Association of the Timing of Atrial Fibrillation Detection and Insular Involvement With the Risk of Embolic Events After Acute Ischemic Stroke.

OBJECTIVE: Atrial fibrillation (AF) detected after insular stroke might arise from autonomic and inflammatory mechanisms triggered by insular damage, and be associated with a low embolic risk. We assessed the association of the timing of AF detection and insular involvement with the risk of embolic events after acute ischemic stroke. METHODS: Acute ischemic stroke patients with AF who underwent brain magnetic resonance imaging at baseline were enrolled. Patients were classified according to the timing of AF detection (AF detected after stroke [AFDAS] or known AF [KAF]) and insular involvement. The primary outcome was embolic events defined as recurrent ischemic stroke, transient ischemic attack, and systemic embolism within 90 days. RESULTS: Of 1,548 patients, 360 had AFDAS with insular cortex lesions (+I), 409 had AFDAS without insular cortex lesions (-I), 349 had KAF+I, and 430 had KAF-I. Cumulative incidence rates of embolic events at 90 days in patients with AFDAS+I, AFDAS-I, KAF+I, and KAF-I were 0.8%, 3.5%, 4.9%, and 3.3%, respectively. Patients with AFDAS-I (adjusted hazard ratio 5.04, 95% confidence interval 1.43-17.75), KAF+I (6.18, 1.78-21.46), and KAF-I (5.26, 1.48-18.69) had a significantly higher risk of embolic events than those with AFDAS+I. INTERPRETATION: Acute ischemic stroke patients with AFDAS and insular cortex lesions had a lower risk of embolic events than those who had AFDAS without insular cortex lesions or those with KAF, regardless of insular involvement. ANN NEUROL 2024;95:338-346.

Fluid-attenuated inversion recovery vascular hyperintensity-diffusion-weighted imaging mismatch and functional outcome after endovascular reperfusion therapy for acute ischemic stroke.

BACKGROUND: Fluid-attenuated inversion recovery vascular hyperintensity (FVH) outside of the diffusion-weighted imaging (DWI) lesion, termed FVH-DWI mismatch, may represent penumbral tissue with good collateral status. METHODS: Consecutive patients who underwent endovascular reperfusion therapy (EVT) for acute internal carotid artery (ICA) or middle cerebral artery (MCA)-M1 occlusion were enrolled. FVH-DWI mismatch score was defined as the number of cortical Alberta Stroke Program Early CT Score areas (I and M1 to M6) that involved FVH but no DWI lesion (0 to 7 points). The outcome measure was set as good functional outcome, defined as a modified Rankin Scale score of 0 to 2, at 90 days after onset. RESULTS: Of 196 consecutive patients who underwent EVT for acute ICA or MCA-M1 occlusion, 32 without brain MRI before EVT were excluded, and the remaining 164 were analyzed. The median FVH-DWI mismatch score was 2 (interquartile range, 0 to 4). At 90 days after EVT, 2 patients were lost-to follow-up, and 73 had good functional outcome. The frequency of good functional outcome at 90 days after EVT increased significantly with increasing FVH-DWI mismatch score (P for trend <0.001). FVH-DWI mismatch score was independently associated with good functional outcome at 90 days after onset (adjusted odds ratio per 1 point,1.46; 95% confidence interval, 1.15-1.89). CONCLUSIONS: Patients with large FVH-DWI mismatch had good functional outcome after EVT for acute ICA or MCA-M1 occlusion.

Intraplaque high-intensity signal on time-of-flight magnetic resonance angiography and restenosis after carotid artery stenting.

OBJECTIVE: To test the hypothesis that intraplaque hemorrhage is a predictor of restenosis after carotid artery stenting (CAS), the association between intraplaque high-intensity signal (HIS) on time-of-flight MR angiography (TOF-MRA), as a marker of intraplaque hemorrhage, and restenosis after CAS was assessed in the present observational study. METHODS: Consecutive patients who underwent initial CAS for atherosclerotic stenosis in the cervical internal carotid artery in the authors' department were enrolled. Of these, patients without preprocedural cervical TOF-MRA were excluded. Outcome measures were ≥ 50% restenosis, defined as a peak systolic velocity of > 1.3 m/sec; or occlusion and ≥ 70% restenosis, defined as a peak systolic velocity of > 2.1 m/sec; or occlusion on carotid duplex ultrasound. RESULTS: Of 230 consecutive patients who underwent initial CAS, 22 without preprocedural cervical TOF-MRA were excluded. Of the remaining 208 patients (mean age 73 years; 33 women), 46 had intraplaque HIS. Ultrasound follow-up was not performed in 4 patients. The median follow-up duration was 3.2 years (interquartile range 1.7-5.1 years). During the follow-up period, 102 patients had ≥ 50% restenosis and 36 had ≥ 70% restenosis. Intraplaque HIS was significantly associated with increased risk of ≥ 50% restenosis (adjusted hazard ratio 2.18; 95% CI 1.28-3.68) and ≥ 70% restenosis (adjusted hazard ratio 3.12; 95% CI 1.32-7.52). CONCLUSIONS: Intraplaque HIS on TOF-MRA was associated with increased risk of restenosis after CAS. The present results indicate that intraplaque hemorrhage is a predictor of restenosis after CAS.

Bridging Therapy With Heparin Before Starting Rivaroxaban in Ischemic Stroke or Transient Ischemic Attack With Non-Valvular Atrial Fibrillation.

BACKGROUND: The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).Methods and Results: Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01-3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant. CONCLUSIONS: The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

Clopidogrel response predicts thromboembolic events associated with coil embolization of unruptured intracranial aneurysms: A prospective cohort study.

OBJECTIVE: Periprocedural thromboembolic events are a serious complication associated with coil embolization of unruptured intracranial aneurysms. However, no established clinical rule for predicting thromboembolic events exists. This study aimed to clarify the significance of adding preoperative clopidogrel response value to clinical factors when predicting the occurrence of thromboembolic events during/after coil embolization and to develop a nomogram for thromboembolic event prediction. METHODS: In this prospective, single-center, cohort study, we included 345 patients undergoing elective coil embolization for unruptured intracranial aneurysm. Thromboembolic event was defined as the occurrence of intra-procedural thrombus formation and postprocedural symptomatic cerebral infarction within 7 days. We evaluated preoperative clopidogrel response and patients' clinical information. We developed a patient-clinical-information model for thromboembolic event using multivariate analysis and compared its efficiency with that of patient-clinical-information plus preoperative clopidogrel response model. The predictive performances of the two models were assessed using area under the receiver-operating characteristic curve (AUC-ROC) with bootstrap method and compared using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: Twenty-eight patients experienced thromboembolic events. The clinical model included age, aneurysm location, aneurysm dome and neck size, and treatment technique. AUC-ROC for the clinical model improved from 0.707 to 0.779 after adding the clopidogrel response value. Significant intergroup differences were noted in NRI (0.617, 95% CI: 0.247-0.987, p < .001) and IDI (0.068, 95% CI: 0.021-0.116, p = .005). CONCLUSIONS: Evaluation of preoperative clopidogrel response in addition to clinical variables improves the prediction accuracy of thromboembolic event occurrence during/after coil embolization of unruptured intracranial aneurysm.

Left Atrial Appendage Flow Velocity and Multiple Infarcts in Cryptogenic Stroke.

BACKGROUND: To validate the hypothesis that cryptogenic stroke with multiple infarcts included embolic stroke due to left atrial appendage (LAA) dysfunction, the present retrospective observational study was aimed to clarify the association between LAA flow velocity (LAA-FV) and multiple infarcts in patients with cryptogenic stroke. METHODS: From consecutive patients with cryptogenic stroke admitted to our hospital within 7 days after onset, patients without brain magnetic resonance imaging (MRI) on admission or without transesophageal echocardiography (TEE) during acute hospitalization were excluded, and the remaining patients were enrolled. Multiplicity of fresh infarcts was assessed using diffusion-weighted images from brain MRI. LAA-FV was defined as LAA peak emptying flow velocity on TEE. RESULTS: Of 786 enrolled patients, 522 patients (66%) had a single infarct, and the remaining 264 patients (34%) had multiple infarcts. The percentage of multiple infarcts decreased with increasing quartiles of LAA-FV (p for trend <0.001). The adjusted odds ratio for multiple infarcts decreased with increasing quartiles of LAA-FV (adjusted odds ratio in the fourth quartile, 0.39; 95% confidence interval, 0.25-0.60; compared with the first quartile). LAA-FV as a continuous variable was negatively associated with multiple infarcts (adjusted odds ratio per 10 cm/s, 0.87; 95% confidence interval, 0.81-0.92). CONCLUSIONS: Reduced LAA-FV on TEE was associated with multiple infarcts in patients with cryptogenic stroke. The present findings indicate that cryptogenic stroke with multiple infarcts includes embolic stroke due to LAA dysfunction.

Left Atrial Size and Ischemic Events after Ischemic Stroke or Transient Ischemic Attack in Patients with Nonvalvular Atrial Fibrillation.

BACKGROUND: The present study aimed to clarify the association between left atrial (LA) size and ischemic events after ischemic stroke or transient ischemic attack (TIA) in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Acute ischemic stroke or TIA patients with NVAF were enrolled. LA size was classified into normal LA size, mild LA enlargement (LAE), moderate LAE, and severe LAE. The ischemic event was defined as ischemic stroke, TIA, carotid endarterectomy, carotid artery stenting, acute coronary syndrome or percutaneous coronary intervention, systemic embolism, aortic aneurysm rupture or dissection, peripheral artery disease requiring hospitalization, or venous thromboembolism. RESULTS: A total of 1,043 patients (mean age, 78 years; 450 women) including 1,002 ischemic stroke and 41 TIA were analyzed. Of these, 351 patients (34%) had normal LA size, 298 (29%) had mild LAE, 198 (19%) had moderate LAE, and the remaining 196 (19%) had severe LAE. The median follow-up duration was 2.0 years (interquartile range, 0.9-2.1). During follow-up, 117 patients (11%) developed at least one ischemic event. The incidence rate of total ischemic events increased with increasing LA size. Severe LAE was independently associated with increased risk of ischemic events compared with normal LA size (multivariable-adjusted hazard ratio, 1.75; 95% confidence interval, 1.02-3.00). CONCLUSION: Severe LAE was associated with increased risk of ischemic events after ischemic stroke or TIA in patients with NVAF.

Bicyclobutane Carboxylic Amide as a Cysteine-Directed Strained Electrophile for Selective Targeting of Proteins.

Expanding the repertoire of electrophiles with unique reactivity features would facilitate the development of covalent inhibitors with desirable reactivity profiles. We herein introduce bicyclo[1.1.0]butane (BCB) carboxylic amide as a new class of thiol-reactive electrophiles for selective and irreversible inhibition of targeted proteins. We first streamlined the synthetic routes to generate a variety of BCB amides. The strain-driven nucleophilic addition to BCB amides proceeded chemoselectively with cysteine thiols under neutral aqueous conditions, the rate of which was significantly slower than that of acrylamide. This reactivity profile of BCB amide was successfully exploited to develop covalent ligands targeting Bruton's tyrosine kinase (BTK). By tuning BCB amide reactivity and optimizing its disposition on the ligand, we obtained a selective covalent inhibitor of BTK. The in-gel activity-based protein profiling and mass spectrometry-based chemical proteomics revealed that the selected BCB amide had a higher target selectivity for BTK in human cells than did a Michael acceptor probe. Further chemical proteomic study revealed that BTK probes bearing different classes of electrophiles exhibited distinct off-target profiles. This result suggests that incorporation of BCB amide as a cysteine-directed electrophile could expand the capability to develop covalent inhibitors with the desired proteome reactivity profile.

Intracranial Subdural Abscess Caused by Actinomyces meyeri Related to Dental Treatment: A Case Report.

Intracranial subdural abscess is a rare condition. Although brain abscess is often reported in relation to dental infection, reports of intracranial subdural abscess are few. Actinomyces spp. forms part of the normal flora of the oral, gastrointestinal, and genital tract, and is rarely the cause of intracranial infection; moreover, the pathogen Actinomyces meyeri is very rare. We report an exceptional case of intracranial subdural abscess caused by A. meyeri and related to dental treatment. A 57-year-old woman initially presented with a 5-day history of headache. Because left arm numbness and weakness became apparent, she was admitted to our department. She had a history of hypertension and dental problems requiring tooth extractions. Diffusion-weighted imaging (DWI) showed a 1-cm right convexity hyperintense mass above the postcentral gyrus. A post-gadolinium T1-weighted image showed a thin hypointense area with peripheral rim enhancement in the right subdural space that appeared to partially thicken in the same location as the DWI-positive mass. She underwent emergent navigation-guided drainage and 4 mL of pus was obtained. Postoperatively, left arm numbness and weakness disappeared. Cultures showed growth of A. meyeri and Fusobacterium nucleatum. She was started on intravenous penicillin G and metronidazole. After a 4-week course of the intravenous antibiotics, her headache gradually improved and the abscess in the subdural space subsided. To our best knowledge this is the first case report of intracranial subdural abscess caused by A. meyeri associated with dental treatment.

Selective Covalent Targeting of Mutated EGFR(T790M) with Chlorofluoroacetamide-Pyrimidines.

Covalent modification of disease-associated proteins with small molecules is a powerful approach for achieving an increased and sustained pharmacological effect. To reduce the potential risk of nonselective covalent modification, molecular design of covalent inhibitors is critically important. We report herein the development of a targeted covalent inhibitor for mutated epidermal growth factor receptor (EGFR) (L858R/T790M) using α-chlorofluoroacetamide (CFA) as the reactive group. The chemically tuned weak reactivity of CFA was suitable for the design of third-generation EGFR inhibitors that possess the pyrimidine scaffold. The structure-activity relationship study revealed that CFA inhibitor 18 (NSP-037) possessed higher inhibition selectivity to the mutated EGFR over wild-type EGFR when compared to clinically approved osimertinib. Mass-based chemical proteomics analyses further revealed that 18 displayed high covalent modification selectivity for the mutated EGFR in living cells. These findings highlight the utility of CFA as a warhead of targeted covalent inhibitors and the potential application of the CFA-pyrimidines for treatment of non-small-cell lung cancer.

A Visual Task Management Application for Acute Ischemic Stroke Care.

Background: To maximize the effect of intravenous (IV) thrombolysis and/or endovascular therapy (EVT) for acute ischemic stroke (AIS), stroke centers need to establish a parallel workflow on the basis of a code stroke (CS) protocol. At Kokura Memorial Hospital (KMH), we implemented a CS system in January 2014; however, the process of information sharing within the team has occasionally been burdensome. Objective: To solve this problem using information communication technology (ICT), we developed a novel application for smart devices, named "Task Calc. Stroke" (TCS), and aimed to investigate the impact of TCS on AIS care. Methods: TCS can visualize the real-time progress of crucial tasks for AIS on a dashboard by changing color indicators. From August 2015 to March 2017, we installed TCS at KMH and recommended its use during normal business hours (NBH). We compared the door-to-computed tomography time, the door-to-complete blood count (door-to-CBC) time, the door-to-needle for IV thrombolysis time, and the door-to-puncture for EVT time among three treatment groups, one using TCS ("TCS-based CS"), one not using TCS ("phone-based CS"), and one not based on CS ("non-CS"). A questionnaire survey regarding communication problems was conducted among the CS teams at 3 months after the implementation of TCS. Results: During the study period, 74 patients with AIS were transported to KMH within 4.5 h from onset during NBH, and 53 were treated using a CS approach (phone-based CS: 26, TSC-based CS: 27). The door-to-CBC time was significantly reduced in the TCS-based CS group compared to the phone-based CS group, from 31 to 19 min (p = 0.043). Other processing times were also reduced, albeit not significantly. The rate of IV thrombosis was higher in the TCS-based CS group (78% vs. 46%, p = 0.037). The questionnaire was correctly filled in by 34/38 (89%) respondents, and 82% of the respondents felt a reduction in communication burden by using the TCS application. Conclusions: TCS is a novel approach that uses ICT to support information sharing in a parallel CS workflow in AIS care. It shortens the processing times of critical tasks and lessens the communication burden among team members.

Factors Associated with Postprocedural Diffusion-Weighted Imaging-Positive Lesions in Endovascular Treatment for Unruptured Cerebral Aneurysms.

BACKGROUND: In endovascular treatment for cerebral aneurysms, the appearance of asymptomatic thromboembolic lesions detected by postprocedural diffusion-weighted imaging (DWI) can be a surrogate marker for estimating the potential risk of symptomatic thromboembolism. The aim of this study was to clarify factors associated with postprocedural DWI-positive lesions in endovascular treatment for unruptured cerebral aneurysms. METHODS: Patients with untreated unruptured cerebral aneurysms undergoing endovascular treatment were consecutively enrolled. Treatment techniques were classified into simple coiling, balloon-assisted coiling, stent-assisted coiling, and flow-diverter placement. Head magnetic resonance imaging was performed within 3 months before and 24 hours after the procedure to assess the appearance of DWI-positive lesions. RESULTS: Among 376 aneurysms in 355 patients that were analyzed, 232 (61.7%) had postprocedural DWI-positive lesions. In univariate analyses, age (P = 0.001), dome size (P < 0.001), neck size (P < 0.001), treatment technique (P = 0.029), and total procedural time (P < 0.001) were significantly associated with postprocedural DWI-positive lesions. In the multiple logistic regression model, older age (odds ratio, 1.33; 95% confidence interval, 1.10-1.60; P = 0.003; per decade), flow-diverter placement (odds ratio, 4.93; 95% confidence interval, 1.33-20.92; P = 0.016; compared with simple coiling), and longer procedural time (odds ratio, 1.66; 95% confidence interval, 1.26-2.21; P < 0.001; per hour) were associated with postprocedural DWI-positive lesions. CONCLUSIONS: Older age, flow-diverter placement, and longer procedural time were associated with postprocedural DWI-positive lesions in endovascular treatment for unruptured cerebral aneurysms.

Prior Anticoagulation and Short- or Long-Term Clinical Outcomes in Ischemic Stroke or Transient Ischemic Attack Patients With Nonvalvular Atrial Fibrillation.

Background We aimed to clarify associations between prior anticoagulation and short- or long-term clinical outcomes in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Methods and Results A total of 1189 ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation who were hospitalized within 7 days after onset were analyzed. Of these, 813 patients (68.4%) received no prior anticoagulation, 310 (26.1%) received prior warfarin treatment with an international normalized ratio ( INR ) <2 on admission, 28 (2.4%) received prior warfarin treatment with an INR ≥2 on admission, and the remaining 38 (3.2%) received prior direct oral anticoagulant treatment. Prior warfarin treatment was associated with a lower risk of death or disability at 3 months compared with no prior anticoagulation ( INR <2: adjusted odds ratio: 0.58; 95% CI, 0.42-0.81; P=0.001; INR ≥2: adjusted odds ratio: 0.40; 95% CI, 0.16-0.97; P=0.043) but was not associated with a lower risk of death or disability at 2 years. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years compared with no prior anticoagulation (adjusted hazard ratio: 2.94; 95% CI, 1.20-6.15; P=0.021). Conclusions Prior warfarin treatment was associated with a lower risk of death or disability at 3 months but was not associated with a lower risk of death or disability at 2 years in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01581502.

Selective and reversible modification of kinase cysteines with chlorofluoroacetamides.

Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0.1-10 µM). The cysteine adduct of the CFA derivative was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline NS-062 significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.

A Case of Posterior Reversible Encephalopathy Syndrome After Surgical Clipping of Unruptured Cerebral Aneurysm.

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is characterized by reversible edematous lesions on imaging examinations, along with symptoms of altered consciousness disorder and seizures. Various factors associated with PRES have been reported. However, we encountered a very rare case that developed after clipping surgery for unruptured cerebral aneurysm. CASE DESCRIPTION: A 74-year-old man with a history of hypertension presented with an unruptured right middle cerebral artery aneurysm and underwent cranial clipping surgery. After surgery, he developed consciousness disorder and epilepsy after delayed awakening from general anesthesia. Radiological examinations revealed multiple edematous lesions, strongly suggesting PRES, and excluding asymmetry consistent with the area of craniotomy. With conservative treatment, symptoms and radiological findings almost disappeared. Symptoms and imaging findings remaining at the area of craniotomy were attributed to the severe difference in cerebral perfusion pressure due to craniotomy. CONCLUSIONS: Based on the literature, this case was considered to represent PRES caused by rapid blood pressure fluctuations accompanying general anesthesia for clipping surgery. Practitioners must keep PRES in mind as a rare complication after clipping for unruptured cerebral aneurysms. PRES developing after craniotomy shows unilaterality and may become severe in the craniotomy area and leave sequelae.

Dural and Pial Arteriovenous Fistulas Connected to the Same Drainer in the Middle Cranial Fossa: A Case Report.

BACKGROUND: Dural arteriovenous fistulas (AVFs) in the middle cranial fossa are rare. Pial AVFs are similarly rare but differ from dural AVFs in that they derive their arterial supply from pial or cortical arterial vessels and do not lie within the intradural region. We report an extremely rare case of dural and pial AVF connected to the same drainer in the middle cranial fossa. CASE DESCRIPTION: In a 58-year-old man with a subcortical hemorrhage in the right temporal lobe, digital subtraction angiography showed a dural AVF in the middle cranial fossa fed by the middle meningeal artery (MMA) and draining into the sphenopetrosal vein. A combination with a small pial AVF connected to the same sphenopetrosal vein was suspected. Open surgery was performed to directly observe the shunt points. Transarterial indocyanine green (ICG) angiography using the MMA via the superficial temporal artery on a skin flap was performed to repeatedly and distinctly evaluate the dural shunt points and to prevent cerebral thromboembolism. Although the dural supply was completely disconnected, the sphenopetrosal vein remained arterialized. ICG angiography revealed pial AVF, which was fed by the cortical arteries draining into the same drainer. The pial supply was completely disconnected, and disappearance of the dural and pial AVF was confirmed. CONCLUSIONS: We report an extremely rare case of dural and pial AVF connected to the same drainer in the middle cranial fossa. To our knowledge, this is the first such case report described in the literature.

Two-Year Outcomes of Anticoagulation for Acute Ischemic Stroke With Nonvalvular Atrial Fibrillation　- SAMURAI-NVAF Study.

BACKGROUND: We determined the 2-year long-term risk-benefit profile in patients with stroke or transient ischemic attack (TIA) receiving warfarin or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry in Japan.Methods and Results:NVAF patients within 7 days after onset of ischemic stroke/TIA were enrolled in 18 stroke centers. Outcome measures included ischemic and bleeding events and death in the 2-year follow-up period. We enrolled 1,116 patients taking either warfarin (650 patients) or DOACs (466 patients) at acute hospital discharge. DOAC users were younger and had lower National Institutes of Health Stroke Scale, CHADS2and discharge modified Rankin Scale scores than warfarin users (P<0.0001 each). Incidences of stroke/systemic embolism (adjusted hazard ratio, 1.07; 95% CI, 0.66-1.72), all ischemic events (1.13; 0.72-1.75), and ischemic stroke/TIA (1.58; 0.95-2.62) were similar between groups. Risks of intracranial hemorrhage (0.32; 0.09-0.97) and death (0.41; 0.26-0.63) were significantly lower for DOAC users. Infection was the leading cause of death, accounting for 40% of deaths among warfarin users. CONCLUSIONS: Stroke/TIA patients receiving DOACs for secondary prevention were younger and had lower stroke severity and risk indices than those receiving warfarin. Estimated cumulative incidences of stroke and systemic embolism within 2 years were similar between warfarin and DOACs users, but those of death and intracranial hemorrhage were significantly lower among DOAC users.

Associations between Pre-Admission Risk Scores and Two-Year Clinical Outcomes in Ischemic Stroke or Transient Ischemic Attack Patients with Non-Valvular Atrial Fibrillation.

BACKGROUND: We aimed to clarify associations between pre-admission risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED) and 2-year clinical outcomes in ischemic stroke or transient ischemic attack (TIA) patients with non-valvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry. METHODS: From 18 Japanese stroke centers, ischemic stroke or TIA patients with NVAF hospitalized within 7 days after onset were enrolled. Outcome measures were defined as death/disability (modified Rankin Scale score ≥3) at 2 years, 2-year mortality, and ischemic or hemorrhagic events within 2 years. RESULTS: A total of 1,192 patients with NVAF (527 women; mean age, 78 ± 10 years), including 1,141 ischemic stroke and 51 TIA, were analyzed. Rates of death/disability, mortality, and ischemic or hemorrhagic events increased significantly with increasing pre-admission CHADS2 (p for trend <0.001 for death/disability and mortality, p for trend = 0.024 for events), CHA2DS2-VASc (p for trend <0.001 for all), and HAS-BLED (p for trend = 0.004 for death/disability, p for trend <0.001 for mortality, p for trend = 0.024 for events) scores. Pre-admission CHADS2 (OR per 1 point, 1.52; 95% CI 1.35-1.71; p <0.001 for death/disability; hazard ratio (HR) per 1 point, 1.23; 95% CI 1.12-1.35; p <0.001 for mortality; HR per 1 point, 1.14; 95% CI 1.02-1.26; p = 0.016 for events), CHA2DS2-VASc (1.55, 1.41-1.72, p < 0.001; 1.21, 1.12-1.30, p < 0.001; 1.17, 1.07-1.27, p < 0.001; respectively), and HAS-BLED (1.33, 1.17-1.52, p < 0.001; 1.23, 1.10-1.38, p < 0.001; 1.18, 1.05-1.34, p = 0.008; respectively) scores were independently associated with all outcome measures. CONCLUSIONS: In ischemic stroke or TIA patients with NVAF, all pre-admission risk scores were independently associated with death/disability at 2 years and 2-year mortality, as well as ischemic or hemorrhagic events within 2 years.

Improving treatment times for patients with in-hospital stroke using a standardized protocol.

BACKGROUND: Previous reports have shown significant delays in treatment of in-hospital stroke (IHS). We developed and implemented our IHS alert protocol in April 2014. We aimed to determine the influence of implementation of our IHS alert protocol. METHODS: Our implementation processes comprise the following four main steps: IHS protocol development, workshops for hospital staff to learn about the protocol, preparation of standardized IHS treatment kits, and obtaining feedback in a monthly hospital staff conference. We retrospectively compared protocol metrics and clinical outcomes of patients with IHS treated with intravenous thrombolysis and/or endovascular therapy between before (January 2008-March 2014) and after implementation (April 2014-December 2016). RESULTS: Fifty-five patients were included (pre, 25; post, 30). After the implementation, significant reductions occurred in the median time from stroke recognition to evaluation by a neurologist (30 vs. 13.5min, p<0.01) and to first neuroimaging (50 vs. 26.5min, p<0.01) and in the median time from first neuroimaging to intravenous thrombolysis (45 vs. 16min, p=0.02). The median time from first neuroimaging to endovascular therapy had a tendency to decrease (75 vs. 53min, p=0.08). There were no differences in the favorable outcomes (modified Rankin scale score of 0-2) at discharge or the incidence of symptomatic intracranial hemorrhage between the two periods. CONCLUSION: Our IHS alert protocol implementation saved time in treating patients with IHS without compromising safety.

Association between the maximal distance of atrial septal protrusion and cryptogenic stroke.

Background and purpose Previous studies have suggested that atrial septal aneurysm is a potential risk factor for cerebral embolism. However, the association between the level of atrial septal protrusion and cerebral embolism is still unclear. The purpose of the present study was to assess the association between the maximal distance of atrial septal protrusion and cryptogenic stroke. Methods A total of 588 consecutive acute ischemic stroke patients (70 ± 11 (mean ± SD) years, 401 men) who underwent transesophageal echocardiography were enrolled. The maximal distance of atrial septal protrusion into the right or left atrium was measured. Atrial septal aneurysm was diagnosed when the maximal distance of atrial septal protrusion was >10 mm. Cryptogenic stroke was defined as non-lacunar ischemic stroke without >50% proximal artery stenosis or occlusion, cardioembolic sources, ≥4 mm atherosclerotic plaques in the aortic arch, or carotid or vertebral artery dissection. Results The rate of cryptogenic stroke increased with the increasing maximal distance of atrial septal protrusion. The maximal distance of atrial septal protrusion (multivariate-adjusted odds ratio (OR) per 1 mm, 1.14; 95% confidence interval (CI), 1.04-1.24; P = 0.003) and atrial septal aneurysm (multivariate-adjusted OR, 4.32; 95% CI, 1.22-20.39; P = 0.022) was independently associated with cryptogenic stroke. Conclusions The maximal distance of atrial septal protrusion was independently associated with cryptogenic stroke.