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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.

Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

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.

Background: Randomized controlled trials (RCTs) proved that short-term (21–90 days) dual antiplatelet therapy (DAPT) reduces the risk of early ischemic recurrences after a noncardioembolic minor stroke or high-risk transient ischemic attack (TIA) without substantially increasing the hemorrhagic risk. We aimed at understanding whether and how real-world use of DAPT differs from RCTs. Methods: READAPT (Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or TIA) is a prospective cohort study including >18-year-old patients treated with DAPT after a noncardioembolic minor ischemic stroke or high-risk TIA from 51 Italian centers. The study comprises a 90-day follow-up from symptom onset. In the present work, we reported descriptive statistics of baseline data of patients recruited up to July 31, 2022, and proportions of patients who would have been excluded from RCTs. We compared categorical data through the χ² test. Results: We evaluated 1070 patients, who had 72 (interquartile range, 62–79) years median age, were mostly Caucasian (1045; 97.7%), and were men (711; 66.4%). Among the 726 (67.9%) patients with ischemic stroke, 226 (31.1%) did not meet the RCT inclusion criteria because of National Institutes of Health Stroke Scale score >3 and 50 (6.9%) because of National Institutes of Health Stroke Scale score >5. Among the 344 (32.1%) patients with TIA, 69 (19.7%) did not meet the RCT criteria because of age, blood pressure, clinical features, duration of TIA, presence of diabetes score 24 hours) DAPT initiation; 776 (72.5%) and 676 (63.2%) patients did not take loading doses of aspirin and clopidogrel, respectively. Overall, 84 (7.8%) patients met the RCT inclusion/exclusion criteria. Conclusions: The real-world use of DAPT is broader than RCTs. Most patients did not meet the RCT criteria because of the severity of ischemic stroke, lower risk of TIA, late DAPT start, or lack of antiplatelet loading dose. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05476081.

Subarachnoid hemorrhage (SAH) carries high mortality and disability rates, which are substantially driven by complications. Early brain injury and vasospasm can happen after SAH and are crucial events to prevent and treat to improve prognosis. In recent decades, immunological mechanisms have been implicated in SAH complications, with both innate and adaptive immunity involved in mechanisms of damage after SAH. The purpose of this review is to summarize the immunological profile of vasospasm, highlighting the potential implementation of biomarkers for its prediction and management. Overall, the kinetics of central nervous system (CNS) immune invasion and soluble factors’ production critically differs between patients developing vasospasm compared to those not experiencing this complication. In particular, in people developing vasospasm, a neutrophil increase develops in the first minutes to days and pairs with a mild depletion of CD45+ lymphocytes. Cytokine production is boosted early on after SAH, and a steep increase in interleukin-6, metalloproteinase-9 and vascular endothelial growth factor (VEGF) anticipates the development of vasospasm after SAH. We also highlight the role of microglia and the potential influence of genetic polymorphism in the development of vasospasm and SAH-related complications.

Background and Purpose: Clinical trials on stroke prevention in patients with atrial fibrillation have consistently shown clinical benefit from either warfarin or non–vitamin K antagonist oral anticoagulants (NOACs). NOAC-treated patients have consistently reported to be at lower risk for intracerebral hemorrhage (ICH) than warfarin-treated patients. The aims of this prospective, multicenter, multinational, unmatched, case-control study were (1) to investigate for risk factors that could predict ICH occurring in patients with atrial fibrillation during NOAC treatment and (2) to evaluate the role of CHA 2 DS 2 -VASc and HAS-BLED scores in the same setting. Methods: Cases were consecutive patients with atrial fibrillation who had ICH during NOAC treatment. Controls were consecutive patients with atrial fibrillation who did not have ICH during NOAC treatment. As within the CHA 2 DS 2 -VASc and HAS-BLED scores there are some risk factors in common, several multivariable logistic regression models were performed to identify independent prespecified predictors for ICH events. Results: Four hundred nineteen cases (mean age, 78.8±8.1 years) and 1526 controls (mean age, 76.0±10.3 years) were included in the study. From the different models performed, independent predictors of ICH were increasing age, concomitant use of antiplatelet agents, active malignancy, high risk of fall, hyperlipidemia, low clearance of creatinine, peripheral artery disease, and white matter changes. Low doses of NOACs (given according to label or not) and congestive heart failure were inversely associated with the risk of ICH. HAS-BLED and CHA 2 DS 2 -VASc scores performed poorly in predicting ICH with areas under the curves of 0.496 (95% CI, 0.468–0.525) and 0.530 (95% CI, 0.500–0.560), respectively. Conclusions: Several risk factors were associated to ICH in patients treated with NOACs for stroke prevention but not HAS-BLED and CHA 2 DS 2 -VASc scores.

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA 2 DS 2 -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Introduction The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing. Materials and Methods Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. Results A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39–2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16–1.80). Discussion our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events. Conclusions Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.

Background and Aim: Despite progress made over the last 30 years, stroke is still a leading cause of disability and mortality; likewise, its burden is expected to increase over the next decades, due to population growth and aging. The development of drugs with better safety-efficacy profiles as well as strategies able to improve ischemic stroke management from the pre-hospital setting is needed. Summary: The pathophysiology of ischemic stroke involves multiple pathways resulting in cerebral artery obstruction and brain tissue ischemia. To date, the only approved drug for acute ischemic stroke is intravenous thrombolytic alteplase. Intravenous thrombolysis (IVT) can be administered alone or in combination with endovascular treatment (EVT) with mechanical thrombectomy, in case of large vessel occlusion and generally within 6 h from symptoms onset. The risk of potential bleeding complications, especially symptomatic intracerebral hemorrhage, is one of the reasons for the reluctance to administer IVT. Tenecteplase is a promising alternative fibrinolytic agent, having a better safety profile than alteplase. Moreover, recent evidences have allowed an extension of the IVT ± EVT time window for patients with unknown onset time and for those with a known onset time thanks to the new “tissue-window” approach guided by advanced neuroimaging techniques, which also helps in collateral circulation estimation. Regarding primary-secondary prevention, researchers are focused on improving the efficacy of antithrombotic drugs with a “hemostasis-sparing” approach. Neuroprotective agents are also under development, particularly stem cells. The COVID-19 pandemic has critically stressed global healthcare systems, with collateral damage resulting in access delivery of only emergency care, such as ischemic stroke. Regarding telemedicine, it has had a minor role in acute stroke management, and with the onset of COVID-19, this role will most likely be adopted to increase access and delivery in stroke assessment, but also in the follow-up.

BACKGROUND Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation. METHODS In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35. FINDINGS Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. INTERPRETATION The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation. FUNDING Bayer.

Stroke is a leading cause of disability and mortality and its burden expected to increase. The only approved drug for acute ischemic stroke (IS) is the intravenous thrombolytic alteplase. The risk of bleeding complications is one of the reasons for the undertreatment of eligible patients. Numerous drugs are currently being developed to improve safety-efficacy.We reviewed literature from 1 January 2000, to 15 January 2022 for the development and testing of novel drugs with the aim of targeting treatment at prevention of ischemic stroke: PubMed, MEDLINE, Google Scholar, and ClinicalTrial.gov.The pathophysiology of IS involves multiple pathways causing cerebral artery obstruction and brain tissue ischemia. Data suggest that tenecteplase is a promising fibrinolytic agent with a superior efficacy-safety profile, compared to alteplase. Current guidelines consider a short-term cycle of mannitol or hypertonic saline to be advisable in patients with space-occupying hemispheric infarction. Regarding primary and secondary prevention, research is primarily focused on identifying mechanisms to improve the safety-efficacy profile using a 'hemostasis-sparing' approach. Further evaluation on those agents that have shown promise for their risk/benefit profiles, would benefit greatly a neurologist's capacity to successfully prevent and treat IS patients.

Background and Purpose— Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non–vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods— Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results— Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95–5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63–9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83–3.16), and CHA 2 DS 2 -VASc score (OR, 1.72 for each point increase; 95% CI, 1.58–1.88) were associated with ischemic events. Among the CHA 2 DS 2 -VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33–0.61). Conclusions— In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA 2 DS 2 -VASc score were associated with increased risk of cerebrovascular events.

Background and Purpose— Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods— We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results— Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients ( P =0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4–3.7; P P =0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2–4.9; P =0.01) end points separately. Conclusions— Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Introduction Despite intravenous thrombolysis (IVT) and endovascular treatment (EVT) have been demonstrated effective in acute ischemic stroke (AIS) due to large vessel occlusions, there are still no conclusive data to guide treatment in stroke due to cervical internal carotid artery (ICA) occlusion. We systematically reviewed available literature to compare IVT, EVT, and bridging (IVT + EVT) and define optimal treatment. Methods Systematic review followed predefined protocol (Open-Science-Framework osf.io/bfykj). MEDLINE, EMBASE, and Cochrane CENTRAL were searched. Results were restricted to studies in English, with sample size ≥ 10 and follow-up ≥30 days. Primary outcomes were favorable outcome (mRS ≤ 2), mortality, and symptomatic intracerebral hemorrhage(sICH), defined according to study original report. Newcastle-Ottawa scale was used for bias assessment. Results Seven records of 930 screened were included in meta-analysis. Quality of studies was low-to-fair in 5, good in 2. IVT (n = 450) did not differ for favorable outcome and mortality compared to EVT (n = 150), though having lower rate of sICH (OR = 0.4, 95% CI 0.2–0.8). Compared to IVT, bridging (IVT + EVT) was associated with higher rate of favorable outcome (OR = 2.2, 95% CI 1.3–3.7). Compared to EVT, bridging (IVT + EVT) provided higher rate of favorable outcome (OR = 1.9, 95% CI 1.1–3.4), with a marginally increased risk of sICH (OR = 2.1, 95% CI 1–4.4) but similar mortality rates. Conclusions Our systematic review highlights that, in acute ischemic stroke associated with isolated cervical ICA occlusion, bridging (IVT + EVT) might lead to higher rate of functional independence at follow-up, without increasing mortality. The low quality of available studies prevents from drawing firm conclusions, and randomized-controlled clinical trials are critically needed to define optimal treatment in this AIS subgroup.

Intracerebral haemorrhage (ICH) is responsible for disproportionately high morbidity and mortality rates. The most used ICH classification system is based on the anatomical site. We used SMASH-U, an aetiological based classification system for ICH by predefined criteria: structural vascular lesions (S), medication (M), amyloid angiopathy (A), systemic disease (S), hypertension (H), or undetermined (U). We aimed to correlate SMASH-U classification of our patients to the intra-hospital mortality rates. We performed a single centre retrospective study at the Santa Maria Della Misericordia Hospital, Perugia (Italy) including consecutive patients between January 2009 and July 2017 assigned with 431 ICD-9 (International Classification of Diseases-9). We classified the included patients using SMASH-U criteria, and we analysed the association between SMASH-U aetiology and ICH risk factors to the outcome defined as intra-hospital mortality, using multivariable logistic regression analysis. The higher intra-hospital mortality rate was detected in the systemic disease (36.1%), medication (31.5%), and undetermined (29.4%) groups. At multivariable analysis, medication and systemic disease groups resulted associated with the outcome (odds ratio 3.47; 95% CI 1.15–10.46; P = 0.02 and 3.64; 95% CI 1.47–9.01; P = 0.005, respectively). Furthermore, age and high NIHSS at admission resulted significantly associated with intra-hospital mortality (odds ratio 1.01; 95% CI 1–1.03; P = 0.04 and 1.12; 95% CI 1.03–1.22; P = 0.008, respectively). In our retrospective study, the aetiology-oriented classification system SMASH-U showed to be potentially predictive of intra-hospital mortality of acute haemorrhagic stroke patients and it may support clinicians in the acute ICH management.

Background: In this randomized trial, currently utilized standard treatments were compared with enoxaparin for the prevention of venous thromboembolism (VTE) in patients with intracerebral hemorrhage (ICH). Methods: Enoxaparin (0.4 mg daily for 10 days) was started after 72 h from the onset of ICH. The primary outcome was symptomatic or asymptomatic deep venous thrombosis as assessed by ultrasound at the end of study treatment. The safety of enoxaparin was also assessed. We included the results of this study in a meta-analysis of all relevant studies comparing anticoagulants with standard treatments or placebo. Results: PREVENTIHS was prematurely stopped after the randomization of 73 patients, due to the low recruitment rate. The prevalence of any VTE at 10 days was 15.8% in the enoxaparin group and 20.0% in the control group (RR 0.79 [95% CI 0.29–2.12]); 2.6% of enoxaparin and 8.6% of standard therapy patients had severe bleedings (RR 0.31 [95% CI 0.03–2.82]). When these results were meta-analyzed with the results of the selected studies (4,609 patients; 194 from randomized trials), anticoagulants were associated with a nonsignificant reduction in any VTE (OR 0.81; 95% CI 0.43–1.51), in pulmonary embolism (OR 0.53; 95% CI, 0.17–1.60), and in mortality (OR 0.85; 95% CI 0.64–1.12) without increase in hematoma enlargement (OR 0.97; 95% CI, 0.31–3.04). Conclusions: In patients with acute ICH, the use of anticoagulants to prevent VTE was safe but the overall level of evidence was low due to the low number of patients included in randomized clinical trials.

Background and Purpose: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention. Methods: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non–Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features. Results: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50–1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53–2.02]). Conclusions: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation–related acute ischemic stroke, who started on oral anticoagulant.

Rapidly available tests might be useful to measure the anticoagulant effect of direct oral anticoagulants (DOAs) in emergency situations as bleedings, surgery, or before thrombolysis. The aim of this study was to assess the effects of DOAs on global thromboelastometry (ROTEM). Coagulation parameters assessed at peak and trough in patients with non-valvular atrial fibrillation receiving apixaban, dabigatran or rivaroxaban at steady-state (patients) were compared to those of healthy volunteers (controls). Citrated blood samples were tested by ROTEM using diluted EXTEM assay, with and without the addition of an anti-FXa catcher, and using ECATEM-B, with and without the addition of an anti-FIIa catcher. Overall 30 patients (10 for each DOA) and 15 controls were included. The mean clotting time (CT) of patients at peak and trough were significantly higher compared to controls. The mean CT was significantly shortened after the addition of the anti-FXa catcher to apixaban (p = 0.005 for peak and p = 0.009 for trough) and to rivaroxaban samples (p = 0.005 for both peak and trough) and after the addition of anti-FIIa cather to dabigatran samples (p = 0.005 for both peak and trough). ROC curve analyses showed a good accuracy for CT and for CT/CT + catcher (CTc) in measuring dabigatran anticoagulant activity (AUC 1.000 and 0.993, respectively); for CT, CT/CTc and clot formation time (CFT)/CFT + catcher (CFTc) in measuring both apixaban activity (0.917, 0.880 and 0.880, respectively) and rivaroxaban activity (0.973, 0.987 and 0.860, respectively). In this study the use of ad-hoc designed reagents and catcher molecules was able to accurately identify DOAs activity at ROTEM.

Background Transient global amnesia (TGA) is characterised by a sudden onset of anterograde amnesia lasting up to 24 hours. One major differential for TGA is transient epileptic amnesia (TEA), which typically lasts Methods We compared the clinical features of TGA ascertained in two independent cohort studies in Oxfordshire, UK (Oxford cohort 1977‐1987 vs. Oxford Vascular Study‐ OXVASC 2002‐2018) to determine the time‐trends of clinical features of TGA. Results were validated in another independent contemporary TGA cohort in Italy (Northern Umbria registry‐NU 2002‐2018). We compared the risk factors, clinical features and long‐term prognosis (major cardiovascular events–MaCE, recurrent TGA and seizure/epilepsy) of patients presenting with episodes lasting Results Overall 639 TGA patients were included (114 Oxford cohort, 100 OXVASC, 425 NU). Compared to the original Oxford cohort, there were more cases with TGA lasting Conclusions Short‐duration TGA episodes (

Background and Purpose— Transient global amnesia (TGA) is known as a benign syndrome, but recent data from neuroradiological studies support an ischemic cause in some cases, which might suggest an increased susceptibility to cerebrovascular events. We determined the long-term risk of stroke after a first TGA in 2 independent prospective cohorts. Methods— In 2 independent prospective cohorts of patients with TGA (OXVASC [Oxford Vascular Study], population-based; NU (Northern Umbria) cohort, TGA registry), cardiovascular risk factors and long-term outcomes, including stroke and major cardiovascular events, were identified on follow-up. Cardiovascular risk factors were treated according to primary prevention guidelines. In OXVASC, the age-/sex-adjusted risk of stroke during follow-up was compared with that expected from the rate in the underlying study population. Results— Among 525 patients with TGA (425 NU and 100 OXVASC), mean (SD) age was 65.1 (9.5) years and 42.5% male. Hypertension (58.1%), dyslipidemia (40.4%), and smoking (36.4%) were the most frequent cardiovascular risk factors. The risk of stroke was similar in the 2 cohorts, with a pooled annual risk of 0.6% (95% CI, 0.4–0.9) and a 5-year cumulative risk of 2.7% (1.1–4.3). Moreover, the stroke risk in OXVASC cases was no greater than that expected in the underlying study population (adjusted relative risk=0.73; 0.12–4.54; P =0.74). Conclusions— TGA does not carry an increased risk of stroke, at least when cardiovascular risk factors are treated according to primary prevention guidelines.

Lacunar syndromes are usually caused by small ischemic lesions called lacunar infarcts. However, non-lacunar infarcts account for about 20% of lacunar syndromes. The aim of this study was to identify clinical predictors of lacunar syndromes led by non-lacunar infarcts. The following single centre, observational study was conducted on an analysis of the “Perugia hospital-based Stroke Registry” database enrolling consecutive patients admitted with ischemic stroke during the period 2010–2017. We evaluated patient risk factors and clinical features linked to stroke syndrome (lacunar/non-lacunar) and to cerebral infarction (lacunar/non-lacunar). Lacunar syndromes were diagnosed in 478 (26.6%) out of 1796 patients. In 104 (21.1%) patients, lacunar syndromes were caused by non-lacunar infarcts. Lacunar syndromes with lacunar infarcts were primarily linked to diabetes (27.8% vs 16.3%) and obesity (7.7% vs 0.9%), while lacunar syndromes with non-lacunar infarcts were linked to a higher risk of atrial fibrillation (22.1% vs 9.4%) and higher National Institute of Health Stroke Scale scores on admission (mean 5.5 ± 3.7 vs 4.7 ± 2.8). On multivariate analysis, atrial fibrillation (OR 1.67, 95% CI 1.09–2.31; p = 0.002) and higher NIHSS (OR 1.12 for each point increase, 95% CI 1.09–1.15; p

Purpose of review The absolute risk of pregnancy-associated intracranial haemorrhage (ICH) has been reported to be relatively low and often associated with high risks of life-long disabilities and mortality. The aim of this narrative review was obtaining a better understanding of the current management practices for ICH, unruptured aneurysms and/or arteriovenous malformations during pregnancy, as well as the effects of future pregnancies, and the uses of oral contraceptive or HRT. Recent finding General guidelines for the management of ICH are used for pregnant women but additional expedient and thorough evaluation of foetal viability and its gestational age are requested. Recent epidemiological data suggest that menopause can be an independent risk factor for the development of aneurysmal subarachnoid haemorrhage. Furthermore, several population-based studies performed on women with aneurysmal subarachnoid haemorrhage observed a lower risk of bleeding with HRT. Summary The current review observed that the management practices for ICH during pregnancy were seen to be somewhat uniform. Whereas, the practices regarding future pregnancies and the prescriptions of either oral contraceptives or HRT do not follow coherent patterns. In light of this, we recommend the establishment of an international registry that would collect data on women with ICH during pregnancy.

Background The relationship between different patterns of atrial fibrillation and early recurrence after an acute ischaemic stroke is unclear. Purpose In a prospective cohort study, we evaluated the rates of early ischaemic recurrence after an acute ischaemic stroke in patients with paroxysmal atrial fibrillation or sustained atrial fibrillation which included persistent and permanent atrial fibrillation. Methods In patients with acute ischaemic stroke, atrial fibrillation was categorised as paroxysmal atrial fibrillation or sustained atrial fibrillation. Ischaemic recurrences were the composite of ischaemic stroke, transient ischaemic attack and symptomatic systemic embolism occurring within 90 days from acute index stroke. Results A total of 2150 patients (1155 females, 53.7%) were enrolled: 930 (43.3%) had paroxysmal atrial fibrillation and 1220 (56.7%) sustained atrial fibrillation. During the 90-day follow-up, 111 ischaemic recurrences were observed in 107 patients: 31 in patients with paroxysmal atrial fibrillation (3.3%) and 76 with sustained atrial fibrillation (6.2%) (hazard ratio (HR) 1.86 (95% CI 1.24–2.81)). Patients with sustained atrial fibrillation were on average older, more likely to have diabetes mellitus, hypertension, history of stroke/ transient ischaemic attack, congestive heart failure, atrial enlargement, high baseline NIHSS-score and implanted pacemaker. After adjustment by Cox proportional hazard model, sustained atrial fibrillation was not associated with early ischaemic recurrences (adjusted HR 1.23 (95% CI 0.74–2.04)). Conclusions After acute ischaemic stroke, patients with sustained atrial fibrillation had a higher rate of early ischaemic recurrence than patients with paroxysmal atrial fibrillation. After adjustment for relevant risk factors, sustained atrial fibrillation was not associated with a significantly higher risk of recurrence, thus suggesting that the risk profile associated with atrial fibrillation, rather than its pattern, is determinant for recurrence.

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3-3.9; P=0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2-4.9; P=0.01) end points separately. Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Background and Purpose: The aim of this study was to investigate for a possible association between both prestroke CHA(2)DS(2)-VASc score and the severity of stroke at presentation, as well as disability and mortality at 90 days, in patients with acute stroke and atrial fibrillation (AF). Methods: This prospective study enrolled consecutive patients with acute ischemic stroke, AF, and assessment of prestroke CHA2DS2-VASc score. Severity of stroke was assessed on admission using the National Institutes of Health Stroke Scale (NIHSS) score (severe stroke: NIHSS >= 10). Disability and mortality at 90 days were assessed by the modified Rankin Scale (mRS = 3). Multiple logistic regression was used to correlate prestroke CHA(2)DS(2)-VASc and severity of stroke, as well as disability and mortality at 90 days. Results: Of the 1020 patients included in the analysis, 606 patients had an admission NIHSS score lower and 414 patients higher than 10. At 90 days, 510 patients had mRS >= 3. A linear correlation was found between the prestroke CHA(2)DS(2)-VASc score and severity of stroke (P = .001). On multivariate analysis, CHA(2)DS(2)-VASc score correlated with severity of stroke (P = .041) and adverse functional outcome (mRS = 3) (P = .001). A logistic regression with the receiver operating characteristic graph procedure (C-statistics) evidenced an area under the curve of .60 (P = .0001) for severe stroke. Furthermore, a correlation was found between prestroke CHA(2)DS(2)-VASc score and lesion size. Conclusions: In patients with AF, in addition to the risk of stroke, a high CHA(2)DS(2)-VASc score was independently associated with both stroke severity at onset and disability and mortality at 90 days.

Background and Purposes— This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. Methods— The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00–1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08–2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P =0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30–1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632–0.763; P =0.0001) for ischemic outcome events and 0.585 (0.493–0.678; P =0.10) for major bleedings. Results— The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529–0.763; P =0.009) for ischemic outcome events and 0.407 (0.275–0.540; P =0.14) for hemorrhagic outcome events. Conclusions— In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings.

Anticoagulant therapy is recommended for the secondary prevention of stroke in patients with atrial fibrillation (AF). T he identification of patients at high risk for early recurrence, which are potential candidates to prompt anticoagulation, is crucial to justify the risk of bleeding associated with early anticoagulant treatment. The aim of this study was to evaluate in patients with acute ischemic stroke and AF the association between findings at trans-thoracic echocardiography (TTE) and 90 days recurrence. In consecutive patients with acute ischemic stroke and AF, TTE was performed within 7 days from hospital admission. Study outcomes were recurrent ischemic cerebrovascular events (stroke or TIA) and systemic embolism. 854 patients (mean age 76.3 +/- A 9.5 years) underwent a TTE evaluation; 63 patients (7.4 %) had at least a study outcome event. Left atrial thrombosis was present in 11 patients (1.3 %) among whom 1 had recurrent ischemic event. Left atrial enlargement was present in 548 patients (64.2 %) among whom 51 (9.3 %) had recurrent ischemic events. The recurrence rate in the 197 patients with severe left atrial enlargement was 11.7 %. On multivariate analysis, the presence of atrial enlargement (OR 2.13; 95 % CI 1.06-4.29, p = 0.033) and CHA(2)DS(2)-VASc score (OR 1.22; 95 % CI 1.04-1.45, p = 0.018, for each point increase) were correlated with ischemic recurrences. In patients with AF-associated acute stroke, left atrial enlargement is an independent marker of recurrent stroke and systemic embolism. The risk of recurrence is accounted for by severe atrial enlargement. TTE-detected left atrial thrombosis is relatively uncommon.

Introduction Atrial fibrillation is an independent risk factor of thromboembolism. Women with atrial fibrillation are at a higher overall risk for stroke compared to men with atrial fibrillation. The aim of this study was to evaluate for sex differences in patients with acute stroke and atrial fibrillation, regarding risk factors, treatments received and outcomes. Methods Data were analyzed from the “Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation” (RAF-study), a prospective, multicenter, international study including only patients with acute stroke and atrial fibrillation. Patients were followed up for 90 days. Disability was measured by the modified Rankin Scale (0–2 favorable outcome, 3–6 unfavorable outcome). Results Of the 1029 patients enrolled, 561 were women (54.5%) ( p Conclusions Women with atrial fibrillation were less likely to receive oral anticoagulants prior to and after stroke compared to men with atrial fibrillation, and when stroke occurred, regardless of the fact that in our study women were younger and with less severe stroke, outcomes did not differ between the sexes.

The aim of this study was to investigate for a possible association between both prestroke CHAThis prospective study enrolled consecutive patients with acute ischemic stroke, AF, and assessment of prestroke CHAOf the 1020 patients included in the analysis, 606 patients had an admission NIHSS score lower and 414 patients higher than 10. At 90 days, 510 patients had mRS ≥3. A linear correlation was found between the prestroke CHAIn patients with AF, in addition to the risk of stroke, a high CHA

Background and Purpose— The best time for administering anticoagulation therapy in acute cardioembolic stroke remains unclear. This prospective cohort study of patients with acute stroke and atrial fibrillation, evaluated (1) the risk of recurrent ischemic event and severe bleeding; (2) the risk factors for recurrence and bleeding; and (3) the risks of recurrence and bleeding associated with anticoagulant therapy and its starting time after the acute stroke. Methods— The primary outcome of this multicenter study was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding within 90 days from acute stroke. Results— Of the 1029 patients enrolled, 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or transient ischemic attack or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding, and 14 (1.4%) major extracranial bleeding. At 90 days, 50% of the patients were either deceased or disabled (modified Rankin score ≥3), and 10.9% were deceased. High CHA 2 DS 2 -VASc score, high National Institutes of Health Stroke Scale, large ischemic lesion and type of anticoagulant were predictive factors for primary study outcome. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared with initiating treatment before 4 or after 14 days: hazard ratio 0.53 (95% confidence interval 0.30–0.93). About 7% of the patients treated with oral anticoagulants alone had an outcome event compared with 16.8% and 12.3% of the patients treated with low molecular weight heparins alone or followed by oral anticoagulants, respectively ( P =0.003). Conclusions— Acute stroke in atrial fibrillation patients is associated with high rates of ischemic recurrence and major bleeding at 90 days. This study has observed that high CHA 2 DS 2 -VASc score, high National Institutes of Health Stroke Scale, large ischemic lesions, and type of anticoagulant administered each independently led to a greater risk of recurrence and bleedings. Also, data showed that the best time for initiating anticoagulation treatment for secondary stroke prevention is 4 to 14 days from stroke onset. Moreover, patients treated with oral anticoagulants alone had better outcomes compared with patients treated with low molecular weight heparins alone or before oral anticoagulants.