Longer and better lives for patients with atrial fibrillation: the 9th AFNET/EHRA consensus conference.

AIMS: Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). METHODS AND RESULTS: Eighty-three international experts met in Münster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF. CONCLUSIONS: Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF.

Service delivery in acute ischemic stroke patients: Does sex matter?

BACKGROUND AND PURPOSE: Women with acute ischemic stroke (AIS) are older and have greater preexisting handicap than men. Given that these factors do not fully explain their poorer long-term outcomes, we sought to investigate potential sex differences in the delivery of acute stroke care in a large cohort of consecutive AIS patients. METHODS: We analyzed all patients from ASTRAL (Acute Stroke Registry and Analysis of Lausanne) from March 2003 to December 2019. Multivariable analyses were performed on acute time metrics, revascularization therapies, ancillary examinations for stroke workup, subacute symptomatic carotid artery revascularization, frequency of change in goals of care (palliative care), and length of hospital stay. RESULTS: Of the 5347 analyzed patients, 45% were biologically female and the median age was 74.6 years. After multiple adjustments, female sex was significantly associated with higher onset-to-door (adjusted hazard ratio [aHR] = 1.09, 95% confidence interval [CI] = 1.04-1.14) and door-to-endovascular-puncture intervals (aHR = 1.15, 95% CI = 1.05-1.25). Women underwent numerically fewer diagnostic examinations (adjusted odds ratio [aOR] = 0.94, 95% CI = 0.85-1.04) and fewer subacute carotid revascularizations (aOR = 0.69, 95% CI = 0.33-1.18), and had longer hospital stays (aHR = 1.03, 95% CI = 0.99-1.07), but these differences were not statistically significant. We found no differences in the rates of acute revascularization treatments, or in the frequency of change of goals of treatments. CONCLUSIONS: This retrospective analysis of a large, consecutive AIS cohort suggests that female sex is associated with unfavorable pre- and in-hospital time metrics, such as a longer onset-to-door and door-to-endovascular-puncture intervals. Such indicators of less effective stroke care delivery may contribute to the poorer long-term functional outcomes in female patients and require further attention.

Secondary stroke prevention in people with atrial fibrillation: treatments and trials.

Atrial fibrillation is one of the most common cardiac arrhythmias and is a major cause of ischaemic stroke. Recent findings indicate the importance of atrial fibrillation burden (device-detected, subclinical, or paroxysmal and persistent or permanent) and whether atrial fibrillation was known before stroke onset or diagnosed after stroke for the risk of recurrence. Secondary prevention in patients with atrial fibrillation and stroke aims to reduce the risk of recurrent ischaemic stroke. Findings from randomised controlled trials assessing the optimal timing to introduce direct oral anticoagulant therapy after a stroke show that early start (ie, within 48 h for minor to moderate strokes and within 4-5 days for large strokes) seems safe and could reduce the risk of early recurrence. Other promising developments regarding early rhythm control, left atrial appendage occlusion, and novel factor XI inhibitor oral anticoagulants suggest that these therapies have the potential to further reduce the risk of stroke. Secondary prevention strategies in patients with atrial fibrillation who have a stroke despite oral anticoagulation therapy is an unmet medical need. Research advances suggest a heterogeneous spectrum of causes, and ongoing trials are investigating new approaches for secondary prevention in this vulnerable patient group. In patients with atrial fibrillation and a history of intracerebral haemorrhage, the latest data from randomised controlled trials on stroke prevention shows that oral anticoagulation reduces the risk of ischaemic stroke but more data are needed to define the safety profile.

Bleeding Outcomes in Patients Treated With Asundexian in Phase II Trials.

BACKGROUND: Phase II trials of asundexian were underpowered to detect important differences in bleeding. OBJECTIVES: The goal of this study was to obtain best estimates of effects of asundexian vs active control/placebo on major and clinically relevant nonmajor (CRNM) and all bleeding, describe most common sites of bleeding, and explore association between asundexian exposure and bleeding. METHODS: We performed a pooled analysis of 3 phase II trials of asundexian in patients with atrial fibrillation (AF), recent acute myocardial infarction (AMI), or stroke. Bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. RESULTS: In patients with AF (n = 755), both asundexian 20 mg and 50 mg once daily vs apixaban had fewer major/CRNM events (3 of 249; incidence rate [IR] per 100 patient-years 5.47 vs 1 of 254 [IR: not calculable] vs 6 of 250 [IR: 11.10]) and all bleeding (12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]). Most common sites of major/CRNM bleeding with asundexian were gastrointestinal, respiratory, urogenital, and skin. There was no significant association between asundexian exposure and major/CRNM bleeding. CONCLUSIONS: Analyses of phase II trials involving >500 bleeds highlight the potential for improved safety of asundexian compared with apixaban and similar safety compared with placebo. Further evidence on the efficacy of asundexian awaits the results of ongoing phase III trials.

Sex and gender publications in brain health: a mapping review of the Asia-Pacific region.

INTRODUCTION: Reporting of sex and gender analysis in medical research has been shown to improve quality of the science and ensures findings are applicable to women and men. There is conflicting evidence on whether efforts by funding agencies and medical journals to encourage reporting of sex and gender analysis has resulted in tangible improvements. This study mapped the inclusion of sex and gender analysis in stroke and dementia research conducted in the Asia-Pacific region. METHODS: A systematic search for Asia-Pacific stroke and dementia research was conducted in PubMed and papers included from the period 2012 to 2022. Eligible studies were reviewed for inclusion of a primary sex or gender focus and categorized by type of sex and gender analysis. Author gender was determined using an algorithm and its associations with inclusion of sex and gender analysis examined. RESULTS: Total Asia-Pacific publications increased from 109 in 2012 to 313 in 2022, but the rate of studies with a primary sex or gender focus did not increase significantly (R2 = 0.06, F(1,9) = 0.59, p = 0.46). Australia, China, India, Japan and South Korea produced the most publications over the study period and were the only countries with at least 50 publications. The impact of author gender was mixed, with female first authorship associated with inclusion of sex or gender analysis and last female authorship associated with studies having a primary sex or gender focus. CONCLUSIONS: In the Asia-Pacific, brain health research is currently centered around high income countries and efforts are needed to ensure research findings are applicable through out the region. While there was a general increase in brain health publications over the last decade, the rate of sex and gender analysis was unchanged. This demonstrates that even with efforts in some countries in place, there is currently a lack of progress in the Asia-Pacific region to produce more research focusing on sex and gender analysis.

Effect of the Factor XIa Inhibitor Asundexian According to Baseline Infarct Pattern and on MRI Covert Infarct Outcomes.

BACKGROUND: Exploratory analysis of the phase 2 PACIFIC-Stroke (Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-Non-Cardioembolic Stroke) randomized trial suggested that asundexian, an oral factor XIa inhibitor, prevents recurrent stroke and transient ischemic attacks in patients with atherosclerotic stroke. In this post hoc exploratory analysis, we hypothesized that asundexian would be more effective in patients enrolled with large, multiple, or cortical acute infarcts on magnetic resonance imaging than in patients enrolled with a single small subcortical acute infarct, and asundexian would prevent incident cortical covert infarcts. METHODS: In this placebo-controlled double-blinded randomized controlled trial, patients with mild-to-moderate noncardioembolic ischemic stroke were assigned to asundexian (10, 20, or 50 mg once daily) or placebo, in addition to antiplatelet therapy. Brain magnetic resonance imagings were required within 72 hours of randomization and repeated at 26 weeks or at discontinuation of the study drug. RESULTS: Of 1808 randomized patients, 1780 (98.5%) had interpretable baseline magnetic resonance imagings, of which 1628 (91.5%) had ≥1 diffusion-weighted imaging positive acute infarcts. Magnetic resonance imaging follow-up was obtained in 1439 patients, of whom 1358 had no symptomatic stroke during the trial period. Compared with placebo, asundexian 50 mg daily conferred a trend toward reduced risk of recurrent ischemic stroke or incident covert infarcts (hazard ratio, 0.71 [95% CI, 0.45-1.11]) and recurrent ischemic stroke or transient ischemic attack (secondary outcome; hazard ratio, 0.59 [95% CI, 0.33-1.06]) that was not evident in patients with single small subcortical infarcts (hazard ratios, 1.14 [95% CI, 0.62-2.10] and 0.93 [95% CI, 0.28-3.06]). Incident cortical covert infarcts were reduced in patients taking asundexian 50 mg, but the difference was not statistically significant (crude incidence ratio, 0.56 [95% CI, 0.28-1.12]). CONCLUSIONS: These exploratory, unconfirmed results suggest that asundexian may prevent new embolic infarcts but not small artery occlusion. The hypothesis that subtypes of covert brain infarcts respond differently to anticoagulant prevention should be tested in future trials. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04304508.

Do stroke services still show sex differences? A multicenter study.

BACKGROUND: The issue of sex differences in stroke has gained concern in the past few years. However, multicenter studies are still required in this field. This study explores sex variation in a large number of patients and compares stroke characteristics among women in different age groups and across different countries. METHODS: This multicenter retrospective cross-sectional study aimed to compare sexes regarding risk factors, stroke severity, quality of services, and stroke outcome. Moreover, conventional risk factors in women according to age groups and among different countries were studied. RESULTS: Eighteen thousand six hundred fifty-nine patients from 9 countries spanning 4 continents were studied. The number of women was significantly lower than men, with older age, more prevalence of AF, hypertension, and dyslipidemia. Ischemic stroke was more severe in women, with worse outcomes among women (p: < 0.0001), although the time to treatment was shorter. Bridging that was more frequent in women (p:0.002). Analyzing only women: ischemic stroke was more frequent among the older, while hemorrhage and TIA prevailed in the younger and stroke of undetermined etiology. Comparison between countries showed differences in age, risk factors, type of stroke, and management. CONCLUSION: We observed sex differences in risk factors, stroke severity, and outcome in our population. However, access to revascularization was in favor of women.

Cerebral microbleeds and asundexian in non-cardioembolic ischemic stroke: Secondary analyses of the PACIFIC-STROKE randomized trial.

BACKGROUND AND AIMS: Cerebral microbleeds are magnetic imaging resonance (MRI) markers of hemorrhage-prone cerebral small vessel disease that predict future risk of ischemic stroke and intracranial hemorrhage (ICrH). There exist concerns about the net benefit of antithrombotic therapy in patients with microbleeds. We aimed to investigate the effects of an oral factor-XIa inhibitor (asundexian), that is hypothesized to inhibit thrombosis without compromising hemostasis, on the development of new microbleeds over time and interactions between microbleeds and asundexian treatment on clinical outcomes. We additionally assessed associations between baseline microbleeds and the risks of clinical and neuroimaging outcomes in patients with non-cardioembolic ischemic stroke. METHODS: This is a secondary analysis of the PACIFIC-STROKE, international, multi-center Phase 2b double-blind, randomized clinical trial. PACIFIC-STROKE enrolled patients aged ⩾ 45 years with mild-to-moderate non-cardioembolic ischemic stroke who presented within 48 h of symptom onset for whom antiplatelet therapy was intended. Microbleeds were centrally adjudicated, and participants with an interpretable T2*-weighted sequence at their baseline MRI were included in this analysis. Patients were randomized to asundexian (10/20/50 mg daily) versus placebo plus standard antiplatelet treatment. Regression models were used to estimate the effects of (1) all pooled asundexian doses and (2) asundexian 50 mg daily on new microbleed formation on 26-week MRIs. Cox proportional hazards or regression models were additionally used to estimate interactions between treatment assignment and microbleeds for ischemic stroke/transient ischemic attack (TIA) (primary outcome), and ICrH, all-cause mortality, hemorrhagic transformation (HT), and new microbleeds (secondary outcomes). RESULTS: Of 1746 participants (mean age, 67.0 ± 10.0; 34% female) with baseline MRIs, 604 (35%) had microbleeds. During a median follow-up of 10.6 months, 7.0% (n = 122) had ischemic stroke/TIA, 0.5% (n = 8) ICrH, and 2.1% (n = 37) died. New microbleeds developed in 10.3% (n = 155) of participants with adequate follow-up MRIs and HT in 31.4% (n = 345). In the total sample of patients with adequate baseline and 26-week follow-up MRIs (n = 1507), new microbleeds occurred in 10.2% of patients assigned to any asundexian dose and 10.5% of patients assigned to placebo (OR, 0.96; 95% CI, 0.66-1.41). There were no interactions between microbleeds and treatment assignment for any of the outcomes (p for interaction > 0.05). The rates of new microbleeds, HT, and ICrH were numerically less in patients with microbleeds assigned to asundexian relative to placebo. The presence of microbleeds was associated with a higher risk of HT (aOR, 1.6; 95% CI, 1.2-2.1) and new microbleeds (aOR, 4.4; 95% CI, 3.0-6.3). CONCLUSION: Factor XIa inhibition with asundexian appears safe in patients with non-cardioembolic ischemic stroke and hemorrhage-prone cerebral small vessel disease marked by microbleeds on MRI. These preliminary findings will be confirmed in the ongoing OCEANIC-STROKE randomized trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04304508.

Association of breastfeeding with mental disorders in mother and child: a systematic review and meta-analysis.

BACKGROUND: Breastfeeding has long been associated with numerous benefits for both mothers and infants. While some observational studies have explored the relationship between breastfeeding and mental health outcomes in mothers and children, a systematic review of the available evidence is lacking. The purpose of this study is to systematically evaluate the association between breastfeeding and mental health disorders in mothers and children. METHODS: We systematically searched MEDLINE and EMBASE from inception to June 2, 2023. The inclusion criteria consisted of all studies evaluating links between breastfeeding and development of mental health disorders in children and mothers. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) while grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of evidence. A random-effects meta-analysis was used if possible, to estimate the odds ratio for the association between breastfeeding and mental health outcomes. The Mantel-Haenszel method was utilised for pooling ORs across studies. Study heterogeneity was assessed using the I2 statistic. RESULTS: Our review identified twenty-one original study. Of these, 18 focused on the association between breastfeeding and child health, assessing depressive disorders, schizophrenia, anxiety disorders, eating disorders and borderline personality disorder. Three studies evaluated the associations between breastfeeding and maternal mental health disorders. Three studies looking at outcomes in children showed no significant association between breastfeeding and occurrence of schizophrenia later in life (OR 0.98; 95% CI 0.57-1.71; I2 = 29%). For depressive disorders (5 studies) and anxiety disorders (3 studies), we found conflicting evidence with some studies showing a small protective effect while others found no effect. The GRADE certainty for all these findings was very low due to multiple limitations. Three studies looking at association between breastfeeding and maternal mental health, were too heterogeneous to draw any firm conclusions. CONCLUSIONS: We found limited evidence to support a protective association between breastfeeding and the development of mental health disorders in children later in life. The data regarding the association between breastfeeding and maternal mental health beyond the postnatal period is also limited. The methodological limitations of the published literature prevent definitive conclusions, and further research is needed to better understand the relationship between breastfeeding and mental health in mothers and children.

Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis.

INTRODUCTION: Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention. METHODS: We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding. RESULTS: Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67-1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87-1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61-1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87-1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65-2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64-2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26-3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77-1.90). CONCLUSION: This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention.

Medical Management Versus Endovascular Treatment for Large-Vessel Occlusion Anterior Circulation Stroke With Low NIHSS.

BACKGROUND: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with National Institutes of Health Stroke Scale score of 0 to 5 is common in clinical practice but has not yet been proven safe and effective. Our objective is to assess whether EVT on top of best medical treatment (BMT) in AIS patients with large-vessel occlusion of the anterior circulation presenting with mild symptoms is beneficial compared with BMT. METHODS: We searched MEDLINE, SCOPUS, and reference lists of retrieved articles published until December 28, 2022. A systematic literature search was conducted to identify clinical trials or observational cohort studies evaluating patients with AIS due to anterior circulation large-vessel occlusion and admission National Institutes of Health Stroke Scale score ≤5 treated with EVT versus BMT alone. The primary outcome was excellent functional outcome (modified Rankin Scale score 0-1) at 3 months. The protocol had been registered before data collection (PROSPERO). RESULTS: Eleven observational eligible studies were included in the meta-analysis, comprising a total of 2019 AIS patients with National Institutes of Health Stroke Scale score ≤5 treated with EVT versus 3171 patients treated with BMT. EVT was not associated with excellent functional outcome (risk ratio, 1.10 [95% CI, 0.93-1.31]). When stratified for different study design (per-protocol versus intention-to-treat), there were no significant subgroup differences. EVT was not associated with good functional outcome (modified Rankin Scale score 0-2; risk ratio, 1.01 [95% CI, 0.89-1.16]) or reduced disability at 3 months (common odds ratio, 0.92 [95% CI, 0.60-1.41]). Symptomatic intracranial hemorrhage was more common in the patients receiving EVT (risk ratio, 3.53 [95% CI, 2.35-5.31]). No correlation was found between EVT and mortality at 3 months (risk ratio, 1.34 [95% CI, 0.83-2.18]). The same overall associations were confirmed in the sensitivity analysis of studies that performed propensity score matching. CONCLUSIONS: EVT appears equivalent to BMT for patients with anterior circulation large-vessel occlusion AIS with low baseline National Institutes of Health Stroke Scale, despite the increased risk for symptomatic intracranial hemorrhage. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022334417.

Delivery of acute ischaemic stroke treatments in the European region in 2019 and 2020.

INTRODUCTION: We assessed best available data on access and delivery of acute stroke unit (SU) care, intravenous thrombolysis (IVT) and endovascular treatment (EVT) in the European region in 2019 and 2020. PATIENTS AND METHODS: We compared national data per number of inhabitants and per 100 annual incident first-ever ischaemic strokes (AIIS) in 46 countries. Population estimates and ischaemic stroke incidence were based on United Nations data and the Global Burden of Disease Report 2019, respectively. RESULTS: The estimated mean number of acute SUs in 2019 was 3.68 (95% CI: 2.90-4.45) per one million inhabitants (MIH) with 7/44 countries having less than one SU per one MIH. The estimated mean annual number of IVTs was 21.03 (95% CI: 15.63-26.43) per 100,000 and 17.14% (95% CI: 12.98-21.30) of the AIIS in 2019, with highest country rates at 79.19 and 52.66%, respectively, and 15 countries delivering less than 10 IVT per 100,000. The estimated mean annual number of EVTs in 2019 was 7.87 (95% CI: 5.96-9.77) per 100,000 and 6.91% (95% CI: 5.15-8.67) of AIIS, with 11 countries delivering less than 1.5 EVT per 100,000. Rates of SUs, IVT and EVT were stable in 2020. There was an increase in mean rates of SUs, IVT and EVT compared to similar data from 2016. CONCLUSION: Although there was an increase in reperfusion treatment rates in many countries between 2016 and 2019, this was halted in 2020. There are persistent major inequalities in acute stroke treatment in the European region. Tailored strategies directed to the most vulnerable regions should be prioritised.

Anticoagulation in acute ischemic stroke patients with mechanical heart valves: To bridge or not with heparin. The ESTREM study.

INTRODUCTION: The best therapeutic strategy for patients with mechanical heart valves (MHVs) having acute ischemic stroke during treatment with vitamin K antagonists (VKAs) remain unclear. Being so, we compared the outcomes for: (i) full dose heparin along with VKA (bridging therapy group) and (ii) restarting VKA without heparin (nonbridging group). PATIENTS AND METHODS: For this multicenter observational cohort study, data on consecutive acute ischemic stroke patients with MHV was retrospectively collected from prospective registries. Propensity score matching (PSM) was adopted to adjust for any treatment allocation confounders. The primary outcome was the composite of stroke, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding at 90 days. RESULTS: Overall, 255 out of 603 patients (41.3%) received bridging therapy: 36 (14.1%) had combined outcome, compared with 28 (8.0%) in the nonbridging group (adjusted OR 1.83; 95% CI 1.05-3.18; p = 0.03). Within the bridging group, 13 patients (5.1%) compared to 12 (3.4%) in the nonbridging group had an ischemic outcome (adjusted OR 1.71; 95% CI 0.84-3.47; p = 0.2); major bleedings were recorded in 23 (9.0%) in the bridging group and 16 (4.6%) in the nonbridging group (adjusted OR 1.88; 95% CI 0.95-3.73; p = 0.07). After PSM, 36 (14.2%) of the 254 bridging patients had combined outcome, compared with 23 (9.1%) of 254 patients in the nonbridging group (OR 1.66; 95% CI 0.95-2.85; p = 0.07). CONCLUSION: Acute ischemic stroke patients with MHV undergoing bridging therapy had a marginally higher risk of ischemic or hemorrhagic events, compared to nonbridging patients.

Six years of the Angels Initiative: Aims, achievements, and future directions to improve stroke care worldwide.

The rate of stroke-related death and disability is four times higher in low- and middle-income countries (LMICs) than in high-income countries (HICs), yet stroke units exist in only 18% of LMICs, compared with 91% of HICs. In order to ensure universal and equitable access to timely, guideline-recommended stroke care, multidisciplinary stroke-ready hospitals with coordinated teams of healthcare professionals and appropriate facilities are essential.Established in 2016, the Angels Initiative is an international, not-for-profit, public-private partnership. It is run in collaboration with the World Stroke Organization, European Stroke Organisation, and regional and national stroke societies in over 50 countries. The Angels Initiative aims to increase the global number of stroke-ready hospitals and to optimize the quality of existing stroke units. It does this through the work of dedicated consultants, who help to standardize care procedures and build coordinated, informed communities of stroke professionals. Angels consultants also establish quality monitoring frameworks using online audit platforms such as the Registry of Stroke Care Quality (RES-Q), which forms the basis of the Angels award system (gold/platinum/diamond) for all stroke-ready hospitals across the world.The Angels Initiative has supported over 1700 hospitals (>1000 in LMICs) that did not previously treat stroke patients to become "stroke ready." Since its inception in 2016, the Angels Initiative has impacted the health outcomes of an estimated 7.46 million stroke patients globally (including an estimated 4.68 million patients in LMICs). The Angels Initiative has increased the number of stroke-ready hospitals in many countries (e.g. in South Africa: 5 stroke-ready hospitals in 2015 vs 185 in 2021), reduced "door to treatment time" (e.g. in Egypt: 50% reduction vs baseline), and increased quality monitoring substantially.The focus of the work of the Angels Initiative has now expanded from the hyperacute phase of stroke treatment to the pre-hospital setting, as well as to the early post-acute setting. A continued and coordinated global effort is needed to achieve the target of the Angels Initiative of >10,000 stroke-ready hospitals by 2030, and >7500 of these in LMICs.

Thrombolysis after dabigatran reversal: A nation-wide Italian multicentre study, systematic review and meta-analysis.

Introduction: Recent anticoagulant intake represents a contraindication for thrombolysis in acute ischemic stroke. Idarucizumab reverses the anticoagulant effect of dabigatran, potentially allowing for thrombolysis. This nation-wide observational cohort study, systematic review, and meta-analysis evaluated the efficacy and safety of thrombolysis preceded by dabigatran-reversal in people with acute ischemic stroke. Patients and methods: We recruited people undergoing thrombolysis following dabigatran-reversal at 17 stroke centers in Italy (reversal-group), people on dabigatran treated with thrombolysis without reversal (no-reversal group), and age, sex, hypertension, stroke severity, and reperfusion treatment-matched controls in 1:7 ratio (control-group). We compared groups for symptomatic intracranial hemorrhage (sICH, main outcome), any brain hemorrhage, good functional outcome (mRS 0-2 at 3 months), and death. The systematic review followed a predefined protocol (CRD42017060274), and odds ratio (OR) meta-analysis was implemented to compare groups. Results: Thirty-nine patients in dabigatran-reversal group and 300 matched controls were included. Reversal was associated with a non-significant increase in sICH (10.3% vs 6%, aOR = 1.32, 95% CI = 0.39-4.52), death (17.9% vs 10%, aOR = 0.77, 95% CI = 0.12-4.93) and good functional outcome (64.1% vs 52.8%, aOR = 1.41, 95% CI = 0.63-3.19). No hemorrhagic events or deaths were registered in no-reversal group (n = 12). Pooling data from 3 studies after systematic review (n = 1879), reversal carried a non-significant trend for sICH (OR = 1.53, 95% CI = 0.67-3.50), death (OR = 1.53, 95% CI = 0.73-3.24) and good functional outcome (OR = 2.46, 95% CI = 0.85-7.16). Discussion and conclusion: People treated with reperfusion strategies after dabigatran reversal with idarucizumab seem to have a marginal increase in the risk of sICH but comparable functional recovery to matched patients with stroke. Further studies are needed to define treatment cost-effectiveness and potential thresholds in plasma dabigatran concentration for reversal.

Prolonged cardiac monitoring for stroke prevention: A systematic review and meta-analysis of randomized-controlled clinical trials.

Introduction: Prolonged cardiac monitoring (PCM) substantially improves the detection of subclinical atrial fibrillation (AF) among patients with history of ischemic stroke (IS), leading to prompt initiation of anticoagulants. However, whether PCM may lead to IS prevention remains equivocal. Patients and methods: In this systematic review and meta-analysis, randomized-controlled clinical trials (RCTs) reporting IS rates among patients with known cardiovascular risk factors, including but not limited to history of IS, who received PCM for more than 7 days versus more conservative cardiac rhythm monitoring methods were pooled. Results: Seven RCTs were included comprising a total of 9048 patients with at least one known cardiovascular risk factor that underwent cardiac rhythm monitoring. PCM was associated with reduction of IS occurrence compared to conventional monitoring (Risk Ratio: 0.76; 95% CI: 0.59-0.96; I 2 = 0%). This association was also significant in the subgroup of RCTs investigating implantable cardiac monitoring (Risk Ratio: 0.75; 95% CI: 0.58-0.97; I 2 = 0%). However, when RCTs assessing PCM in both primary and secondary prevention settings were excluded or when RCTs investigating PCM with a duration of 7 days or less were included, the association between PCM and reduction of IS did not retain its statistical significance. Regarding the secondary outcomes, PCM was related to higher likelihood for AF detection and anticoagulant initiation. No association was documented between PCM and IS/transient ischemic attack occurrence, all-cause mortality, intracranial hemorrhage, or major bleeding. Conclusion: PCM may represent an effective stroke prevention strategy in selected patients. Additional RCTs are warranted to validate the robustness of the reported associations.

Sex differences in outcome after carotid revascularization in symptomatic and asymptomatic carotid artery stenosis.

OBJECTIVE: Sex differences regarding the safety and efficacy of carotid revascularization in carotid artery stenosis have been addressed in several studies with conflicting results. Moreover, women are underrepresented in clinical trials, leading to limited conclusions regarding the safety and efficacy of acute stroke treatments. METHODS: A systematic review and meta-analysis was performed by literature search including four databases from January 1985 to December 2021. Sex differences in the efficacy and safety of revascularization procedures, including carotid endarterectomy (CEA) and carotid artery stenting (CAS), for symptomatic and asymptomatic carotid artery stenoses were analyzed. RESULTS: Regarding CEA in symptomatic carotid artery stenosis, the stroke risk in men (3.6%) and women (3.9%) based on 99,495 patients (30 studies) did not differ (P = .16). There was also no difference in the stroke risk by different time frames up to 10 years. Compared with men, women treated with CEA had a significantly higher stroke or death rate at 4 months (2 studies, 2565 patients; 7.2% vs 5.0%; odds ratio [OR], 1.49; 95% confidence interval [CI], 1.04-2.12; I2 = 0%; P = .03), and a significantly higher rate of restenosis (1 study, 615; 17.2% vs 6.7%; OR, 2.81; 95% CI, 1.66-4.75; P = .0001). For CAS in symptomatic artery stenosis, data showed a non-significant tendency toward higher peri-procedural stroke in women, whereas for asymptomatic carotid artery stenosis, data based on 332,344 patients showed that women (compared with men) after CEA had similar rates of stroke, stroke or death, and the composite outcome stroke/death/myocardial infarction. The rate of restenosis at 1 year was significantly higher in women compared with men (1 study, 372 patients; 10.8% vs 3.2%; OR, 3.71; 95% CI, 1.49-9.2; P = .005). Furthermore, CAS in asymptomatic patients was associated with low risk of a postprocedural stroke in both sexes, but a significantly higher risk of in-hospital myocardial infarction in women than men (8445 patients, 1.2% vs 0.6%; OR, 2.01; 95% CI, 1.23-3.28; I2 = 0%; P = .005). CONCLUSIONS: A few sex-differences in short-term outcomes after carotid revascularization for symptomatic and asymptomatic carotid artery stenosis were found, although there were no significant differences in the overall stroke. This indicates a need for larger multicenter prospective studies to evaluate these sex-specific differences. More women, including those aged over 80 years, need to be enrolled in randomized controlled trials, to better understand if sex differences exist and to tailor carotid revascularization accordingly.

Effects of Direct Oral Anticoagulants' Nonrecommended Dose in Atrial Fibrillation: A Meta-Analysis.

BACKGROUND: The efficacy and safety profiles of nonrecommended direct oral anticoagulant (DOAC) doses in patients with nonvalvular atrial fibrillation (NVAF) are still undefined. SUMMARY: We searched for randomized controlled trials and observational studies that compared nonrecommended versus recommended doses of DOACs, published up to December 2021. Primary study outcomes were ischemic stroke/transient ischemic attack/systemic embolism (IS/TIA/SE) and major bleeding (MB). All-cause mortality was a secondary outcome. We determined pooled odds ratios (ORs) between groups of patients with a random-effect model. Twenty-three studies with 175,801 patients were included. Nonrecommended doses were associated with a higher risk of IS/TIA/SE and all-cause mortality, but not of MB as compared to recommended doses of DOACs (OR 1.25 [95% CI: 1.14-1.38], OR 1.69 [95% CI: 1.31-2.18] and OR 1.10 [95% CI: 0.93-1.31], respectively). The nonrecommended low dose was associated with an increased risk of IS/TIA/SE and all-cause death (OR 1.21 [95% CI: 1.05-1.39] and OR 1.66 [95% CI: 1.18-2.35], respectively) but not of MB (OR 1.01 [95% CI: 0.83-1.22] as compared to recommended doses. Subgroup analysis of nonrecommended low doses of DOACs showed a nonsignificant increase in IS/TIA/SE in Asians (OR 1.17 [95% CI: 0.89-1.54] vs. non-Asian (OR 1.21 [95% CI: 1.07-1.36]). KEY MESSAGES: Compared with recommended doses, nonrecommended low doses of DOACs increase the risk of ischemic events without decreasing the risk of bleeding. For Asians, the efficacy of DOACs seemed preserved despite the nonrecommended low-dose prescription. Clinicians should carefully adhere to recommended DOAC prescription advice in managing NVAF patients.

Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a systematic review and meta-analysis.

OBJECTIVE: There has been limited systematic evaluation of outcomes and drivers of inappropriate non-vitamin K antagonist oral anticoagulants (NOACs) dosing among patients with atrial fibrillation (AF). This review identified and systematically evaluated literature on clinical and economic outcomes of inappropriate NOAC dosing and associated patient characteristics. METHODS: MEDLINE, Embase, Cochrane Library, International Pharmaceutical Abstracts, Econlit, PubMed and NHS EEDs databases were searched for English language observational studies from all geographies published between 2008 and 2020, examining outcomes of, or factors associated with, inappropriate NOAC dosing in adult patients with AF. RESULTS: One hundred and six studies were included in the analysis. Meta-analysis showed that compared with recommended NOAC dosing, off-label underdosing was associated with a null effect on stroke outcomes (ischaemic stroke and stroke/transient ischaemic attack (TIA), stroke/systemic embolism (SE) and stroke/SE/TIA). Meta-analysis of 15 studies examining clinical outcomes of inappropriate NOAC dosing found a null effect of underdosing on bleeding outcomes (major bleeding HR=1.04, 95% CI 0.90 to 1.19; p=0.625) but an increased risk of all-cause mortality (HR=1.28, 95% CI 1.10 to 1.49; p=0.006). Overdosing was associated with an increased risk of major bleeding (HR=1.41, 95% CI 1.07 to 1.85; p=0.013). No studies were found examining economic outcomes of inappropriate NOAC dosing. Narrative synthesis of 12 studies examining drivers of inappropriate NOAC dosing found that increased age, history of minor bleeds, hypertension, congestive heart failure and low creatine clearance (CrCl) were associated with an increased risk of underdosing. There was insufficient evidence to assess drivers of overdosing. CONCLUSIONS: Our analysis suggests that off-label underdosing of NOACs does not reduce bleeding outcomes. Patients prescribed off-label NOAC doses are at an increased risk of all-cause mortality. These data underscore the importance of prescriber adherence to NOAC dosing guidelines to achieve optimal clinical outcomes for patients with AF. PROSPERO REGISTRATION NUMBER: CRD42020219844.