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Although epidemiological studies have demonstrated significant associations of long-term exposure to particulate matter (PM) air pollution with stroke, evidence on the long-term effects of PM exposure on cause-specific stroke incidence is scarce and inconsistent. We incorporated 33,282 and 33,868 individuals aged 35-75 years without a history of ischemic or hemorrhagic stroke at the baseline in 2014, who were followed up till 2021. Residential exposures to particulate matter with an aerodynamic diameter less than 2.5 μm (PM 2.5 ) and particulate matter with an aerodynamic diameter less than 10 μm (PM 10 ) for each participant were predicted using a satellite-based model with a spatial resolution of 1 × 1 km. We employed time-varying Cox proportional hazards models to assess the long-term effect of PM pollution on incident stroke. We identified 926 cases of ischemic stroke and 211 of hemorrhagic stroke. Long-term PM exposure was significantly associated with increased incidence of both ischemic and hemorrhagic stroke, with almost 2 times higher risk on hemorrhagic stroke. Specifically, a 10 μg/m³ increase in 3-year average concentrations of PM 2.5 was linked to a hazard ratio (HR) of 1.35 (95% confidence interval (CI): 1.18-1.54) for incident ischemic stroke and 1.79 (95% CI: 1.36-2.34) for incident hemorrhagic stroke. The HR related to PM 10 , though smaller, remained statistically significant, with a HR of 1.25 for ischemic stroke and a HR of 1.51 for hemorrhagic stroke. The excess risks are larger among rural residents and individuals with lower educational attainment. The present cohort study contributed to the mounting evidence on the increased risk of incident stroke associated with long-term PM exposures. Our results further provide valuable evidence on the heightened sensitivity of hemorrhagic stroke to air pollution exposures compared with ischemic stroke., 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 Ltd. All rights reserved.)

Background: Limited attention has been paid to the health effects of long-term PM 1 exposure on stroke admission. Current investigations exploring the long-term PM exposure effect are largely based on observational studies, and PM generally is not allocated randomly to participants. Using traditional regression models might confuse messaging and hinder policy recommendations for pollution control and disease prevention policies., Methods: We conducted a cohort study among 36,271 adults from one of the largest cities in China in 2015 and followed up through 2020. Hazard ratios of stroke admissions following long-term PM 1 exposure were estimated via a causal inference approach, marginal structural time-varying Cox proportional hazard model, accounting for multiple confounders. Additionally, several sensitivity analyses and impact modification analyses were carried out., Results and Discussion: Associations with 1 μg/m 3 increase in long-term PM 1 were identified for total (HR, 1.079; 95 %CI, 1.012-1.151) and ischemic stroke admissions (HR, 1.092; 95 %CI, 1.018-1.171). The harmful associations varied with exposure duration, initially increasing and then decreasing. The 2-3 years cumulative exposure was associated with a 3.3-5.4 % raised risk for total stroke. For every 1 μg/m³ increase in long-term PM 1 exposure, females exhibited a higher risk of both total and ischemic stroke (13 % and 16 %) than men (4 % and 5 %). Low-exposure individuals (whose annual PM 1 concentrations were under the third quartile among the annual concentrations for all the participants) exhibited greater sensitivity to PM 1 effects (total stroke: 1.079 vs. 1.107; ischemic stroke: 1.092 vs. 1.116). The results underline the importance of safeguarding low-exposed people in highly polluted areas and suggest that long-term PM 1 exposure may increase stroke admission risk, warranting attention to vulnerable groups., 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. Published by Elsevier Inc.)

Background: Stroke is the second leading cause of death for all human beings and poses a serious threat to human health. Environmental exposure to a mixture of metals may be associated with the occurrence and development of stroke, but the evidence in the Chinese population is not yet conclusive., Objectives: This study evaluated the association between stroke risk and 13 metals METHODS: Metal concentrations in whole blood samples from 100 stroke cases and 100 controls were measured by ICP-MS. The cumulative impact of mixed metal on stroke risk was investigated by using three statistical models, BKMR, WQS and QGC., Results: The case group had higher concentrations of Mg, Mn, Zn, Se, Sn, and Pb than the control group (p<0.05). BKMR model indicated a correlation between the risk of stroke and exposure to mixed metals. WQS model showed that Mg (27.2 %), Se (25.1 %) and Sn (14.8 %) were positively correlated with stroke risk (OR=1.53; 95 %Cl: 1.03-2.37, p=0.013). The QGC model showed that Mg (49.2 %) was positively correlated with stroke risk, while Ti (31.7 %) was negatively correlated with stroke risk., Conclusions: Mg may be the largest contributor to the cumulative effect of mixed metal exposure on stroke risk, and the interaction between metals requires more attention. These findings could provide scientific basis for effectively preventing stroke by managing metals in the environment., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study investigated whether initial SGLT2 (sodium-glucose cotransporter 2) inhibitor-based treatment is superior to metformin-based regimens as a primary prevention strategy among low-risk patients with diabetes., Methods and Results: In this nationwide cohort study, a total of 38 496 patients with diabetes with low cardiovascular risk were identified (age 62.0±11.6 years, men 50%) from January 1 to December 31, 2016. Patients receiving SGLT2 inhibitors-based and metformin-based regimens were 1:2 matched by propensity score. Study outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, stroke, and progression to end-stage renal disease. Compared with 1928 patients receiving metformin-based regimens, 964 patients receiving SGLT2 inhibitor-based regimens had similar all-cause mortality (hazard ratio [HR], 0.75 [95% CI, 0.51-1.12]), cardiovascular death (HR, 0.69 [95% CI, 0.25-1.89]), hospitalization for heart failure (HR, 1.06 [95% CI, 0.59-1.92]), stroke (HR, 0.78 [95% CI, 0.48-1.27]), and progression to end-stage renal disease (HR, 0.88 [95% CI, 0.32-2.39]). However, SGLT2 inhibitors were associated with a lower risk of all-cause mortality (HR, 0.47 [95% CI, 0.23-0.99]; P for interaction=0.008) and progression to end-stage renal disease (HR, 0.22 [95% CI, 0.06-0.82]; P for interaction=0.04) in patients under the age of 65., Conclusions: In comparison to metformin-based regimens, SGLT2 inhibitor-based regimens showed a similar risk of all-cause mortality and adverse cardiorenal events. SGLT2 inhibitors might be considered as first-line therapy in select low-risk patients, for example, younger patients with diabetes.

Background: Rates of dual antiplatelet therapy (DAPT) after high-risk transient ischemic attack or minor ischemic stroke (TIAMIS) are suboptimal. We performed a cost-effectiveness analysis to characterize the parameters of a quality improvement (QI) intervention designed to increase DAPT use after TIAMIS., Methods and Results: We constructed a decision tree model that compared current national rates of DAPT use after TIAMIS with rates after implementing a theoretical QI intervention designed to increase appropriate DAPT use. The base case assumed that a QI intervention increased the rate of DAPT use to 65% from 45%. Costs (payer and societal) and outcomes (stroke, myocardial infarction, major bleed, or death) were modeled using a lifetime horizon. An incremental cost-effectiveness ratio <$100 000 per quality-adjusted life year was considered cost-effective. Deterministic and probabilistic sensitivity analyses were performed. From the payer perspective, a QI intervention was associated with $9657 in lifetime cost savings and 0.18 more quality-adjusted life years compared with current national treatment rates. A QI intervention was cost-effective in 73% of probabilistic sensitivity analysis iterations. Results were similar from the societal perspective. The maximum acceptable, initial, 1-time payer cost of a QI intervention was $28 032 per patient. A QI intervention that increased DAPT use to at least 51% was cost-effective in the base case., Conclusions: Increasing DAPT use after TIAMIS with a QI intervention is cost-effective over a wide range of costs and proportion of patients with TIAMIS treated with DAPT after implementation of a QI intervention. Our results support the development of future interventions focused on increasing DAPT use after TIAMIS.

Background: Methamphetamine use has emerged as a major risk factor for cardiovascular and cerebrovascular disease in young adults. The aim of this study was to investigate a possible association of methamphetamine use with cardioembolic stroke., Methods and Results: We performed a retrospective study of patients with acute ischemic stroke admitted at our medical center between 2019 and 2022. All patients were screened for methamphetamine use and cardiomyopathy, defined as left ventricular ejection fraction ≤45%. Among 938 consecutive patients, 46 (4.9%) were identified as using methamphetamine. Compared with the nonmethamphetamine group (n=892), the methamphetamine group was significantly younger (52.8±9.6 versus 69.7±15.2 years; P <0.001), included more men (78.3% versus 52.8%; P <0.001), and had a significantly higher rate of cardiomyopathy (30.4% versus 14.0%; P <0.01). They were also less likely to have a history of atrial fibrillation (8.7% versus 33.4%; P <0.01) or hyperlipidemia (28.3% versus 51.7%; P <0.01). Compared with patients with cardiomyopathy without methamphetamine use, the patients with cardiomyopathy with methamphetamine use had significantly lower left ventricular ejection fraction (26.0±9.59% versus 32.47±9.52%; P <0.01) but better functional outcome at 3 months, likely attributable to significantly younger age and fewer comorbidities. In the logistic regression model of clinical variables, methamphetamine-associated cardiomyopathy was found to be significantly associated with cardioembolic stroke (odds ratio, 1.79 [95% CI, 1.04-3.06]; P <0.05)., Conclusions: We demonstrate that methamphetamine use is significantly associated with cardiomyopathy and cardioembolic stroke in young adults.

While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0-3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R 2  = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p < 0.001) and a 11% decrease in the composite clinical outcome (HR 0.89; 95% CI 0.81, 1.00; p = 0.015). These results were comparable to those of a rules-based clinical algorithm used for benchmarking, for which each 10% increase in algorithm-consistent dosing independently predicted a 6.10% increase in TTR (95% CI 5.67, 6.54, p < 0.001) and a 10% decrease in the composite outcome (HR 0.90; 95% CI 0.83, 0.98, p = 0.018). Our findings suggest that a deep reinforcement learning algorithm can optimize time in therapeutic range for patients taking warfarin. A digital clinical decision support system to promote algorithm-consistent warfarin dosing could optimize time in therapeutic range and improve clinical outcomes in atrial fibrillation globally., (© 2024. The Author(s).)

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.)

Background and Aim: Atrial fibrillation (AF) is the most frequently observed cardiac arrhythmia in clinical settings. Obesity can influence the efficacy of the treatment administered, which requires a larger dose and more time to accomplish therapeutic targets due to altered pathophysiology. Our study aimed to assess the overall efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) versus warfarin in AF patients with morbid obesity (BMI > 40 kg/m2 and/or weight > 120 kg) to prevent complications., Methods: We conducted a literature search on PubMed, Web of Science, the Cochrane Library, and Scopus till October 2022 for articles addressing the efficacy and safety of NOACs versus warfarin for the treatment of AF in morbidly obese patients. We performed the meta-analysis with RevMan software version 5.4 and Open Meta Analyst. The main outcomes assessed were stroke, major bleeding, and minor bleeding after anticoagulation, as did the history of comorbidities and risk factors in morbidly obese patients. Quality assessment was performed using Cochrane's ROB-2 tool and the Newcastle-Ottawa scale., Results: Regarding major bleeding events, pooled data showed that patients taking NOACs had a significantly lower risk than patients taking warfarin (OR = 0.54, 95% CI: [0.41-0.70]; p < 0.00001). However, for minor bleeding, there was a nonsignificant effect of NOACs on reducing the risk of bleeding (OR = 0.72, 95% CI = 0.47-1.09; p = 0.12), which became highly significant in favor of NOACs after sensitivity analysis (OR = 0.55, 95% CI = 0.49-0.61]; p < 0.00001). There was a significant difference in the incidence of stroke between the NOAC group and the warfarin group (OR = 0.69, 95% CI = 0.60-0.80]; p < 0.00001). According to the results of the single-arm study analysis, the overall effect of all the outcomes was associated with a high risk of disease development in patients receiving NOACs., Conclusion: Our meta-analysis showed a favorable effect of NOACs vs warfarin in morbidly obese patients. Some outcomes were not significantly different, which calls for future research to better assess their safety and efficacy in this particular weight group., Trial Registration: The study was registered with PROSPERO under registration number CRD42022362493 on October 2022., (© 2024. The Author(s).)

Background: Antithrombotic therapy after left atrial appendage closure (LAAC) in patients at high risk of bleeding remains controversial. We present real-world clinical outcomes of LAAC., Methods and results: Data from 74 consecutive patients who received LAAC therapy between January 2020 and June 2022 were analyzed. Patients received 1 of 3 antithrombotic therapies according to the bleeding risk category or clinical event. Regimen 1 was based on a prior study, regimen 2 comprised a lower antiplatelet drug dose without dual antiplatelet therapy, and regimen 3 was antiplatelet drug administration for as long as possible to patients with uncontrollable bleeding who were required to stop anticoagulant drugs. Overall, 73 (98.6%) procedures were successful. Of them, 16 (21.9%) patients were selected for regimen 1, 46 (63.0%) for regimen 2, and 11 (15.1%) for regimen 3. Device-related thrombosis (13% vs. 0% vs. 0%, P=0.0257) only occurred with regimen 1. There was no difference in major bleeding event rates (6% vs. 2% vs. 9%, P=0.53)., Conclusions: The post-LAAC antithrombotic regimen was modified without major concerns.

Background: The HELT-E 2 S 2 score, which assigns 1 point to Hypertension, Elderly aged 75-84 years, Low body mass index <18.5 kg/m 2 , and Type of atrial fibrillation (AF: persistent/permanent), and 2 points to Extreme Elderly aged ≥85 years and previous Stroke, has been proposed as a new risk stratification for strokes in Japanese AF patients, but has not yet undergone external validation., Methods and results: We evaluated the prognostic performance of the HELT-E 2 S 2 score for stroke risk stratification using 2 large-scale registries in Japanese AF patients (n=7,020). During 23,241 person-years of follow-up (mean follow-up 1,208±450 days), 287 ischemic stroke events occurred. The C-statistic using the HELT-E 2 S 2 score was 0.661 (95% confidence interval [CI], 0.629-0.692), which was numerically higher than with the CHADS 2 score (0.644, 95% CI 0.613-0.675; P=0.15 vs. HELT-E 2 S 2 ) or CHA 2 DS 2 -VASc score (0.650, 95% CI, 0.619-0.680; P=0.37 vs. HELT-E 2 S 2 ). In the SAKURA AF Registry, the C-statistic of the HELT-E 2 S 2 score was consistently higher than the CHADS 2 and CHA 2 DS 2 -VASc scores across all 3 types of facilities comprising university hospitals, general hospitals, and clinics. However, in the RAFFINE Study, its superiority was only observed in general hospitals., Conclusions: The HELT-E 2 S 2 score demonstrated potential value for risk stratification, particularly in a super-aged society such as Japan. However, its superiority over the CHADS 2 or CHA 2 DS 2 -VASc scores may vary across different hospital settings.

Background: The association between metals and stroke has been reported, but the mediating role of inflammation between metals and stroke remains unclear., Methods: We included 9326 adults from the National Health and Nutrition Examination Survey in this study. Through least absolute selection and shrinkage operator (LASSO) regression, weighted quantile sum (WQS) regression, logistic regression, linear regression, restricted cubic spline analysis, and mediation analysis, we explored the association between metals and stroke, as well as the association between metals and inflammatory indicators, and further evaluated the mediating effect of inflammatory indicators on the association between selected metals and stroke risk., Results: The results of the present study suggested positive associations between mixed metals, cadmium and uranium and stroke risk. There is a positive correlation and dose‒response relationship between cadmium and C-reactive protein (CRP). Moreover, CRP mediates 10.1% of the association between cadmium and stroke., Conclusions: At the epidemiological level, CRP mediates the association between cadmium and stroke risk, suggesting that inflammation may be a potential mechanism for metal-induced stroke., 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 Elsevier Ltd. All rights reserved.)

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: Intravenous thrombolysis (IVT) with alteplase or tenecteplase before mechanical thrombectomy is the recommended treatment for large-vessel occlusion acute ischemic stroke. There are divergent data on whether these agents differ in terms of early recanalization (ER) rates before mechanical thrombectomy, and little data on their potential differences stratified by ER predictors such as IVT to ER evaluation (IVT-to-ER eval ) time, occlusion site and thrombus length., Methods: We retrospectively compared the likelihood of ER after IVT with tenecteplase or alteplase in anterior circulation large-vessel occlusion acute ischemic stroke patients from the PREDICT-RECANAL (alteplase) and Tenecteplase Treatment in Ischemic Stroke (tenecteplase) French multicenter registries. ER was defined as a modified Thrombolysis in Cerebral Infarction score 2b-3 on the first angiographic run, or noninvasive vascular imaging in patients with early neurological improvement. Analyses were based on propensity score overlap weighting (leading to exact balance in patient history, stroke characteristics, and initial management between groups) and confirmed with adjusted logistic regression (sensitivity analysis). A stratified analysis based on pre-established ER predictors (IVT-to-ER eval time, occlusion site, and thrombus length) was conducted., Results: Overall, 1865 patients were included. ER occurred in 156/787 (19.8%) and 199/1078 (18.5%) patients treated with tenecteplase or alteplase, respectively (odds ratio, 1.09 [95% CI, 0.83-1.44]; P =0.52). A differential effect of tenecteplase versus alteplase on the probability of ER according to thrombus length was observed ( P interaction =0.003), with tenecteplase being associated with higher odds of ER in thrombi >10 mm (odds ratio, 2.43 [95% CI, 1.02-5.81]; P =0.04). There was no differential effect of tenecteplase versus alteplase on the likelihood of ER according to the IVT-to-ER eval time ( P interaction =0.40) or occlusion site ( P interaction =0.80)., Conclusions: Both thrombolytics achieved ER in one-fifth of patients with large-vessel occlusion acute ischemic stroke without significant interaction with IVT-to-ER eval time and occlusion site. Compared with alteplase, tenecteplase was associated with a 2-fold higher likelihood of ER in larger thrombi., Competing Interests: Disclosures All reported disclosures were outside the submitted work. Dr Yger reported reimbursement for conference registration fees from Pfizer and Boehringer-Ingelheim. Dr Chausson received a grant and personal fees (consultancy, lectures) from Boehringer Ingelheim and Bristol-Myers-Squibb. Dr Marnat reported consulting fees from Stryker neurovascular, Microvention Europe, Balt Extrusion; paid lectures for Medtronic and Johnson & Johnson, compensation from Phenox Inc. Dr Clarençon received personal fees from Medtronic, Stryker, Balt Extrusion, Microvention (consultant) and Penumbra (lectures); from ClinSearch (study core laboratory); from Artedrone (board member) and a conflict of interest with Intradys and Collavidence (stock options). Dr Turc received lecturing fees from Guerbet France. Dr Alamowitch received lecturing fees from Boehringer-Ingelheim, Astra-Zeneca, Pfizer and Amgen, and research grants from Boehringer-Ingelheim and Roche-Shugai. Drs Alamowitch and Turc were members of the module writing groups of the European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischemic stroke. Dr Turc was also a member of the module writing groups of the ESO - European Society for Minimally Invasive Neurological Therapy (ESMINT) expedited recommendation on indication for intravenous thrombolysis before mechanical thrombectomy in patients with acute ischemic stroke and anterior circulation large-vessel occlusion. No other disclosures were reported.

Background: Short-term dual antiplatelet therapy (DAPT) reduces early stroke recurrence after mild noncardioembolic ischemic stroke (NCIS). We aim to evaluate temporal trends and determinants of DAPT prescription after mild NCIS in the Florida Stroke Registry, a statewide registry across Get With The Guidelines-Stroke participating hospitals., Methods: In this cross-sectional analysis of a cohort study, we included patients with mild NCIS (National Institutes of Health Stroke Scale score ≤3) who were potentially eligible for DAPT across 168 Florida Stroke Registry participating hospitals between January 2010 and September 2022. Using antiplatelet prescription as the dependent variable (DAPT versus single antiplatelet therapy), we fit logistic regression models adjusted for patient-related factors, hospital-related factors, clinical presentation, vascular risk factors, and ischemic stroke subtype, to obtain adjusted odds ratios (aORs) with 95% CIs., Results: From 283 264 Florida Stroke Registry ischemic stroke patients during the study period, 109 655 NCIS were considered eligible. Among these, 37 058 patients with National Institutes of Health Stroke Scale score >3 were excluded, resulting in a sample of 72 597 mild NCIS (mean age 68±14 years; female 47.3%). Overall, 24 693 (34.0%) patients with mild NCIS were discharged on DAPT and 47 904 (66.0%) on single antiplatelet therapy. DAPT prescription increased from 25.7% in 2010 to 52.8% in 2022 ( β /year 2.5% [95% CI, 1.5%-3.4%]). Factors associated with DAPT prescription were premorbid antiplatelet therapy (aOR, 4.66 [95% CI, 2.20-9.88]), large-artery atherosclerosis (aOR, 1.68 [95% CI, 1.43-1.97]), diabetes (aOR, 1.29 [95% CI, 1.13-1.47]), and hyperlipidemia (aOR, 1.24 [95% CI, 1.10-1.39]), whereas female sex (aOR, 0.83 [95% CI, 0.75-0.93]), being non-Hispanic Black patients (compared with non-Hispanic White patients; aOR, 0.78 [95% CI, 0.68-0.90]), admission to a Thrombectomy-capable Stroke Center (compared with Comprehensive Stroke Center; aOR, 0.78 [95% CI, 0.66-0.92]), time-to-presentation 1 to 7 days from last seen well (compared with <24 h; aOR, 0.86 [95% CI, 0.76-0.96]), and small-vessel disease stroke (aOR, 0.81 [95% CI, 0.72-0.94]) were associated with not receiving DAPT at discharge., Conclusions: Despite a temporal trend increase in DAPT prescription after mild NCIS, we found substantial underutilization of evidence-based DAPT associated with significant disparities in stroke care., Competing Interests: Disclosures Drs Del Brutto and Yin receive research salary support from the Florida Stroke Registry (FSR) COHAN-R3. Drs Gardener, Hao, Gutierrez, and Rundek receive research salary support from the FSR COHAN-R2. Dr Rose received honoraria for consulting or speaker bureau from Atricure, Boston Scientific, Cheisi-USA, CSL-Behring, and Medtronic. Dr Alkhachroum is supported by KL2 Career Development Award from the Miami CTSI NCATS UL1TR002736 and by the National Institutes of Health/National Institute of Neurological Disorders and Stroke under Award Number K23NS126577 and R21NS128326. Dr Sur is supported by KL2 Career Development Award from the Miami CTSI NCATS KL2TR002737 and research salary support from the FSR COHAN-R3. Dr Asdaghi receives research salary support from the FSR COHAN-R2 and compensations from the American Heart Association for employment in Stroke editorial board. Dr Romano reports compensation from Genentech USA Inc. for data and safety monitoring services, stock holdings in Vycor Medical, and receives research salary support from the FSR COHAN-R2. The other authors report no conflicts.

Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce atherosclerotic cardiovascular disease (ASCVD) events in patients with prior ASCVD and type 2 diabetes; however, this benefit is uncertain in patients without established ASCVD. Methods and Results Large-scale cardiovascular outcome randomized controlled trials or their prespecified subgroup analyses were selected, evaluating SGLT2 inhibitors versus placebo for primary prevention of ASCVD (inception, March 2023). The primary outcome was atherosclerotic major adverse cardiovascular events (MACEs), which was a composite of cardiovascular mortality, myocardial infarction, and stroke. The secondary outcomes were individual components of MACEs and all-cause mortality. The outcomes were reported as random-effect relative risk (RR) with a 95% CI. This analysis, comprising 23 987 patients enrolled in 5 randomized controlled trials with a mean follow-up duration of ≈135 weeks, found no significant reduction in atherosclerotic MACEs with SGLT2 inhibitors in comparison to placebo (RR, 0.85 [95% CI, 0.71-1.01]; P =0.07; I 2 =44). There were no significant differences in cardiovascular mortality (RR, 0.93 [95% CI, 0.77-1.14]; P =0.50; I 2 =0), myocardial infarction (RR, 0.88 [95% CI, 0.69-1.11]; P =0.28; I 2 =23), and stroke (RR, 0.84 [95% CI, 0.62-1.16]; P =0.29; I 2 =46). SGLT2 inhibitors significantly improved all-cause mortality (RR, 0.85 [95% CI, 0.72-1.0]; P =0.04; I 2 =23). On subgroup analyses, the use of SGLT2 inhibitors led to significant reductions in MACEs (RR, 0.74 [95% CI, 0.61-0.89]; P =0.001), myocardial infarction (RR, 0.67 [95% CI, 0.47-0.97]; P =0.03), and stroke (RR, 0.61 [95% CI, 0.41-0.91]; P =0.01) primarily in patients with chronic kidney disease along with type 2 diabetes, whereas these benefits were not observed in patients with type 2 diabetes without chronic kidney disease. Conclusions SGLT2 inhibitors significantly reduced atherosclerotic MACEs in subjects having both chronic kidney disease and type 2 diabetes without established ASCVD.

Context: Proton pump inhibitors (PPIs) are widely used drugs for gastric acid-related diseases and may affect the gut microbiome., Objective: We aimed to evaluate the associations of PPI use with risks of cardiovascular disease (CVD) and all-cause mortality in patients with type 2 diabetes (T2D)., Methods: We analyzed the associations of PPI use with risks of coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), stroke, and all-cause mortality in 19 229 adults with T2D using data from the UK Biobank study., Results: During a median follow-up of 10.9 to 11.2 years, we documented 2971 CAD, 1827 MI, 1192 HF, and 738 stroke cases, along with 2297 total deaths. PPI use was significantly associated with higher risks of CAD (hazard ratio [HR], 1.27; 95% CI, 1.15-1.40), MI (HR, 1.34; 95% CI, 1.18-1.52), HF (HR, 1.35; 95% CI, 1.16-1.57), and all-cause mortality (HR, 1.30; 95% CI, 1.16-1.45). No statistically significant association was observed between PPI use and stroke (HR, 1.11; 95% CI, 0.90-1.36). The results were consistent in the subgroup analyses stratified by factors including indications of PPI, antidiabetic medication use, and antiplatelet drug use. Analyses in a 1:1 propensity score-matched cohort of PPI users vs nonusers yielded similar results., Conclusion: Our data suggest that PPI use is associated with higher risks of CVD events and mortality among patients with T2D. The benefits and risks of PPI use should be carefully balanced among patients with T2D, and monitoring of adverse CVD events during PPI therapy should be enhanced., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: It is unclear whether infarct location affects stroke recurrence after index ischemic stroke. We aimed to compare the risk of stroke recurrence and the responses to dual antiplatelets with ticagrelor-aspirin versus clopidogrel-aspirin between patients with posterior circulation infarct (PCI) and those with anterior circulation infarct (ACI) after minor stroke or transient ischemic attack., Methods: Data were obtained from the double-blind CHANCE-2 trial (Ticagrelor or Clopidogrel With Aspirin in High-Risk Patients With Acute Nondisabling Cerebrovascular Events II), which was conducted across 202 centers in China from September 2019 to March 2021. Patients with positive diffusion-weighted imaging were included and classified into PCI and ACI groups according to the hyperintense lesions on diffusion-weighted imaging. The primary efficacy and safety outcomes were a new stroke and severe or moderate bleeding within 90 days, respectively., Results: A total of 4168 patients were included in this substudy, with 1427 PCI and 2741 ACI. During the 90-day follow-up, the risk of stroke recurrence in patients with PCI was similar to that with ACI (7.4% versus 8.3%; adjusted hazard ratio, 1.01 [95% CI, 0.79-1.29]; P =0.94). In comparison with clopidogrel-aspirin, ticagrelor-aspirin significantly reduced the risk of stroke recurrence in both the PCI (hazard ratio, 0.59 [95% CI, 0.40-0.89]; P =0.01) and ACI groups (hazard ratio, 0.65 [95% CI, 0.50-0.85]; P =0.002). There was no treatment-by-infarct location interaction ( P value for interaction, 0.92). The risk of severe or moderate bleeding was similar between PCI and ACI patients ( P =0.19). However, the risk of any bleeding increased on ticagrelor-aspirin than clopidogrel-aspirin treatment in PCI and ACI patients ( P =0.02 and 0.002, respectively)., Conclusions: Our study demonstrated that stroke recurrence was similar between PCI and ACI in patients with minor stroke or transient ischemic attack. Additionally, ticagrelor-aspirin was superior to clopidogrel-aspirin in reducing the risk of stroke within 90 days in both PCI and ACI patients., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04078737.

Background: Long-term exposure to air pollutants is associated with increased stroke incidence, morbidity, and mortality; however, research on the association of pollutant exposure with poststroke hospital readmissions is lacking., Methods: We assessed associations between average annual carbon monoxide (CO), nitrogen dioxide (NO 2 ), ozone (O 3 ), particulate matter 2.5, and sulfur dioxide (SO 2 ) exposure and 30-day all-cause hospital readmission in US fee-for-service Medicare beneficiaries age ≥65 years hospitalized for ischemic stroke in 2014 to 2015. We fit Cox models to assess 30-day readmissions as a function of these pollutants, adjusted for patient and hospital characteristics and ambient temperature. Analyses were then stratified by treating hospital performance on the Centers for Medicare and Medicaid Services risk-standardized 30-day poststroke all-cause readmission measure to determine if the results were independent of performance: low (Centers for Medicare and Medicaid Services rate for hospital <25th percentile of national rate), high (>75th percentile), and intermediate (all others)., Results: Of 448 148 patients with stroke, 12.5% were readmitted within 30 days. Except for tropospheric NO 2 (no national standard), average 2-year CO, O 3 , particulate matter 2.5, and SO 2 values were below national limits. Each one SD increase in average annual CO, NO 2 , particulate matter 2.5, and SO 2 exposure was associated with an adjusted 1.1% (95% CI, 0.4-1.9%), 3.6% (95% CI, 2.9%-4.4%), 1.2% (95% CI, 0.2%-2.3%), and 2.0% (95% CI, 1.1%-3.0%) increased risk of 30-day readmission, respectively, and O 3 with a 0.7% (95% CI, 0.0%-1.5%) decrease. Associations between long-term air pollutant exposure and increased readmissions persisted across hospital performance categories., Conclusions: Long-term air pollutant exposure below national limits was associated with increased 30-day readmissions after stroke, regardless of hospital performance category. Whether air quality improvements lead to reductions in poststroke readmissions requires further research.

Aim: It is not well known how comorbidities may change the prognosis of atrial fibrillation (AF) patients. This study was aimed to analyze the impact of cardiovascular disease on this population. Materials & methods: EMIR was a multicenter, prospective study, including 1433 AF patients taking rivaroxaban for ≥6 months. Data were analyzed according to the presence of vascular disease. Results: Coronary artery disease was detected in 16.4%, peripheral artery disease/aortic plaque in 6.7%, vascular disease in 28.3%. Patients with coronary artery disease had higher rates (per 100 patient-years) of major adverse cardiovascular events (2.98 vs 0.71; p < 0.001) and cardiovascular death (1.79 vs 0.41; p = 0.004). Those with vascular disease had higher rates of thromboembolic events (1.47 vs 0.44; p = 0.007), major adverse cardiovascular events (2.03 vs 0.70; p = 0.004), and cardiovascular death (1.24 vs 0.39; p = 0.025). Patients with peripheral artery disease/aortic plaque had similar rates. Conclusion: AF patients with vascular disease have a higher risk of non-embolic outcomes.

Background: The aim of this study was to determine the effect of smoking status on subsequent stroke risk in patients with minor ischemic stroke or TIA and to determine whether smoking modifies the effect of clopidogrel-based DAPT on subsequent stroke risk., Methods: This was a post-hoc analysis of the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, which had a 90-day follow-up period. We used multivariable Cox regression and subgroup interaction analysis to determine the effect of smoking on the risk of subsequent ischemic stroke and major hemorrhage, respectively., Results: Data from 4877 participants enrolled in the POINT trial were analyzed. Among these, 1004 were current smokers and 3873 were non-smokers at the time of index event. Smoking was associated with a non-significant trend toward an increased risk of subsequent ischemic stroke during follow up (adjusted HR, 1.31 (95% CI, 0.97-1.78), p  = 0.076). The effect of clopidogrel on ischemic stroke did not differ between non-smokers (HR, 0.74 (95% CI, 0.56-0.98), p  = 0.03) and smokers (HR, 0.63 (95% CI, 0.37-1.05), p  = 0.078), p for interaction = 0.572. Similarly, the effect of clopidogrel on major hemorrhage did not differ between non-smokers (hazard ratio, 1.67 (95% CI, 0.40-7.00), p  = 0.481) and smokers (HR, 2.59 (95% CI, 1.08-6.21), p  = 0.032), p for interaction = 0.613., Conclusions: In this post-hoc analysis of the POINT trial we found that the effect of clopidogrel on reducing subsequent ischemic stroke as well as risk of major hemorrhage did not depend on smoking status, indicating that smokers benefit to a similar degree from DAPT as non-smokers., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr. de Havenon is funded by NIH-NINDS, has received investigator initiated clinical research funding from Regeneron, AMGEN, and AMAG pharmaceuticals, has received consultant fees from Integra and Novo Nordisk, has equity in TitinKM and Certus, and receives author fees from UpToDate. Dr. Easton received funding for his role in the POINT trial which was sponsored by NIH/NINDS but received drug and placebo from Sanofi. Dr. Johnston received research support from AstraZeneca. The POINT trial was sponsored by NIH/NINDS but received drug and placebo from Sanofi. Dr. Lang reported previously owning stock in Walmart, Target, and Johnson & Johnson outside the submitted work., (© European Stroke Organisation 2022.)

Background: Intracranial occlusion site, contrast permeability, and clot burden are thrombus characteristics that influence alteplase-associated reperfusion. In this study, we assessed the reperfusion efficacy of tenecteplase and alteplase in subgroups based on these characteristics in a pooled analysis of the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke)., Methods: Patients with large vessel occlusion were randomized to treatment with tenecteplase (0.25 or 0.4 mg/kg) or alteplase before thrombectomy in hospitals across Australia and New Zealand (2015-2019). The primary outcome, early reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion on first-pass angiogram. We compared the effect of tenecteplase versus alteplase overall, and in subgroups, based on the following measured with computed tomography angiography: intracranial occlusion site, contrast permeability (measured via residual flow grades), and clot burden (measured via clot burden scores). We adjusted for covariates using mixed effects logistic regression models., Results: Tenecteplase was associated with higher odds of early reperfusion (75/369 [20%] versus alteplase: 9/96 [9%], adjusted odds ratio [aOR], 2.18 [95% CI, 1.03-4.63]). The difference between thrombolytics was notable in occlusions with low clot burden (tenecteplase: 66/261 [25%] versus alteplase: 5/67 [7%], aOR, 3.93 [95% CI, 1.50-10.33]) when compared to high clot burden lesions (tenecteplase: 9/108 [8%] versus alteplase: 4/29 [14%], aOR, 0.58 [95% CI, 0.16-2.06]; P interaction =0.01). We did not observe an association between contrast permeability and tenecteplase treatment effect (permeability present: aOR, 2.83 [95% CI, 1.00-8.05] versus absent: aOR, 1.98 [95% CI, 0.65-6.03]; P interaction =0.62). Tenecteplase treatment effect was superior with distal M1 or M2 occlusions (53/176 [30%] versus alteplase: 4/42 [10%], aOR, 3.73 [95% CI, 1.25-11.11]), but both thrombolytics had limited efficacy with internal carotid artery occlusions (tenecteplase 1/73 [1%] versus alteplase 1/19 [5%], aOR, 0.22 [95% CI, 0.01-3.83]; P interaction =0.16)., Conclusions: Tenecteplase demonstrates superior early reperfusion versus alteplase in lesions with low clot burden. Reperfusion efficacy remains limited in internal carotid artery occlusions and lesions with high clot burden. Further innovation in thrombolytic therapies are required.

Despite recent advances in treatment and prevention, stroke remains a leading cause of morbidity and mortality. There is a critical need to identify novel modifiable risk factors for disease, including environmental agents. A body of evidence has accumulated suggesting that elevated levels of ambient air pollutants may not only trigger cerebrovascular events in susceptible people (short-term exposures) but also increase the risk of future events (long-term average exposures). This review assesses the updated evidence for both short and long-term exposure to ambient air pollution as a risk factor for stroke incidence and outcomes. It discusses the potential pathophysiologic mechanisms and makes recommendations to mitigate exposure on a personal and community level. The evidence indicates that reduction in air pollutant concentrations represent a significant population-level opportunity to reduce risk of cerebrovascular disease.

Aims: Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC)., Methods and Results: BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death., Conclusion: The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF., One-Sentence Summary: In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation., Competing Interests: Conflict of interest: Dr Hijazi reports lecture and consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer and Roche Diagnostics International. Dr Benz has nothing to disclose. Mr Lindbäck reports institutional research grant from Roche Diagnostics International. Dr Alexander reports institutional research grants from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring, Humacyte, and XaTek and consulting or honoraria payments from AbbVie, Akros, Artivion/CryoLife, AtriCure, Bristol Myers Squibb, Ferring, GlaxoSmithKline, Janssen, Pfizer, Portola, and Quantum Genomics. Dr Connolly reports institutional research grants and honoraria from Boehringer Ingelheim, Portola/Alexion Pharmaceuticals, Bristol Myers Squibb/Pfizer, Bayer, and Daiichi Sankyo. Dr Eikelboom reports institutional research grants and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, and Sanofi. Dr Granger reports grants and consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Janssen Pharmaceutica Products, L.P., Medtronic Foundation, Novartis; grants from Daiichi Sankyo, AKROS, Apple, GlaxoSmithKline, AstraZeneca, the U.S. Food and Drug Administration; consulting fees from Abbvie, Abiomed, Athos Therapeutic, LLC, Bayer Corporation US, Boston Scientific Corporation, Espero BioPharma, National Institutes of Health, Philips, Rhoshan Pharmaceuticals, Roche Diagnostics, CeleCor Therapeutics, Correvio, Merck, NovoNordisk. Drs. Kastner and Ziegler are employees of Roche Diagnostics GmbH. Dr Lopes reports institutional research grants and consulting fees from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; consulting fees from Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck, and Portola. Dr Oldgren reports institutional research grants and fees paid to his institution for advisory boards and lectures from Roche Diagnostics International; fees paid to his institution for advisory boards, study steering committees, and lectures from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, and Sanofi; fees paid to his institution for advisory boards, safety committees, and lectures from Daichii Sankyo. Dr Siegbahn reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, and Roche Diagnostics International. Dr Wallentin reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics International, Merck & Co; consulting fees from Abbott; holds two patents involving GDF-15 licensed to Roche Diagnostics (EP2047275B1 and US8951742B2)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Stroke is the second most common cause of death and disability in the world. Many studies have found fine particulate matter (PM 2.5 ) exposure to be associated with an increased risk of atherosclerotic cardiovascular disease, mostly focusing on ischemic heart disease and acute myocardial infarction. In a national analysis conducted in Israel-an area with unique climate conditions and high air pollution levels, we estimated the association between short-term PM 2.5 exposure and ischemic stroke, intracerebral hemorrhage (ICH), or transient ischemic attacks (TIA). Using the Israeli National Stroke Registry, we obtained information on all stroke cases across Israel in 2014-2018. We obtained daily PM 2.5 exposures from spatiotemporally resolved exposure models. We restricted the analytical data to days in which PM 2.5 levels did not exceed the Israeli 24 h standard (37.5 µg/m 3 ). We repeated the analysis with a stratification by sociodemographic characteristics and comorbidities. For all outcomes, the exposure-response curves were nonlinear. PM 2.5 exposure was associated with a higher ischemic stroke risk, with larger effect estimates at higher exposure levels. Although nonsignificant, the exposure-response curve for TIA was similar. The associations with ICH were nonsignificant throughout the PM 2.5 exposure distribution. The associations with ischemic stroke/TIA were larger among women, non-Jewish individuals, older adults, and individuals with diabetes, hypertension, and ischemic heart disease. In conclusion, short-term PM 2.5 exposure is associated with a higher risk for ischemic stroke and possibly TIA, even when PM 2.5 concentrations do not exceed the Israeli air quality guideline threshold. Vulnerability to the air pollution effects differed by age, sex, ethnicity, and comorbidities.

Background: Despite major advances, transcatheter aortic valve replacement (TAVR) is still associated with procedure-specific complications. Although previous studies reported lower bleeding rates in patients receiving protamine for heparin reversal, the optimal protamine-to-heparin dosing ratio is unknown., Hypothesis: The aim of this study was a comparison of two different heparin antagonization regimens for the prevention of bleeding complications after TAVR., Methods: The study included 1446 patients undergoing TAVR, of whom 623 received partial and 823 full heparin antagonization. The primary endpoint was a composite of 30-day mortality, life-threatening, and major bleeding. Safety endpoints included stroke and myocardial infarction at 30 days., Results: Full antagonization of heparin resulted in lower rates of the primary endpoint as compared to partial heparin reversal (5.6% vs. 10.4%, p < .01), which was mainly driven by lower rates of life-threatening (0.5% vs. 1.6%, p = .05) and major bleeding (3.2% vs. 7.5%, p < .01). Moreover, the incidence of major vascular complications was significantly lower in patients with full heparin reversal (3.5% vs. 7.5%, p < .01). The need for red-blood-cell transfusion was lower in patients receiving full as compared to partial heparin antagonization (10.4% vs. 15.9%, p < .01). No differences were observed in the incidence of stroke and myocardial infarction between patients with full and partial heparin reversal (2.2% vs. 2.6%, p = .73 and 0.2% vs. 0.4%, p = .64, respectively)., Conclusions: Full heparin antagonization resulted in significantly lower rates of life-threatening and major bleeding after TAVR as compared to partial heparin reversal. The occurrence of stroke and myocardial infarction was low and comparable between both groups., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Anticoagulation with warfarin in Asian patients with atrial fibrillation (AF) often has been decreased as an international normalized ratio (INR) of prothrombin time 1.6-2.6 due to fear of bleeding, although universal criteria recommend an INR of 2.0-3.0. In this randomized, open-label trial, low-intensity anticoagulation (INR 1.6-2.6) was compared with standard-intensity anticoagulation (INR 2.0-3.0) with warfarin. A total 616 patients with AF and at least 1 risk factor for stroke were randomized to low-intensity anticoagulation (n = 308) and standard-intensity anticoagulation (n = 308) groups. The intention-to-treat analysis was performed to determine differences. The baseline characteristics of the two groups were comparable. New-onset stroke occurred in 2 patients (0.44% per year) in the low-intensity group and 5 patients (1.05% per year) in the standard-intensity group (HR 0.42, 95% CI 0.08-2.15). Major bleeding occurred in 4 patients (0.89% per year) in the low-intensity group and 5 patients (1.06% per year) in the standard-intensity group (HR 0.84, 95% CI 0.22-3.11). The rate of the net clinical outcome (composite of stroke, systemic embolism, major bleeding, and death) was 1.33% per year in the low-intensity group compared with 2.12% per year in the standard-intensity group (HR 0.63, 95% CI 0.23-1.72). In Asian patients with AF, clinical outcomes were not different between low-intensity and standard-intensity anticoagulation with warfarin.

Patients with atrial fibrillation (AF) have an increased risk of stroke and systemic thromboembolism. Diagnosis of AF is commonly encountered in the emergency department (ED). The purpose of this study was to assess the number of patients with new-onset AF appropriately initiated on oral anticoagulation (AC) during their ED encounter. This retrospective analysis included patients discharged from the ED from July 2016 to July 2021 with a new diagnosis of AF. Patients were excluded if they were on AC before admission. The major endpoint was to identify the percentage of patients discharged from the ED without initiating AC. Minor endpoints included the average CHA2DS2-VASc scores and the reason for not initiating AC. A total of 380 patients were included in the final analysis. Of the 245 patients found to be indicated for AC, only 131 patients (53.5%) were initiated on AC and 114 patients (46.5%) were discharged without initiating AC. Almost half of the patients who presented to the ED with a new diagnosis of AF and indicated for AC were discharged without AC.

Reperfusion therapy administration timing in acute ischaemic stroke is the main determinant of patients' mortality and long-term disability. Indeed, the first hour from the stroke onset is defined the "golden hour", in which the treatment has the highest efficacy and lowest side effects. Delayed ambulance transport, inappropriate triage and difficulty in accessing CT scans lead to delayed onset to treatment time (OTT) in clinical practice. To date brain CT scan is needed to rule out intracranial haemorrhage, which is a major contraindication to thrombolytic therapy. The availability, dimension and portability make CT suitable mainly for intrahospital use, determining further delays in the therapies administration. This review aims at evaluating portable neurophysiology technologies developed with the scope of speeding up the diagnostic phase of acute stroke and, therefore, the initiation of intravenous thrombolysis. Medline databases were explored for studies concerning near infrared spectroscopy (NIRS), bioelectrical impedance spectroscopy (BIS) and Microwave imaging (MWI) as methods for stroke diagnosis. A total of 1368 articles were found, and 12 of these fit with our criteria and were included in the review. For each technology, the following parameters were evaluated: diagnostic accuracy, ability to differentiate ischaemic and haemorrhagic stroke, diagnosis time from stroke onset, portability and technology readiness level (TRL). All the described methods seem to be able to identify acute stroke even though the number of studies is very limited. Low cost and portability make them potentially usable during ambulance transport, possibly leading to a reduction of stroke OTT along with the related huge benefits in terms of patients outcome and health care costs. In addition, unlike standard imaging techniques, neurophysiological techniques could allow continuous monitoring of patients for timely intrahospital stroke diagnosis.KEY MESSAGESFirst hour from the stroke onset is defined the "golden hour", in which the treatment has the highest efficacy and lowest side effects.The delay for stroke onset to brain imaging time is one of the major reasons why only a minority of patients with acute ischaemic stroke are eligible to reperfusion therapies.Neurophysiology techniques (NIRS, BIS and MWI) could have a potential high impact in reducing the time to treatment in stroke patients.

Several randomized controlled trials have demonstrated the benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic stroke in patients with diabetes. In this review, we summarize and discuss the potential mechanisms of stroke protection by GLP-1RAs. GLP-1RAs exert multiple anti-atherosclerotic effects contributing to stroke prevention such as enhanced plaque stability, reduced vascular smooth muscle proliferation, increased nitric oxide, and improved endothelial function. GLP-1RAs also lower the risk of stroke by reducing traditional stroke risk factors including hyperglycemia, hypertension, and dyslipidemia. Independently of these peripheral actions, GLP-1RAs show direct cerebral effects in animal stroke models, such as reduction of infarct volume, apoptosis, oxidative stress, neuroinflammation, excitotoxicity, blood-brain barrier permeability, and increased neurogenesis, neuroplasticity, angiogenesis, and brain perfusion. Despite these encouraging findings, further research is still needed to understand more thoroughly the mechanisms by which GLP-1RAs may mediate stroke protection specifically in the human diabetic brain., (© 2022. The Author(s).)

Background: In atherosclerotic stroke, lipid-lowering treatment with a target LDL (low-density lipoprotein) cholesterol of <70 compared with 100±10 mg/dL reduced the risk of subsequent cardiovascular events. This post hoc analysis explored the relative effects of the combination of statin and ezetimibe (dual therapy) and statin monotherapy in achieving the lower LDL cholesterol target and in reducing the risk of major vascular events, as compared with the higher target group., Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 or 100±10 mg/dL, using statin and/or ezetimibe as needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event., Results: Among 2860 patients enrolled, patients who were on dual therapy during the trial in the lower target group had a higher baseline LDL cholesterol as compared to patients on statin monotherapy (141±38 versus 131±36, respectively, P <0.001). In patients on dual therapy and on statin monotherapy, the achieved LDL cholesterol was 66.2 and 64.1 mg/dL respectively, and the primary outcome was reduced during dual therapy as compared with the higher target group (HR, 0.60 [95% CI, 0.39-0.91]; P =0.016) but not during statin monotherapy (HR, 0.92 [95% CI, 0.70-1.20]; P =0.52), with no significant increase in intracranial bleeding., Conclusions: In the TST trial (Treat Stroke to Target), targeting an LDL cholesterol of < 70 mg/dL with a combination of statin and ezetimibe compared with 100±10 mg/dL consistently reduced the risk of subsequent stroke., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01252875. URL: clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

Aims: Little is known about rural-urban differences in the treatment and outcomes in patients with atrial fibrillation (AF). We aimed to assess whether the initiation of oral anticoagulant (OAC) therapy in patients with AF differs between those with rural and urban residence., Methods: The registry-based FinACAF cohort covers all patients with AF from all levels of care in Finland. Patients were divided into rural and urban categories and into urbanization degree tertiles based on their municipality of residence at the time of AF diagnosis. The outcome was the first redeemed OAC prescription., Results: We identified 222 419 patients (50.1% female; mean age 72.8 (SD 13.2) years) with incident AF during 2007-2018. Urban residence was associated with a lower rate of OAC therapy initiation (adjusted subdistribution hazard ratio (SHR) (95% CI) 0.96 (0.95-0.97)). Correspondingly, an inverse graded dose-response relationship was observed between higher urbanization degree tertile and OAC initiation rate (highest tertile compared to lowest: adjusted SHR (95% CI) 0.94 (0.93-0.95)). The adoption of direct oral anticoagulants for stroke prevention was faster among patients with urban residence., Conclusion: This nationwide cohort study documented that urban residence is associated with a slightly lower rate of OAC therapy initiation in patients with incident AF, but faster adoption of direct oral anticoagulant use., Competing Interests: Conflict of Interest Disclosures: Konsta Teppo: none. Jussi Jaakkola: none. Ville Langén: none. Fausto Biancari: none Olli Halminen: none. Jukka Putaala: Dr. Putaala reports personal fees from Boehringer-Ingelheim, personal fees and other from Bayer, grants and personal fees from BMS-Pfizer, personal fees from Portola, other from Amgen, personal fees from Herantis Pharma, personal fees from Terve Media, other from Vital Signum, personal fees from Abbott, outside the submitted work. Pirjo Mustonen: Consultant: Roche, BMS-Pfizer-alliance, Novartis Finland, Boehringer Ingelheim, MSD Finland. Jari Haukka: Consultant: Research Janssen R&D; Speaker: Bayer Finland. Miika Linna: Speaker: BMSPfizer-alliance, Bayer, Boehringer-Ingelheim. Juha Hartikainen: Research grants: The Finnish Foundation for Cardiovascular Research, EU Horizon 2020, EU FP7. Advisory Board Member: BMS-Pfizer-alliance, Novo Nordisk, Amgen. Speaker: Cardiome, Bayer. K.E. Juhani Airaksinen: Research grants: The Finnish Foundation for Cardiovascular Research; Speaker: Bayer, Pfizer and Boehringer-Ingelheim. Member in the advisory boards: Bayer, Pfizer and AstraZeneca. Mika Lehto: Consultant: BMS-Pfizer-alliance, Bayer, Boehringer-Ingelheim, and MSD; Speaker: BMS-Pfizer-alliance, Bayer, Boehringer Ingelheim, MSD, Terve Media and Orion Pharma. Research grants: Aarne Koskelo Foundation, The Finnish Foundation for Cardiovascular Research, and Helsinki and Uusimaa Hospital District research fund, Boehringer-Ingelheim.

Background: Current guidelines equally recommend direct oral anticoagulants (DOACs) and warfarin for atrial fibrillation (AF) patients with a bioprosthetic valve (BPV); however, there are limited data comparing DOACs and warfarin in AF patients with an aortic BPV., Methods and results: This post-hoc subgroup analysis of a multicenter, prospective, observational registry (BPV-AF Registry) aimed to compare DOACs and warfarin in AF patients with an aortic BPV. The primary outcome was a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. The analysis included 479 patients (warfarin group, n=258; DOAC group, n=221). Surgical aortic valve replacement was performed in 74.4% and 36.7% of patients in the warfarin and DOAC groups, respectively. During a mean follow up of 15.5 months, the primary outcome occurred in 45 (17.4%) and 32 (14.5%) patients in the warfarin and DOAC groups, respectively. No significant difference was found in the primary outcome between the 2 groups (adjusted hazard ratio: 0.88, 95% confidence interval: 0.51-1.50). No significant multiplicative interaction was observed between the anticoagulant effects and type of aortic valve procedure (P=0.577)., Conclusions: Among AF patients with an aortic BPV, no significant difference was observed in the composite outcome of adverse clinical events between patients treated with warfarin and those treated with DOACs, suggesting that DOACs can be used as alternatives to warfarin in these patients.

Background: Increasing studies have found that PM2.5 has large adverse effects on stroke mortality. We want to investigate the long-term trends in the mortality of stroke attributable to ambient particulate matter pollution and household air pollution to provide evidence facilitating the design of policy., Methods: The deaths data of stroke and its subtypes attributable to PM2.5 were obtained from the Global Burden of Disease (GBD) 2019, analyzed by Joinpoint regression software and the age-period-cohort (APC) method to assess the magnitude of the trends in mortality and the temporal trends in the mortality rate by age, period, and cohort., Results: From 1990 to 2019, the age-standardized mortality rate (ASMR) attributable to PM2.5 exposure trended downwards, but the trends of ambient particulate matter pollution and household air pollution were opposite. The trends varied among subtypes, the AAPC of intracerebral hemorrhage, ischemic stroke, and subarachnoid hemorrhage attributable to PM2.5 were 0.7, 2.5, and-3.3%, respectively. The longitudinal age curve of the APC model showed that the mortality rates due to PM2.5 exposure increased with age. The period RRs of ischemic stroke due to ambient particulate matter pollution increased significantly. The cohort RRs of ambient particulate matter pollution increased among those born from 1905 to 1990. The net drifts of all subtypes attributable to PM2.5 were below 0, but owing to the increase of ambient particulate matter pollution, the range of the decline was small. Males had higher net drift values, compared with females., Conclusions: Ambient particulate matter pollution has become the main type of PM2.5 leading to stroke in China. PM2.5 exposure is more harmful to ischemic stroke, males, and elderly. Chinese government should pay attention to the long-term impact of ambient air pollution on stroke and take effective public health policies and interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Zhou, Li, Liang, Zhou, Zou and Zhou.)

We aimed to compare the ability to balance baseline covariates and explore the impact of residual confounding between conventional and machine learning approaches to derive propensity scores (PS). The Health Insurance Review and Assessment Service database (January 2012-September 2019) was used. Patients with atrial fibrillation (AF) who initiated oral anticoagulants during July 2015-September 2018 were included. The outcome of interest was stroke/systemic embolism. To estimate PS, we used a logistic regression model (i.e., a conventional approach) and a generalized boosted model (GBM) which is a machine learning approach. Both PS matching and inverse probability of treatment weighting were performed. To evaluate balance achievement, standardized differences, p -values, and boxplots were used. To explore residual confounding, E-values and negative control outcomes were used. In total, 129,434 patients were identified. Although all baseline covariates were well balanced, the distribution of continuous variables seemed more similar when GBM was applied. E-values ranged between 1.75 and 2.70 and were generally higher in GBM. In the negative control outcome analysis, slightly more nonsignificant hazard ratios were observed in GBM. We showed GBM provided a better ability to balance covariates and had a lower impact of residual confounding, compared with the conventional approach in the empirical example of comparative effectiveness analysis.

Objective: To assess baseline characteristics and antithrombotic treatment (ATT) prescription patterns in patients enrolled in the third phase of the GLORIA-AF Registry Program, evaluate predictors of treatment prescription, and compare results with phase II., Methods: GLORIA-AF is a large, global, prospective registry program, enrolling patients with newly diagnosed nonvalvular atrial fibrillation (AF) at risk of stroke. Patients receiving dabigatran were followed for two years in phase II, and all patients were followed for 3 years in phase III. Phase II started when dabigatran became available; phase III started when the characteristics of patients receiving dabigatran became roughly comparable with those receiving vitamin K antagonists (VKAs)., Results: Between 2014 and 2016, 21,241 patients were enrolled in phase III. In total, 82% of patients were prescribed oral anticoagulation ([OAC]; 59.5% novel/nonvitamin K oral anticoagulants [NOACs], 22.7% VKAs). A further 11% of patients were prescribed antiplatelets without OAC and 7% were prescribed no ATT. A high stroke risk was the main driver of OAC prescription. Factors associated with prescription of VKA over NOAC included type of site, region, physician specialty, and impaired kidney function., Conclusion: Over the past few years, data from phase III of GLORIA-AF show that OACs have become the standard treatment option, with most newly diagnosed AF patients prescribed a NOAC. However, in some regions a remarkable proportion of patients remain undertreated. In comparison with phase II, more patients received NOACs in phase III while the prescription of VKA decreased. VKAs were preferred over NOACs in patients with impaired kidney function., Competing Interests: L Beier declares no conflicts of interest at the time of manuscript writing and is now an employee of Novartis Pharma GmbH. S Lu was an employee of Boehringer Ingelheim at the time of manuscript writing and is now employed by Biogen Inc. S Marler, C Teutsch, K Zint, L Baker and M Paquette are employees of Boehringer Ingelheim. L Riou França was an employee of Boehringer Ingelheim at the time of manuscript writing and is now employed by Sanofi-Aventis. GYH Lip is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. No fees are received personally. MV Huisman reports grants from ZonMW Dutch Healthcare Fund, grants and fees to the hospital from Boehringer Ingelheim, Pfizer-BMS, Bayer HealthCare, Aspen, Daiichi-Sankyo, outside the submitted work. JL Halperin has engaged in consulting activities with Boehringer Ingelheim, for advisory activities involving anticoagulants, and he is a member of the Executive Steering Committee of the GLORIA-AF Registry. H-C Diener has received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from: Abbott, Bayer Vital, Bristol-Myers Squibb (BMS), Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portola, Sanofi-Aventis, and WebMD Global. Financial support for research projects was provided by Boehringer Ingelheim. Dr Diener chairs the Treatment Guidelines Committee of the German Society of Neurology and contributed to the EHRA and ESC guidelines for the treatment of AF. C-S Ma has received honoraria for lectures from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, BMS, Johnson & Johnson, and Pfizer. DB Bartels was an employee of Boehringer Ingelheim at time of manuscript writing and is now an employee at UCB Pharma GmbH. SJ Dubner has received consultancy fees for serving as a steering committee member for Boehringer Ingelheim; he also holds research grants from St Jude Medical. P Lyrer has received honoraria for contribution to advisory boards from Boehringer Ingelheim, BMS, Bayer, Pfizer, Daiichi Sankyo, and Ricordati, and research grants from the Swiss Heart Foundation, Swiss National Foundation, Bayer, Sanofi, Acticor, and the University Hospital Basel foundation (propatient). J Senges has received honoraria for contribution to advisory boards from Boehringer Ingelheim. KJ Rothman declares no conflicts of interest.

Although growing evidence suggests that N,N-diethyl- m- toluamide (DEET) has adverse effects on public health, the relationship of DEET with cardiovascular disease (CVD) is still largely unknown. The purpose of this study was, therefore, to evaluate the association between DEET exposure and total and specific CVD among the US adults. In this cross-sectional study, a total of 5,972 participants were selected from the National Health and Nutrition Examination Survey (NHANES) 2007-2014. CVD was defined as a combination of congestive heart failure (CHF), coronary heart disease (CHD), angina, heart attack, or stroke. Logistic regression models were used to evaluate the association between DEET metabolites and the risks of total and specific CVD. Compared to the lowest quartile, 3-(diethylcarbamoyl) benzoic acid (DCBA) in the highest quartile was associated with the increased risks of CVD (odds ratio [OR]: 1.32, 95% CI: 1.03-1.68, P for trend = 0.025) and CHD (OR: 1.57, 95% CI: 1.10-2.25, P for trend = 0.017), after adjustment for potential covariates. Nevertheless, exposure to DCBA was not significantly associated with heart attack, CHF, angina, and stroke. Further studies are required to confirm these findings and identify the underlying mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yan, Wang, Xu, Jiang, Xiong, Cao, Wang, Wang, Zhang, Wang, Sun, Hou and Wei.)

Background: Millions of women worldwide use exogenous hormones as oral contraceptives or hormone replacement therapy. Still, time-dependent and long-term consequences of exogenous hormones on stroke risk remains unclear., Methods: We examined the association between self-reported oral contraceptive and hormone replacement therapy use and stroke risk in 257 194 women from the UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Exposures were analyzed as time-varying variables in Cox regression models., Results: During first year of oral contraceptive use, an increased event rate of any stroke was observed (hazard ratio [HR], 2.49 [95% CI, 1.44-4.30]), while the hazards were found to be comparable during remaining years of use (HR, 1.00 [95% CI, 0.86-1.14]), compared with nonusers. Similarly, first year of hormone replacement therapy use was associated with higher hazard rates of any stroke (HR, 2.12 [95% CI, 1.66-2.70]), as well as cause-specific stroke, including ischemic stroke (HR, 1.93 [95% CI, 1.05-3.57]) and subarachnoid hemorrhage (HR, 2.17 [95% CI, 1.25-3.78]), which remained increased for any stroke during remaining years of use (HR, 1.18 [95% CI, 1.05-1.31]), and after discontinuation (HR, 1.16 [95% CI, 1.02-1.32])., Conclusions: Oral contraceptive use and hormone replacement therapy were associated with an increased risk of stroke, especially during the first year of use, possibly due to immediate changes in hemostatic balance. This study provides new insights on the effects of hormone exposure on stroke risk and provide evidence of not only an overall risk but also a pronounced effects seen in the beginning of treatment.

Opiate use is related to neuropathological disorders, stroke and stroke attributable risk factors. However, secondary exposure to opiate in relation to the above-mentioned complications is studied only in animal models and remains to be evaluated in human populations. We tested whether passive exposure to opiate is associated with stroke and the known stroke predictive factors. We carried out a cross-sectional study of 1541 never smoker women who participated in the Rafsanjan Cohort Study (RCS) with their husbands (2015-2017 recruitment phase). RCS is one of the 19 geographic districts of the Prospective Epidemiological Research Studies in Iran (PERSIAN cohort study). Unadjusted and adjusted multiple logistic regression analyses were performed to evaluate the relationship between second-hand opiate exposure (husband opiate smoking after marriage) and the odds ratio of stroke and the following stroke risk factors and predictive parameters: overweight/obesity (BMI > 25), cholesterol (chol) > 200 mg/dl, fasting blood sugar (FBS) > 125 mg/dl, low density lipoprotein (LDL) > 100 mg/dl, triglyceride (TG) >  = 150 mg/dl, hypertension, diabetes, and chronic headache. We observed a significant increased adjusted odds ratio (OR) of stroke (OR = 3.43, 95% CI:1.33-8.82) and its risk factors LDL > 100 mg/dl (OR = 1.37, 95% CI:1.01-1.87) and FBS > 125 mg/dl (OR = 1.58, 95% CI:1.08-2.30) in women associated with husbands' opiate smoking. This relationship was observed after adjusting for the confounding parameters including age, education years, and first-degree family history of the relevant diseases. The increased odds ratio for stroke and high LDL displayed a dose-sensitive trend with years of husband's opiate smoking after marriage (respective p-trends: 0.02 & 0.01). We did not observe a significant association between passive opiate smoking and high TG, high Chol or the diseases diabetes, hypertension and chronic headache. However, 89% increased odds ratio of chronic headache was observed to be associated with passive opiate smoking for more than 10 years (OR = 1.89, 95% CI:1.02-3.50). We found an increased risk of stroke and high LDL and FBS in women associated with passive opiate smoking. Furthermore, a dose-sensitive connection was found between the risks of stroke, high LDL and chronic headache with the years of passive opiate exposure. Our results point to the necessity of the future analyses, which further assess whether passive opiate exposure could be considered as an independent risk factor for stroke and metabolic diseases., (© 2022. The Author(s).)

Although particulate matter (PM) is a major risk factor for stroke, its effects on hospital outpatients admitted for stroke have not been documented in Korea. In addition, recent studies have reported that the effects of PM 10 on circulatory mortality changed over time. We aimed to estimate the effects of PM 10 on stroke and their temporal heterogeneity in seven major cities of Korea during the period 2002-2015. The study period was divided into five years of moving time windows, and city-specific PM 10 effects on ischemic and hemorrhagic stroke outpatients were calculated. We pooled the estimates using meta-analysis and plotted them into a sequence to identify their temporal trends. A 10 µg/m 3 increase of PM 10 was significantly associated with increments in hospital outpatients admitted for ischemic stroke (0.24%, 95% CI: 0.04%, 0.44%), but not for hemorrhagic stroke (0.33%, 95% CI: -0.06%, 0.73%). Effect estimates for strokes increased during the period 2003-2013 but decreased after. For the first time, we have estimated the effects of PM 10 on hospital outpatients admitted for stroke in Korea. The observed temporal trend in PM 10 effects was similar to patterns of circulatory mortality, suggesting that the temporal heterogeneity in PM 10 effects might be due to systematic causes rather than random fluctuations.

Background Real-world data on low baseline low-density lipoprotein cholesterol (LDL-C) levels and long-term postdischarge cardiovascular outcomes in patients with acute coronary syndrome are limited. Methods and Results Of the 10 719 patients enrolled in the Korean registry of acute myocardial infarction between January 2004 and August 2014, we identified 5532 patients who were event free from death, recurrent myocardial infarction, or stroke during the in-hospital period after successful percutaneous coronary intervention. The co-primary outcomes were 3-point major adverse cardiovascular events (a composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death) and cardiovascular death at 5 years. Of 5532 patients with acute myocardial infarction (mean age, 62.1±12.8 years; 75.0% men), 446 cardiovascular deaths (8.1%) and 695 three-point major adverse cardiovascular events (12.6%) occurred at 5 years. In the continuous analysis of LDL-C, the risk of cardiovascular events increased steeply as LDL-C levels decreased from 100 mg/dL. For categorical analysis of LDL-C (<70, 70-99, and ≥100 mg/dL), as LDL-C levels decreased, clinical outcomes worsened (237/3759 [6.3%] in LDL-C ≥100 mg/dL versus 123/1291 [9.5%] in LDL-C 70-99 mg/dL versus 86/482 [17.8%] in LDL-C <70 mg/dL for cardiovascular death; P -trend<0.001; and 417/3759 [11.1%] in LDL-C ≥100 mg/dL versus 172/1291 [13.3%] in LDL-C 70-99 mg/dL versus 106/482 [22.2%] in LDL-C <70 mg/dL for 3-point major adverse cardiovascular event; P -trend<0.001). In a Cox time-to-event multivariable model with LDL-C levels ≥100 mg/dL as the reference, the baseline LDL-C level <70 mg/dL was independently associated with an increased incidence of cardiovascular death (adjusted hazard ratio, 1.68 [95% CI, 1.30-2.17]) and 3-point major adverse cardiovascular event (adjusted hazard ratio, 1.37 [95% CI, 1.10-1.71]). Conclusions In this Korean acute myocardial infarction registry, the baseline LDL-C level <70 mg/dL was significantly associated with an increased incidence of long-term cardiovascular events after discharge. (COREA [Cardiovascular Risk and Identification of Potential High-Risk Population]-Acute Myocardial Infarction Registry; NCT02806102). Registration URL: https://www.clinicaltrials.gov/; Unique identifier: NCT02806102.

Acute ischemic stroke (AIS) represents an important cause of disability and death. Since only a minor percentage of patients with AIS are eligible for acute therapy, the management of risk factors is mandatory. An important risk factor of AIS is hyperlipemia. The current guidelines recommend a strict correction of it. Statins are recommended as the first-line treatment, while proprotein convertase subtilin/kexin type 9 (PCSK-9) inhibitors are administered as a second or even third option when the goal for a low-density lipoprotein cholesterol (LDL-C) level is not achieved. PCSK-9 inhibitors effectively decrease the LDL-C levels through the inhibition of PCSK-9-LDL-receptor complex formation. The in-depth understanding of the PCSK-9 protein mechanism in the metabolism of LDL-C led to the development of effective targeted approaches. Furthermore, a better understanding of the LDL-C metabolic pathway led to the development of newer approaches, which increased the therapeutic options. This article aims to offer an overview of the PCSK-9 inhibitors and their mechanism in reducing the LDL-C levels. Moreover, we will present the main indications of the current guidelines for patients with hyperlipemia and for those who have suffered an acute ischemic stroke, as well as the importance of LDL-C reduction in decreasing the rate of a recurrence.

Objective: To evaluate the frequency of emergency department (ED) revisits among elderly patients with gastrointestinal bleeding secondary to anticoagulant treatment and identify factors associated with an increased risk of ED revisits., Methods: A 3-year retrospective observational study was designed, including elderly patients (≥65 years) with atrial fibrillation and undergoing oral anticoagulation therapy who visited the ED for gastrointestinal bleeding. To evaluate the risk factors for 30-day revisit, a multivariate analysis was designed including comorbidities, concomitant treatment, change in anticoagulant treatment and prescription of direct-acting oral anticoagulants., Results: 80 patients were included. At discharge, anticoagulation therapy was modified in 21 (26.2%) patients; and changed from an oral anticoagulant to heparin in 17 (21.2%) patients and to another oral anticoagulant in 4 (5.0%) patients. Anticoagulant treatment was withdrawn in 5 (6.3%) patients at discharge. Eleven (13.7%) patients revisited the ED 30 days after hospital discharge for bleeding episodes. No differences in the frequency of revisit to the ED were observed in the patients who changed their anticoagulant treatment at discharge. In the multivariate analysis, chronic kidney disease was the only factor significantly associated with revisits at 30 days., Conclusions: Elderly patients who experience a first episode of gastrointestinal bleeding have a high risk of revisiting the ED for a bleeding episode, with no particular differences between the types of anticoagulant prescribed at discharge., Competing Interests: Competing interests: JR, AJ and MAM declare potential conflict of interest with Behringer., (© European Association of Hospital Pharmacists 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immunization stress-related responses presenting as stroke-like symptoms could develop following COVID-19 vaccination. Therefore, this study aimed to describe the clinical characteristics of immunization stress-related responses causing stroke-like events following COVID-19 vaccination in Thailand., Methods: We conducted a retrospective study of the secondary data of reported adverse events after COVID-19 immunization that presented with neurologic manifestations. Between March 1 and July 31, 2021, we collected and analyzed the medical records of 221 patients diagnosed with stroke-like symptoms following immunization. Two majority types of vaccines were used at the beginning of the vaccination campaign, including CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca). Demographic and medical data included sex, age, vaccine type, sequence dose, time to event, laboratory data, and recovery status as defined by the modified Rankin score. The affected side was evaluated for associations with the injection site., Results: Overall, 221 patients were diagnosed with immunization stress-related responses (stroke-like symptoms) following CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca) vaccinations. Most patients (83.7%) were women. The median (interquartile range) age of onset was 34 (28-42) years in patients receiving CoronaVac and 46 (33.5-60) years in those receiving ChAdOx1. The median interval between vaccination and symptom onset for each vaccine type was 60 (16-960) min and 30 (8.8-750) min, respectively. Sensory symptoms were the most common symptomology. Most patients (68.9%) developed symptoms on the left side of the body; 99.5% of the patients receiving CoronaVac and 100% of those receiving ChAdOx1 had a good outcome (modified Rankin scores ≤2, indicating slight or no disability)., Conclusions: Immunization stress-related responses presenting as stroke-like symptoms can develop after COVID-19 vaccination. Symptoms more likely to occur on the injection side are transient (i.e., without permanent pathological deficits). Public education and preparedness are important for administering successful COVID-19 vaccination programs., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the risks of recurrent stroke and major bleeding events with clopidogrel and aspirin use among patients aged 80 years or older., Patients and Methods: This retrospective cohort study was conducted using the Full Population Data of the Health and Welfare Database in Taiwan. Patients aged 80 years or older who received monotherapy with clopidogrel or aspirin following hospitalization for primary acute ischemic stroke between January 1, 2009, and December 31, 2018, were included. Inverse probability of treatment weighting was used to balance measured covariates between clopidogrel and aspirin users. Measured outcomes included recurrent acute ischemic stroke, acute myocardial infarction, composite cardiovascular events (recurrent stroke or acute myocardial infarction), intracranial hemorrhage, major gastrointestinal tract bleeding, and composite major bleeding events (intracranial hemorrhage or major gastrointestinal tract bleeding)., Results: A total of 15,045 patients were included in the study, 1979 of whom used clopidogrel and 13,066 who used aspirin following hospitalization for primary acute ischemic stroke. Clopidogrel use was associated with significantly lower risk of recurrent acute ischemic stroke (hazard ratio [HR], 0.89; 95% CI, 0.83 to 0.96; P=.002), composite cardiovascular events (HR, 0.88; 95% CI, 0.82 to 0.95; P<.001), intracranial hemorrhage (HR, 0.71; 95% CI, 0.56 to 0.90; P=.005), and composite major bleeding events (HR, 0.89; 95% CI, 0.80 to 0.99; P=.04) compared with aspirin use., Conclusion: In patients aged 80 years or older with primary acute ischemic stroke, clopidogrel users had lower risks of recurrent stroke and the composite cardiovascular events compared with aspirin users. Clopidogrel users also had lower risks of intracranial hemorrhage and the composite major bleeding events compared with aspirin users., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)