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Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet).Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use.Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years).Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023. Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet).Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use.Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years).Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023.

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.

Context Correction of hyponatremia might represent an additional treatment for improving stroke patients’ clinical outcomes. Objective Admission hyponatremia is associated with worse clinical outcome in stroke patients, but whether normalization of hyponatremia improves outcome is unknown. We investigated whether normalization of hyponatremia affects patients’ disability, mortality, and stroke recurrence within 3 months; length of hospitalization; and discharge destination. Design This was a registry-based analysis of data collected between January 2016 and December 2018. We linked data from Swiss Stroke Registry (SSR) with electronic patients’ records for extracting sodium values. Setting We analyzed data of hospitalized patients treated at University Hospital of Basel. Patients Stroke patients whose data and informed consent were available. Main outcome measure Modified Rankin Scale (mRS) score at 3 months. The tested hypothesis was formulated after SSR data collection but before linkage with electronic patients’ records. Results Of 1995 patients, 144 (7.2%) had hyponatremia on admission; 102 (70.8%) reached normonatremia, and 42 (29.2%) remained hyponatremic at discharge. An increase of initial sodium was associated with better functional outcome at 3 months (odds ratio [OR] 0.94; 95% CI, 0.90-0.99, for a shift to higher mRS per 1 mmol/L sodium increase). Compared with normonatremic patients, patients who remained hyponatremic at discharge had a worse functional outcome at 3 months (odds ratio 2.46; 95% CI, 1.20-5.03, for a shift to higher mRS). No effect was found on mortality, recurrence, or length of hospitalization. Conclusions In hospitalized acute stroke patients, persistent hyponatremia is associated with worse functional outcome. Whether active correction of hyponatremia improves outcome remains to be determined in prospective studies.

Background: The DEFUSE-3 and DAWN trials showed that mechanical thrombectomy (MT) improves the outcome of selected patients with anterior circulation large vessel occlusions (LVO) up to 24 h after stroke onset. However, it is unknown whether only those patients fulfilling the trial inclusion criteria benefit, or whether benefit is seen in a broader range of patients presenting between 6 and 24 h. Aims: We determined whether fulfilling the DEFUSE-3 and DAWN selection criteria affects outcomes in MT patients in clinical practice. Methods: We reviewed adult patients with LVO treated with MT between 6 and 24 h after stroke onset at five Swiss stroke centers between 2014 and 2021. We compared two groups: (1) patients who satisfied neither DEFUSE-3 nor DAWN criteria (NDND) and (2) those who satisfied DEFUSE-3 or DAWN criteria (DOD). We used logistic regression to examine the impact of trial eligibility on two safety outcomes (symptomatic intracranial hemorrhage [sICH] and all-cause mortality at 3 months) and two efficacy outcomes (modified Rankin Score [mRS] shift toward lower categories and mRS of 0–2 at 3 months). Results: Of 174 patients who received MT, 102 (59%) belonged to the NDND group. Rates of sICH were similar between the NDND group and the DOD group (3% vs. 4%, p = 1.00). Multivariable regression revealed no differences in 3-month all-cause mortality (aOR 2.07, 95% CI 0.64–6.84, p = 0.23) or functional outcomes (mRS shift: acOR 0.81, 95% CI 0.37–1.79, p = 0.60; mRS 0–2: aOR 0.91, 95% CI 0.31–2.57, p = 0.85). Conclusion: Among adult patients with LVO treated with MT between 6 and 24 h, safety and efficacy outcomes were similar between DEFUSE-3/DAWN eligible and ineligible patients. Our data provide a compelling rationale for randomized trials with broader inclusion criteria for MT.

Background: The probability to receive intravenous thrombolysis (IVT) for treatment of acute ischemic stroke declines with increasing age and is consequently the lowest in very elderly patients. Safety concerns likely influence individual IVT treatment decisions. Using data from a large IVT registry, we aimed to provide more evidence on safety of IVT in the very elderly. Methods: In this prospective multicenter study from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry, we compared patients ≥90 years with those Results: Of 16 974 eligible patients, 976 (5.7%) were ≥90 years. Patients ≥90 years had higher median National Institutes of Health Stroke Scale on admission (12 versus 8) and were more often dependent prior to the index stroke (prestroke modified Rankin Scale score of ≥3; 45.2% versus 7.4%). Occurrence of symptomatic intracranial hemorrhage (5.7% versus 4.4%, odds ratio adjusted 1.14 [0.83–1.57]) did not differ significantly between both groups. However, the probability of death (odds ratio adjusted 3.77 [3.14–4.53]) and poor functional outcome (odds ratio adjusted 2.63 [2.13–3.25]) was higher in patients aged ≥90 years. Results for the sample of centenarians (n=21) were similar. Conclusions: The probability of symptomatic intracranial hemorrhage after IVT in very elderly patients with stroke did not exceed that of their younger counterparts. The higher probability of death and poor functional outcome during follow-up in the very elderly seems not to be related to IVT treatment. Very high age itself should not be a reason to withhold IVT.

Zusammenfassung. Die intrazerebrale Hirnblutung ist für ca. 10–15% aller Hirnschläge verantwortlich und betrifft in der Schweiz ca. 1’500–2’000 Patienten pro Jahr. Bei der Akutbehandlung ist eine interdisziplinäre Behandlung durch spezialisierte Experten in einer zertifizierten Stroke Unit oder einem Stroke Center von entscheidender Bedeutung. Ein simples ABC-care bundle (Antikoagulation revertieren, Blutdruck kontrollieren, Neurochirurgen informieren) kann das Outcome signifikant verbessern. Trotz einer hohen Mortalität sind ca. ein Drittel aller Patienten nach einer Hirnblutung funktionell unabhängig und der weitverbreitete Pessimismus ist unangebracht. Über 80% aller Hirnblutungen werden durch verschiedene Formen cerebraler Mikroangiopathien verursacht und die Risiken für eine erneute Hirnblutung oder einen ischämischen Hirnschlag unterscheiden sich deutlich. Hirnblutungspatienten sind vaskuläre Hochrisikopatienten mit einer chronischen, cerebrovaskulären Erkrankung. Sie sollten langfristig und regelmässig von neurovaskulären Spezialisten behandelt werden, um wichtige Fragen (Blutdruckmanagement, antithrombotische Therapie/Antikoagulation, spezialisierte Neurorehabilitation zur Verbesserung insbesondere neurokognitiver Defizite, Therapie zusätzlicher Komplikationen, z. B. Epilepsie) individuell zu klären und die optimale Behandlung für die Patienten zu gewährleisten. Viele aktuelle Studien werden in den nächsten Jahren wichtige Ergebnisse liefern, um die Behandlung der Hirnblutung weiter zu verbessern.

ObjectiveTo investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF).MethodsWe analysed consecutive patients with AF with an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke.ResultsAmong 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy.ConclusionsStroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed.Trial registration numberISRCTN48292829.

ObjectiveTo evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis.MethodsData from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET.ResultsOf 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET−). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0–4.0] vs 3 [IQR 1.0–4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups.ConclusionsPatients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.

Introduction Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous. Patients and methods In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3–6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: 15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: Results Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia – of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia – and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (ORadjusted 1.25 (1.05–1.48)) and mortality (ORadjusted 1.58 (1.27–1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome (ORadjusted 1.29 (1.07–1.55) and 1.48 (1.09–2.02)) and mortality (ORadjusted 1.45 (1.15–1.84) and ORadjusted 2.00 (1.46–2.75)). Each haemoglobin level decrease by 1 g/dl independently increased the risk of poor outcome (ORadjusted 1.07 (1.02–1.11)) and mortality (ORadjusted 1.08 (1.02–1.15)). Anaemia was not associated with occurrence of symptomatic intracranial haemorrhage. Polyglobulia did not change any outcome. Discussion The more severe the anaemia, the higher the probability of poor outcome and death. Severe anaemia might be a target for interventions in hyperacute stroke. Conclusion Anaemia on admission, but not polyglobulia, is a strong and independent predictor of poor outcome and mortality in intravenous thrombolysis-treated stroke patients.

BACKGROUND AND PURPOSE In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages (ICHs) associated with the use of non-vitamin K antagonist oral anticoagulants (NOAC-ICH) or with vitamin K antagonists (VKA-ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF). METHODS Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post-stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta-analysis of available observational studies reporting 30-day mortality rates from NOAC-ICH or VKA-ICH onset was additionally performed. RESULTS During 5970 patient-years of follow-up 71 participants had an ICH, of whom 20 were NOAC-ICH and 51 VKA-ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA-ICH patients. There was a non-significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient-years) than in those with NOACs (three events per 2623 patient-years; hazard ratio 0.32, 95% confidence interval 0.09-1.14). Three-month functional outcomes were similar (P > 0.2) in the two groups. The meta-analysis showed a lower 30-day mortality risk for patients with NOAC-ICH compared to VKA-ICH (relative risk 0.70, 95% confidence interval 0.51-0.95). CONCLUSIONS Non-vitamin K oral anticoagulants for intracranial haemorrhages and VKA-ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA-ICH.

Background: Endovascular treatment in large artery occlusion stroke reduces disability. However, the impact of anesthesia type on clinical outcomes remains uncertain. Methods: We compared consecutive patients in the Swiss Stroke Registry with anterior circulation stroke receiving endovascular treatment with or without general anesthesia (GA). The primary outcome was disability on the modified Rankin Scale after 3 months, analyzed with ordered logistic regression. Secondary outcomes included dependency or death (modified Rankin Scale score ≥ 3), National Institutes of Health Stroke Scale after 24 hours, symptomatic intracranial hemorrhage with ≥ 4 points worsening on National Institutes of Health Stroke Scale within 7 days, and mortality. Coarsened exact matching and propensity score matching were performed to adjust for indication bias. Results: One thousand two hundred eighty-four patients (GA: n=851, non-GA: n=433) from 8 Stroke Centers were included. Patients treated with GA had higher modified Rankin Scale scores after 3 months than patients treated without GA, in the unmatched (odds ratio [OR], 1.75 [1.42–2.16]; P P =0.020), and the propensity score matching analysis (n=568; OR, 1.61 [1.20–2.15]; P =0.001). In the coarsened exact matching analysis, there were no significant differences in National Institutes of Health Stroke Scale after 1 day (estimated coefficient 2.61 [0.59–4.64]), symptomatic intracranial hemorrhage (OR, 1.06 [0.30–3.75]), dependency or death (OR, 1.42 [0.91–2.23]), or mortality (OR, 1.65 [0.94–2.89]). In the propensity score matching analysis, National Institutes of Health Stroke Scale after 24 hours (estimated coefficient, 3.40 [1.76–5.04]), dependency or death (OR, 1.49 [1.07–2.07]), and mortality (OR, 1.65 [1.11–2.45]) were higher in the GA group, whereas symptomatic intracranial hemorrhage did not differ significantly (OR, 1.77 [0.73–4.29]). Conclusions: This large study showed worse functional outcome after endovascular treatment of anterior circulation stroke with GA than without GA in a real-world setting. This finding appears to be independent of known differences in patient characteristics between groups.

Background: Data on the safety and effectiveness of once-daily (QD) versus twice-daily (BID) direct oral anticoagulants (DOAC) in comparison to vitamin K antagonists (VKA) and to one another in patients with atrial fibrillation (AF) and recent stroke are scarce. Patients and methods: Based on prospectively obtained data from the observational registry Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients(NOACISP)-LONGTERM (NCT03826927) from Basel, Switzerland, we compared the occurrence of the primary outcome – the composite of recurrent ischemic stroke, major bleeding, and all-cause death – among consecutive AF patients treated with either VKA, QD DOAC, or BID DOAC following a recent stroke using Cox proportional hazards regression including adjustment for potential confounders. Results: We analyzed 956 patients (median age 80 years, 46% female), of whom 128 received VKA (13.4%), 264 QD DOAC (27.6%), and 564 BID DOAC (59%). Over a total follow-up of 1596 patient-years, both QD DOAC and BID DOAC showed a lower hazard for the composite outcome compared to VKA (adjusted HR [95% CI] 0.69 [0.48, 1.01] and 0.66 [0.47, 0.91], respectively). Upon direct comparison, the hazard for the composite outcome did not differ between patients treated with QD versus BID DOAC (adjusted HR [95% CI] 0.94 [0.70, 1.26]). Secondary analyses focusing on the individual components of the composite outcome revealed no clear differences in the risk-benefit profile of QD versus BID DOAC. Discussion and conclusion: The overall benefit of DOAC over VKA seems to apply to both QD and BID DOAC in AF patients with a recent stroke, without clear evidence that one DOAC dosing regimen is more advantageous than the other.

ObjectiveSerum neurofilament light chain (sNfL) is increasingly used as a neuroaxonal injury biomarker in the elderly. Besides age, little is known about how other physiological factors like renal function and body mass index (BMI) alter its levels. Here, we investigated the association of estimated glomerular filtration rate (eGFR) and BMI with sNfL in a large sample of elderly patients with atrial fibrillation (AF).MethodsThis is a cross-sectional analysis from the Swiss-AF Cohort (NCT02105844). We measured sNfL using an ultrasensitive single-molecule array assay. We calculated eGFR using the chronic kidney disease epidemiology collaboration (CKD-EPI) creatinine (eGFRcrea) and creatinine–cystatin C (eGFRcrea–cys) formulas, and BMI from weight and height measurements. We evaluated the role of eGFR and BMI as determinants of sNfL levels using multivariable linear regression and the adjusted R2 (R2adj).ResultsAmong 2,277 Swiss-AF participants (mean age 73.3 years), eGFRcrea showed an inverse curvilinear association with sNfL after adjustment for age and cardiovascular comorbidities. BMI also showed an independent, inverse linear association with sNfL. The R2adj of models with age, eGFRcrea, and BMI alone was 0.26, 0.35, and 0.02, respectively. A model with age and eGFRcrea combined explained 45% of the sNfL variance. Sensitivity analyses (i) further adjusting for vascular brain lesions (N = 1,402 participants with MRI) and (ii) using eGFRcrea–cys yielded consistent results.InterpretationIn an elderly AF cohort, both renal function and BMI were associated with sNfL, but only renal function explained a substantial proportion of the sNfL variance. This should be taken into account when using sNfL in elderly patients or patients with cardiovascular disease.

OBJECTIVE We assessed whether hematoma expansion (HE) and favorable outcome differ according to type of intracerebral hemorrhage (ICH). METHODS Among participants with ICH enrolled in the TICH-2 (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) trial, we assessed baseline scans for hematoma location and presence of cerebral amyloid angiopathy (CAA) using computed tomography (CT, simplified Edinburgh criteria) and magnetic resonance imaging (MRI; Boston criteria) and categorized ICH as lobar CAA, lobar non-CAA, and nonlobar. The main outcomes were HE and favorable functional outcome. We constructed multivariate regression models and assessed treatment effects using interaction terms. RESULTS A total of 2,298 out of 2,325 participants were included with available CT (98.8%; median age = 71 years, interquartile range = 60-80 years; 1,014 female). Additional MRI was available in 219 patients (9.5%). Overall, 1,637 participants (71.2%) had nonlobar ICH; the remaining 661 participants (28.8%) had lobar ICH, of whom 202 patients had lobar CAA-ICH (8.8%, 173 participants according to Edinburgh and 29 participants according to Boston criteria) and 459 did not (lobar non-CAA, 20.0%). For HE, we found a significant interaction of lobar CAA ICH with time from onset to randomization (increasing risk with time, pinteraction

Supplemental material, sj-docx-1-wso-10.1177_17474930221140793 for Mechanical thrombectomy for large vessel occlusion between 6 and 24 h: outcome comparison of DEFUSE-3/DAWN eligible versus non-eligible patients by Tolga D Dittrich, Peter B Sporns, Lilian F Kriemler, Salome Rudin, Anh Nguyen, Annaelle Zietz, Alexandros A Polymeris, Christopher Tränka, Sebastian Thilemann, Benjamin Wagner, Valerian L Altersberger, Ines Piot, Filip Barinka, Martin Hänsel, Henrik Gensicke, Stefan T Engelter, Philippe A Lyrer, Raoul Sutter, Christian H Nickel, Mira Katan, Nils Peters, Lars Michels, Zsolt Kulcsár, Grzegorz M Karwacki, Marco Pileggi, Carlo Cereda, Susanne Wegener, Leo H Bonati, Urs Fischer, Marios Psychogios and Gian Marco De Marchis in International Journal of Stroke

Atrial fibrillation (AF) is the most common arrhythmia, becomes more prevalent with increasing age and is linked to neurological complications, including most notably ischemic stroke, but also cognitive dysfunction. The recent introduction of direct oral anticoagulants (DOAC) significantly advanced the management of patients with AF. Large-scale randomized controlled trials showed that – for most patients – DOAC are at least as effective as vitamin K antagonists (VKA) in preventing ischemic stroke but have the advantage of a lower risk for intracranial hemorrhage (ICH). However, clinically important patient populations were underrepresented or excluded in these trials, and more refined aspects which are important in clinical practice, including concomitant stroke etiologies or brain pathologies, medication adherence, neuroimaging characteristics or biomarker signatures were not addressed. Therefore, several research gaps and challenges remained for neurologists treating patients with AF, of which we selected 4 aspects to focus on in the following topics that comprise this PhD thesis. The first topic focused on 3 high-risk subgroups of patients with AF treated with oral anticoagulants who were underrepresented or excluded from the large randomized trials. These were (i) stroke patients aged 85 years and older (“the oldest-old”), (ii) severely affected stroke patients dependent on the daily help of others, and (iii) stroke patients with concomitant cerebral small vessel disease. In the first main project of this PhD thesis we examined the performance of DOAC versus VKA in the oldest-old patients with recent stroke and AF in a large pooled analysis across 7 cohort studies. Facing the paucity of randomized evidence, many physicians have been reluctant to use DOAC in these patients. With this project, we provided new evidence that the benefits of DOAC over VKA are preserved in the oldest old with recent stroke, without any signal of a safety concern regarding risk of ICH. In an additional project from our local cohort, we showed that the favourable profile of DOAC over VKA was preserved also among patients with AF and recent stroke who were dependent on the daily help of others, a patient subgroup for which no data existed previously. Finally, we showed in the same cohort that concomitant cerebral small vessel disease in anticoagulated patients with AF and recent stroke was associated with an unfavorable clinical course, but the risk for ischemic stroke remained higher than the risk for ICH, even in the presence of small vessel disease. The latter two projects fall within the scope of this PhD thesis, but do not constitute its main body. Although both manuscripts were published in peer-reviewed journals, for the purpose of this thesis their presentation is restricted to abstracts. Our findings in the first topic of this PhD thesis advance the evidence for the use of anticoagulants in high-risk patient subgroups with AF and recent stroke. The second topic examined ischemic stroke occurring despite anticoagulant therapy in AF patients. With the increasing use of oral anticoagulants, this scenario represents a growing challenge in everyday clinical practice, indicating the need to elucidate the underlying causes and – based on these – the optimal subsequent management strategies. We addressed this issue in the second main project of this PhD thesis in a large retrospective analysis pooling data of prospectively collected patients from 11 stroke centers. We found that the causes of stroke despite anticoagulation in AF patients were heterogeneous, but form three main clusters, all of which were comparably important. These included (i) competing stroke mechanisms other than AF-related cardioembolism, and (ii) insufficient anticoagulation due to prescription errors and nonadherence, suggesting that individualized treatment approaches to address these causes are necessary. Importantly, the third and most common cause was AF-related cardioembolism despite sufficient anticoagulation, indicating the need to develop novel preventive strategies beyond the currently available anticoagulants. Furthermore, in this project we were able to demonstrate that AF patients with stroke despite anticoagulation represent a high-risk patient population, with higher than expected rates of stroke recurrence and other unfavorable outcomes. Finally, we showed also in this population that subsequent treatment with DOAC was associated with better outcomes than VKA treatment. Interestingly, neither any specific switch between DOAC nor antiplatelets as add-on treatment to anticoagulation seemed to confer any benefit, although both approaches are often employed in clinical practice. This study advanced the evidence for the preferential use of DOAC over VKA in AF patients with stroke despite anticoagulation, for whom no data existed so far, while demonstrating the need for more individualized and novel treatment approaches in these high-risk patients. The third topic of this PhD thesis was the adherence of stroke patients to DOAC. Unlike VKA, DOAC require no coagulation monitoring and have short half-lives, which has raised concerns about nonadherence in AF patients treated with DOAC. This is particularly pertinent to patients with stroke, as shown in the second topic of this PhD thesis. In order to examine the medication-taking behaviour and the effect of an adherence-enhancing intervention in patients with recent stroke, we designed, initiated, and undertook the MAAESTRO study. MAAESTRO has been a joint venture with the Pharmaceutical Care Research Group of the University of Basel and has used electronic monitoring as the main method to assess adherence, data on which have been scarce so far. MAAESTRO comprises an initial observational phase and a subsequent randomized controlled interventional phase. MAAESTRO successfully concluded recruitment in July 2021 with reaching the predefined goal of n=130 participants. The observational study phase has now been completed, but as follow-up in the interventional phase is ongoing, the main study results are not part of this PhD thesis. Still, we present the published study protocol and the first results from the observational phase on the patterns of DOAC-taking behaviour, as well as an exploratory analysis on how adherence was impacted by the COVID-19 lockdown as abstracts, as these publications fall within the scope of this PhD thesis, but do not formally constitute its main body. The fourth and final topic of this PhD thesis focused on cognitive dysfunction as a neurological complication of AF. While stroke is a well-known consequence of AF, there is increasing evidence that AF is also linked to cognitive dysfunction independent of ischemic stroke, but the mechanisms underlying this association are unclear. To preserve cognitive function in the growing population of elderly AF patients, a better understanding of these mechanisms is needed. Using data from the multicenter Swiss-AF Cohort Study, in the third main project of this PhD thesis we investigated serum neurofilament light chain (sNfL), a novel blood-based biomarker of neuronal damage, as a tool to explore the mechanisms through which neurological disease occurs in AF. In a cross-sectional analysis, we showed that sNfL is inversely associated with brain volume and cognitive function, thereby demonstrating that it represents a relevant biomarker of brain health in AF patients. Furthermore, we showed that neuronal loss measured by sNfL is associated with age, diabetes mellitus, heart failure, blood pressure and vascular brain lesions, observations which provide mechanistic insights into the occurrence of neurological disease in AF. Finally, in the fourth main project of this PhD thesis, we additionally investigated in this elderly cardiovascular cohort how renal function and body mass index contribute to sNfL levels in order to gain insights into the homeostasis (i.e., clearance and distribution) of this biomarker in the blood compartment. A better understanding of this is necessary towards further establishing this neurological biomarker in cardiovascular and dementia research. We showed that both renal function and body mass index were strongly, inversely associated with sNfL, but only renal function explained a relevant proportion of its variance. With this project we provided evidence for the importance of accounting for renal function in future sNfL-based investigations in elderly cardiovascular populations, in whom chronic kidney disease is highly prevalent.

Supplemental material, sj-docx-2-wso-10.1177_17474930221140793 for Mechanical thrombectomy for large vessel occlusion between 6 and 24 h: outcome comparison of DEFUSE-3/DAWN eligible versus non-eligible patients by Tolga D Dittrich, Peter B Sporns, Lilian F Kriemler, Salome Rudin, Anh Nguyen, Annaelle Zietz, Alexandros A Polymeris, Christopher Tränka, Sebastian Thilemann, Benjamin Wagner, Valerian L Altersberger, Ines Piot, Filip Barinka, Martin Hänsel, Henrik Gensicke, Stefan T Engelter, Philippe A Lyrer, Raoul Sutter, Christian H Nickel, Mira Katan, Nils Peters, Lars Michels, Zsolt Kulcsár, Grzegorz M Karwacki, Marco Pileggi, Carlo Cereda, Susanne Wegener, Leo H Bonati, Urs Fischer, Marios Psychogios and Gian Marco De Marchis in International Journal of Stroke

Supplemental material, sj-docx-1-eso-10.1177_23969873221099477 for Once versus twice daily direct oral anticoagulants in patients with recent stroke and atrial fibrillation by Alexandros A Polymeris, Annaelle Zietz, Fabian Schaub, Louisa Meya, Christopher Traenka, Sebastian Thilemann, Benjamin Wagner, Lisa Hert, Valerian L Altersberger, David J Seiffge, Flurina Lyrer, Tolga Dittrich, Ines Piot, Josefin Kaufmann, Lea Barone, Ludvig Dahlheim, Sophie Flammer, Nikolaos S Avramiotis, Nils Peters, Gian Marco De Marchis, Leo H Bonati, Henrik Gensicke, Stefan T Engelter and Philippe A Lyrer in European Stroke Journal

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.

OBJECTIVE We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia. METHODS We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (

Background and Purpose: Data on the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with stroke attributable to atrial fibrillation (AF) who were dependent on the daily help of others at hospital discharge are scarce. Methods: Based on prospectively obtained data from the observational Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-longterm registry from Basel, Switzerland, we compared the occurrence of the primary outcome—the composite of recurrent ischemic stroke, major bleeding, and all-cause death—among consecutive patients with AF-stroke treated with either VKAs or DOACs between patients dependent (defined as modified Rankin Scale score, 3–5) and patients independent at discharge. We used simple, adjusted, and weighted Cox proportional hazards regression to account for potential confounders. Results: We analyzed 801 patients (median age 80 years, 46% female), of whom 391 (49%) were dependent at discharge and 680 (85%) received DOACs. Over a total follow-up of 1216 patient-years, DOAC- compared to VKA-treated patients had a lower hazard for the composite outcome (hazard ratio [HR], 0.58 [95% CI, 0.42–0.81]), as did independent compared to dependent patients (HR, 0.54 [95% CI, 0.40–0.71]). There was no evidence that the effect of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome differed between dependent (HR dependent , 0.68 [95% CI, 0.45–1.01]) and independent patients (HR independent , 0.44 [95% CI, 0.26–0.75]) in the simple model ( P interaction =0.212). Adjusted (HR dependent , 0.74 [95% CI, 0.49–1.11] and HR independent , 0.51 [95% CI, 0.30–0.87]; P interaction =0.284) and weighted models (HR dependent , 0.79 [95% CI, 0.48–1.31] and HR independent , 0.46 [95% CI, 0.26–0.81]; P interaction =0.163) yielded concordant results. Secondary analyses focusing on the individual components of the composite outcome were consistent to the primary analyses. Conclusions: The benefits of DOACs in patients with atrial fibrillation with a recent stroke were maintained among patients who were dependent on the help of others at discharge. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03826927.

Intracerebral haemorrhage - acute event and chronic disease

Background: We determined the frequency of different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their association with clinical characteristics and outcomes. Methods: We analyzed data from consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014-2019). Etiology of ICH was determined according to prespecified, mutually exclusive categories. We assessed prevalence of ICH etiologies, their association with clinical characteristics, functional independence (modified Rankin Scale 0-2), mortality, recurrent ICH and ischemic stroke at 3 months. Results: We included 2584 patients (median age 72y, IQR 64-82, 46.6% female, median NIHSS 10; IQR 3-15). 2037 patients (80%) had hypertension and 553 (22.3%) were on anticoagulants. Distribution of etiologies was as follows: Hypertension (n=1216 patients; 47.1% of all / 56.3% of patients with hypertension), unknown etiology (n=542, 21.0%), antithrombotic therapy (n=225, 8.7% of all / 38% of patients on anticoagulants), cerebral amyloid angiopathy (CAA, n=211, 8.2%), macro-vascular (n=121, 4.7%), other determined etiologies (n=269, 10.4%). Patients with hypertensive ICH had significantly higher NIHSS (median 9; IQR 4-16) and blood pressure levels (median systolic 176; IQR 156-195) on admission. Patients with CAA had significantly lower NIHSS at baseline (median 5; IQR 2-12). Three month follow-up was available for 2109/2584 patients (81.6%). 820 (38.9%) were functionally independent, 658 have died (31.2%). Hypertensive ICH was associated with an increased rate of functional independence (aOR =1.42, 95%CI 1.06-1.90, p=0.02). 5.2% of patients had a cerebrovascular event within 3 months. CAA was associated with a high risk of recurrent ICH (HR 6.95, 95%CI 3.05-15.84, p Conclusions: In Swiss Stroke Units and Centers, one of two patients has ICH from a different cause than hypertension. The rate of functionally independent patients at 3 months seems higher than mortality. Absolute and relative risks of recurrent ICH and ischemic stroke after recent ICH differ among underlying etiologies.