Search

Objective: This study investigated the predictive value of serum MDA and 4-HNE levels on early neurological deterioration (END) after recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients., Methods: This study analyzed 287 AIS patients with standard-dose rt-PA IVT. Clinical baseline and pathological data were recorded before rt-PA IVT, and neurologic deficit was assessed by NIHSS. AIS patients were classified into Non-END and END groups. Serum MDA and 4-HNE levels were determined by ELISA and their correlations with NIHSS scores were evaluated. AIS patients were allocated into groups with high and low MDA or 4-HNE expression, and post-IVT END incidence was compared. Independent risk indexes for post-IVT END and the predictive value of serum MDA+4-HNE levels on post-IVT END were assessed., Results: Serum MDA and 4-HNE were higher in AIS patients with post-IVT END. NIHSS score showed a positive correlation with serum MDA and 4-HNE levels. MDA levels were positively correlated with 4-HNE levels in AIS patients. END after IVT was increased in AIS patients with high MDA/4-HNE expression. FBG, lymphocyte percentage, PLR, NIHSS score, serum MDA, and 4-HNE levels were independent risk factors for END after IVT. The diagnostic efficacy of MDA+4-HNE in assessing post-IVT END in AIS patients (sensitivity 92.00 %, specificity 82.70 %) was higher than MDA or 4-HNE alone., Conclusion: Serum MDA and 4-HNE levels were higher in AIS patients with post-IVT END than in those with non-END, and MDA+4-HNE possessed a higher predictive value for post-IVT END in AIS patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: In January 2023, the US Centers for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine., Objective: To evaluate stroke risk after administration of (1) either brand of the COVID-19 bivalent vaccine, (2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration), and (3) a high-dose or adjuvanted influenza vaccine., Design, Setting, and Participants: Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022, through February 4, 2023., Exposures: Receipt of (1) either brand of the COVID-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary)., Main Outcomes and Measures: Stroke risk (nonhemorrhagic stroke, transient ischemic attack, combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window., Results: There were 5 397 278 Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there were no statistically significant associations between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100 000 doses, 3.13 [95% CI, 0.05-6.22]) and a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100 000 doses, 3.33 [95% CI, 0.46-6.20]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100 000 doses, 1.65 [95% CI, 0.43-2.87])., Conclusions and Relevance: Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination.

Background: Our primary objective was to assess the association between joint exposure to various air pollutants and the risk of ischemic stroke (IS) and the modification of the genetic susceptibility., Methods: This observational cohort study included 307 304 British participants from the United Kingdom Biobank, who were stroke-free and possessed comprehensive baseline data on genetics, air pollutant exposure, alcohol consumption, and dietary habits. All participants were initially enrolled between 2006 and 2010 and were followed up until 2022. An air pollution score was calculated to assess joint exposure to 5 ambient air pollutants, namely particulate matter with diameters equal to or <2.5 µm, ranging from 2.5 to 10 µm, equal to or <10 µm, as well as nitrogen oxide and nitrogen dioxide. To evaluate individual genetic risk, a polygenic risk score for IS was calculated for each participant. We adjusted for demographic, social, economic, and health covariates. Cox regression models were utilized to estimate the associations between air pollution exposure, polygenic risk score, and the incidence of IS., Results: Over a median follow-up duration of 13.67 years, a total of 2476 initial IS events were detected. The hazard ratios (95% CI) of IS for per 10 µg/m 3 increase in particulate matter with diameters equal to or <2.5 µm, ranging from 2.5 to 10 µm, equal to or <10 µm, nitrogen dioxide, and nitrogen oxide were 1.73 (1.33-2.14), 1.24 (0.88-1.70), 1.13 (0.89-1.33), 1.03 (0.98-1.08), and 1.04 (1.02-1.07), respectively. Furthermore, individuals in the highest quintile of the air pollution score exhibited a 29% to 66% higher risk of IS compared with those in the lowest quintile. Notably, participants with both high polygenic risk score and air pollution score had a 131% (95% CI, 85%-189%) greater risk of IS than participants with low polygenic risk score and air pollution score., Conclusions: Our findings suggested that prolonged joint exposure to air pollutants may contribute to an increased risk of IS, particularly among individuals with elevated genetic susceptibility to IS., Competing Interests: Disclosures None.

Background: The unfavorable effect of proton pump inhibitors (PPIs) on cardiovascular (CV) outcomes and mortality was reported in the general population. We investigated the impact of PPIs on CV outcomes and total mortality in older people with diabetes mellitus (DM) for whom evidence is missing., Methods: Using administrative health databases of the Lombardy Region, we analyzed the risk of myocardial infarction (MI), ischemic stroke and total mortality in individuals with DM (≥65 years of age) exposed to PPIs in 2015 and followed up to 2021. The outcomes were analyzed using a multivariable-adjusted Cox proportional hazards model to compute hazard ratios (HRs) with 95% confidence intervals (CIs). HRs between PPI users and non-users were also estimated in selected subgroups. A sensitivity analysis was also performed in a 1:1 propensity score matching population., Results: A total of 284,068 patients were included in the analysis (49.4% PPI users, 50.6% non-PPI users). A higher prevalence of comorbidities and medications was reported in PPI users as compared with non-users. During a median follow-up of 6.7 years, the use of PPIs was associated with a higher risk for ischemic stroke (HR 1.14, 95% CI 95% 1.08-1.20), MI (HR 1.36, 95% CI 1.31-1.41) and total mortality (HR 1.24, 95% CI 1.22-1.26). These risks were higher in PPI users regardless of the PPI type. Among sexes, previous CV diseases, and insulin subgroups, the use of PPIs was correlated with a statistically significant increased risk of ischemic stroke in men, in individuals without a history of CV disease, and in those who were not treated with insulin. A significantly higher risk of MI was associated with PPIs for all subgroups, as well as for total mortality, with the exception of patients with a previous history of CV diseases. The sensitivity analysis confirmed the results of the unmatched cohort., Conclusions: Our findings confirmed an increased risk of CV events and all-cause mortality in a large population of older adults with DM exposed to PPIs. This could have an important impact on public health and costs for National Health Service, therefore a regular assessment of PPI appropriateness is recommended, particularly in this population., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background:  Dementia and atrial fibrillation (AF) have many shared risk factors. Besides, patients with dementia are under-represented in randomized trials, and even if AF is present, oral anticoagulants (OACs) are not prescribed frequently. This study aimed to report the incidence of newly diagnosed AF in dementia patients, and the impacts of use of vitamin K antagonist (VKA; e.g., warfarin) and non-VKA OAC (NOACs) on stroke and bleeding outcomes., Methods:  Our study utilized the Taiwan National Health Insurance Research Database. A total of 554,074 patients with dementia were compared with 554,074 age- and sex-matched patients without dementia regarding the risk of incident AF. Among patients with dementia who experienced incident AF, the risks of clinical events of patients treated with warfarin or NOACs were compared with those without OACs (reference group)., Results:  The risk of incident AF was greater for patients with dementia compared with those without (adjusted hazard ratio [aHR]: 1.054; 95% confidence interval [CI]: 1.040-1.068 for all types of dementia, aHR: 1.035; 95% CI: 1.020-1.051 for presenile/senile dementia, and aHR: 1.125; 95% CI: 1.091-1.159 for vascular dementia). Among patients with dementia and experienced incident AF, warfarin use was associated with a higher risk of ischemic stroke (aHR: 1.290; 95% CI: 1.156-1.440), intracranial hemorrhage (ICH; aHR: 1.678; 95% CI: 1.346-2.090), and major bleeding (aHR: 1.192; 95% CI: 1.073-1.323) compared with non-OACs. NOAC use was associated with a lower risk of ischemic stroke (aHR: 0.421; 95% CI: 0.352-0.503) and composite risk of ischemic stroke or major bleeding (aHR: 0.544; 95% CI: 0.487-0.608) compared with non-OACs. These results were consistent among the patients after the propensity matching., Conclusion:  In this large nationwide cohort, the risk of newly diagnosed AF was higher in patients with dementia (all dementia, presenile/senile dementia, and vascular dementia) compared with those without dementia. For patients with dementia who experienced incident AF, NOAC use was associated with a better clinical outcome compared with non-OAC. Patients with dementia require a holistic approach to their care and management, including the use of NOACs to reduce the risks of clinical events., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Proton-pump inhibitors (PPIs) are prescribed to treat gastric acid - related diseases, while they may also have potential risks to population health. Recent studies suggested that a potential mechanism explaining the association between PPIs and cardiovascular diseases (CVD) includes the inhibition of the nitrate - nitrite - nitric oxide (NO) pathway. However, previous observational studies showed controversial results of the association. In addition, the inhibition of the NO pathway due to PPIs use may lead to peripheral vascular diseases (PVD); however, none of the studies explore the PPI-PVD association. Therefore, this study aimed to evaluate the association of PPIs with circulatory diseases (CVD, ischemic strokes or IS, and PVD)., Methods: We conducted a retrospective hospital - based cohort study from Oct 2010 to Sep 2017 in Songkhla province, Thailand. PPIs and histamine 2 - receptor antagonists ( H2RAs ) prescriptions were collected from electronic pharmacy records, while diagnostic outcomes were retrieved from electronic medical records at Songklanagarind hospital. Patients were followed up with an on - treatment approach. Cox proportional hazard models were applied to measure the association comparing PPIs vs H2RAs after 1:1 propensity - score - matching. Sub - group analysis, multi - bias E - values, and array - based sensitivity analysis for some covariates were used to assess the robustness of associations., Results: A total of 3,928 new PPIs and 3,928 H2RAs users were included in the 1:1 propensity score - matched cohort. As compared with H2RAs, the association of PPIs with CVD, IS, and PVD, the hazard ratios were 1.76 95% CI = [1.40-2.20] for CVD, 3.53 95% CI = [2.21-5.64] for ischemic strokes, and 17.07 95% CI = [13.82-76.25] for PVD. The association between PPIs and each outcome was significant with medication persistent ratio of over 50%. In addition, the association between PPIs and circulatory diseases was robust to unmeasured confounders ( i.e. , smoking and alcohol)., Conclusion: PPIs were associated with circulatory diseases, particularly ischemic strokes in this hospital-based cohort study, whereas, the strength of associations was robust to unmeasured confounders., Competing Interests: The authors declare that they have no competing interests., (© 2024 Pannoi et al.)

Background: Strokes after left atrial appendage closure (LAAC) prophylaxis are generally less severe than those after warfarin prophylaxis-thought to be secondary to more hemorrhagic strokes with warfarin. Hemorrhagic strokes are similarly infrequent with direct oral anticoagulant (DOAC) prophylaxis, so the primary subtype after either LAAC or DOAC prophylaxis is ischemic stroke (IS)., Objectives: The purpose of this study was to compare the severity of IS using the modified Rankin Scale in atrial fibrillation patients receiving prophylaxis with DOACs vs LAAC., Methods: A retrospective analysis was performed of consecutive patients undergoing LAAC at 8 centers who developed an IS (IS LAAC ) compared with contemporaneous consecutive patients who developed IS during treatment with DOACs (IS DOAC ). The primary outcome was disabling/fatal stroke (modified Rankin Scale 3-5) at discharge and 3 months later., Results: Compared with IS DOAC patients (n = 322), IS LAAC patients (n = 125) were older (age 77.2 ± 13.4 years vs 73.1 ± 11.9 years; P = 0.002), with higher HAS-BLED scores (3.0 vs 2.0; P = 0.004) and more frequent prior bleeding events (54.4% vs 23.6%; P < 0.001), but similar CHA 2 DS 2 -VASc scores (5.0 vs 5.0; P = 0.28). Strokes were less frequently disabling/fatal with IS LAAC than IS DOAC at both hospital discharge (38.3% vs 70.3%; P < 0.001) and 3 months later (33.3% vs 56.2%; P < 0.001). Differences in stroke severity persisted after propensity score matching. By multivariate regression analysis, IS LAAC was independently associated with fewer disabling/fatal strokes at discharge (OR: 0.22; 95% CI: 0.13-0.39; P < 0.001) and 3 months (OR: 0.25; 95% CI: 0.12-0.50; P < 0.001), and fewer deaths at 3 months (OR: 0.28; 95% CI: 0.12-0.64; P < 0.001)., Conclusions: Ischemic strokes in patients with atrial fibrillation are less often disabling or fatal with LAAC than DOAC prophylaxis., Competing Interests: Funding Support and Author Disclosures Dr Turagam has served as a consultant for Biosense Webster and Sanofi. Dr Nair has served as a consultant for and receives honoraria for speaking engagements from Boston Scientific, Johnson and Johnson, and Medtronic. Dr Doshi has served as a consultant to Boston Scientific, Biosense Webster, and Abbott Vascular. Dr Valderrabano has received scientific research support from and served as a consultant to Circa; has received research support from and served as a consultant to Biosense Webster; and has served as a consultant to Abbott. Dr Dukkipati has received payment for Farapulse acquisition from Boston Scientific; and has equity in Manual Surgical Sciences. Dr Natale has served as a consultant for Abbott, Baylis, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. Dr Reddy has served as an unpaid consultant to Boston Scientific; unrelated to this paper, he has served as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, Anumana, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, and Valcare; unrelated to this work, has served as a consultant for Abbott, AtriAN, Biosense Webster, BioTel Heart, Biotronik, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, Gore and Associates, Impulse Dynamics, Medtronic, Novartis, Philips, and Pulse Biosciences; and has equity in DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study is to monitor, identify, and compare the adverse events (AEs) related to tenecteplase and alteplase, with the objective of exploring the potential safety of tenecteplase for acute ischemic stroke (AIS) and guiding its use to enhance patient safety., Methods: In order to evaluate the disproportionality of AEs associated with tenecteplase and alteplase in real-world data, four algorithms (ROR, PRR, BCPNN, EBGM) were utilized as measures to detect signals of AEs related to both drugs. Subsequently, Breslow-Day statistical analysis was applied to compare the RORs of the main system organ classes (SOCs) and key preferred terms (PTs) between tenecteplase and alteplase., Results: A statistical analysis was performed utilizing data gleaned from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, encompassing 19,514,140 case reports from 2004Q1 to 2023Q1. There were 1,004 cases where tenecteplase was reported as the primary suspected (PS) and 2,363 tenecteplase-related adverse drug reactions (ADRs) at the PTs level were identified, the two data of alteplase were 10,945 and 25,266, respectively. The occurrence of drug-induced ADRs was analyzed across 27 organ systems, The analysis revealed several expected ADRs, such as Haemorrhage, Hypersensitivity which were consistent with the two drug-labels. It is of note that the signal strengths of 'death,' 'ventricular fibrillation,' 'cardiogenic shock' and 'pneumonia aspiration' at the PT level were markedly higher for tenecteplase than for alteplase, whereas the signal strength of 'angioedema' at the PT level was significantly higher for alteplase in comparison to tenecteplase. Additionally, unexpected significant ADRs associated with ocular adverse reactions and pneumonia aspiration at the PT level were identified, indicating potential AEs not currently mentioned in the drug instructions., Conclusion: This study identified and compared signals of ADRs associated with tenecteplase and alteplase, although tenecteplase is as effective as alteplase and has advantages such as ease of use and affordability, it cannot replace alteplase in the treatment of AIS until its safety profile is fully recognized. Additionally, previously unreported ocular ADRs and pneumonia were identified, providing valuable insights into the relationship between ADRs and the use of these thrombolytic drugs. These findings underscore the importance of continuous monitoring and effective detection of AEs to ultimately enhance the safety of AIS patients undergoing thrombolytic therapy.

Aims: The study aimed to estimate the cost-effectiveness of CYP2C19 genotype-guided antiplatelet therapy using cilostazol and ticagrelor as an alternative to clopidogrel, compared to conventional antiplatelet therapy with clopidogrel and aspirin., Methods: A 90-day decision tree and 30-year Markov model were employed to assess the costs and quality-adjusted life years (QALYs) of personalized antiplatelet therapy for patients with minor ischemic stroke and high-risk transient ischemic attack, compared to conventional antiplatelet therapy in the Chinese healthcare system. The primary outcome was the incremental cost-effectiveness ratio (ICER). The data sources included clinical trials, published literature, official documents and local prices. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to confirm the robustness of the findings., Results: The base-case analysis indicated that the CYP2C19 genotype-guided antiplatelet strategy was cost-effective, and cilostazol group and ticagrelor group yielded an ICER of 3327.40 US dollars (USD)/QALY and 3426.92 USD/QALY, respectively, which were less than threshold. The one-way sensitivity analysis showed the results were robust, where the most sensitive parameter was the disability distribution in the modified Rankin scale 3-5. The probabilistic analysis showed that the CYP2C19 genotype-guided antiplatelet therapy with either cilostazol or ticagrelor was 100% cost-effective under the willingness-to-pay threshold., Conclusions: CYP2C19 genotype-guided antiplatelet therapy using cilostazol and ticagrelor as an alternative to clopidogrel appeared to be more cost-effective than conventional antiplatelet therapy for acute minor ischemic stroke and high-risk transient ischemic attack patients over 30 years in China., (© 2023 British Pharmacological Society.)

Objectives: To investigate the oral anticoagulants (OACs) use after acute ischemic stroke (AIS) and prognosis of patients with atrial fibrillation (AF)., Methods: This was a real-world follow-up research of AIS patients with AF admitted to 5 hospitals in northwestern China. We visited these individuals every 6 months to check the type, dosage of OACs, and to record IS recurrence, bleeding, and death events and modified Rankin Scale (mRS) scores until December 2022. When one of the following occurring first was endpoint: IS recurrence, death or study end. Patients were divided into continuous anticoagulation group and non-continuous anticoagulation group based on whether they continued to take OACs from the moment they were discharged until the endpoint. We further analyzed the association between anticoagulation persistence and outcomes., Results: Among all 250 patients with OACs indication, 147 patients (58.8 %) received OACs at discharge. Only 37.9 % of patients (39/103) started OACs after discharge. Of the 147 patients treated with OACs, 21.8 % (32/147) discontinued anticoagulation after discharge. 239 of the 250 patients had completed the median 40-month follow-up with 91 patients in continuous anticoagulation group and 148 patients in non-continuous anticoagulation group. In the multivariate COX regression, non-continuous anticoagulation was an independent risk factor for poor prognosis (mRS>2) in AIS patients with AF (1.452[1.011, 2.086], p = 0.043)., Conclusions: This study revealed an upward trend in the use rate of OACs, but low OACs rates that meet guideline-based criteria and low anticoagulation persistence in AF patients after AIS in the northwestern China. Discontinuous anticoagulation was associated with an increased risk of poor prognosis in these patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials., Methods: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke., Results: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001)., Conclusion: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: The benefit of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) and intermediate stroke risk is debated. In a nationwide Norwegian cohort with a non-sex CHA2DS2-VASc risk score of one, this study aimed to investigate (i) stroke and bleeding risk in AF patients with and without OAC treatment, and (ii) the risk of stroke in non-anticoagulated individuals with and without AF., Methods: A total of 1 118 762 individuals including 34 460 AF patients were followed during 2011-18 until ischaemic stroke, intracranial haemorrhage, increased CHA2DS2-VASc score, or study end. One-year incidence rates (IRs) were calculated as events per 100 person-years (%/py). Cox regression models provided adjusted hazard ratios (aHRs [95% confidence intervals])., Results: Among AF patients, the ischaemic stroke IR was 0.51%/py in OAC users and 1.05%/py in non-users (aHR 0.47 [0.37-0.59]). Intracranial haemorrhage IR was 0.28%/py in OAC users and 0.19%/py in non-users (aHR 1.23 [0.88-1.72]). Oral anticoagulant use was associated with an increased risk of major bleeding (aHR 1.37 [1.16-1.63]) but lower risk of the combined outcome of ischaemic stroke, major bleeding, and mortality (aHR 0.57 [0.51-0.63]). Non-anticoagulated individuals with AF had higher risk of ischaemic stroke compared to non-AF individuals with the same risk profile (aHR 2.47 [2.17-2.81])., Conclusions: In AF patients at intermediate risk of stroke, OAC use was associated with overall favourable clinical outcomes. Non-anticoagulated AF patients had higher risk of ischaemic stroke compared to the general population without AF with the same risk profile., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Japanese version of high bleeding risk (J-HBR) criteria was domestically proposed to identify patients at HBR after percutaneous coronary intervention (PCI). The applicability of J-HBR on bleeding events has been validated, while whether J-HBR predicts ischemic events is uncertain. This bi-center registry included 904 patients with acute myocardial infarction (MI) undergoing primary PCI. Patients were stratified by the J-HBR major (1 point) and minor (0.5 point) criteria. Patients with J-HBR ≥ 1 point were diagnosed as having HBR. The primary endpoint was major adverse cardiovascular events (MACE), a composite of cardiovascular death, recurrent MI, and ischemic stroke, after discharge. Of the 904 patients, 451 (49.9%) had the J-HBR. The primary endpoint more frequently occurred in patients with J-HBR than in those without (10.9% vs. 4.9%, p < 0.001) during the median follow-up period of 522 days. Probability of MACE was progressively increased with the increase in the number of J-HBR major and minor criteria, in which severe anemia, severe chronic kidney disease, prior heart failure, peripheral artery disease, and prior ischemic stroke were identified as significant factors associated with MACE. In patients with acute MI undergoing PCI, the J-HBR criteria were predictive for ischemic outcomes after discharge, suggesting that the J-HBR criteria may be useful to identify patients at high bleeding and ischemic risks., (© 2023. Springer Nature Japan KK, part of Springer Nature.)

Patients with left ventricular assist devices (LVADs) receive anticoagulation to decrease the risk of thrombosis. Various circumstances require discontinuing anticoagulation in LVAD patients, but the risks entailed are not well defined. In a retrospective review of LVAD implantation procedures, we examined the effect of time off anticoagulation on thrombosis and mortality rates after implantation. An international normalized ratio ≤ 1.5 was used to screen for patients taken off anticoagulation. Patients were divided into three groups by the cumulative number of days off anticoagulation: no discontinuation, short-term discontinuation (< 30 days), and long-term discontinuation (≥ 30 days). Rates of ischemic stroke, pump thrombosis, and mortality were compared among groups. Of 245 patients who underwent LVAD implantation during the study, 70 (28.6%) were off anticoagulation during follow-up: 37 (15.1%) had short-term discontinuation (median, 11 days), and 33 (13.5%) had long-term discontinuation (median, 124 days). Patients with long-term discontinuation had a higher rate of ischemic stroke (adjusted hazard ratio 8.5, p = 0.001) and death (adjusted hazard ratio 3.9, p = 0.001). The three groups did not differ in pump thrombosis rate. We conclude that after LVAD implantation, discontinuing anticoagulation for ≥ 30 days is independently associated with an increased risk of ischemic stroke and death., (© 2022. The Japanese Society for Artificial Organs.)

Abstract: BACKGROUND: Stroke care guidelines recommend early mobilization of acute ischemic stroke patients, but there are sparse data regarding early mobilization of stroke patients receiving thrombolytic therapy. We developed the Providence Early Mobility for Stroke (PEMS) protocol to mobilize patients to their highest individual tolerance within 24 hours of stroke admission in 2010, and it has been in continuous use at our primary and comprehensive stroke centers for over a decade. In this study, we evaluated the PEMS protocol in all patients treated with intravenous alteplase without endovascular treatment. METHODS : This retrospective study includes 318 acute ischemic stroke patients treated with alteplase who were admitted to 2 urban stroke centers between January 2013 and December of 2017 and were mobilized with the PEMS protocol within 24 hours of receiving alteplase. Safety of PEMS was assessed by change in National Institutes of Health Stroke Scale at 24 hours by time first mobilized. Using multivariate and logistic regression models, we analyzed time first mobilized and 90-day modified Rankin scale (mRS). RESULTS : Median time first mobilized was 9 hours from administration of alteplase. For every hour delay in mobilization, the odds of being slightly or moderately disabled (mRS, 2-3) at 90 days increased by 7% (adjusted odds ratio, 1.07; P = .004), and the odds of being severely disabled or dead (mRS, 4-6) at 90 days increased by 7% (adjusted odds ratio, 1.07; P = .02). In addition, for every hour delay in mobilization, 24-hour National Institutes of Health Stroke Scale increased by 1.8%. DISCUSSION: Our results support that the PEMS protocol is safe, and possibly beneficial, for acute ischemic stroke patients treated with intravenous alteplase. Our protocol differs from other very early mobility protocols because it does not prescribe a "dose" of activity. Instead, each patient was mobilized to his/her individual highest degree as soon as it was safe to do so., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 American Association of Neuroscience Nurses.)

Background: The selection of appropriate treatments for Acute Ischemic Stroke (AIS), including Intravenous (IV) tissue plasminogen activator (tPA) and Mechanical thrombectomy, is a critical aspect of clinical decision-making. Timely treatment is essential, with recommended administration of therapies within 4.5 h of symptom onset. However, patients with unknown Time Since Stroke (TSS), are often excluded from thrombolysis, even if the stroke onset exceeds 6 h. Current clinical guidelines propose using multimodal Magnetic Resonance Imaging (MRI) to assess various mismatches., Methods: The review explores the significance of automatic methods based on Artificial Intelligence (AI) algorithms that utilize multiple MRI features to identify patients who are most likely to benefit from acute reperfusion therapies. These AI methods include TSS classification and patient selection for therapies in the late time window (>6 h) using MRI images to provide detailed stroke information., Results: The review discusses the challenges and limitations in the existing mismatch methods, which may lead to missed opportunities for reperfusion therapy. To address these limitations, AI approaches have been developed to enhance accuracy and support clinical decision-making. These AI methods have shown promising results, outperforming traditional mismatch assessments and providing improved sensitivity and specificity in identifying patients eligible for reperfusion therapies., Discussion: In summary, the integration of AI algorithms utilizing multiple MRI features has the potential to enhance accuracy, improve patient outcomes, and positively influence the decision-making process in AIS. However, ongoing research and collaboration among clinicians, researchers, and technologists are vital to realize the full potential of AI in optimizing stroke management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Purpose of Review: To review the evidence regarding stroke and recent myocardial infarction (MI), reduced left ventricular ejection fraction, left ventricular thrombus (LVT), and wall motion abnormalities (WMA)., Recent Findings: The risk of ischemic stroke associated with acute MI has been greatly reduced with reperfusion treatments that improved myocardium salvage. Acute ischemic stroke is an uncommon complication of diagnostic coronary angiography and percutaneous coronary intervention. For established LVT, anticoagulation is superior to antiplatelet medications to reduce the risk of ischemic stroke. The duration of anticoagulation should be at least 3 to 6 months. Direct oral anticoagulants have been used off-label in this context. In patients with low ejection fraction or WMA, there is no evidence that anticoagulation is superior to antiplatelet treatment in preventing ischemic stroke. In patients with ischemic stroke and recent MI (< 3 months), type of MI (STEMI or NSTEMI), timing, and location should be considered when deciding whether intravenous thrombolysis should be used for stroke treatment. Mechanical thrombectomy should be considered as a therapeutic alternative to intravenous thrombolysis in patients with acute ischemic stroke due to large-vessel occlusion and recent MI. Most guidelines regarding prevention of ischemic stroke in patients with these cardiac causes of stroke are derived from expert opinion. There is a need for high quality evidence to support stroke prevention treatments in these patients., (© 2023. The Author(s).)

Purpose: Guidelines recommend high-intensity statin treatment after ischemic stroke, but evidence is sparse on the effectiveness and safety of different statin treatment intensities. We examined effectiveness and safety outcomes among patients initiating high-intensity versus moderate-intensity statins after ischemic stroke., Methods: In this population-based new-user active-comparator cohort study, we used the Danish Stroke Registry, covering all Danish hospitals, to identify patients with a first-time ischemic stroke during 2012-2021. Using multiple Danish registries, patients who redeemed a statin prescription within 21 days after stroke admission were classified as high-intensity statin initiators or moderate-intensity statin initiators. Propensity score inverse probability of treatment weighting was used to balance patient characteristics. We used competing risk methods to compute 5 year risk differences (RDs) and Cox proportional hazards regression to compute 5 year hazard ratios (HRs) of stroke recurrence, myocardial infarction, heart failure, venous thromboembolism, and all-cause mortality (effectiveness outcomes) and diabetes, liver disease, and kidney disease (safety outcomes)., Results: High-intensity ( n  = 13,032) and moderate-intensity ( n  = 14,355) statin initiators were identified. Risks of most examined effectiveness outcomes were comparable between statin intensities. There was no clear association between statin intensity and stroke recurrence (RD: 0.8% [95% CI: 0.1, 1.4], HR: 1.08 [95% CI: 0.96, 1.22]). All-cause mortality was slightly reduced among high-intensity statin initiators (RD: -1.1% [95% CI: -0.1, -2.1], HR: 0.93 [95% CI: 0.85, 1.01]. Risks of most safety outcomes were comparable between statin intensities, but high-intensity statin use was associated with an increased risk of diabetes (RD: 1.2% [95% CI: 0.4, 1.9], HR: 1.10 [95% CI: 1.00, 1.21])., Discussion and Conclusion: Compared with initiation of moderate-intensity statins, initiation of high-intensity statins after ischemic stroke was associated with similar risks of most effectiveness and safety outcomes. However, mortality risk was reduced, and diabetes risk was increased., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FB, NS, HTS, BOE and EHP have nothing to declare. CHF owns stock in Novo Nordisk. KA was employed at Dept. of Clinical Epidemiology during the work with this manuscript, but he is now an employee of Novo Nordisk “A/S”. The Department of Clinical Epidemiology, Aarhus University Hospital, receives funding from private and public institutions as research grants administered by Aarhus University. None of these grants has any relation to the present study.

Objective: The effects of serotonin reuptake inhibition induced by antidepressants on ischemic stroke and its pathophysiology remain unclear despite the frequent use of antidepressants and high fatality of ischemic stroke. We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition., Design: Retrospective cohort study., Participants: The cohort consisted of older adult patients who were treated with antidepressants., Measurements: We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition using Korea's National Health Insurance System-Senior Cohort. Exposure to antidepressants was categorized by type (strong, intermediate, or weak serotonin reuptake inhibitors [SRIs]) and by the mean prescribed dose per day and treatment duration. The risk for the strong and intermediate SRIs group was compared with that of the weak SRIs group using a Cox proportional hazards regression model., Results: Of 97,411 were weak SRIs users, and 107,152 and 18,783 were users of strong and intermediate SRIs. The risk of ischemic stroke was 1.192- and 1.057-fold higher in strong and intermediate SRI users, respectively than in weak SRI users. Hazard ratios were increased in higher dose and shorter duration user groups. The risk increased 1.753-fold in strong SRI users with anticonvulsants and 1.387-fold in intermediate SRI users with PPIs., Conclusion: The use of strong and intermediate SRIs should be considered carefully in older adult patients, especially when high-dose antidepressants are prescribed even for a short duration., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Daily exposure to ambient air pollution is associated with stroke morbidity and mortality; however, the association between hourly exposure to air pollutants and risk of emergency hospital admissions for stroke and its subtypes remains relatively unexplored., Methods: We obtained hourly concentrations of fine particulate matter (PM 2.5 ), respirable particulate matter (PM 10 ), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), ozone (O 3 ), and carbon monoxide (CO) from the China National Environmental Monitoring Center. We conducted a time-stratified case-crossover study among 86 635 emergency hospital admissions for stroke across 10 hospitals in 3 cities (Jinhua, Hangzhou, and Zhoushan) in Zhejiang province, China, between January 1, 2016 and December 31, 2021. Using a conditional logistic regression combined with a distributed lag linear model, we estimated the association between hourly exposure to multiple air pollutants and risk of emergency hospital admissions for total stroke, ischemic stroke, hemorrhagic stroke, and undetermined type., Results: Hourly exposure to PM 2.5 , PM 10 , NO 2 , and SO 2 was associated with an increased risk of hospital admissions for total stroke and ischemic stroke. The associations were most pronounced during the concurrent hour of exposure and lasted for ≈2 hours. We found that the risk was more pronounced among male patients or those aged <65 years old., Conclusions: Our findings suggest that exposure to PM 2.5 , PM 10 , NO 2 , and SO 2 , but not CO and O 3 , is associated with emergency hospital admissions for total stroke or ischemic stroke shortly after exposure. Implementing targeted pollution emission reduction measures may have significant public health implications in controlling and reducing the burden of stroke., Competing Interests: Disclosures None.

Aim: To evaluate the effect of inclisiran therapy on parameters of lipid metabolism in hospitalized patients with acute ischemic stroke., Material and Methods: A prospective, observational, non-randomized study was performed. The study included 12 patients with acute ischemic stroke prescribed with a combination lipid-lowering therapy with inclisiran (284 mg as a single dose). At 15 days after the start of therapy, changes in blood lipid composition were assessed. For quantitative variables, median, maximum and minimum values were determined. The significance of differences between related samples in quantitative variables was assessed using the Mann-Whitney test., Results: Before the start of combination lipid-lowering therapy, total cholesterol (TC) was 7.33 mmol/l and low-density lipoprotein C (LDL-C) was 5.23 mmol/l. At 15 days after the start of inclisiran therapy, TC significantly decreased by 52.1 % and LDL-C decreased by 71.1 %. The proportion of patients who reached the LDL-C goal was 66.7 %. There were no adverse events considered by the investigators to be related with the therapy., Conclusion: The strategy of early administration of inclisiran (or its combination with a statin) in patients with ischemic stroke allows safe achievement of a significant reduction in LDL-C already in 15 days after the start of therapy.

Aims: Guidelines on the management of atrial fibrillation (AF) have evolved significantly during the past two decades, but the concurrent developments in real-life management and prognosis of AF are unknown. We assessed trends in the treatment and outcomes of patients with incident AF between 2007 and 2017., Methods and Results: The registry-based nationwide FinACAF (Finnish AntiCoagulation in Atrial Fibrillation) cohort covers all patients with AF in Finland from all levels of care. We determined the proportion of patients who were treated with oral anticoagulants (OACs) or rhythm control therapies, experienced an ischaemic stroke or bleeding event requiring hospitalization, or died within 1-year follow-up after AF diagnosis. We identified 206 909 patients (mean age 72.6 years) with incident AF. During the study period, use of OACs increased from 43.6 to 76.3%, and the increase was most evident in patients with at least moderate stroke risk. One-year mortality decreased from 13.3 to 10.6%, and the ischaemic stroke rate from 5.3 to 2.2%. The prognosis especially improved in patients over 75 years of age. Concurrently, a small increase in major bleeding events was observed. Use of catheter ablation increased continuously over the study period, but use of other rhythm-control therapies decreased after 2013., Conclusion: Stroke prevention with OACs in patients with incident AF improved considerably from 2007 to 2017 in Finland. This development was accompanied by decreasing 1-year mortality and the reduction of the ischaemic stroke rate by more than half, particularly among elderly patients, whereas there was only slight increase in severe bleeding events., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Anticoagulation significantly reduces the risk of ischaemic stroke in patients with atrial fibrillation (AF). There are a proportion of patients with known AF who remain off anticoagulation. Aims This study aims to retrospectively compare the baseline characteristics, treatments and functional outcomes between patients with ischaemic stroke and known AF based on their anticoagulation status., Methods: A single-centre, retrospective review of consecutive patients with an ischaemic stroke and a known history of AF was conducted., Results: Two hundred four patients with an ischaemic stroke had documented AF prior to the index admission, of which 126 were anticoagulated. Median admission National Institutes of Health Stroke Scale score was lower for anticoagulated patients, though not statistically significant (5.1 vs 7.0, P = 0.09). Median baseline modified Rankin score (mRS) did not significantly differ. Nonanticoagulated patients were more likely to have large vessel occlusions (37.2% vs 23.8%, P = 0.04) and more likely to receive intravenous thrombolysis (15.4% vs 1.6%, P < 0.01). There was no difference in rates of endovascular clot retrieval between groups (P > 0.05). Unfavourable functional outcome at 90 days (mRS ≥ 3) did not significantly differ between groups (P = 0.51). A total of 38.5% of nonanticoagulated patients had no documented reason for this. Of the patients who survived the index admission, 81.5% of patients who were not anticoagulated on admission received anticoagulation., Conclusions: Baseline anticoagulation was associated with milder stroke severity in ischaemic stroke patients with known AF. There was no significant difference in functional outcomes at 90 days between groups. Larger observational studies are required to further assess this cohort., (© 2023 Royal Australasian College of Physicians.)

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.)

Background: The risk-benefit balance of antithrombotic therapy administration for blunt cerebrovascular injuries (BCVI) patients with concomitant injuries at high risk for bleeding is an ongoing therapeutic conundrum for trauma clinicians. We performed a systematic review to assess the reported efficacy and safety of treatment in this population with respect to prevention of ischemic stroke and risk of hemorrhagic complications., Study Design: A systematic electronic literature search of MEDLINE, EMBASE, Cochrane Library, and Web of Science databases was performed from January 1, 1996 to December 31, 2021. Studies were included if they reported treatment-stratified clinical outcomes after antithrombotic therapy in BCVI patients with concomitant injuries at high risk of bleeding into a critical site. Data were extracted from selected studies by two independent reviewers, including the main outcomes of interest were BCVI-related ischemic stroke rates and rates of hemorrhagic complications., Results: Of the 5,999 studies reviewed, 10 reported on the effects of treating BCVI patients with concurrent traumatic injuries and were included for review. In the pooled data, among patients with BCVI and concomitant injury who received any form of antithrombotic therapy, the BCVI-related stroke rate was 7.6%. The subgroup of patients who did not receive therapy had an overall BCVI-related stroke rate of 34%. The total rate of hemorrhagic complications in the treated population was 3.4%., Conclusions: In BCVI patients with concomitant injuries at high risk for bleeding, antithrombotic use reduces the risk of ischemic strokes with a low reported risk of serious hemorrhagic complications., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Although tirofiban and endovascular thrombectomy have been widely used in the treatment of acute ischemic stroke (AIS) patients, the effectiveness of their combined application remains a subject of debate. This study aimed to assess the efficacy and safety of tirofiban in direct thrombectomy for AIS with anterior circulation vessel occlusion., Methods: A total of 204 patients undergoing direct thrombectomy between January 2020 and December 2021 for AIS with anterior circulation vessel occlusion from four hospitals were included in this study. Patients at high risk of reocclusion with severe atherosclerosis, those who achieved successful recanalization for ≥ 3 stent retriever passes, or those who underwent emergency stenting or balloon angioplasty for severe residual stenosis were treated with tirofiban. Following a low-dose intra-arterial bolus (0.25-1 mg) immediately after endovascular treatment, tirofiban was administered continuously through intravenous infusion (0.1 μg/kg/min) for 12-24 hours. The primary efficacy outcome was evaluated using the 90-day modified Rankin Scale score. The safety outcome was assessed using symptomatic intracerebral hemorrhage (sICH) and mortality rates., Results: The tirofiban group and nontirofiban group each included 102 patients. The favorable outcome rate in the tirofiban group was significantly higher than that in the nontirofiban group (53.9% vs 35.3%, p = 0.007). However, the sICH and 90-day mortality rates were lower in the tirofiban group, despite a lack of statistical significance (sICH: 15.7% vs 16.7%, p = 0.849; 90-day mortality: 16.67% vs 24.51%, p = 0.166). Finally, it was found that older patients (> 72 years), male patients, patients with admission National Institutes of Health Stroke Scale scores > 14, patients with a time from onset to reperfusion > 327 minutes, and patients with a medical history of diabetes tend to benefit from tirofiban treatment., Conclusions: This study suggests that tirofiban combined with direct thrombectomy improves functional outcomes of AIS and reduces the 90-day mortality rate. Therefore, it could be considered as a suitable treatment option for AIS patients with anterior circulation vessel occlusion.

Background: Use of combinations of long-acting β 2 agonists/long-acting muscarinic antagonists (LABA/LAMA) in patients with chronic obstructive pulmonary disease (COPD) is increasing. Nevertheless, existing evidence on cardiovascular risk associated with LABA/LAMA versus another dual combination, LABA/inhaled corticosteroids (ICS), was limited and discrepant., Aim: The present cohort study aimed to examine comparative cardiovascular safety of LABA/LAMA and LABA/ICS with a target trial emulation framework, focusing on dual fixed-dose combination (FDC) therapies., Methods: We identified patients with COPD who initiated LABA/LAMA FDC or LABA/ICS FDC from a nationwide Taiwanese database during 2017-2020. The outcome of interest was a hospitalized composite cardiovascular events of acute myocardial infarction, unstable angina, heart failure, cardiac dysrhythmia, and ischemic stroke. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for composite and individual cardiovascular events after matching up to five LABA/LAMA FDC initiators to one LABA/ICS FDC initiator using propensity scores (PS)., Results: Among 75,926 PS-matched patients, use of LABA/LAMA FDC did not show a higher cardiovascular risk compared to use of LABA/ICS FDC, with a HR of 0.89 (95% CI, 0.78-1.01) for the composite events, 0.80 (95% CI, 0.61-1.05) for acute myocardial infarction, 1.48 (95% CI, 0.68-3.25) for unstable angina, 1.00 (95% CI, 0.80-1.24) for congestive heart failure, 0.62 (95% CI, 0.37-1.05) for cardiac dysrhythmia, and 0.82 (95% CI, 0.66-1.02) for ischemic stroke. The results did not vary substantially in several pre-specified sensitivity and subgroup analyses., Conclusion: Our findings provide important reassurance about comparative cardiovascular safety of LABA/LAMA FDC treatment among patients with COPD., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Lipid paradox of low LDL-C may cause physicians to be reluctant to use statins in acute ischemic stroke (AIS) patients with low LDL-C levels at admission., Objective: This study investigated the association between LDL-C levels and early vascular outcomes and assessed the potential interaction effect between LDL-C and statin pretreatment on early outcomes., Patients and Methods: This was a study of a prospective, multicenter, registry of AIS patients with admission LDL-C. The subjects were divided into 3 groups according to LDL-C levels: low LDL-C (≤100 mg/dL); intermediate LDL-C (>100, <130 mg/dL); and high LDL-C (≥130 mg/dL). The primary early vascular outcome was a composite of stroke (ischemic or hemorrhagic), myocardial infarction and all-cause mortality within 3 months. The associations of LDL-C levels as a continuous variable and the risks of primary outcome using Cox proportional hazards models with restricted cubic splines were explored., Results: A total of 32,505 patients (age, 69 ± 12; male, 58.6%) were analyzed. The 3 groups showed significant differences in the 3-month primary outcome, with highest events in the low LDL-C group; after adjustment, no significant associations with the 3-month primary outcome remained. U-shaped nonlinear relationships of LDL-C levels with the 3-month primary outcome were observed (P non-linearity <0.001), with substantial relationships in the no pretreatment subgroup., Conclusions: The relationships between admission LDL-C levels and early outcomes are complex but appear to be paradoxical in patients with low LDL-C and no statin pretreatment. The results suggest that statin pretreatment might offset the paradoxical response of low LDL-C on early vascular outcomes. Further study would be warranted., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Background: Atrial fibrillation (AF) and congestive heart failure often coexist due to their shared risk factors leading to potential worse outcome, particularly cerebrovascular events. The aims of this study were to calculate the rates of ischemic and severe bleeding events in ischemic stroke patients having both AF and reduced ejection fraction (rEF) (⩽40%), compared to ischemic stroke patients with AF but without rEF., Methods: We performed a retrospective analysis that drew data from prospective studies. The primary outcome was the composite of either ischemic (stroke or systemic embolism), or hemorrhagic events (symptomatic intracranial bleeding and severe extracranial bleeding)., Results: The cohort for this analysis comprised 3477 patients with ischemic stroke and AF, of which, 643 (18.3%) had also rEF. After a mean follow-up of 7.5 ± 9.1 months, 375 (10.8%) patients had 382 recorded outcome events, for an annual rate of 18.0%. While the number of primary outcome events in patients with rEF was 86 (13.4%), compared to 289 (10.2%) for the patients without rEF; on multivariable analysis rEF was not associated with the primary outcome (OR 1.25; 95% CI 0.84-1.88). At the end of follow-up, 321 (49.9%) patients with rEF were deceased or disabled (mRS ⩾3), compared with 1145 (40.4%) of those without rEF; on multivariable analysis, rEF was correlated with mortality or disability (OR 1.35; 95% CI 1.03-1.77)., Conclusions: In patients with ischemic stroke and AF, the presence of rEF was not associated with the composite outcome of ischemic or hemorrhagic events over short-term follow-up but was associated with increased mortality or disability.

Background: Data on the impact of competing stroke etiologies in stroke patients with atrial fibrillation (AF) are scarce., Methods: We used prospectively obtained data from an observational registry (Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-(NOACISP)-LONGTERM) of consecutive AF-stroke patients treated with oral anticoagulants. We compared the frequency of (i) the composite outcome of recurrent ischemic stroke (IS), intracerebral hemorrhage (ICH) or all-cause death as well as (ii) recurrent IS alone among AF-stroke patients with versus without competing stroke etiologies according to the TOAST classification. We performed cox proportional hazards regression modeling adjusted for potential confounders. Furthermore, the etiology of recurrent IS was assessed., Results: Among 907 patients (median age 81, 45.6% female), 184 patients (20.3%) had competing etiologies, while 723 (79.7%) had cardioembolism as the only plausible etiology. During 1587 patient-years of follow-up, patients with additional large-artery atherosclerosis had higher rates of the composite outcome (adjusted HR [95% CI] 1.64 [1.11, 2.40], p  = 0.017) and recurrent IS (aHR 2.96 [1.65, 5.35 ], p  < 0.001), compared to patients with cardioembolism as the only plausible etiology. Overall 71 patients had recurrent IS (7.8%) of whom 26.7% had a different etiology than the index IS with large-artery-atherosclerosis (19.7%) being the most common non-cardioembolic cause., Conclusion: In stroke patients with AF, causes other than cardioembolism as competing etiologies were common in index or recurrent IS. Concomitant presence of large-artery-atherosclerosis seems to indicate an increased risk for recurrences suggesting that stroke preventive means might be more effective if they also address competing stroke etiologies in AF-stroke patients., Clinical Trial Registration: NCT03826927.

Introduction: Ischaemic stroke patients with atrial fibrillation (AF) are at high risk of stroke recurrence despite oral anticoagulation therapy. Patients with cardiovascular comorbidities may take both antiplatelet and oral anticoagulation therapy (OAC/AP). Our study aims to evaluate the safety and efficacy of OAC/AP therapy as secondary prevention in people with AF and ischaemic stroke., Patients and Methods: We performed a post-hoc analysis of pooled individual data from multicenter prospective cohort studies and compared outcomes in the OAC/AP cohort and patients on DOAC/VKA anticoagulation alone (OAC cohort). Primary outcome was a composite of ischaemic stroke, systemic embolism, intracranial bleeding, and major extracranial bleeding, while secondary outcomes were ischaemic and haemorrhagic events considered separately. A multivariable logistic regression analysis was performed to identify independent predictors for outcome events. To compare the risk of outcome events between the two cohorts, the relation between the survival function and the set of explanatory variables were calculated by Cox proportional hazard models and the results were reported as adjusted hazard ratios (HR). Finally another analysis was performed to compare the overall risk of outcome events in both OAC/AP and OAC cohorts after propensity score matching (PSM)., Results: During a mean follow-up time of 7.5 ± 9.1 months (median follow-up time 3.5 months, interquartile range ±3), 2284 stroke patients were on oral anticoagulants and 215 were on combined therapy. The multivariable model demonstrated that the composite outcome is associated with age (OR: 1.03, 95% CI: 1.01-1.04 for each year increase) and concomitant antiplatelet therapy (OR: 2.2, 95% CI: 1.48-3.27), the ischaemic outcome with congestive heart failure (OR: 1.55, 95% CI: 1.02-2.36) and concomitant antiplatelet therapy (OR: 1.93, 95% CI: 1.19-3.13) and the haemorrhagic outcome with age (OR: 1.03, 95% CI: 1.01-1.06 for each year increase), alcoholism (OR: 2.15, 95% CI: 1.06-4.39) and concomitant antiplatelet therapy (OR: 2.22, 95% CI: 1.23-4.02). Cox regression demonstrated a higher rate of the composite outcome (hazard ratio of 1.93 [95% CI, 1.35-2.76]), ischaemic events (HR: 2.05 [95% CI: 1.45-2.87]) and bleeding outcomes (HR: 1.90 [95% CI, 1.06-3.40]) in OAC/AP cohort. After PSM analysis, the composite outcome remained more frequent in people treated with OAC + AP (RR: 1.70 [95% CI, 1.05-2.74])., Discussion: Secondary prevention with combination of oral anticoagulant and antiplatelet therapy after ischaemic stroke was associated with worse outcomes in our cohort., Conclusion: Further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischaemic stroke in patients with atrial fibrillation.

The acute ischemic stroke therapy of choice is the application of Alteplase, a drug containing the enzyme tissue-type plasminogen activator (tPa) which rapidly destabilizes blood clots. A central hallmark of stroke pathology is blood-brain barrier (BBB) breakdown associated with tight junction (TJ) protein degradation, which seems to be significantly more severe under therapeutic conditions. The exact mechanisms how tPa facilitates BBB breakdown are not entirely understood. There is evidence that an interaction with the lipoprotein receptor-related protein 1 (LRP1), allowing tPa transport across the BBB into the central nervous system, is necessary for this therapeutic side effect. Whether tPa-mediated disruption of BBB integrity is initiated directly on microvascular endothelial cells or other brain cell types is still elusive. In this study we could not observe any changes of barrier properties in microvascular endothelial cells after tPa incubation. However, we present evidence that tPa causes changes in microglial activation and BBB breakdown after LRP1-mediated transport across the BBB. Using a monoclonal antibody targeting the tPa binding sites of LRP1 decreased tPa transport across an endothelial barrier. Our results indicate that limiting tPa transport from the vascular system into the brain by coapplication of a LRP1-blocking monoclonal antibody might be a novel approach to minimize tPa-related BBB damage during acute stroke therapy., (© 2023 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

Objective: To explore the association between the use of metformin and the risk of ischemic stroke in patients with type 2 diabetes., Methods: A prospective cohort study was designed from the Fangshan family cohort in Beijing. According to metformin use at baseline, 2 625 patients with type 2 diabetes in Fangshan, Beijing were divided into metformin group or non-metformin group and the incidence of ischemic stroke between the different groups during follow-up was estimated and compared by Cox proportional hazard regression model. The participants with metformin were first compared with all the parti-cipants who did not use metformin, and then were further compared with those who did not use hypoglycemic agents and those who used other hypoglycemic agents., Results: The patients with type 2 diabetes were with an average age of (59.5±8.7) years, and 41.9% of them were male. The median follow-up time was 4.5 years. A total of 84 patients developed ischemic stroke during follow-up, with a crude incidence of 6.4 (95% CI : 5.0-7.7) per 1 000 person-years. Among all the participants, 1 149 (43.8%) took metformin, 1 476 (56.2%) were metformin non-users, including 593 (22.6%) used other hypoglycemic agents, and 883 (33.6%) did not use any hypoglycemic agents. Compared with metformin non-users, the Hazard ratio ( HR ) for ischemic stroke in metformin users was 0.58 (95% CI : 0.36-0.93; P = 0.024). Compared with other hypoglycemic agents, HR was 0.48 (95% CI : 0.28-0.84; P < 0.01); Compared with the group without hypoglycemic agents, HR was 0.65 (95% CI : 0.37-1.13; P =0.13). The association between metformin and ischemic stroke was statistically significant in the patients ≥ 60 years old compared with all the metformin non-users and those who used other hypoglycemic agents ( HR : 0.48, 95% CI : 0.25-0.92; P < 0.05). Metformin use was associated with a lower incidence of ischemic stroke in the patients with good glycemic control (0.32, 95% CI : 0.13-0.77; P < 0.05). In the patients with poor glycemic control, and the association was not statistically significant ( HR : 0.97, 95% CI : 0.53-1.79; P >0.05). There was an interaction between glycemic control and metformin use on incidence of ischemic stroke ( P interaction < 0.05). The results of the sensitivity analysis were consistent with the results in the main analysis., Conclusion: Among patients with type 2 diabetic in rural areas of northern China, metformin use was associated with lower incidence of ischemic stroke, especially in patients older than 60 years. There was an interaction between glycemic control and metformin use in the incidence of ischemic stroke.

Context: The effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic/hemorrhagic stroke and transient ischemic attacks (TIA) in type 2 diabetes mellitus (T2DM) remains undetermined., Objective: To pool effects of GLP-1RAs on adverse cerebrovascular outcomes and investigate impact of baseline variables on these effects., Methods: PubMed, Embase, Web of Science, Cochrane Library, and clinical trial registry websites were searched for randomized controlled trials (RCTs) ≥24 weeks duration in adults with T2DM (PROSPERO: CRD42022331547). Adjudicated cerebrovascular events in GLP-1RA treatment vs control arms were pooled together to calculate risk ratios (RR) using fixed-effects model. Subgroup analysis was performed based on individual drugs, treatment duration, and baseline patient characteristics. Quality of evidence was assessed using GRADE framework., Results: We identified 28 RCTs involving 74 148 patients (57% male; median [range], age 58 [52-67] years, BMI 32 [25.4-37.2] kg/m2, T2DM duration 9 [3.5-15.4] years, treatment duration 52 [24-259] weeks). GLP-1RA use in T2DM was associated with significantly decreased risk of adverse cerebrovascular outcomes vs placebo/active comparator (RR, 0.83; 95% CI, 0.76-0.91; I2 = 0%). Pooling data from cardiovascular outcome trials (n = 8), GLP-1RA treatment vs placebo was associated with reduced risk of nonfatal stroke (RR, 0.85; 95% CI, 0.76-0.94; I2 = 0%) but not fatal stroke (RR, 0.80; 95% CI, 0.61-1.05; I2 = 0%). GLP-1RA use was associated with reduced risk of ischemic stroke (RCTs = 12; RR, 0.73; 95% CI, 0.60-0.89; I2 = 0%), composite of ischemic stroke/TIA (RCTs = 16; RR, 0.76; 95% CI, 0.65-0.90; I2 = 0%), but not hemorrhagic stroke (RCTs = 3; RR, 0.92; 95% CI, 0.51-1.64; I2 = 0%). Treatment benefits differed according to baseline eGFR and diabetes duration (P interaction < .1). Benefits were statistically significant for dulaglutide, subcutaneous/oral semaglutide (P < .05). Sensitivity analysis, excluding shorter-acting lixisenatide, eliminated the heterogeneity between individual GLP-1RA effects., Conclusion: GLP-1RAs, particularly longer-acting formulations, reduced ischemic cerebrovascular events in T2DM. Observed benefits were significantly higher in patients with shorter T2DM duration and higher eGFR., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A comprehensive evaluation is necessary to identify the etiologic factors in order to select optimal stroke-prevention measures. Atrial fibrillation is one of the most important stroke causes. Although anticoagulant therapy is the treatment of choice for patients with nonvalvular atrial fibrillation, it should not be considered uniformly to treat all patients given the high mortality associated with anticoagulant-related hemorrhages. The authors propose a risk-stratified individualized approach for stroke prevention in patients with nonvalvular atrial fibrillation by considering nonpharmacologic approaches for patients at high hemorrhage risk or otherwise unsuitable for lifelong anticoagulation., Competing Interests: Disclosure T. Ranasinghe: no disclosures. M.E. Gurol: Neurocardiology section editor, American Heart Association Stroke journal; Chair, WSO Task Force on Cerebral Small Vessel Diseases and Vascular Cognitive Impairment; Member, WSO Brain & Heart Task Force; M.E.G.’s hospital received research funding from AVID, Pfizer, and Boston Scientific Corporation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Tenecteplase administered to patients with ischaemic stroke in a mobile stroke unit (MSU) has been shown to reduce the perfusion lesion volumes and result in ultra-early recovery. We now seek to assess the cost-effectiveness of tenecteplase in the MSU., Methods: A within-trial (TASTE-A) economic analysis and a model-based long-term cost-effectiveness analysis were performed. This post hoc within-trial economic analysis utilised the patient-level data (intention to treat, ITT) prospectively collected over the trial to calculate the difference in both healthcare costs and quality-adjusted life years (QALYs, estimated from modified Rankin scale score). A Markov microsimulation model was developed to simulate the long-term costs and benefits., Results: In total, there were 104 patients with ischaemic stroke randomised to tenecteplase ( n  = 55) or alteplase ( n  = 49) treatment groups, respectively in the TASTE-A trial. The ITT-based analysis showed that treatment with tenecteplase was associated with non-signficantly lower costs (A$28,903 vs A$40,150 ( p  = 0.056)) and greater benefits (0.171 vs 0.158 ( p  = 0.457)) than that for the alteplase group over the first 90 days post the index stroke. The long-term model showed that tenecteplase led to greater savings in costs (-A$18,610) and more health benefits (0.47 QALY or 0.31 LY gains). Tenecteplase-treated patients had reduced costs for rehospitalisation (-A$1464), nursing home care (-A$16,767) and nonmedical care (-A$620) per patient., Conclusions: Treatment of ischaemic stroke patients with tenecteplase appeared to be cost-effective and improve QALYs in the MSU setting based on Phase II data. The reduced total cost from tenecteplase was driven by savings from acute hospitalisation and reduce need for nursing home care.

Intravenous thrombolysis (IVT) treatment with alteplase (rtPA) is an essential part of the routine treatment of patients with ischemic stroke since its introduction in the late 1990s. Rapid treatment is of essential importance. For patients with an unclear time window, various mismatch concepts have been established to identify salvageable brain tissue prior to IVT. Numerous official contraindications for rtPA are not evidence-based; for example, current data from observational studies show that systemic thrombolytic treatment is possible even in patients receiving direct oral anticoagulant (DOAC) treatment. Tenecteplase (TNK) is an alternative thrombolytic agent with some pharmacologic advantages. The most recent guidelines indicate that TNK is particularly advantageous over rtPA in patients treated in combination with endovascular stroke therapy (EST). The combination of IVT and EST should primarily be performed in the 4.5‑h time window in patients without contraindications; in the later time window EST alone is conceivable if it can be performed without delay., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Atrial fibrillation (AF) associates with higher Alzheimer's disease (AD) and vascular dementia risks but the clinical implications have been scarcely investigated. We examined the association between AD or vascular dementia and adverse outcomes in AF patients., Methods: Cohort study between January 2000 and 2017. AF patients were divided into two groups according to vascular dementia or AD, and balanced using propensity score matching (PSM). During 4-years of follow-up, incident intracranial hemorrhages (ICH), the composite of ischemic stroke/transient ischemic attack (TIA), hospitalizations, and all-cause deaths, were recorded., Results: Two thousand three hundred seventy-seven AF patients with dementia (1225 with vascular dementia, and 1152 with AD) were identified. Following a PSM, 615 patients were included in each cohort (i.e., 1:1) and all variables were well-matched. After PSM, 22 (3.6%) patients with vascular dementia and 55 (8.1%) patients with AD had incident ICH during follow-up (hazard ratio [HR]: 2.22, 95% confidence interval [CI]: 1.33-3.70, log-rank p = 0.002). Overall, 237 (38.5%) patients with vascular dementia and 193 (31.4%) patients with AD, developed an ischemic stroke/TIA. The risk of ischemic stroke/TIA was 1.32-fold higher in vascular dementia (HR: 1.32, 95% CI: 1.09-1.59, log-rank p = 0.003). The risk of rehospitalization (HR: 1.14, 95% CI: 1.01-1.31), and mortality (HR: 1.25, 95% CI: 1.01-1.58) were also higher among AF patients with vascular dementia compared to AD., Conclusions: The two forms of dementia in AF patients are associated with different prognosis, with AD being associated with a higher risk of ICH, and vascular dementia with a higher risk of stroke/TIA, hospitalization, and mortality., (© 2023 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Aims: The prognosis of patients with atrial fibrillation (AF) and ischemic stroke while taking oral anticoagulation is poorly understood. This study aimed to characterize the outcomes of patients following a stroke event while on oral anticoagulation., Methods and Results: Individual participant data from five pivotal randomized trials of antithrombotic therapy in AF were used to assess the outcomes of patients with a post-randomization ischemic stroke while on study medication (warfarin, standard-, or lower-dose direct oral anticoagulant regimen) during trial follow-up. The primary outcome was recurrent ischemic stroke after the first post-randomization ischemic stroke. The primary analysis included 1163 patients with a first post-randomization ischemic stroke while on study medication (median age 73 years, 39.3% female, 35.4% history of stroke before trial enrollment). During a median continued follow-up of 337 days, 74 patients had a recurrent ischemic stroke [cumulative incidence at 1 year: 7.0%, 95% confidence interval (CI) 5.2%-8.7%]. The cumulative incidence of mortality at 3 months after stroke was 12.4% (95% CI 10.5%-14.4%). Consistent results for the incidence of recurrent ischemic stroke at 1 year were obtained in an analysis accounting for the competing risk of death (6.2%, 95% CI 4.8%-7.9%) and in a landmark analysis excluding the first 2 weeks after the index stroke and only including patients without permanent study drug discontinuation since then (6.8%, 95% CI 4.6%-8.9%)., Conclusion: Patients with AF and ischemic stroke while on oral anticoagulation are at increased risk of recurrent ischemic stroke and death. These patients currently have an unmet medical need., Competing Interests: Conflict of interest A.P.B. has nothing to disclose. S.H.H. reports consulting and lecture fees from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, and Pfizer. J.W.E. reports institutional research grants and honoraria from AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline, Janssen, and Sanofi. A.P.C. has nothing to disclose. R.P.G. reports honoraria for CME programs and lectures from Artivion, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Janssen, Pfizer, SAJA Pharmaceuticals, Samsung, and Servier; grants and personal fees from Amgen, Daiichi Sankyo, and Merck; and grants from Anthos Therapeutics outside the submitted work. C.B.G. reports personal fees from Bayer AG and Boston Scientific; grants and personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Janssen, and Pfizer; grants from Daiichi Sankyo during the conduct of the study; personal fees from AbbVie, Espero, Medscape, Medtronic Inc., Merck, the National Institutes of Health, Novo Nordisk, Roche, Rho Pharmaceuticals, CeleCor, Correvio, Philips, Abiomed, and Anthos Therapeutics; grants from Akros, AstraZeneca, the US Food and Drug Administration, GlaxoSmithKline, Medtronic Foundation, and Apple; and grants and personal fees from Novartis and The Medicines Company outside the submitted work. J.H. reports salary support from T32 training grant T32HL069749. Z.H. reports lecture fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Roche Diagnostics and consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche Diagnostics. He receives research support from the Swedish Society for Medical Research (S17–0133), the Swedish Heart-Lung Foundation (20200722), and Uppsala University Hospital, Sweden.. D.A.M. reports being a member of the Thrombolysis in Myocardial Infarction (TIMI) Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc., Daiichi Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals Inc., Roche, Siemens Healthcare Diagnostics Inc., The Medicines Company, and Zora Biosciences. M.R.P. reports research grants from Bayer AG, Janssen, HeartFlow, and the National Heart, Lung, and Blood Institute (NHBLI) and advisory board/consulting from Bayer AG, Janssen, and Novartis. D.J.S. reports institutional research funding from the Swiss Heart Foundation, the Swiss National Science Foundation, the Bangerter-Rhyner Foundation, and Portola/Alexion Pharmaceuticals. A.S. reports research support from the National Institutes of Health (NIH) [National Institute of Neurological Disorders and Stroke (NINDS) U01NS102289 and National Institute on Aging (NIA) UF1NS120871), Canadian Institutes for Health Research, Heart and Stroke Foundation of Canada, and the Marta and Owen Boris Foundation. He has additionally received research support from Daiichi Sankyo, Bristol Myers Squibb, Bayer AG, and Servier Canada, as well as advisory/speakers bureau honoraria from Daiichi Sankyo, Bayer AG, Takeda Pharmaceutical Company, and Servier Canada. L.W. reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics, and Merck & Co and consulting fees from Abbott. He holds two patents involving GDF-15 licensed to Roche Diagnostics (EP2047275B1 and US8951742B2). Q.Y. has nothing to disclose. S.J.C. reports institutional research grants and honoraria from Boehringer Ingelheim, Portola/Alexion Pharmaceuticals, Bristol Myers Squibb/Pfizer, Bayer AG, and Daiichi Sankyo., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Tenecteplase is a genetically engineered fibrinolytic with growing interest in the treatment of acute ischemic stroke. Compared to alteplase, tenecteplase is effective for neurologic improvement following ischemic stroke in patients with large vessel occlusions who are eligible for thrombectomy and for mild ischemic strokes with National Institutes of Health Stroke Scale of 0 to 5., Objective: The purpose of this study is to determine if safety outcomes are different in patients receiving tenecteplase and alteplase for acute ischemic stroke., Methods: This retrospective cohort reviewed all patients who received alteplase or tenecteplase from January 2019 to December 2020. Patients admitted before April 28, 2020, received alteplase intravenous bolus over 1 minute followed by an infusion over 1 hour, for a total of 0.9 mg/kg. Patients admitted after this date received tenecteplase 0.25 mg/kg as an intravenous bolus over 5 to 10 seconds. Any patient transferring from an outside facility was excluded. The primary outcome was major bleeding., Results: There was no significant difference in major bleeding between alteplase and tenecteplase (40 [18%] vs 21 [18.1%], P = 0.985). There was no significant difference in all-cause inpatient mortality for alteplase versus tenecteplase (10 [5%] vs 5 [4%], P = 0.934) or in adverse events between the groups (22 [9%] vs 14 [12%], P = 0.541) for alteplase and tenecteplase, respectively., Conclusions and Relevance: Tenecteplase had similar rates of major bleeding versus alteplase and may be a reasonable alternative in the treatment of acute ischemic stroke.

Purpose of Review: Atrial fibrillation (AF) is a major risk factor for systemic embolism and ischaemic stroke. Furthermore, AF-related strokes are associated with higher mortality, greater disability, longer hospital stays and lower rates of hospital discharge than strokes caused by other reasons. The aim of this review to summarise the existing evidence on the association of AF with ischemic stroke and provide insights on the pathophysiological mechanisms and the clinical management of patients with AF in order to reduce the burden of ischemic stroke., Recent Findings: Beyond Virchow's triad, several pathophysiological mechanisms associated with structural changes in the left atrium, which may precede the identification of AF, may contribute to the increased risk of arterial embolism in AF patients. Individualised thromboembolic risk stratification based on CHA 2 DS 2 -VASc score and clinically relevant biomarkers provides essential tool towards a personalised holistic approach in thromboembolism prevention. Anticoagulation remains the cornerstone of stroke prevention moving from vitamin K antagonists (VKA) to safer non-vitamin K direct oral anticoagulants in the majority of AF patients. Despite the efficacy and safety of oral anticoagulation, still the equilibrium between thrombosis and haemostasis in AF patients remains suboptimal and future directions in anticoagulation and cardiac intervention may provide novel treatment options in stroke prevention. This review summarises the pathophysiologic mechanisms of thromboembolism, aiming the current and potential future perspectives in stroke prevention in AF patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Direct oral anticoagulants (DOACs) are essential in ischemic stroke/systemic embolism (SE) prevention among patients with nonvalvular atrial fibrillation (NVAF). This study compared the risk of ischemic stroke/SE among patients with NVAF who discontinued DOACs following the first fill ("one-and-done") relative to patients who continued DOACs beyond the first fill ("continuers")., Methods: De-identified data from Symphony Health, an ICON plc Company, PatientSource ® , April 1, 2017 to October 31, 2020, were used to identify adults with NVAF initiated on DOACs (index date). Patients with only one DOAC claim during the 90-day landmark period starting on the index date were classified as one-and-done and the remaining as continuers. Inverse probability of treatment weighting was used to balance baseline characteristics in the cohorts. Time from the landmark period end to the first ischemic stroke/SE event or, among those without the event, to clinical activity or data end was compared between balanced cohorts using survival analysis., Results: Of patients initiating DOACs, 23.6% were classified as one-and-done users. After weighting was performed, 241,159 and 238,889 patients comprised the one-and-done and continuer cohorts, respectively. At 12 months of follow-up, the probability of ischemic stroke/SE was 1.44% in the one-and-done cohort and 1.00% in the continuer cohort [hazard ratio (95% confidence interval) 1.44 (1.34-1.54); p < 0.0001]. Results at earlier and later time points and in a sensitivity analysis with a 75-day landmark period were similar., Conclusion: A substantial proportion of patients were one-and-done DOAC users, which was associated with significantly higher risk of ischemic stroke/SE events. There is an unmet need to improve access and encourage continuous use of DOACs among patients with NVAF so that severe and fatal complications may be mitigated., (© 2023. The Author(s).)

Aims: The impact of adherence to oral anticoagulation has not been reported in terms of absolute risk, which would enhance patients' understanding and treatment adherence., Methods and Results: This retrospective cohort study analysed data from the National Health Insurance Database of Korea, from January 2010 to December 2018, on 84 227 patients with non-valvular atrial fibrillation (NVAF). The participants were analysed according to their overall adherence to oral anticoagulants (OACs) and further divided into four groups: non-vitamin K antagonist oral anticoagulant (NOAC) adherent, vitamin K antagonist (VKA) adherent, NOAC non-adherent, and VKA non-adherent. The incidence of ischaemic stroke, major bleeding, and death was compared between the four groups using risk difference, number needed to treat and number needed to harm. Among the participants, 50 178 were adherent to (OACs), while 34 049 were non-adherent. The incidence of major bleeding was higher in the adherent group (4.49%; 95% confidence interval, 4.11-4.85%) than in the non-adherent group (3.61%; 3.16-4.06%), and the incidence of ischaemic stroke was higher in the non-adherent group (7.68%; 7.08-8.33%) than in the adherent group (5.61%; 5.17-6.07%). In terms of risk difference, adherence to OACs increased the risk of major bleeding by 0.87% and decreased the risk of ischaemic stroke by 2.08%. This finding suggests that one additional major bleeding event occurred for every 115 adherent patients, and one additional ischaemic stroke event was prevented for every 48 adherent patients., Conclusion: The benefits of OAC adherence in NVAF patients for ischaemic stroke prevention exceeding the risk of bleeding are shown more clearly in terms of absolute risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: In randomized trials, direct oral anticoagulants (DOAC) were non-inferior to the vitamin-K-antagonist (VKA) warfarin in preventing stroke/embolism in patients with atrial fibrillation (AF). DOAC are substrates for P-glycoprotein (P-gp), CYP3A4 and CYP2C9. The activity of these enzymes is modulated by several drugs which might induce pharmacokinetic drug-drug interactions (DDI). Drugs affecting platelet function have the potential for pharmacodynamic DDI of DOAC., Areas Covered: The literature was searched for: 'dabigatran,' 'rivaroxaban,' 'edoxaban,' or 'apixaban' and drugs affecting platelet function, CYP3A4-, CYP2C9- or P-gp-activity. Reports about bleeding and embolic events attributed to DDI with DOAC in AF-patients were found for 43 of 171 drugs with interacting potential (25%), most frequently with antiplatelet and nonsteroidal anti-inflammatory drugs. Whereas a co-medication of platelet-affecting drugs is invariably reported to increase the bleeding risk, the findings regarding P-gp-, CYP3A4- and CYP2C9- activity-affecting drugs are ambiguous., Expert Opinion: Tests for plasma DOAC-levels and information about DDI of DOAC should be widely available and user-friendly. If advantages and disadvantages of DOAC and VKA can be investigated exhaustively, individualized anticoagulant therapy can be offered to patients, considering co-medication, comorbidities, genetic and geographic factors and the health care system.

Antiplatelet therapy (APT) plays an important role in the prevention of ischaemic stroke (IS). Our aim was to assess the influence of short-term single APT (SAPT) and dual APT (DAPT) on the prognosis of patients with acute IS with and without cerebral microbleeds (CMBs). We conducted a single-centre, retrospective, observational cohort study of patients with acute IS who underwent susceptibility-weighted imaging (SWI) to determine the presence of CMBs between January 2015 and December 2020. The patients were treated with either DAPT or SAPT and followed up for at least 2 years. The primary endpoint was a composite of recurrent IS and intracerebral haemorrhage (ICH), while either recurrent IS or ICH was considered as other endpoints. We computed weighted Kaplan-Meier curves and identified risk factors using the Cox proportional hazards model. Among the 581 enrolled patients, those with CMBs (n = 225; P = 0.004) had a higher risk of the primary endpoint than those without CMBs (n = 356), especially higher risk of recurrent IS (P = 0.029). In the SAPT group, the presence of CMBs increased the risk of the primary endpoint (P = 0.013), especially that of recurrent IS (P = 0.019). In the DAPT group, the occurrence of ICH was higher in patients with CMBs (P = 0.031). The CMB distribution did not influence the risk of recurrent IS or ICH. In patients with acute IS and CMBs, DAPT may offset the risk of recurrent IS due to CMBs but increase the risk of ICH., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Studies have estimated the associations of short-term exposure to ambient air pollution with ischemic stroke. However, the joint associations of ischemic stroke with air pollution as a mixture remain unknown., Methods: We employed a time-stratified case-crossover study to investigate 824,808 ischemic stroke patients across China. We calculated daily mean concentrations of particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5), maximum 8-h average for O3 (MDA8 O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO) across all monitoring stations in the city where the IS patients resided. We conducted conditional logistic regression models to estimate the exposure-response associations., Results: Results from single-pollutant models showed positive associations of hospital admission for ischemic stroke with PM2.5 (excess risk [ER] = 0.38%, 95% confidence interval [CI]: 0.29% to 0.47%, for 10 μg/m3), MDA8 O3 (ER = 0.29%, 95% CI: 0.18% to 0.40%, for 10 μg/m3), NO2 (ER = 1.15%, 95% CI: 0.92% to 1.39%, for 10 μg/m3), SO2 (ER = 0.82%, 95% CI: 0.53% to 1.11%, for 10 μg/m3) and CO (ER = 3.47%, 95% CI: 2.70% to 4.26%, for 1 mg/m3). The joint associations (ER) with all air pollutants (for interquartile range width increases in each pollutant) estimated by the single-pollutant model was 8.73% and was 4.27% by the multipollutant model. The joint attributable fraction of ischemic stroke attributable to air pollutants based on the multipollutant model was 7%., Conclusions: Short-term exposures to PM2.5, MDA8 O3, NO2, SO2, and CO were positively associated with increased risks of hospital admission for ischemic stroke. The joint associations of air pollutants with ischemic stroke might be overestimated using single-pollutant models. See video abstract at, http://links.lww.com/EDE/C8., Competing Interests: The author reports no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Within the last year, four randomised-controlled clinical trials (RCTs) have been published comparing intravenous thrombolysis (IVT) with tenecteplase and alteplase in acute ischaemic stroke (AIS) patients with a non-inferiority design for three of them. An expedited recommendation process was initiated by the European Stroke Organisation (ESO) and conducted according to ESO standard operating procedure based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. We identified three relevant Population, Intervention, Comparator, Outcome (PICO) questions, performed systematic reviews of the literature and meta-analyses, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert consensus statements were provided if insufficient evidence was available to provide recommendations based on the GRADE approach. For patients with AIS of <4.5 h duration who are eligible for IVT, tenecteplase 0.25 mg/kg can be used as a safe and effective alternative to alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS of <4.5 h duration who are eligible for IVT, we recommend against using tenecteplase at a dose of 0.40 mg/kg (low evidence, strong recommendation). For patients with AIS of <4.5 h duration with prehospital management with a mobile stroke unit who are eligible for IVT, we suggest tenecteplase 0.25 mg/kg over alteplase 0.90 mg/kg (low evidence, weak recommendation). For patients with large vessel occlusion (LVO) AIS of <4.5 h duration who are eligible for IVT, we recommend tenecteplase 0.25 mg/kg over alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS on awakening from sleep or AIS of unknown onset who are selected with non-contrast CT, we recommend against IVT with tenecteplase 0.25 mg/kg (low evidence, strong recommendation). Expert consensus statements are also provided. Tenecteplase 0.25 mg/kg may be favoured over alteplase 0.9 mg/kg for patients with AIS of <4.5 h duration in view of comparable safety and efficacy data and easier administration. For patients with LVO AIS of <4.5 h duration who are IVT-eligible, IVT with tenecteplase 0.25 mg/kg is preferable over skipping IVT before MT, even in the setting of a direct admission to a thrombectomy-capable centre. IVT with tenecteplase 0.25 mg/kg may be a reasonable alternative to alteplase 0.9 mg/kg for patients with AIS on awakening from sleep or AIS of unknown onset and who are IVT-eligible after selection with advanced imaging., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Intellectual and financial disclosures of the module working group members are presented in Supplemental Table., (© European Stroke Organisation 2023.)

Background: Acute ischemic stroke (AIS) is a medical emergency leading to morbidity and mortality. Thrombolytic therapy is currently the mainstay for the management of AIS owing to its improvement in neurologic function at 3 months., Objectives: The objective of this study was to compare the frequency of dosing errors made with tenecteplase versus alteplase administration in management of AIS. The secondary objectives evaluated efficacy outcomes of intensive care unit length of stay (LOS), hospital LOS, and time from door to needle and safety outcomes of bleeding and all-cause mortality between groups., Methods: This multicenter retrospective cohort study included patients with AIS treated with thrombolytics (tenecteplase or alteplase). The study evaluated patients at 9 different hospitals in a Texas Network between August 2018 and August 2020., Results: There were 3808 patients evaluated for inclusion and 359 were included: 171 in the tenecteplase group and 188 in the alteplase group. There were no differences found in dosing errors between tenecteplase and alteplase (25.7% vs. 32.4%, P = 0.16). There was no difference in all-cause mortality (tenecteplase 1.8% vs. alteplase 5.3%, P = 0.09) or bleeding events (tenecteplase 8.8% vs. alteplase 7.4%, P = 0.64). Patients who received tenecteplase had improved door to needle time < 60 minutes (tenecteplase 60% vs. alteplase 49%, P = 0.04)., Conclusion: There was no difference in dosing errors between tenecteplase and alteplase for the management of AIS. Tenecteplase was associated with shorter door to needle times, which may be caused by simpler administration times. Institutions could consider strategies to mitigate dosing errors for thrombolytic therapies., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD) is one of the most common comorbidities in breast cancer survivors. Recently, the target population and treatment period for aromatase inhibitor (AI) treatment in breast cancer patients has been expanding. However, information on adverse CVD events from the long-term use of AI is still lacking. The aim of this study was to investigate the CVD side effects of AI treatment and to evaluate the changes in lipid profile during AI treatment. A systematic search of PubMed (Medline), EMBASE, and Cochrane Library databases reporting on cardiovascular outcomes or lipid profiles change in adult female breast cancer patients (>19 years old) with AI was performed. The pooled analysis of 25 studies showed that the prevalence rate of any type of cardiovascular disease was 6.08 per 100 persons (95% CI 2.91-10.31). Angina was the most common type of heart-related cardiovascular event accounting for 3.85 per 100 persons, followed by any type of stroke (3.34) and venous thromboembolism (2.95). Ischemic stroke (OR 1.39, 95% CI 1.07-1.81) and myocardial infarction (OR 1.30, 95% CI 0.88-1.93) were more common in AI compared with tamoxifen, whereas the prevalence of venous thromboembolism (OR 0.61, 95% CI 0.37-1) was significantly lower in the AI group. In addition, treatment with AI for 6-12 months showed a decrease in HDL-cholesterol and an increase in LDL-cholesterol and total cholesterol. Various CVDs can occur when using AI, and in particular, the risk of MI and ischemic stroke increases in comparison with the adverse effect of tamoxifen. The occurrence of CVD might be related to the deterioration of the lipid profile after AI treatment. Therefore, a customized individualization strategy considering each patient's CV risk factors is needed during AI treatment.