotective mechanism of OEA on motor function recovery after stroke still is unexplored. Therefore, the aim of this study was to explore the effects of OEA treatment on angiogenesis, neurogenesis, and white matter repair in the peri-infarct region after cerebral ischemia., Experimental Procedure: The adult male rats were subjected to 2 h of middle cerebral artery occlusion. The rats were treated with 10 and 30 mg/kg OEA or vehicle daily starting from day 2 after ischemia induction until they were sacrificed., Key Results and Conclusions: The results revealed that OEA increased cortical angiogenesis, neural progenitor cells (NPCs) proliferation, migration, and differentiation. OEA treatment enhanced the survival of newborn neurons and oligodendrogenesis, which eventually repaired the cortical neuronal injury and improved motor function after ischemic stroke. Meanwhile, OEA treatment promoted the differentiation of oligodendrocyte progenitor cells (OPCs) and oligodendrogenesis by activating the PPARα signaling pathway. Our results showed that OEA restores motor function by facilitating cortical angiogenesis, neurogenesis, and white matter repair in rats after ischemic stroke. Therefore, we demonstrate that OEA facilitates functional recovery after ischemic stroke and propose the hypothesis that the long-term application of OEA mitigates the disability after stroke., (© 2023 John Wiley & Sons Ltd.)

Background: Outcome after acute spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume. ICH expansion occurs in about 20% of people with acute ICH. Early haemostatic therapy might improve outcome by limiting ICH expansion. This is an update of a Cochrane Review first published in 2006, and last updated in 2018., Objectives: To examine 1. the effects of individual classes of haemostatic therapies, compared with placebo or open control, in adults with acute spontaneous ICH, and 2. the effects of each class of haemostatic therapy according to the use and type of antithrombotic drug before ICH onset., Search Methods: We searched the Cochrane Stroke Trials Register, CENTRAL (2022, Issue 8), MEDLINE Ovid, and Embase Ovid on 12 September 2022. To identify further published, ongoing, and unpublished randomised controlled trials (RCTs), we scanned bibliographies of relevant articles and searched international registers of RCTs in September 2022., Selection Criteria: We included RCTs of any haemostatic intervention (i.e. procoagulant treatments such as clotting factor concentrates, antifibrinolytic drugs, platelet transfusion, or agents to reverse the action of antithrombotic drugs) for acute spontaneous ICH, compared with placebo, open control, or an active comparator., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcome was death/dependence (modified Rankin Scale (mRS) 4 to 6) by day 90. Secondary outcomes were ICH expansion on brain imaging after 24 hours, all serious adverse events, thromboembolic adverse events, death from any cause, quality of life, mood, cognitive function, Barthel Index score, and death or dependence measured on the Extended Glasgow Outcome Scale by day 90., Main Results: We included 20 RCTs involving 4652 participants: nine RCTs of recombinant activated factor VII (rFVIIa) versus placebo/open control (1549 participants), eight RCTs of antifibrinolytic drugs versus placebo/open control (2866 participants), one RCT of platelet transfusion versus open control (190 participants), and two RCTs of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) (47 participants). Four (20%) RCTs were at low risk of bias in all criteria. For rFVIIa versus placebo/open control for spontaneous ICH with or without surgery there was little to no difference in death/dependence by day 90 (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.05; 7 RCTs, 1454 participants; low-certainty evidence). We found little to no difference in ICH expansion between groups (RR 0.81, 95% CI 0.56 to 1.16; 4 RCTs, 220 participants; low-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 0.81, 95% CI 0.30 to 2.22; 2 RCTs, 87 participants; very low-certainty evidence; death from any cause: RR 0.78, 95% CI 0.56 to 1.08; 8 RCTs, 1544 participants; moderate-certainty evidence). For antifibrinolytic drugs versus placebo/open control for spontaneous ICH, there was no difference in death/dependence by day 90 (RR 1.00, 95% CI 0.93 to 1.07; 5 RCTs, 2683 participants; high-certainty evidence). We found a slight reduction in ICH expansion with antifibrinolytic drugs for spontaneous ICH compared to placebo/open control (RR 0.86, 95% CI 0.76 to 0.96; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.02, 95% CI 0.75 to 1.39; 4 RCTs, 2599 participants; high-certainty evidence; death from any cause: RR 1.02, 95% CI 0.89 to 1.18; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in quality of life, mood, or cognitive function (quality of life: mean difference (MD) 0, 95% CI -0.03 to 0.03; 2 RCTs, 2349 participants; mood: MD 0.30, 95% CI -1.98 to 2.57; 2 RCTs, 2349 participants; cognitive function: MD -0.37, 95% CI -1.40 to 0.66; 1 RCTs, 2325 participants; all high-certainty evidence). Platelet transfusion likely increases death/dependence by day 90 compared to open control for antiplatelet-associated ICH (RR 1.29, 95% CI 1.04 to 1.61; 1 RCT, 190 participants; moderate-certainty evidence). We found little to no difference in ICH expansion between groups (RR 1.32, 95% CI 0.91 to 1.92; 1 RCT, 153 participants; moderate-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.46, 95% CI 0.98 to 2.16; 1 RCT, 190 participants; death from any cause: RR 1.42, 95% CI 0.88 to 2.28; 1 RCT, 190 participants; both moderate-certainty evidence). For PCC versus FFP for anticoagulant-associated ICH, the evidence was very uncertain about the effect on death/dependence by day 90, ICH expansion, all serious adverse events, and death from any cause between groups (death/dependence by day 90: RR 1.21, 95% CI 0.76 to 1.90; 1 RCT, 37 participants; ICH expansion: RR 0.54, 95% CI 0.23 to 1.22; 1 RCT, 36 participants; all serious adverse events: RR 0.27, 95% CI 0.02 to 3.74; 1 RCT, 5 participants; death from any cause: RR 0.49, 95% CI 0.16 to 1.56; 2 RCTs, 42 participants; all very low-certainty evidence)., Authors' Conclusions: In this updated Cochrane Review including 20 RCTs involving 4652 participants, rFVIIa likely results in little to no difference in reducing death or dependence after spontaneous ICH with or without surgery; antifibrinolytic drugs result in little to no difference in reducing death or dependence after spontaneous ICH, but result in a slight reduction in ICH expansion within 24 hours; platelet transfusion likely increases death or dependence after antiplatelet-associated ICH; and the evidence is very uncertain about the effect of PCC compared to FFP on death or dependence after anticoagulant-associated ICH. Thirteen RCTs are ongoing and are likely to increase the certainty of the estimates of treatment effect., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from porcine brain, which has potential neuroprotective properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. This is an update of a review first published in 2010 and last updated in 2020., Objectives: To assess the benefits and harms of Cerebrolysin or Cerebrolysin-like agents for treating acute ischaemic stroke., Search Methods: We searched the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, and LILACS in May 2022 and a number of Russian databases in June 2022. We also searched reference lists, ongoing trials registers, and conference proceedings., Selection Criteria: Randomised controlled trials (RCTs) comparing Cerebrolysin or Cerebrolysin-like agents started within 48 hours of stroke onset and continued for any length of time, with placebo or no treatment in people with acute ischaemic stroke., Data Collection and Analysis: Three review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, extracted data, and applied GRADE criteria to the evidence., Main Results: Seven RCTs (1773 participants) met the inclusion criteria of the review. In this update we added one RCT of Cerebrolysin-like agent Cortexin, which contributed 272 participants. We used the same approach for risk of bias assessment that was re-evaluated for the previous update: we added consideration of the public availability of study protocols and reported outcomes to the selective outcome reporting judgement, through identification, examination, and evaluation of study protocols. For the Cerebrolysin studies, we judged the risk of bias for selective outcome reporting to be unclear across all studies; for blinding of participants and personnel to be low in three studies and unclear in the remaining four; and for blinding of outcome assessors to be low in three studies and unclear in four studies. We judged the risk of bias for generation of allocation sequence to be low in one study and unclear in the remaining six studies; for allocation concealment to be low in one study and unclear in six studies; and for incomplete outcome data to be low in three studies and high in the remaining four studies. The manufacturer of Cerebrolysin supported three multicentre studies, either totally, or by providing Cerebrolysin and placebo, randomisation codes, research grants, or statisticians. We judged two studies to be at high risk of other bias and the remaining five studies to be at unclear risk of other bias. We judged the study of Cortexin to be at low risk of bias for incomplete outcome data and at unclear risk of bias for all other domains. All-cause death: Cerebrolysin or Cortexin probably result in little to no difference in all-cause death (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.65 to 1.41; 6 trials, 1689 participants; moderate-certainty evidence). None of the included studies reported on poor functional outcome, defined as death or dependence at the end of the follow-up period, early death (within two weeks of stroke onset), quality of life, or time to restoration of capacity for work. Only one study clearly reported on the cause of death: cerebral infarct (four in the Cerebrolysin and two in the placebo group), heart failure (two in the Cerebrolysin and one in the placebo group), pulmonary embolism (two in the placebo group), and pneumonia (one in the placebo group). Non-death attrition (secondary outcome): Cerebrolysin or similar peptide mixtures may result in little to no difference in non-death attrition, but the evidence is very uncertain, with a considerable level of heterogeneity (RR 0.72, 95% CI 0.38 to 1.39; 6 trials, 1689 participants; very low-certainty evidence). Serious adverse events (SAEs): Cerebrolysin probably results in little to no difference in the total number of people with SAEs (RR 1.16, 95% CI 0.81 to 1.66; 3 trials, 1335 participants; moderate-certainty evidence). This comprised fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38; 3 trials, 1335 participants; moderate-certainty evidence) and an increase in the total number of people with non-fatal SAEs (RR 2.39, 95% CI 1.10 to 5.23; 3 trials, 1335 participants; moderate-certainty evidence). In the subgroup of dosing schedule 30 mL for 10 days (cumulative dose 300 mL), the increase was more prominent (RR 2.87, 95% CI 1.24 to 6.69; 2 trials, 1189 participants). Total number of people with adverse events: Cerebrolysin or similar peptide mixtures may result in little to no difference in the total number of people with adverse events (RR 1.03, 95% CI 0.92 to 1.14; 4 trials, 1607 participants; low-certainty evidence)., Authors' Conclusions: Moderate-certainty evidence indicates that Cerebrolysin or Cerebrolysin-like peptide mixtures derived from cattle brain probably have no beneficial effect on preventing all-cause death in acute ischaemic stroke. Moderate-certainty evidence suggests that Cerebrolysin probably has no beneficial effect on the total number of people with serious adverse events. Moderate-certainty evidence also indicates a potential increase in non-fatal serious adverse events with Cerebrolysin use., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Patients with impaired left ventricular (LV) function can develop LV thrombus, a potentially life-threatening condition due to risk of stroke and embolization. Conventional treatment with vitamin K antagonists (VKAs; e.g., warfarin) puts patients at risk of bleeding, and the use of direct oral anticoagulants (DOACs) appears promising, although data are scant. We searched the published English language literature for randomized controlled trials (RCTs) comparing DOACs with VKAs in LV thrombus. End points were failure to resolve, thromboembolic events (stroke, embolism), bleeding, or any adverse event (composite of thromboembolism or bleeding), or all-cause death. Data were pooled and analyzed in hierarchical Bayesian models. In three eligible RCTs, 141 patients were studied during an average of 4.6 months (53.8 patient-years; n = 71 assigned to DOAC, n = 70 assigned to VKA). A similar number of patients in each treatment arm demonstrated failure to resolve (DOAC: 14/71 vs. VKA: 15/70) and death events (3/71 vs. 4/70). However, patients on DOACs suffered fewer strokes/thromboembolic events (1/71 vs. 7/70; log odds ratio [OR], -2.02 [95% credible interval (CI 95 ), -4.53 to -0.31]) and fewer bleeding events (2/71 vs. 9/70; log OR, -1.62 [CI 95 , -3.43 to -0.26]), leading to fewer patients on DOACs with any adverse event versus VKAs (3/71 vs. 16/70; log OR, -1.93 [CI 95 , -3.33 to -0.75]). In conclusion, pooled analysis of RCT data favors DOACs over VKAs in patients with LV thrombus in terms of both efficacy and safety., (© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Direct oral anticoagulants (DOACs) are indicated for the prevention of stroke in nonvalvular atrial fibrillation. Although Food and Drug Administration labeling for DOACs uses estimated creatinine clearance according to the Cockcroft-Gault (C-G) equation, estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is often reported. The objectives of this study were to evaluate DOAC dosing discordance and to determine whether discordance based on various estimates of kidney function is associated with bleeding or thromboembolism. The study was an institutional review board approved retrospective analysis of patients at UPMC Presbyterian Hospital from January 1, 2010, to December 12, 2016. Data were obtained through electronic medical records. Adults who received a medication charge for rivaroxaban or dabigatran, had a diagnosis code for atrial fibrillation, and had a serum creatinine within 3 days of DOAC initiation were included. Doses were considered discordant if the calculated dose based on CKD-EPI did not match the patient's dose during index admission, if dosed correctly using C-G. Association of discordance with dabigatran, rivaroxaban, and clinical outcomes was determined using odds ratios and 95% confidence intervals. Rivaroxaban discordance was present among 49 of the 644 (8%) patients who were dosed correctly with C-G. Dabigatran discordance was present among 17 of the 590 (3%) patients who were dosed correctly. Discordance with rivaroxaban was found to increase the risk of thromboembolism when using CKD-EPI (odds ratio, 2.83; 95% CI, 1.02-7.79, P = .045) versus C-G. Our findings emphasize the need to dose DOACs, specifically rivaroxaban, appropriately in patients with nonvalvular atrial fibrillation., (© 2023, The American College of Clinical Pharmacology.)

Neurotrophic factors (NTFs) are involved in the pathophysiology of neurological disorders such as dementia, stroke and traumatic brain injury (TBI), and constitute molecular targets of high interest for the therapy of these pathologies. In this review we provide an overview of current knowledge of the definition, discovery and mode of action of five NTFs, nerve growth factor, insulin-like growth factor 1, brain derived NTF, vascular endothelial growth factor and tumor necrosis factor alpha; as well as on their contribution to brain pathology and potential therapeutic use in dementia, stroke and TBI. Within the concept of NTFs in the treatment of these pathologies, we also review the neuropeptide preparation Cerebrolysin, which has been shown to resemble the activities of NTFs and to modulate the expression level of endogenous NTFs. Cerebrolysin has demonstrated beneficial treatment capabilities in vitro and in clinical studies, which are discussed within the context of the biochemistry of NTFs. The review focuses on the interactions of different NTFs, rather than addressing a single NTF, by outlining their signaling network and by reviewing their effect on clinical outcome in prevalent brain pathologies. The effects of the interactions of these NTFs and Cerebrolysin on neuroplasticity, neurogenesis, angiogenesis and inflammation, and their relevance for the treatment of dementia, stroke and TBI are summarized., (© 2023 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.)

We conducted a meta-analysis to evaluate the clinical efficacy of berberine (BBR) in treating acute ischemic stroke (AIS), explore its anti-inflammatory effects, and assess its potential applications for AIS patients. We comprehensively searched nine databases from inception until July 1, 2022, to identify clinical trials investigating the use of BBR in treating AIS. We performed statistical analyses using RevMan5.4 software and focused on primary outcomes such as inflammatory markers as well as secondary outcomes including immune system indicators, relevant biomarkers, carotid artery atherosclerosis, and adverse reactions. Our analysis included data from 17 clinical trials involving 1670 patients with AIS. Our results revealed that BBR in combination with conventional treatment significantly reduced levels of high-sensitivity C-reactive protein (hs-CRP), macrophage migration inhibitory factor (MIF), interleukin-6 (IL-6), complement C3, hypoxic inducible factor-1 α (HIF-1α), cysteine protease-3 (Caspase-3), the national institutes of health stroke scale (NIHSS), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), carotid intima-media thickness (IMT), the number of unstable plaques, and carotid crouse score on ultrasound when compared with conventional treatment alone. Furthermore, combining BBR with conventional treatment may improve the overall effective rate. Therefore, our findings suggest that BBR can be used as an adjuvant therapy for AIS due to its ability to reduce inflammatory cytokine levels, providing a novel therapeutic option for AIS. However, larger randomized controlled trials are necessary to confirm these results., (© 2023 John Wiley & Sons Ltd.)

Whether there are differences in direct oral anticoagulants efficacy and safety in patients with atrial fibrillation (AF) combined with hypertension is unclear. We therefore conducted a multicenter retrospective cohort study to assess the differences in the efficacy and safety of direct oral anticoagulants in patients with AF combined with hypertension. This multicenter retrospective cohort study was based on data from 15 centers in China and included 2086 patients with AF. We divided the patients into dabigatran and rivaroxaban groups according to their direct oral anticoagulants. Propensity score matching was used to balance the covariates between the groups. Due to our limited sample size, the number of cases of some clinical events with low incidence was small. During a mean follow-up period of 10 months, a total of 268 (12.9%) bleeding events occurred, including 27 (1.3%) major bleeding events and 241 (11.6%) minor bleeding events, and 45 (2.2%) thromboembolic events. In patients with AF combined with hypertension, rivaroxaban was associated with a higher major bleeding incidence than dabigatran (odds ratio [OR], 2.89 [95% confidence interval [CI, 1.22-6.87]; P = .012). In contrast, the risk of thromboembolism and minor bleeding was similar for rivaroxaban (OR, 0.55 [95%CI, 0.29-1.01]; P = .069) and dabigatran (OR, 0.82 [95%CI, 0.63-1.08]; P = .150). Based on the results of this study, in patients with AF and hypertension treated with direct oral anticoagulants, the incidence of thromboembolism and minor bleeding was not statistically different between dabigatran and rivaroxaban, but compared with rivaroxaban, dabigatran was associated with a lower risk of major bleeding., (© 2023, The American College of Clinical Pharmacology.)

Background: Different first-line drug classes for patients with hypertension are often assumed to have similar effectiveness with respect to reducing mortality and morbidity outcomes, and lowering blood pressure. First-line low-dose thiazide diuretics have been previously shown to have the best mortality and morbidity evidence when compared with placebo or no treatment. Head-to-head comparisons of thiazides with other blood pressure-lowering drug classes would demonstrate whether there are important differences., Objectives: To compare the effects of first-line diuretic drugs with other individual first-line classes of antihypertensive drugs on mortality, morbidity, and withdrawals due to adverse effects in patients with hypertension. Secondary objectives included assessments of the need for added drugs, drug switching, and blood pressure-lowering., Search Methods: Cochrane Hypertension's Information Specialist searched the Cochrane Hypertension Specialized Register, CENTRAL, MEDLINE, Embase, and trials registers to March 2021. We also checked references and contacted study authors to identify additional studies. A top-up search of the Specialized Register was carried out in June 2022., Selection Criteria: Randomized active comparator trials of at least one year's duration were included. Trials had a clearly defined intervention arm of a first-line diuretic (thiazide, thiazide-like, or loop diuretic) compared to another first-line drug class: beta-blockers, calcium channel blockers, alpha adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, direct renin inhibitors, or other antihypertensive drug classes. Studies had to include clearly defined mortality and morbidity outcomes (serious adverse events, total cardiovascular events, stroke, coronary heart disease (CHD), congestive heart failure, and withdrawals due to adverse effects)., Data Collection and Analysis: We used standard Cochrane methodological procedures., Main Results: We included 20 trials with 26 comparator arms randomizing over 90,000 participants. The findings are relevant to first-line use of drug classes in older male and female hypertensive patients (aged 50 to 75) with multiple co-morbidities, including type 2 diabetes. First-line thiazide and thiazide-like diuretics were compared with beta-blockers (six trials), calcium channel blockers (eight trials), ACE inhibitors (five trials), and alpha-adrenergic blockers (three trials); other comparators included angiotensin II receptor blockers, aliskiren (a direct renin inhibitor), and clonidine (a centrally acting drug). Only three studies reported data for total serious adverse events: two studies compared diuretics with calcium channel blockers and one with a direct renin inhibitor. Compared to first-line beta-blockers, first-line thiazides probably result in little to no difference in total mortality (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.84 to 1.10; 5 trials, 18,241 participants; moderate-certainty), probably reduce total cardiovascular events (5.4% versus 4.8%; RR 0.88, 95% CI 0.78 to 1.00; 4 trials, 18,135 participants; absolute risk reduction (ARR) 0.6%, moderate-certainty), may result in little to no difference in stroke (RR 0.85, 95% CI 0.66 to 1.09; 4 trials, 18,135 participants; low-certainty), CHD (RR 0.91, 95% CI 0.78 to 1.07; 4 trials, 18,135 participants; low-certainty), or heart failure (RR 0.69, 95% CI 0.40 to 1.19; 1 trial, 6569 participants; low-certainty), and probably reduce withdrawals due to adverse effects (10.1% versus 7.9%; RR 0.78, 95% CI 0.71 to 0.85; 5 trials, 18,501 participants; ARR 2.2%; moderate-certainty). Compared to first-line calcium channel blockers, first-line thiazides probably result in little to no difference in total mortality (RR 1.02, 95% CI 0.96 to 1.08; 7 trials, 35,417 participants; moderate-certainty), may result in little to no difference in serious adverse events (RR 1.09, 95% CI 0.97 to 1.24; 2 trials, 7204 participants; low-certainty), probably reduce total cardiovascular events (14.3% versus 13.3%; RR 0.93, 95% CI 0.89 to 0.98; 6 trials, 35,217 participants; ARR 1.0%; moderate-certainty), probably result in little to no difference in stroke (RR 1.06, 95% CI 0.95 to 1.18; 6 trials, 35,217 participants; moderate-certainty) or CHD (RR 1.00, 95% CI 0.93 to 1.08; 6 trials, 35,217 participants; moderate-certainty), probably reduce heart failure (4.4% versus 3.2%; RR 0.74, 95% CI 0.66 to 0.82; 6 trials, 35,217 participants; ARR 1.2%; moderate-certainty), and may reduce withdrawals due to adverse effects (7.6% versus 6.2%; RR 0.81, 95% CI 0.75 to 0.88; 7 trials, 33,908 participants; ARR 1.4%; low-certainty). Compared to first-line ACE inhibitors, first-line thiazides probably result in little to no difference in total mortality (RR 1.00, 95% CI 0.95 to 1.07; 3 trials, 30,961 participants; moderate-certainty), may result in little to no difference in total cardiovascular events (RR 0.97, 95% CI 0.92 to 1.02; 3 trials, 30,900 participants; low-certainty), probably reduce stroke slightly (4.7% versus 4.1%; RR 0.89, 95% CI 0.80 to 0.99; 3 trials, 30,900 participants; ARR 0.6%; moderate-certainty), probably result in little to no difference in CHD (RR 1.03, 95% CI 0.96 to 1.12; 3 trials, 30,900 participants; moderate-certainty) or heart failure (RR 0.94, 95% CI 0.84 to 1.04; 2 trials, 30,392 participants; moderate-certainty), and probably reduce withdrawals due to adverse effects (3.9% versus 2.9%; RR 0.73, 95% CI 0.64 to 0.84; 3 trials, 25,254 participants; ARR 1.0%; moderate-certainty). Compared to first-line alpha-blockers, first-line thiazides probably result in little to no difference in total mortality (RR 0.98, 95% CI 0.88 to 1.09; 1 trial, 24,316 participants; moderate-certainty), probably reduce total cardiovascular events (12.1% versus 9.0%; RR 0.74, 95% CI 0.69 to 0.80; 2 trials, 24,396 participants; ARR 3.1%; moderate-certainty) and stroke (2.7% versus 2.3%; RR 0.86, 95% CI 0.73 to 1.01; 2 trials, 24,396 participants; ARR 0.4%; moderate-certainty), may result in little to no difference in CHD (RR 0.98, 95% CI 0.86 to 1.11; 2 trials, 24,396 participants; low-certainty), probably reduce heart failure (5.4% versus 2.8%; RR 0.51, 95% CI 0.45 to 0.58; 1 trial, 24,316 participants; ARR 2.6%; moderate-certainty), and may reduce withdrawals due to adverse effects (1.3% versus 0.9%; RR 0.70, 95% CI 0.54 to 0.89; 3 trials, 24,772 participants; ARR 0.4%; low-certainty). For the other drug classes, data were insufficient. No antihypertensive drug class demonstrated any clinically important advantages over first-line thiazides., Authors' Conclusions: When used as first-line agents for the treatment of hypertension, thiazides and thiazide-like drugs likely do not change total mortality and likely decrease some morbidity outcomes such as cardiovascular events and withdrawals due to adverse effects, when compared to beta-blockers, calcium channel blockers, ACE inhibitors, and alpha-blockers., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Pelvic, hip, and long bone fractures can result in significant bleeding at the time of injury, with further blood loss if they are treated with surgical fixation. People undergoing surgery are therefore at risk of requiring a blood transfusion and may be at risk of peri-operative anaemia. Pharmacological interventions for blood conservation may reduce the risk of requiring an allogeneic blood transfusion and associated complications., Objectives: To assess the effectiveness of different pharmacological interventions for reducing blood loss in definitive surgical fixation of the hip, pelvic, and long bones., Search Methods: We used a predefined search strategy to search CENTRAL, MEDLINE, PubMed, Embase, CINAHL, Transfusion Evidence Library, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) from inception to 7 April 2022, without restrictions on language, year, or publication status. We handsearched reference lists of included trials to identify further relevant trials. We contacted authors of ongoing trials to acquire any unpublished data., Selection Criteria: We included randomised controlled trials (RCTs) of people who underwent trauma (non-elective) surgery for definitive fixation of hip, pelvic, and long bone (pelvis, tibia, femur, humerus, radius, ulna and clavicle) fractures only. There were no restrictions on gender, ethnicity, or age. We excluded planned (elective) procedures (e.g. scheduled total hip arthroplasty), and studies published since 2010 that had not been prospectively registered. Eligible interventions included: antifibrinolytics (tranexamic acid, aprotinin, epsilon-aminocaproic acid), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants, and non-fibrin sealants., Data Collection and Analysis: Two review authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE. We did not perform a network meta-analysis due to lack of data., Main Results: We included 13 RCTs (929 participants), published between 2005 and 2021. Three trials did not report any of our predefined outcomes and so were not included in quantitative analyses (all were tranexamic acid versus placebo). We identified three comparisons of interest: intravenous tranexamic acid versus placebo; topical tranexamic acid versus placebo; and recombinant factor VIIa versus placebo. We rated the certainty of evidence as very low to low across all outcomes. Comparison 1. Intravenous tranexamic acid versus placebo Intravenous tranexamic acid compared to placebo may reduce the risk of requiring an allogeneic blood transfusion up to 30 days (RR 0.48, 95% CI 0.34 to 0.69; 6 RCTs, 457 participants; low-certainty evidence) and may result in little to no difference in all-cause mortality (Peto odds ratio (Peto OR) 0.38, 95% CI 0.05 to 2.77; 2 RCTs, 147 participants; low-certainty evidence).  It may result in little to no difference in risk of participants experiencing myocardial infarction (risk difference (RD) 0.00, 95% CI -0.03 to 0.03; 2 RCTs, 199 participants; low-certainty evidence), and cerebrovascular accident/stroke (RD 0.00, 95% CI -0.02 to 0.02; 3 RCTs, 324 participants; low-certainty evidence).  We are uncertain if there is a difference between groups for risk of deep vein thrombosis (Peto OR 2.15, 95% CI 0.22 to 21.35; 4 RCTs, 329 participants, very low-certainty evidence), pulmonary embolism (Peto OR 1.08, 95% CI 0.07 to 17.66; 4 RCTs, 329 participants; very low-certainty evidence), and suspected serious drug reactions (RD 0.00, 95% CI -0.03 to 0.03; 2 RCTs, 185 participants; very low-certainty evidence). No data were available for number of red blood cell units transfused, reoperation, or acute transfusion reaction. We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures), and upgraded the evidence for transfusion requirement for a large effect.  Comparison 2. Topical tranexamic acid versus placebo We are uncertain if there is a difference between topical tranexamic acid and placebo for risk of requiring an allogeneic blood transfusion (RR 0.31, 95% CI 0.08 to 1.22; 2 RCTs, 101 participants), all-cause mortality (RD 0.00, 95% CI -0.10 to 0.10; 1 RCT, 36 participants), risk of participants experiencing myocardial infarction (Peto OR 0.15, 95% CI 0.00 to 7.62; 1 RCT, 36 participants), cerebrovascular accident/stroke (RD 0.00, 95% CI -0.06 to 0.06; 1 RCT, 65 participants); and deep vein thrombosis (Peto OR 1.11, 95% CI 0.07 to 17.77; 2 RCTs, 101 participants).  All outcomes reported were very low-certainty evidence. No data were available for number of red blood cell units transfused, reoperation, incidence of pulmonary embolism, acute transfusion reaction, or suspected serious drug reactions. We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), inconsistency (moderate heterogeneity), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures, and high risk of attrition and reporting biases in one trial). Comparison 3. Recombinant factor VIIa versus placebo   Only one RCT of 48 participants reported data for recombinant factor VIIa versus placebo, so we have not presented the results here., Authors' Conclusions: We cannot draw conclusions from the current evidence due to lack of data. Most published studies included in our analyses assessed the use of tranexamic acid (compared to placebo, or using different routes of administration).  We identified 27 prospectively registered ongoing RCTs (total target recruitment of 4177 participants by end of 2023). The ongoing trials create six new comparisons: tranexamic acid (tablet + injection) versus placebo; intravenous tranexamic acid versus oral tranexamic acid; topical tranexamic acid versus oral tranexamic acid; different intravenous tranexamic acid dosing regimes; topical tranexamic acid versus topical fibrin glue; and fibrinogen (injection) versus placebo., (Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

In patients with acute ischemic stroke (AIS), the effect of salvianolic acids for injection (SAFI) as the secondary treatment after intravenous thrombolysis (IVT) is unclear. We aimed to evaluate the efficacy of SAFI for patients with AIS undergoing IVT. We searched seven electronic databases and two registries from inception to July 24, 2022, for randomized controlled trials (RCTs) assessing the effect of SAFI plus recombinant tissue plasminogen activator (rt-PA) on the functional recovery compared to rt-PA alone in patients with AIS. Two independent authors selected RCTs, extracted data, and assessed the risk of bias. A meta-analysis was conducted. Eight RCTs involving 682 patients with AIS were included. Compared to patients receiving intravenous rt-PA alone, those receiving intravenous rt-PA combined with SAFI had a higher likelihood of achieving favorable functional outcomes at 3 months. In addition, the use of SAFI for 2 weeks was associated with better neurological recovery. The evidence of benefit was confirmed by trial sequential analysis (TSA). The incidence of intracranial hemorrhage did not differ between the two groups. In patients with AIS, intravenous rt-PA combined with SAFI might achieve better functional outcomes. However, further high-quality studies are needed to firmly establish the clinical efficacy of SAFI., (© 2023 John Wiley & Sons Ltd.)

Background and Purpose: Acute ischaemic stroke patients with cerebral small vessel disease (CSVD), including cerebral microbleeds (CMBs) and white matter hyperintensities (WMHs), have worse outcomes. The effect was investigated of two blood pressure strategies (intensive vs. standard) and blood pressure variability (BPV) after reperfusion according to CSVD burden in the BP TARGET trial., Methods: Patients with available magnetic resonance imaging at baseline were included. CMBs were described as absent or present and WMH severity was described according to the Fazekas classification (0-1, absent-mild; 2-3, moderate to severe). Outcomes consisted of any intracerebral hemorrhage (ICH) at 24 h and favorable outcome at 90 days (modified Rankin Scale score between 0 and 2)., Results: In all, 246 patients were included. The intensive systolic blood pressure target was not associated with lower rates of ICH or favorable outcome according to CSVD subgroups (all p values >0.35). Several BPV parameters were associated with increased odds of ICH in patients with CMBs but not in patients without CMBs (diastolic blood pressure coefficient of variation, odds ratio 2.06, 95% confidence interval [CI] 1.13-3.77, in patients with ≥1 CMB vs. 0.94, 95% CI 0.68-1.31, in patients without CMBs, p het  = 0.026). Several diastolic BPV parameters were associated with worse outcomes in patients with severe WMHs but not in patients without WMHs (diastolic blood pressure coefficient of variation, odds ratio 0.32, 95% CI 0.17-0.61, in patients with severe WMHs vs. 1.09, 95% CI 0.67-1.79, in patients without WMHs; p het  = 0.003)., Conclusion: No effect of the intensive systolic blood pressure management strategy was found on ICH occurrence or functional outcome according to CSVD burden. BPV was associated with higher odds of ICH in patients with CMBs and worse outcome in patients with moderate-to-severe WMHs., (© 2023 European Academy of Neurology.)

Background: Acute ischemic stroke (AIS) is the abrupt reduction of blood flow to a certain area of the brain which causes neurologic dysfunction. Different types of percutaneous arterial endovascular interventions have been developed, but as yet there is no consensus on the optimal therapy for people with AIS., Objectives: To compare the safety and efficacy of different types of percutaneous arterial endovascular interventions for treating people with AIS., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 4 of 12, 2022), MEDLINE Ovid (1946 to 13 May 2022), Embase (1947 to 15 May 2022), Science Citation Index Web of Science (1900 to 15 May 2022), Scopus (1960 to 15 May 2022), and China Biological Medicine Database (CBM; 1978 to 16 May 2022). We also searched the ClinicalTrials.gov trials register and the World Health Organization (WHO) International Clinical Trials Registry Platform to 16 May 2022., Selection Criteria: Randomized controlled trials (RCTs) comparing one percutaneous arterial endovascular intervention with another in treating adult patients who have a clinical diagnosis of AIS due to large vessel occlusion and confirmed by imaging evidence, including thrombo-aspiration, stent-retrieval thrombectomy, aspiration-retriever combined technique, and thrombus mechanical fragmentation., Data Collection and Analysis: Two review authors independently performed the literature searches, identified eligible trials, and extracted data. A third review author participated in discussions to reach consensus decisions when any disputes occurred. We assessed risk of bias and applied the GRADE approach to evaluate the quality of the evidence. The primary outcome was rate of modified Rankin Scale (mRS) of 0 to 2 at three months. Secondary outcomes included the rate of modified Thrombolysis In Cerebral Infarction (mTICI) of 2b to 3 postprocedure, all-cause mortality within three months, rate of intracranial hemorrhage on imaging at 24 hours, rate of symptomatic intracranial hemorrhage at 24 hours, and rate of procedure-related adverse events within three months., Main Results: Four RCTs were eligible. The current meta-analysis included two trials with 651 participants comparing thrombo-aspiration with stent-retrieval thrombectomy. We judged the quality of evidence to be high in both trials according to Cochrane's risk of bias tool RoB 2. There were no significant differences between thrombo-aspiration and stent-retrieval thrombectomy in rate of mRS of 0 to 2 at three months (risk ratio [RR] 0.97, 95% confidence interval [CI] 0.82 to 1.13; P = 0.68; 633 participants; 2 RCTs); rate of mTICI of 2b to 3 postprocedure (RR 1.01, 95% CI 0.95 to 1.07; P = 0.77; 650 participants; 2 RCTs); all-cause mortality within three months (RR 1.01, 95% CI 0.74 to 1.37; P = 0.95; 633 participants; 2 RCTs); rate of intracranial hemorrhage on imaging at 24 hours (RR 1.03, 95% CI 0.86 to 1.24; P = 0.73; 645 participants; 2 RCTs); rate of symptomatic intracranial hemorrhage at 24 hours (RR 0.90, 95% CI 0.49 to 1.68; P = 0.75; 645 participants; 2 RCTs); and rate of procedure-related adverse events within three months (RR 0.98, 95% CI 0.68 to 1.41; P = 0.90; 651 participants; 2 RCTs). Another two included studies reported no differences for the comparisons of combined therapy versus stent-retrieval thrombectomy or thrombo-aspiration. One RCT is ongoing., Authors' Conclusions: This review did not establish any difference in safety and effectiveness between the thrombo-aspiration approach and stent-retrieval thrombectomy for treating people with AIS. Furthermore, the combined group did not show any obvious advantage over either intervention applied alone., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background and Purpose: There are limited data regarding safety and effectiveness of concurrent intraarterial thrombolytics as adjunct to mechanical thrombectomy in acute ischemic stroke patients with basilar artery occlusion., Methods: We analyzed data from a prospective multicenter registry to assess the independent effect of intraarterial thrombolysis on (1) favorable outcome (modified Rankin Scale 0-3) at 90 days; (2) symptomatic intracranial hemorrhage (sICH) within 72 hours; and (3) death within 90 days post-enrollment after adjustment for potential confounders., Results: There was no difference in the adjusted odds of achieving favorable outcome at 90 days (odds ratio [OR] = 1.1, 95% confidence interval [CI]: 0.73-1.68) in patients who received intraarterial thrombolysis (n = 126) compared with those who did not receive intraarterial thrombolysis (n = 1546) despite significantly higher use in patients with postprocedure modified Thrombolysis in Cerebral Infarction (mTICI) grade <3. There were no differences in adjusted odds of sICH within 72 hours (OR = 0.8, 95% CI: 0.31-2.08) or death within 90 days (OR = 0.91, 95% CI: 0.60-1.37). In subgroup analyses, intraarterial thrombolysis was associated with (nonsignificantly) higher odds of achieving a favorable outcome at 90 days among patients aged between 65 and 80 years, those with National Institutes of Health Stroke Scale score <10, and those with postprocedure mTICI grade 2b., Conclusions: Our analysis supported the safety of intraarterial thrombolysis as adjunct to mechanical thrombectomy in acute ischemic stroke patients with basilar artery occlusion. Identification of patient subgroups in whom intraarterial thrombolytics appeared to be more beneficial may assist in future clinical trial designs., (© 2023 American Society of Neuroimaging.)

This study was designed to evaluate antiplatelet effect and therapeutic effect of ginkgo diterpene lactone meglumine injection (GDLI) in acute ischemic stroke (AIS) patients. In this randomized, double-blind, placebo-controlled trial, we randomly assigned 70 inpatients within 48 hr after the onset of AIS to combination therapy with GDLI and aspirin (GDLI at a dose of 25 mg/d for 14 days plus aspirin at a dose of 100 mg/d for 90 days) or to placebo plus aspirin in a ratio of 1:1. Platelet function, the National Institute of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were evaluated. A good outcome was defined as NIHSS scores decrease ≥5 or mRS scores decrease ≥2. Results showed that arachidonic acid induced maximum platelet aggregation rate (AA-MAR) and mean platelet volume (MPV) of the GDLI-aspirin group were much lower than that of the aspirin group (p = 0.013 and p = 0.034, respectively) after the 14-day therapy. The combination of GDLI and aspirin was superior to aspirin alone, and had significant impact on the good outcome at day 90 (ORadj 7.21 [95%CI, 1.03-50.68], p = 0.047). In summary, GDLI has antiplatelet effect and can improve the prognosis of AIS patients., (© 2023 John Wiley & Sons Ltd.)

Background and Purpose: The best reperfusion treatment for patients with mild acute ischaemic stroke harbouring proximal anterior circulation large vessel occlusion (LVO) is unknown. The aim was to compare the safety and efficacy of intravenous thrombolysis (IVT) plus endovascular thrombectomy (EVT) versus IVT alone in LVO patients with mild symptoms., Methods: From the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis and Thrombectomy Register (SITS-ISTR), were included: (i) consecutive acute ischaemic stroke patients, (ii) treated within 4.5 h from symptoms onset, (iii) baseline National Institutes of Health Stroke Scale (NIHSS) score ≤5 and (iv) intracranial internal carotid artery [ICA], M1 or T occlusion [defined as occlusion of ICA terminal bifurcation]. After propensity score matching, 3-month functional outcomes (modified Rankin Scale [mRS] 0-1 and 0-2) and safety outcomes (symptomatic intracerebral haemorrhage and death) were compared (via univariable and multivariable logistic [and ordinal] regression analyses) in patients treated with IVT + EVT versus IVT alone., Results: In all, 1037 patients were included. After propensity score matching (n = 312 per group), IVT + EVT was independently associated with poor functional outcomes (adjusted odds ratio [aOR] 0.46 for mRS 0-1, 95% confidence interval [CI] 0.30-0.72, p = 0.001; aOR 0.52 for mRS 0-2, 95% CI 0.32-0.84, p = 0.007; aOR 1.61 for 1-point shift in mRS score, 95% CI 1.12-2.32, p = 0.011), with no significant differences in safety outcomes compared to IVT alone, despite numerically higher rates of symptomatic intracerebral haemorrhage (3.3% vs. 1.1%; p = 0.082), a higher rate of any haemorrhagic transformation (17.6% vs. 7.3%; p < 0.001) and subarachnoid haemorrhage (7.9% vs. 1.5%; p = 0.002) in the IVT + EVT group., Discussion: In anterior circulation LVO patients presenting with NIHSS score ≤5, IVT + EVT (vs. IVT alone) was associated with poorer 3-month functional outcome. Randomized controlled trials are needed to elucidate the best treatments in mild LVO patients., (© 2023 European Academy of Neurology.)

Background and Purpose: The aim was to evaluate the temporal trends, characteristics and in-hospital outcomes of patients hospitalized with acute ischaemic stroke (AIS) between those with and without current or historical malignancies., Methods: Adult hospitalizations with a primary diagnosis of AIS were identified from the National Inpatient Sample database 2007-2017. Logistic regression was used to compare the differences in the utilization of AIS interventions and in-hospital outcomes. For further analysis, subgroup analyses were performed stratified by cancer subtypes., Results: There were 892,862 hospitalizations due to AIS, of which 108,357 (12.14%) had a concurrent diagnosis of current cancer (3.41%) or historical cancer (8.72%). After adjustment for confounders, patients with current malignancy were more likely to have worse clinical outcomes. The presence of historical cancers was not associated with an increase in poor clinical outcomes. Additionally, AIS patients with current malignancy were less likely to receive intravenous thrombolysis (adjusted odds ratio 0.66, 95% confidence interval 0.63-0.71). Amongst the subgroups of AIS patients treated with intravenous thrombolysis or mechanical thrombectomy, outcomes varied by cancer types. Notably, despite these acute stroke interventions, outcome remains poor in AIS patients with lung cancer., Conclusions: Although AIS patients with malignancy generally have worse in-hospital outcomes versus those without, there were considerable variations in these outcomes according to different cancer types and the use of AIS interventions. Finally, treatment of these AIS patients with a current or historical cancer diagnosis should be individualized., (© 2023 European Academy of Neurology.)

Background and Purpose: Sex-based differences in acute ischemic stroke are a well-known phenomenon. We aimed to explore these differences between women and men in the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial., Methods: We compared baseline demographic and imaging characteristics (visual fluid-attenuated inversion recovery [FLAIR] positivity, relative FLAIR signal intensity, collateral status) between women and men in all screened patients. In randomized patients (i.e., those with diffusion-weighted imaging (DWI)-FLAIR mismatch), we evaluated a modifying role of sex on the treatment effect of alteplase in multivariable logistic regression, with treatment adjusted for National Institute of Health Stroke Scale (NIHSS) score and age. Dependent variables were modified Rankin Scale (mRS) score of 0-1 at 90 days and distribution of mRS scores at 90 days., Results: Of 1362 screened patients, 529 (38.8%) were women. Women were older than men, had higher baseline NIHSS scores and smoked less frequently. FLAIR positivity of the DWI lesion was equally present in women (174/529, 33.1%) and men (273/833, 33.3%; p = 1.00) and other imaging variables also did not differ between the sexes. In a total of 503 randomized patients, of whom 178 were women (35.4%), sex did not modify the treatment effect of alteplase on mRS score 0-1 or on the total distribution of mRS scores., Conclusion: As in many other stroke trials, more men than women were included in the WAKE-UP trial, but the presence of a visual DWI-FLAIR mismatch and the relative FLAIR signal intensity did not differ between the sexes. The treatment effect of alteplase was not modified by sex., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Astrocytic nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a potential therapeutic target of ischaemic preconditioning (IPC). Icariside II (ICS II) is a naturally occurring flavonoid derived from Herba Epimedii with Nrf2 induction potency. This study was designed to clarify if exposure to ICS II mimicks IPC neuroprotection and if Nrf2 from astrocytes contributes to ICS II preconditioning against ischaemic stroke., Experimental Approach: Mice with transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischaemia and primary astrocytes challenged with oxygen-glucose deprivation (OGD) were used to explore the neuroprotective effect of ICS II preconditioning. Additionally, Nrf2-deficient mice were pretreated with ICS II to determine whether ICS II exerts its neuroprotection by activating Nrf2., Key Results: ICS II pretreatment mitigated cerebral injury in the mouse model of ischaemic stroke along with improving long-term recovery. Furthermore, proteomics screening identified Nrf2 as a crucial gene evoked by ICS II treatment and required for the anti-oxidative effect and anti-inflammatory effect of ICS II. Also, ICS II directly bound to Nrf2 and reinforced the transcriptional activity of Nrf2 after MCAO. Moreover, ICS II pretreatment exerted cytoprotective effects on astrocyte cultures following lethal OGD exposure, by promoting Nrf2 nuclear translocation and activating the OXPHOS/NF-κB/ferroptosis axis, while neuroprotection was decreased in Nrf2-deficient mice and Nrf2 siRNA blocked effects of ICS II., Conclusion and Implications: ICS II preconditioning provides robust neuroprotection against ischaemic stroke via the astrocytic Nrf2-mediated OXPHOS/NF-κB/ferroptosis axis. Thus, ICS II could be a promising Nrf2 activator to treat ischaemic stroke., (© 2022 British Pharmacological Society.)

Background and Purpose: Although increasing evidence illustrated that the bidirectional communication between the brain and the gut is closely related to the occurrence of various complex diseases. Limited effort has been made to explore the influence of intestinal flora on the risk of ischaemic stroke. The present study aims to identify microbiota and specialized microbiota metabolites related to the occurrence and treatment of ischaemic stroke., Experimental Approach: The role of microbiota in the occurrence and the treatment of ischaemic stroke was evaluated on ischaemia/reperfusion (I/R), pseudo-germ-free and faecal transplantation animals. The target microbiota and specialized metabolites were identified by comparing their distribution in flora and metabolomic profiles in ischaemic stroke patients and animals with compared with healthy controls. The effects and mechanisms involved of the targeted metabolites in ischaemic stroke were explored in ischaemia/reperfusion rats, hypoxia/reoxygenation PC12 cells and LPS-induced inflammatory BV2 cells., Key Results: Both ischaemic stroke patients and I/R rats had significant accumulation of branched-chain amino acids, which were closely associated with gut microflora dysbiosis and the development of ischaemic stroke. Lactobacillus helveticus (L.hel) and Lactobacillus brevis (L.bre) are identified as the microbiota most affected by ischaemia/reperfusion modelling and treatment. L.hel and L.bre colonization exhibited significant neuroprotective activity and could greatly alleviate the accumulation of branched-chain amino acids. In addition, branched-chain amino acid (BCAA) accumulation was shown to exacerbate microglia-induced neuroinflammation by activating AKT/STAT3/NF-κB signalling., Conclusion and Implications: Our findings demonstrated the crucial role of intestinal flora and microbiota metabolites in the occurrence and treatment of ischaemic stroke., (© 2022 British Pharmacological Society.)

The pharmacokinetics (PK) of tenecteplase in patients with acute ischemic stroke has not been extensively studied. This study aimed to describe PK characteristics of tenecteplase in patients with acute myocardial infarction (AMI) using a population PK approach and to assess applicability of the findings to patients with acute ischemic stroke by means of external validation. A population PK model was developed using nonlinear mixed-effects modeling based on the phase II TIMI 10B study in patients with AMI (785 PK observations from 103 patients). The statistical and clinical impact of selected covariates on PK parameters were evaluated by a stepwise covariate modeling procedure and simulations, respectively. The performance of the final model was evaluated for patients with acute ischemic stroke using summary statistics of tenecteplase concentrations of 75 patients from investigator-initiated study N1811s. Tenecteplase PK was well described by a 2-compartment linear model, incorporating allometric scaling of clearance and volume parameters and weight-normalized creatinine clearance on clearance. Simulations showed that the identified covariates (weight and creatinine clearance) were of limited influence on exposure at the intended dosing regimen for patients with acute ischemic stroke. The model overpredicted mean tenecteplase plasma concentrations from N1811s by 39%, but 72% of the distribution from N1811s was within the 90% prediction interval of the model predictions. The PK characteristics of tenecteplase in patients with AMI were well described by the final model. Simulations from the model indicated that no specific dose recommendations based on covariates are warranted for patients with AMI., (© 2022 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background and Purpose: Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil β 1 adrenoceptors (β1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that β1AR blockade will improve stroke outcomes., Experimental Approach: Rats were subjected to middle cerebral artery occlusion-reperfusion to evaluate the effect on stroke of the selective β1AR blocker metoprolol (12.5 mg·kg -1 ) when injected i.v. 10 min before reperfusion., Key Results: Magnetic resonance imaging and histopathology analysis showed that pre-reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol-treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti-inflammatory phenotype (N2, YM1 + ). Additional inflammatory models demonstrated that metoprolol specifically blocked neutrophil migration via β1AR and excluded a significant effect on the glia compartment. Consistently, metoprolol did not protect the brain in neutrophil-depleted rats upon stroke. In patients suffering an ischaemic stroke, β1AR blockade by metoprolol reduced circulating neutrophil-platelet co-aggregates., Conclusions and Implications: Our findings describe that β1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: This is an update of the Cochrane Review last published in 2017. Survivors of stroke due to intracerebral haemorrhage (ICH) are at risk of major adverse cardiovascular events (MACE). Antithrombotic (antiplatelet or anticoagulant) treatments may lower the risk of ischaemic MACE after ICH, but they may increase the risk of bleeding., Objectives: To determine the overall effectiveness and safety of antithrombotic drugs on MACE and its components for people with ICH., Search Methods: We searched the Cochrane Stroke Group Trials Register (5 October 2021). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library 2021, Issue 10), MEDLINE Ovid (from 1948 to October 2021) and Embase Ovid (from 1980 to October 2021). The online registries of clinical trials searched were the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (5 October 2021). We screened the reference lists of included randomised controlled trials (RCTs) for additional, potentially relevant RCTs., Selection Criteria: We selected RCTs in which participants with ICH of any age were allocated to a class of antithrombotic treatment as intervention or comparator., Data Collection and Analysis: In accordance with standard methodological procedures recommended by Cochrane, two review authors assessed each selected RCT for its risk of bias and extracted data independently. The primary outcome was a composite of MACE, and secondary outcomes included death, individual components of the MACE composite, ICH growth, functional status and cognitive status. We estimated effects using the frequency of outcomes that occurred during the entire duration of follow-up and calculated a risk ratio (RR) for each RCT. We grouped RCTs separately for analysis according to 1) the class(es) of antithrombotic treatment used for the intervention and comparator, and 2) the duration of antithrombotic treatment use (short term versus long term). We pooled the intention-to-treat populations of RCTs using a fixed-effect model for meta-analysis, but used a random-effects model if RCTs differed substantially in their design or there was considerable heterogeneity (I 2 ≥ 75%) in their results. We applied GRADE to assess the certainty of the evidence., Main Results: We identified seven new completed RCTs for this update, resulting in the inclusion of a total of nine RCTs based in secondary care, comprising 1491 participants (average age ranged from 61 to 79 years and the proportion of men ranged from 44% to 67%). The proportion of included RCTs at low risk of bias, by category was: random sequence generation (67%), allocation concealment (67%), performance (22%), detection (78%), attrition (89%), and reporting (78%). For starting versus avoiding short-term prophylactic dose anticoagulation after ICH, no RCT reported MACE. The evidence is very uncertain about the effect of starting short-term prophylactic dose anticoagulation on death (RR 1.00, 95% CI 0.59 to 1.70, P = 1.00; 3 RCTs; very low-certainty evidence), venous thromboembolism (RR 0.84, 95% CI 0.51 to 1.37, P = 0.49; 4 RCTs; very low-certainty evidence), ICH (RR 0.24, 95% CI 0.04 to 1.38, P = 0.11; 2 RCTs; very low-certainty evidence), and independent functional status (RR 2.03, 95% CI 0.78 to 5.25, P = 0.15; 1 RCT; very low-certainty evidence) over 90 days. For starting versus avoiding long-term therapeutic dose oral anticoagulation for atrial fibrillation after ICH, starting long-term therapeutic dose oral anticoagulation probably reduces MACE (RR 0.61, 95% CI 0.40 to 0.94, P = 0.02; 3 RCTs; moderate-certainty evidence) and probably reduces all major occlusive vascular events (RR 0.27, 95% CI 0.14 to 0.53, P = 0.0002; 3 RCTs; moderate-certainty evidence), but probably results in little to no difference in death (RR 1.05, 95% CI 0.62 to 1.78, P = 0.86; 3 RCTs; moderate-certainty evidence), probably increases intracranial haemorrhage (RR 2.43, 95% CI 0.88 to 6.73, P = 0.09; 3 RCTs; moderate-certainty evidence), and may result in little to no difference in independent functional status (RR 0.98, 95% CI 0.78 to 1.24, P = 0.87; 2 RCTs; low-certainty evidence) over one to three years. For starting versus avoiding long-term antiplatelet therapy after ICH, the evidence is uncertain about the effects of starting long-term antiplatelet therapy on MACE (RR 0.89, 95% CI 0.64 to 1.22, P = 0.46; 1 RCT; moderate-certainty evidence), death (RR 1.08, 95% CI 0.76 to 1.53, P = 0.66; 1 RCT; moderate-certainty evidence), all major occlusive vascular events (RR 1.03, 95% CI 0.68 to 1.55, P = 0.90; 1 RCT; moderate-certainty evidence), ICH (RR 0.52, 95% CI 0.27 to 1.03, P = 0.06; 1 RCT; moderate-certainty evidence) and independent functional status (RR 0.95, 95% CI 0.77 to 1.18, P = 0.67; 1 RCT; moderate-certainty evidence) over a median follow-up of two years. For adults within 180 days of non-cardioembolic ischaemic stroke or transient ischaemic attack and a clinical history of prior ICH, there was no evidence of an effect of long-term cilostazol compared to aspirin on MACE (RR 1.33, 95% CI 0.74 to 2.40, P = 0.34; subgroup of 1 RCT; low-certainty evidence), death (RR 1.65, 95% CI 0.55 to 4.91, P = 0.37; subgroup of 1 RCT; low-certainty evidence), or ICH (RR 1.29, 95% CI 0.35 to 4.69, P = 0.70; subgroup of 1 RCT; low-certainty evidence) over a median follow-up of 1.8 years; all major occlusive vascular events and functional status were not reported., Authors' Conclusions: We did not identify beneficial or hazardous effects of short-term prophylactic dose parenteral anticoagulation and long-term oral antiplatelet therapy after ICH on important outcomes. Although there was a significant reduction in MACE and all major occlusive vascular events after long-term treatment with therapeutic dose oral anticoagulation for atrial fibrillation after ICH, the pooled estimates were imprecise, the certainty of evidence was only moderate, and effects on other important outcomes were uncertain. Large RCTs with a low risk of bias are required to resolve the ongoing dilemmas about antithrombotic treatment after ICH., (Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Although concomitant medications have been raised as a factor affecting hemorrhage during direct oral anticoagulant (DOAC) therapy, details remain unelucidated. This study was conducted to clarify the relationship between concomitant medications with possible pharmacokinetic interactions and number of concomitant medications, and bleeding and embolism in patients with nonvalvular atrial fibrillation on DOACs. The subjects were 1010 patients prescribed DOACs from a single-center at the Teikyo University Hospital between April 2011 and June 2018. This study was an exploratory analysis and investigated their course between the first prescription and December 2018, including the presence or absence of clinically relevant bleeding, gastrointestinal bleeding, and major cardiovascular and cerebrovascular events. Impacts of medications were evaluated by the general linear model with inverse probability-weighted propensity score. The observation period was 2272 patient-years. The rate of bleeding was 4.7%/year, gastrointestinal bleeding was 2.8%/year, and major cardiovascular and cerebrovascular events were 2.0%/year. Taking 10 or more oral medications concurrently was a significant risk for gastrointestinal bleeding (hazard ratio, 2.046 [95%CI, 1.188-3.526]; P = .010). Nonsteroidal anti-inflammatory drugs were the only significant risk for gastrointestinal bleeding. Clinicians should be aware of gastrointestinal bleeding when using DOACs with patients taking more than 10 medications and/or nonsteroidal anti-inflammatory drugs., (© 2022, The American College of Clinical Pharmacology.)

Background: Antidepressants may be useful in the treatment of abnormal crying associated with stroke. This is an update of a Cochrane Review first published in 2004 and last updated in 2019., Objectives: To evaluate the benefits and harms of pharmaceutical treatment in people with emotionalism after stroke., Search Methods: We searched the Cochrane Stroke Group Register, CENTRAL, MEDLINE, Embase, four other databases, and three trials registers (May 2022)., Selection Criteria: We included randomised controlled trials (RCTs) and quasi-RCTs comparing psychotropic medication to placebo in people with stroke and emotionalism (also known as emotional lability, pathological crying or laughing, emotional incontinence, involuntary emotional expression disorder, and pseudobulbar affect)., Data Collection and Analysis: Two review authors independently selected trials, assessed risk of bias, extracted data from all included trials, and used GRADE to assess the certainty of the body of evidence. We calculated the mean difference (MD) or standardised mean difference (SMD) for continuous data and the risk ratio (RR) for dichotomous data, with 95% confidence intervals (CIs). We assessed heterogeneity using the I 2 statistic. The primary emotionalism measures were the proportion of participants achieving at least a 50% reduction in abnormal emotional behaviour at the end of treatment, improved score on the Center for Neurologic Study - Lability Scale (CNS-LS) or Clinician Interview-Based Impression of Change (CIBIC), or diminished tearfulness., Main Results: We did not identify any new trials for this update. We included seven trials with a total of 239 participants. Two trials had a cross-over design, but outcome data were not available from the first phase (precross-over) in an appropriate format for inclusion as a parallel randomised controlled trial (RCT). Thus, the results of the review are based on five trials with a total of 213 participants. It is uncertain whether fluoxetine increases the number of people who have a 50% reduction in emotionalism when compared to placebo (risk ratio (RR) 0.26, 95% CI 0.09 to 0.77; P = 0.02; 1 trial, 19 participants) because the certainty of evidence is very low. Sertraline may lead to little to no difference in Center for Neurologic Study - Lability Scale (CNS-LS) scores and Clinician Interview-Based Impression of Change (CIBIC) scores when compared to placebo (RR 0.20, 95% CI 0.03 to 1.50; P = 0.12; 1 trial, 28 participants; low-certainty evidence). Antidepressants probably increase the number of people who experience a reduction in tearfulness (RR 0.32, 95% CI 0.12 to 0.86; P = 0.02; 3 trials, 164 participants; moderate-certainty evidence). No trials were found that evaluated the impact of other pharmaceutical interventions. Only two trial authors systematically recorded and reported adverse events, resulting in limited data on the potential harms of treatment. Six trials reported death as an adverse event and found no difference between the groups (antidepressants versus placebo) in the number of deaths reported (RR 0.59, 95% CI 0.08 to 4.50; P = 0.61; 172 participants; moderate-certainty evidence). This review provides very low- to moderate-certainty evidence that antidepressants may reduce the frequency and severity of emotionalism. The included trials were small and had some degree of bias., Authors' Conclusions: Antidepressants may reduce the frequency and severity of crying or laughing episodes when compared to placebo, based on very low-certainty evidence. Our conclusions must be qualified by several methodological deficiencies in the trials and interpreted with caution despite the effect being very large. The effect does not seem specific to one drug or class of drugs. More reliable data are required before appropriate conclusions can be made about the treatment of post-stroke emotionalism. Future trialists investigating the effect of antidepressants in people with emotionalism after stroke should consider developing and using a standardised method to diagnose emotionalism, determine severity, and assess change over time; provide treatment for a sufficient duration and follow-up to better assess rates of relapse or maintenance; and include careful assessment and complete reporting of adverse events., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background and Purpose: Treatment of acute ischemic stroke is heavily contingent upon time, as there is a strong relationship between time clock and tissue progression. Work has established imaging biomarker assessments as surrogates for time since stroke (TSS), namely, by comparing signal mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging. Our goal was to develop an automatic technique for determining TSS from imaging that does not require subspecialist radiology expertise., Methods: Using 772 patients (66 ± 9 years, 319 women), we developed and externally evaluated a deep learning network for classifying TSS from MR images and compared algorithm predictions to neuroradiologist assessments of DWI-FLAIR mismatch. Models were trained to classify TSS within 4.5 hours and performance metrics with confidence intervals were reported on both internal and external evaluation sets., Results: Three board-certified neuroradiologists' DWI-FLAIR mismatch assessments, based on majority vote, yielded a sensitivity of .62, a specificity of .86, and a Fleiss' kappa of .46 when used to classify TSS. The deep learning method performed similarly to radiologists and outperformed previously reported methods, with the best model achieving an average evaluation accuracy, sensitivity, and specificity of .726, .712, and .741, respectively, on an internal cohort and .724, .757, and .679, respectively, on an external cohort., Conclusion: Our model achieved higher generalization performance on external evaluation datasets than the current state-of-the-art for TSS classification. These results demonstrate the potential of automatic assessment of onset time from imaging without the need for expertly trained radiologists., (© 2022 American Society of Neuroimaging.)

The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE-UP trial, comparing 127 imaging-selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio-topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network-informed imaging biomarkers and improved prognostication in ischemic stroke., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: The purpose was to determine whether prior use of antiplatelet therapy modifies the effect of dual antiplatelet therapy in patients with acute minor ischaemic stroke or transient ischaemic attack., Methods: A systematic review and meta-analysis of randomized controlled trials was performed comparing dual antiplatelet therapy to aspirin that reported subgroup analysis by prior antiplatelet use, adhering to the Cochrane Collaboration Guidelines. A fixed-effects meta-analysis was used to estimate a pooled treatment effect overall in subgroups with prior aspirin therapy and without prior aspirin therapy. Difference in treatment effect was assessed by testing p for interaction. The primary outcome measure was recurrent vascular events., Results: Three eligible randomized controlled trials were identified, including 4831 participants with pre-existing antiplatelet use and 16,236 participants without pre-existing aspirin use. Recurrent vascular events occurred in 7.2% (95% confidence interval [CI] 4.3-10) of those without pre-existing aspirin use versus 7.3% (95% CI 4.1-10) of those receiving prior aspirin therapy. Effect of dual antiplatelet therapy on the primary outcome measure was consistent in participants with no prior aspirin use (odds ratio 0.75, 95% CI 0.66-0.84) compared to those taking aspirin before randomization (odds ratio 0.79, 95% CI 0.63-0.998) (p interaction = 0.66). The number needed to treat in the aspirin-naïve group was 55 (95% CI 37-107) compared to 66 (95% CI 32 to -746) in those on prior aspirin therapy., Conclusions: It was found that the effectiveness of dual antiplatelet therapy in patients with minor ischaemic stroke or high risk transient ischaemic attack does not significantly differ in patients with prior aspirin exposure; therefore there should be no influence on the decision to use dual antiplatelet therapy., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: The progressive nature of epileptogenesis raises the question of whether the latent period may already carry information about the characteristics of the subsequent epilepsy. This study aimed to explore whether the time from stroke to epilepsy onset was related to the risk of drug resistance in patients with poststroke epilepsy (PSE)., Methods: Patients with epilepsy secondary to cerebral infarct or spontaneous intracerebral hemorrhage were included. Study outcome was the occurrence of drug resistance defined as failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication schedules to achieve sustained seizure freedom., Results: One hundred fifty-nine patients with PSE and a median follow-up of 5 (interquartile range [IQR] = 3-9) years were included. In the study cohort, 29 (18.2%) participants were drug resistant. The median length of the time interval between stroke and PSE onset was 13 (IQR = 7-15) months in drug-resistant patients and 19 (IQR = 14-42) months (p &lt; 0.001) in patients with seizure control. According to multivariable regression analysis, the time from stroke to PSE was an independent predictor of drug resistance (p &lt; 0.001). The risk of drug resistance was highest when the onset of PSE occurred within the first months from stroke and decreased progressively with a steeper decline over the first 12 months., Conclusions: Substantial variability may exist in the pathways leading to PSE and distinguish patients with a variable risk of drug resistance., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Cerebral small vessel disease is a progressive disease of the brain's deep perforating blood vessels. It is usually diagnosed based on lesions seen on brain imaging. Cerebral small vessel disease is a common cause of stroke but can also cause a progressive cognitive decline. As antithrombotic therapy is an established treatment for stroke prevention, we sought to determine whether antithrombotic therapy might also be effective in preventing cognitive decline in people with small vessel disease., Objectives: To assess the effects of antithrombotic therapy for prevention of cognitive decline in people with small vessel disease on neuroimaging but without dementia., Search Methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Review Group's Specialised Register, and the Cochrane Stroke Group's Specialised Register; the most recent search was on 21 July 2021. We also searched MEDLINE, Embase, four other databases and two trials registries. We searched the reference lists of the articles retrieved from these searches. As trials with a stroke focus may include relevant subgroup data, we complemented these searches with a focussed search of all antithrombotic titles in the Cochrane Stroke Group database.  SELECTION CRITERIA: We included randomised controlled trials (RCT) of people with neuroimaging evidence of at least mild cerebral small vessel disease (defined here as white matter hyperintensities, lacunes of presumed vascular origin and subcortical infarcts) but with no evidence of dementia. The trials had to compare antithrombotic therapy of minimum 24 weeks' duration to no antithrombotic therapy (either placebo or treatment as usual), or compare different antithrombotic treatment regimens. Antithrombotic therapy could include antiplatelet agents (as monotherapy or combination therapy), anticoagulants or a combination., Data Collection and Analysis: Two review authors independently screened all the titles identified by the searches. We assessed full texts for eligibility for inclusion according to our prespecified selection criteria, extracted data to a proforma and assessed risk of bias using the Cochrane tool for RCTs. We evaluated the certainty of evidence using GRADE. Due to heterogeneity across included participants, interventions and outcomes of eligible trials, it was not possible to perform meta-analyses., Main Results: We included three RCTs (3384 participants). One study investigated the effect of antithrombotic therapy in participants not yet on antithrombotic therapy; two studies investigated the effect of additional antithrombotic therapy, one in a population already taking a single antithrombotic agent and one in a mixed population (participants on an antithrombotic drug and antithrombotic-naive participants). Intervention and follow-up durations varied from 24 weeks to four years. Jia 2016 was a placebo-controlled trial assessing 24 weeks of treatment with DL-3-n-butylphthalide (a compound with multimodal actions, including a putative antiplatelet effect) in 280 Chinese participants with vascular cognitive impairment caused by subcortical ischaemic small vessel disease, but without dementia. There was very low-certainty evidence for a small difference in cognitive test scores favouring treatment with DL-3-n-butylphthalide, as measured by the 12-item Alzheimer's Disease Assessment Scale-Cognitive subscale (adjusted mean difference -1.07, 95% confidence interval (CI) -2.02 to -0.12), but this difference may not be clinically relevant. There was also very low-certainty evidence for greater proportional improvement measured with the Clinician Interview-Based Impression of Change-Plus Caregiver Input (57% with DL-3-n-butylphthalide versus 42% with placebo; P = 0.01), but there was no difference in other measures of cognition (Mini-Mental State Examination and Clinical Dementia Rating) or function. There was no evidence of a difference in adverse events between treatment groups. The SILENCE RCT compared antithrombotic therapy (aspirin) and placebo during four years of treatment in 83 participants with 'silent brain infarcts' who were on no prior antithrombotic therapy. There was very low-certainty evidence for no difference between groups across various measures of cognition and function, rates of stroke or adverse events. The Secondary Prevention of Subcortical Stroke Study (SPS3) compared dual antiplatelet therapy (clopidogrel plus aspirin) to aspirin alone in 3020 participants with recent lacunar stroke. There was low-certainty evidence of no effect on cognitive outcomes as measured by the Cognitive Abilities Screening Instruments (CASI) assessed annually over five years. There was also low-certainty evidence of no difference in the annual incidence of mild cognitive decline between the two treatment groups (9.7% with dual antiplatelet therapy versus 9.9% with aspirin), or the annual stroke recurrence rate (2.5% with dual antiplatelet therapy versus 2.7% with aspirin). Bleeding risk may be higher with dual antiplatelet therapy (hazard ratio (HR) 2.15, 95% CI 1.49 to 3.11; low certainty evidence), but there may be no significant increase in intracerebral bleeding risk (HR 1.52, 95% CI 0.79 to 2.93; low-certainty evidence). None of the included trials assessed the incidence of new dementia., Authors' Conclusions: We found no convincing evidence to suggest any clinically relevant cognitive benefit of using antithrombotic therapy in addition to standard treatment in people with cerebral small vessel disease but without dementia, but there may be an increased bleeding risk with this approach. There was marked heterogeneity across the trials and the certainty of the evidence was generally poor., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background and Purpose: Atrial fibrillation (AF) in stroke patients can be classified as either "known AF" (KAF), defined as AF confirmed before stroke onset, or "AF detected after stroke" (AFDAS), defined as AF diagnosed after stroke onset. While KAF is considered primarily cardiogenic, AFDAS includes patients with stroke-triggered neurogenic arrhythmias. This study aimed to investigate the clinical course of stroke, functional outcomes and the value of oral anticoagulation (OAC) for secondary prevention according to AF subtype., Methods: Acute ischemic stroke patients were consecutively enrolled and AF was classified as AFDAS or KAF. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and 3-month functional outcomes were measured on the modified Rankin scale. Inverse probability weighting was applied to adjust for baseline confounders in patients with AFDAS and KAF. Multivariate logistic regression models were calculated to investigate the value of OAC for secondary prevention., Results: A total of 822 stroke patients with AF were included, of whom 234 patients (28.5%) had AFDAS. AFDAS patients had a lower prevalence of coronary artery disease, heart failure, and sustained AF, but higher rates of large vessel occlusion compared to KAF patients. NIHSS scores were lower in patients on pre-stroke anticoagulation. OAC for secondary prevention was associated with favorable 3-month functional outcome (odds ratio 7.60, 95% confidence interval 3.42-16.88) independently of AF subtype. The rate of stroke recurrence did not differ significantly., Conclusions: Clinical characteristics suggest that AFDAS might comprise a distinct pathophysiological and clinical entity among stroke patients with AF. The benefit of anticoagulation for secondary prevention was not affected by AF subtype., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN) study, initiated in November of the year 2000, is now widely recognized as having been a landmark study in the history of clinical trials. We look at why this is the case by considering its key features and impact. These key features are: the use of Bayesian design and analysis; the use of the normal dynamic linear model; the response adaptive nature of the study; the use of real-time dosing decisions; and the use of an integrated model to predict 90-day response on the Scandinavian Stroke Scale. Our overall conclusion is that the ASTIN study's main impact came from showing the clinical trial community the feasibility of the novel design and analysis used when most of these key features were rarely used in industry trials, let alone used together in one trial in a disease area with a tremendous unmet medical need., (© 2022 John Wiley & Sons Ltd.)