Toward Individual Treatment in Cervical Artery Dissection: Subgroup Analysis of the TREAT-CAD Randomized Trial.

OBJECTIVE: Uncertainty remains regarding antithrombotic treatment in cervical artery dissection. This analysis aimed to explore whether certain patient profiles influence the effects of different types of antithrombotic treatment. METHODS: This was a post hoc exploratory analysis based on the per-protocol dataset from TREAT-CAD (NCT02046460), a randomized controlled trial comparing aspirin to anticoagulation in patients with cervical artery dissection. We explored the potential effects of distinct patient profiles on outcomes in participants treated with either aspirin or anticoagulation. Profiles included (1) presenting with ischemia (no/yes), (2) occlusion of the dissected artery (no/yes), (3) early versus delayed treatment start (median), and (4) intracranial extension of the dissection (no/yes). Outcomes included clinical (stroke, major hemorrhage, death) and magnetic resonance imaging outcomes (new ischemic or hemorrhagic brain lesions) and were assessed for each subgroup in separate logistic models without adjustment for multiple testing. RESULTS: All 173 (100%) per-protocol participants were eligible for the analyses. Participants without occlusion had decreased odds of events when treated with anticoagulation (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.07-0.86). This effect was more pronounced in participants presenting with cerebral ischemia (n = 118; OR = 0.16, 95% CI = 0.04-0.55). In the latter, those with early treatment (OR = 0.26, 95% CI = 0.07-0.85) or without intracranial extension of the dissection (OR = 0.34, 95% CI = 0.11-0.97) had decreased odds of events when treated with anticoagulation. INTERPRETATION: Anticoagulation might be preferable in patients with cervical artery dissection presenting with ischemia and no occlusion or no intracranial extension of the dissection. These findings need confirmation. ANN NEUROL 2024;95:886-897.

Intravenous Thrombolysis 4.5-9 Hours After Stroke Onset: A Cohort Study from the TRISP Collaboration.

OBJECTIVE: To investigate the safety and effectiveness of intravenous thrombolysis (IVT) >4.5-9 hours after stroke onset, and the relevance of advanced neuroimaging for patient selection. METHODS: Prospective multicenter cohort study from the ThRombolysis in Ischemic Stroke Patients (TRISP) collaboration. Outcomes were symptomatic intracranial hemorrhage, poor 3-month functional outcome (modified Rankin scale 3-6) and mortality. We compared: (i) IVT >4.5-9 hours versus 0-4.5 hours after stroke onset and (ii) within the >4.5-9 hours group baseline advanced neuroimaging (computed tomography perfusion, magnetic resonance perfusion or magnetic resonance diffusion-weighted imaging fluid-attenuated inversion recovery) versus non-advanced neuroimaging. RESULTS: Of 15,827 patients, 663 (4.2%) received IVT >4.5-9 hours and 15,164 (95.8%) within 4.5 hours after stroke onset. The main baseline characteristics were evenly distributed between both groups. Time of stroke onset was known in 74.9% of patients treated between >4.5 and 9 hours. Using propensity score weighted binary logistic regression analysis (onset-to-treatment time >4.5-9 hours vs onset-to-treatment time 0-4.5 hours), the probability of symptomatic intracranial hemorrhage (ORadjusted 0.80, 95% CI 0.53-1.17), poor functional outcome (ORadjusted 1.01, 95% CI 0.83-1.22), and mortality (ORadjusted 0.80, 95% CI 0.61-1.04) did not differ significantly between both groups. In patients treated between >4.5 and 9 hours, the use of advanced neuroimaging was associated with a 50% lower mortality compared with non-advanced imaging only (9.9% vs 19.7%; ORadjusted 0.51, 95% CI 0.33-0.79). INTERPRETATION: This study showed no evidence in difference of symptomatic intracranial hemorrhage, poor outcome, and mortality in selected stroke patients treated with IVT between >4.5 and 9 hours after stroke onset compared with those treated within 4.5 hours. Advanced neuroimaging for patient selection was associated with lower mortality. ANN NEUROL 2023;94:309-320.

Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation.

BACKGROUND: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk. METHODS: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation. RESULTS: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death. CONCLUSION: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.

Biomarker, Imaging, and Clinical Factors Associated With Overt and Covert Stroke in Patients With Atrial Fibrillation.

BACKGROUND: Atrial fibrillation is a major risk factor for stroke and silent brain infarcts. We studied whether a multimodal approach offers additional insights to the CHA2DS2-VASc score in predicting stroke or new brain infarcts on magnetic resonance imaging (MRI) over a 2-year follow-up. METHODS: Swiss-AF is a prospective, multicenter cohort study of patients with known atrial fibrillation. We included patients with available brain MRI both at enrollment and 2 years later. The dates of the baseline and follow-up visits ranged from March 2014 to November 2020. The primary outcome was assessed 2 years after baseline and was defined as a composite of clinically identified stroke or any new brain infarct on the 2-year MRI. We compared a multivariable logistic regression model including prespecified clinical, biomarker, and baseline MRI variables to the CHA2DS2-VASc score. RESULTS: We included 1232 patients, 89.8% of them taking oral anticoagulants. The primary outcome occurred in 78 patients (6.3%). The following baseline variables were included in the final multivariate model and were significantly associated with the primary outcome: white matter lesion volume in milliliters (adjusted odds ratio [aOR], 1.91 [95% CI, 1.45-2.56]), NT-proBNP (N-terminal pro-B-type natriuretic peptide; aOR, 1.75 [95% CI, 1.20-2.63]), GDF-15 (growth differentiation factor-15; aOR, 1.68 [95% CI, 1.11-2.53]), serum creatinine (aOR, 1.50 [95% CI, 1.02-2.22]), IL (interleukin)-6 (aOR, 1.37 [95% CI, 1.00-1.86]), and hFABP (heart-type fatty acid-binding protein; aOR, 0.48 [95% CI, 0.31-0.73]). Overall performance and discrimination of the new model was superior to that of the CHA2DS2-VASc score (C statistic, 0.82 [95% CI, 0.77-0.87] versus 0.64 [95% CI, 0.58-0.70]). CONCLUSIONS: In patients with atrial fibrillation, a model incorporating white matter lesion volume on baseline MRI and selected blood markers yielded new insights on residual stroke risk despite a high proportion of patients on oral anticoagulants. This may be relevant to develop further preventive measures.

Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (Pinteraction=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02866838.

Mechanical Thrombectomy Versus Best Medical Treatment in the Late Time Window in Non-DEFUSE-Non-DAWN Patients: A Multicenter Cohort Study.

BACKGROUND: We assessed the efficacy and safety of mechanical thrombectomy (MT) in adult stroke patients with anterior circulation large vessel occlusion presenting in the late time window not fulfilling the DEFUSE-3 (Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging trial) and DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct trial) inclusion criteria. METHODS: Cohort study of adults with anterior circulation large vessel occlusion admitted between 6 and 24 hours after last-seen-well at 5 participating Swiss stroke centers between 2014 and 2021. Mismatch was assessed by computer tomography or magnetic resonance imaging perfusion with automated software (RAPID or OLEA). We excluded patients meeting DEFUSE-3 and DAWN inclusion criteria and compared those who underwent MT with those receiving best medical treatment alone by inverse probability of treatment weighting using the propensity score. The primary efficacy end point was a favorable functional outcome at 90 days, defined as a modified Rankin Scale score shift toward lower categories. The primary safety end point was symptomatic intracranial hemorrhage within 7 days of stroke onset; the secondary was all-cause mortality within 90 days. RESULTS: Among 278 patients with anterior circulation large vessel occlusion presenting in the late time window, 190 (68%) did not meet the DEFUSE-3 and DAWN inclusion criteria and thus were included in the analyses. Of those, 102 (54%) received MT. In the inverse probability of treatment weighting analysis, patients in the MT group had higher odds of favorable outcomes compared with the best medical treatment alone group (modified Rankin Scale shift: acOR, 1.46 [1.02-2.10]; P=0.04) and lower odds of all-cause mortality within 90 days (aOR, 0.59 [0.37-0.93]; P=0.02). There were no significant differences in symptomatic intracranial hemorrhage (MT versus best medical treatment alone: 5% versus 2%, P=0.63). CONCLUSIONS: Two out of 3 patients with anterior circulation large vessel occlusion presenting in the late time window did not meet the DEFUSE-3 and DAWN inclusion criteria. In these patients, MT was associated with higher odds of favorable functional outcomes without increased rates of symptomatic intracranial hemorrhage. These findings support the enrollment of patients into ongoing randomized trials on MT in the late window with more permissive inclusion criteria.

Cerebral Amyloid Angiopathy and the Risk of Hematoma Expansion.

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  < 0.001) and baseline ICH volume (constant risk regardless of volume, pinteraction  < 0.001) but no association between type of ICH and risk of HE or favorable outcome. Tranexamic acid significantly reduced the risk of HE (adjusted odds ratio = 0.7, 95% confidence interval = 0.6-1.0, p = 0.020) without statistically significant interaction with type of ICH (pinteraction  = 0.058). Tranexamic acid was not associated with favorable outcome. INTERPRETATION: Risk of HE in patients with lobar CAA-ICH was not independently increased but seems to have different dynamics compared to other types of ICH. The time window for treatment of CAA-ICH to prevent HE may be longer. ANN NEUROL 2022;92:921-930.

Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation.

OBJECTIVE: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years. METHODS: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted, and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk. RESULTS: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR≥85y  = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR<85y  = 0.79, 95%-CI [0.66, 0.95]) in simple (pinteraction  = 0.129), adjusted (pinteraction  = 0.094) or weighted (pinteraction  = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1). INTERPRETATION: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2022;91:78-88.

Global Cortical Atrophy Is Associated with an Unfavorable Outcome in Stroke Patients on Oral Anticoagulation.

INTRODUCTION: Measures of cerebral small vessel disease (cSVD), such as white matter hyperintensities (WMH) and cerebral microbleeds (CMB), are associated with an unfavorable clinical course in stroke patients on oral anticoagulation (OAC) for atrial fibrillation (AF). Here, we investigated whether similar findings can be observed for global cortical atrophy (GCA). METHODS: Registry-based prospective observational study of 320 patients treated with OAC following AF stroke. Patients underwent magnetic resonance imaging (MRI) allowing assessment of GCA. Using the simplified visual Pasquier scale, the severity of GCA was categorized as follows: 0: no atrophy, 1: mild atrophy; 2: moderate atrophy, and 3: severe atrophy. Using adjusted logistic and Cox regression analysis, we investigated the association of GCA using a composite outcome measure, comprising: (i) recurrent acute ischemic stroke (IS); (ii) intracranial hemorrhage (ICH); and (iii) death. RESULTS: In our time to event analysis after adjusting for potential confounders (i.e., WMH, CMB, age, sex, diabetes, arterial hypertension, coronary heart disease, hyperlipidemia, and antiplatelet use), GCA was associated with an increased risk for the composite outcome in all three degrees of atrophy (grade 1: aHR 3.95, 95% CI 1.34-11.63, p = 0.013; grade 2: aHR 3.89, 95% CI 1.23-12.30, p = 0.021; grade 3: aHR 4.16, 95% CI 1.17-14.84, p = 0.028). CONCLUSION: GCA was associated with our composite outcome also after adjusting for other cSVD markers (i.e., CMB, WMH) and age, indicating that GCA may potentially serve as a prognostic marker for stroke patients with atrial fibrillation on oral anticoagulation.

Endovascular Treatment for Acute Ischemic Stroke With or Without General Anesthesia: A Matched Comparison.

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<0.001), the coarsened exact matching (n=332-524, using multiple imputations of missing values; OR, 1.60 [1.08-2.36]; 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.

Brief Consent Methods Enable Rapid Enrollment in Acute Stroke Trial: Results From the TICH-2 Randomized Controlled Trial.

BACKGROUND: Seeking consent rapidly in acute stroke trials is crucial as interventions are time sensitive. We explored the association between consent pathways and time to enrollment in the TICH-2 (Tranexamic Acid in Intracerebral Haemorrhage-2) randomized controlled trial. METHODS: Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours. RESULTS: Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557; 68%) or 2-stage consent (260; 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%]; 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38-93) minutes for doctor consent, 55 (37-95) minutes for 2-stage patient, 69 (43-110) minutes for 2-stage relative, 75 (48-124) minutes for 1-stage patient, and 90 (56-155) minutes for 1-stage relative consents (P<0.001). Two-stage consent was associated with onset-to-randomization time of ≤3 hours compared with 1-stage consent (adjusted odds ratio, 1.9 [95% CI, 1.5-2.4]). Doctor consent increased the odds (adjusted odds ratio, 2.3 [1.5-3.5]) while relative consent reduced the odds of randomization ≤3 hours (adjusted odds ratio, 0.10 [0.03-0.34]) compared with patient consent. Only 2 of 771 patients (0.3%) in the 2-stage pathways withdrew consent when full consent was sought later. Two-stage consent process did not result in higher withdrawal rates or loss to follow-up. CONCLUSIONS: The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study.

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 CHA2DS2-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.

Intravenous Thrombolysis in Patients With Ischemic Stroke Aged ≥90 Years: A Cohort Study From the TRISP Collaboration.

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 <90 years using symptomatic intracranial hemorrhage (ECASS [European Cooperative Acute Stroke Study]-II criteria), death, and poor functional outcome in survivors (modified Rankin Scale score 3-5 for patients with prestroke modified Rankin Scale score ≤2 and modified Rankin Scale score 4-5 for patients prestroke modified Rankin Scale ≥3) at 3 months as outcomes. We calculated adjusted odds ratio with 95% CI using logistic regression models. 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 ratioadjusted 1.14 [0.83-1.57]) did not differ significantly between both groups. However, the probability of death (odds ratioadjusted 3.77 [3.14-4.53]) and poor functional outcome (odds ratioadjusted 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.

Early versus late start of direct oral anticoagulants after acute ischaemic stroke linked to atrial fibrillation: an observational study and individual patient data pooled analysis.

OBJECTIVE: The optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start. METHODS: This is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH. RESULTS: A total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke. CONCLUSIONS: Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start.

Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation.

OBJECTIVE: To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF). METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: Stroke 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 NUMBER: ISRCTN48292829.

Association of the COVID-19 outbreak with acute stroke care in Switzerland.

BACKGROUND AND PURPOSE: In Switzerland, the COVID-19 incidence during the first pandemic wave was high. Our aim was to assess the association of the outbreak with acute stroke care in Switzerland in spring 2020. METHODS: This was a retrospective analysis based on the Swiss Stroke Registry, which includes consecutive patients with acute cerebrovascular events admitted to Swiss Stroke Units and Stroke Centers. A linear model was fitted to the weekly admission from 2018 and 2019 and was used to quantify deviations from the expected weekly admissions from 13 March to 26 April 2020 (the "lockdown period"). Characteristics and 3-month outcome of patients admitted during the lockdown period were compared with patients admitted during the same calendar period of 2018 and 2019. RESULTS: In all, 28,310 patients admitted between 1 January 2018 and 26 April 2020 were included. Of these, 4491 (15.9%) were admitted in the periods March 13-April 26 of the years 2018-2020. During the lockdown in 2020, the weekly admissions dropped by up to 22% compared to rates expected from 2018 and 2019. During three consecutive weeks, weekly admissions fell below the 5% quantile (likelihood 0.38%). The proportion of intracerebral hemorrhage amongst all registered admissions increased from 7.1% to 9.3% (p = 0.006), and numerically less severe strokes were observed (median National Institutes of Health Stroke Scale from 3 to 2, p = 0.07). CONCLUSIONS: Admissions and clinical severity of acute cerebrovascular events decreased substantially during the lockdown in Switzerland. Delivery and quality of acute stroke care were maintained.

Oral Anticoagulants in Atrial Fibrillation Patients With Recent Stroke Who Are Dependent on the Daily Help of Others.

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 outcome­the composite of recurrent ischemic stroke, major bleeding, and all-cause death­among consecutive patients with AF-stroke treated with either VKAs or DOACs between patients dependent (defined as modified Rankin Scale score, 3­5) 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, 0.42­0.81]), as did independent compared to dependent patients (HR, 0.54 [95% CI, 0.40­0.71]). There was no evidence that the effect of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome differed between dependent (HRdependent, 0.68 [95% CI, 0.45­1.01]) and independent patients (HRindependent, 0.44 [95% CI, 0.26­0.75]) in the simple model (Pinteraction=0.212). Adjusted (HRdependent, 0.74 [95% CI, 0.49­1.11] and HRindependent, 0.51 [95% CI, 0.30­0.87]; Pinteraction=0.284) and weighted models (HRdependent, 0.79 [95% CI, 0.48­1.31] and HRindependent, 0.46 [95% CI, 0.26­0.81]; Pinteraction=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.

Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation.

OBJECTIVE: It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed. METHODS: We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585). INTERPRETATION: Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group. ANN NEUROL 2020.

Insights Into Direct Oral Anticoagulant Therapy Implementation of Stroke Survivors with Atrial Fibrillation in an Ambulatory Setting.

OBJECTIVES: To describe how stroke survivors with atrial fibrillation implement direct oral anticoagulant treatment and propose appropriate metrics to describe adherence. MATERIALS AND METHODS: Stroke patients with atrial fibrillation electronically recorded their self-administered direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) during a 6-month observation phase after hospitalisation for ischemic stroke. Taking and timing adherence, correct dosing days, drug holidays, time of the day and day of the week subsets, dose-to-dose intervals and longest intervals between two consecutive doses were calculated from electronic monitoring data to describe and discuss the implementation phase of adherence. RESULTS: Data from 41 patients were analysed. Median age was 77 (IQR = 69-84), 63.4% were male and the majority suffered a mild stroke (median NIHSS: 1). Mean taking and timing adherence exceeded 90%. Correct dosing occurred in 86.6% of the days. Seven patients (17.1%) had intake pauses of three or more consecutive days. Patients with twice-daily regimen (70.7%) had higher taking adherence in the morning than in the evening (94.4% versus 89.9%; p = 0.001). No therapy- or anamneses-related characteristic was associated with taking adherence. CONCLUSIONS: Although adherence to direct oral anticoagulants of stroke patients with atrial fibrillation exceeded 90%, deviant intake patterns such as drug holidays and missed evening doses were common and raise concerns. Appropriate adherence metrics calculated from electronic monitoring data may guide healthcare professionals elucidating patient-tailored adherence-enhancing interventions. ClinicalTrials.gov registration number: NCT03344146.

[Stroke Unit- / Stroke Center Care]. / Stroke Unit- / Stroke Center-Management.

Stroke Unit- / Stroke Center Care Abstract. About 16'000 people in Switzerland suffer from stroke, each year. In Switzerland, 23 Stroke units and Stroke centers are available to provide individual care for the vast majority of stroke patients. Comprehensive, interdisciplinary therapeutic strategies are standardized and include prevention and therapy of acute complications, expedited diagnostic workup, and early rehabilitation. Stroke units not only reduce mortality and permanent disability in stroke patients, but-alongside advanced recanalization therapies-represent the cornerstone of modern stroke care. The following article gives a detailed overview of core tasks and the current standards of treatment in stroke unit care.