Yoshinari Nagakane

Introduction: To investigate the association of intracranial atherosclerotic disease (ICAD), alone and comorbid with cerebral small vessel disease (SVD), with ischemic or hemorrhagic events in patients receiving antithrombotic therapy. Patients and Methods: In this prospective, multicenter, observational study, baseline brain MRI was performed to assess SVD (white matter hyperintensities, cerebral microbleeds, lacunes, enlarged perivascular spaces [PVS]), nonlacunar infarcts, and ICAD. SVD burden was defined as SVD score > 2. ICAD was classified as normal‐to‐mild, moderate, and severe stenosis‐to‐occlusion. The outcomes were any ischemic event, ischemic stroke, major bleeding, intracranial hemorrhage, and all‐cause mortality. We assessed associations of ICAD with outcomes via Cox regression and mediation analyses, adjusting for SVD burden. Results: Among 5250 patients (mean age: 71 ± 11 years, 33% women), 3947 (75%) received antiplatelets and 1304 (25%) anticoagulants at baseline. ICAD was normal‐to‐mild in 3781 (72%), moderate in 571 (11%), and severe‐to‐occluded in 894 (17%). SVD burden was observed in 1400 (27%). ICAD was associated with a higher frequency of non‐lacunar infarcts and a lower frequency of PVS. There was no graded association between ICAD severity and SVD burden. During a median follow‐up of 2 years, 278 ischemic events, 197 ischemic strokes, 97 major bleedings, 55 intracranial hemorrhages, and 217 deaths occurred. Severe‐to‐occluded ICAD independently increased the risk of any ischemic event (adjusted hazard ratio: 1.39 [1.03–1.86]) and mortality (2.01 [1.48–2.74]); coexisting SVD burden further increased the risk of all outcomes. ICAD directly affected ischemic events, while mortality was mainly driven by its additive interaction with SVD. Conclusions: ICAD increases the risk of any ischemic events and, with comorbid SVD, contributes to hemorrhagic events and excess mortality.

An 88‐year‐old woman presented with sudden‐onset dysarthria and left hemiparesis. The National Institutes of Health Stroke Scale score was 17. Computed tomography angiography showed right internal carotid artery occlusion with preserved middle cerebral artery perfusion via the anterior communicating artery. Perfusion imaging revealed hypoperfusion in the right posterior limb of the internal capsule. Intravenous thrombolysis and mechanical thrombectomy achieved complete recanalization with neurological improvement. Follow‐up magnetic resonance imaging showed infarction in the right corona radiata but not in the internal capsule. The improvement was attributed to reperfusion of the internal capsule territory supplied by the anterior choroidal artery.

Enlarged perivascular spaces (ePVSs) are considered to increase the risk of stroke. However, data regarding the benefits and risks of antithrombotic therapy in patients with ePVSs are currently limited. This study assessed the association between ePVSs and the risks of hemorrhagic or ischemic events in patients taking antithrombotic agents. This prospective, multicenter observational study enrolled patients with cerebrovascular or cardiovascular diseases who had newly started or were continuing to take oral antithrombotic agents at 52 hospitals across Japan between 2016 and 2019. Baseline multimodal MRI was performed for all of the study participants. The images were then centrally evaluated for cerebral small vessel disease (SVD), including white matter hyperintensities, cerebral microbleeds, lacunes, and basal ganglia-enlarged perivascular spaces (BGPVSs). BGPVSs were categorized as 0, 1-10, 11-20, or ≥21. Outcomes included major bleeding, intracranial hemorrhage, ischemic events, ischemic stroke, and mortality. Multivariable Cox proportional hazards models were used for the BGPVSs (in categorical and ordinal forms), adjusted for patient demographics, vascular risk factors, and other SVD markers. Of the total 5,065 patients (1,663 women; median age 74 [interquartile range 67-81] years), antiplatelets and anticoagulants were administered at the baseline to 3,820 (75.4%) and 1,502 (29.7%) patients, respectively. Their BGPVS distributions were as follows: 0, 475 (9.4%); 1-10, 2,615 (51.6%); 11-20, 1,267 (25.0%); and 21+, 708 patients (14.0%). Over a median follow-up period of 2.0 (interquartile range 1.8-2.0) years, we noted 266 ischemic events, 188 ischemic strokes, 92 major bleeding events, 54 intracranial hemorrhages, and 198 deaths. Higher BGPVS was associated with an increased risk of major bleeding (BGPVS ≥21: adjusted hazard ratio [aHR] 4.04, 95% CI 1.17-13.92; per-unit increase: aHR 1.38, 95% CI 1.07-1.77) and ischemic stroke (BGPVS ≥21: aHR 2.58, 95% CI 1.21-5.50; per-unit increase: aHR 1.28, 95% CI 1.07-1.53) but was not significantly associated with higher risks of ischemic events, intracranial hemorrhage, or mortality. Higher BGPVS burdens are associated with higher risks of ischemic stroke and major bleeding in patients receiving antithrombotic therapy. BGPVSs may serve as useful imaging biomarkers for vascular risk assessment and personalized therapy.

Background: Timely recognition of oral anticoagulant use is critical in acute stroke but is often hampered by impaired consciousness and unavailable medication history. We investigated whether routinely available coagulation tests, prothrombin time–international normalized ratio and activated partial thromboplastin time, paired with machine learning can identify anticoagulant exposure at presentation. Methods: We performed a multicenter diagnostic modeling study using the Japan Stroke Data Bank. Adults with ischemic or hemorrhagic stroke admitted in 2016 to 2021 comprised the derivation cohort; those in 2022 formed a temporally distinct validation cohort. Three models (random forest, extreme gradient boosting, and neural network) used prothrombin time–international normalized ratio and activated partial thromboplastin time as predictors to classify anticoagulant status: vitamin K antagonist, direct oral anticoagulant, or none. Discrimination (area under the receiver operating characteristic curve and area under the precision‐recall curve), calibration, and decision curve analysis were assessed. Model outputs were implemented as bedside probability heat maps. Results: Among 30 767 patients (derivation n=24 857; validation n=5910), vitamin K antagonist/direct oral anticoagulant use was 4.5%/8.2% in derivation and 2.8%/9.5% in validation. In the validation cohort, the neural network yielded the best performance: area under the receiver operating characteristic curve, 0.933 (95% CI, 0.908–0.955) and area under the precision‐recall curve, 0.52 (95% CI, 0.44–0.61) for vitamin K antagonist; area under the receiver operating characteristic curve, 0.841 (95% CI, 0.822–0.858) and area under the precision‐recall curve, 0.39 (95% CI, 0.35–0.43) for direct oral anticoagulant, with preserved calibration and highest net benefit across clinically relevant thresholds. Heat maps summarized class probabilities over the prothrombin time–international normalized ratio×activated partial thromboplastin time space to support rapid inference. Conclusions: A simple machine learning model using only prothrombin time–international normalized ratio and activated partial thromboplastin time classified vitamin K antagonist and direct oral anticoagulant exposure with high accuracy and practical clinical utility. This tool assists emergency decision‐making when medication history is unknown, supporting the safety and timeliness of acute stroke care.

Background: Antithrombotic agents are essential for preventing cerebrovascular and cardiovascular diseases; however, bleeding complications remain a major concern, particularly among elderly patients and those receiving combination therapy. Aims: We designed the Bleeding with Antithrombotic Therapy 2 (BAT2) Study, a prospective multicenter registry involving hospitals from a clinical research network in Japan, to clarify the risk of bleeding events in patients taking antithrombotic agents for cerebrovascular and cardiovascular diseases in recent clinical settings. Methods: This prospective, multicenter, observational study followed bleeding and ischemic events for up to 2 years in patients with cerebrovascular and cardiovascular diseases. The primary outcome was major bleeding, and secondary outcomes included intracranial hemorrhage (ICH). Results: The 5250 patients enrolled comprised 3134 (70 ± 11 years; male, 66.6%; HASBLED ⩾ 3, 32.8%) treated with single antiplatelet therapy (SAPT), 551 (71 ± 11 years; 25.8%; 40.8%, respectively) with dual antiplatelet therapy (DAPT), 870 (75 ± 10 years; 37.1%; 39.8%, respectively) with direct oral anticoagulant (DOAC) alone, 433 (72 ± 12 years; 34.2%; 41.4%, respectively) with warfarin alone, 143 (76 ± 8 years; 16.8%; 42.7%, respectively) with DOAC plus antiplatelet agents (AP), and 119 (73 ± 12 years; 18.5%; 47.5%, respectively) with warfarin plus AP. During follow-up (median, 1.98 years), 93 patients experienced major bleeding, and 55 developed ICH. Compared with the SAPT group (37 events, 0.63%/year), the DOAC (18 events, 1.12%/year; adjusted hazard ratio (aHR) = 1.94, 95% confidence interval (CI) = 1.09–3.46), warfarin (16 events, 2.02%/year; 3.44, 1.90–6.23), and DOAC plus AP groups (six events, 2.24%/year; 3.07, 1.28–7.35) exhibited significantly higher risks of major bleeding after multivariable adjustment. DAPT (aHR 2.47, 95% CI = 1.11–5.48), warfarin (5.38, 2.65–10.92), and DOAC plus AP (3.86, 1.30–11.47) had significantly higher risks of ICH than SAPT. The DAPT (2.28, 95% CI = 1.65–3.14), DOAC plus AP (1.96, 1.08–3.56), and warfarin plus AP (2.83, 1.62–4.92) groups showed significantly higher risks of ischemic events than the SAPT group. Conclusion: Oral anticoagulant alone and DOAC with antiplatelet therapy were associated with higher risks of major bleeding events than SAPT in long-term follow-up for patients with stroke and cardiovascular disease.

BACKGROUND: Defining the risk of developing major bleeding, especially intracranial hemorrhage (ICH), or ischemic stroke (IS) in patients receiving antithrombotic therapy is crucial. Existing risk prediction tools would inadequately assess the net clinical benefit of antithrombotic therapy. We aimed to develop novel risk scores incorporating covert vascular brain injury to personalize the risk assessment of major bleeding, ICH, and IS in patients receiving antithrombotic therapy. METHODS: The prospective, multicenter, observational study (BAT2 [Bleeding With Antithrombotic Therapy Study-2]) enrolled patients receiving oral antiplatelets or anticoagulants from 52 hospitals across Japan between 2016 and 2019. Multimodal brain magnetic resonance imaging was performed at baseline under prespecified conditions to determine cerebral small vessel disease (white matter hyperintensity, cerebral microbleed, lacune, enlarged perivascular space, and cortical superficial siderosis), nonlacunar infarct, and intracranial artery disease with central reading. Risk scores, collectively termed the BAT2 scores, were developed separately to evaluate the comparative risks of (1) major bleeding, (2) ICH, and (3) IS based on covariates from Cox proportional hazards models and clinical relevance. Model performance was assessed with the Harrell C-index and calibration slope adjusted for optimism via bootstrapping. RESULTS: Of 5378 patients enrolled, 5250 were analyzed (mean age, 71±11 years, 33% women); 93 experienced major bleeding, including 55 had ICH, and 197 had IS during a median follow-up of 2.0 years. Predictors for bleeding included age, underweight, renal impairment, hypertension, cerebral microbleed, lacune, and antithrombotic treatment type. Predictors for ICH further included deep white matter hyperintensity but not renal impairment. For IS, predictors included age, renal impairment, diabetes, atrial fibrillation, lacune, cerebral microbleed, nonlacunar infarct, and intracranial artery disease. Prediction performance showed optimism-adjusted C-index and calibration slope of 0.69 (95% CI, 0.64–0.74) and 0.82 (95% CI, 0.62–1.06) for bleeding, 0.75 (95% CI, 0.67–0.80) and 0.80 (95% CI, 0.56–1.02) for ICH, and 0.64 (95% CI, 0.60–0.68) and 0.92 (95% CI, 0.73–1.18) for IS. CONCLUSIONS: The BAT2 scores may help optimize the balance between risks and benefits of antithrombotic therapy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02889653. URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000023669.

Patients with acute branch atheromatous disease often experience early neurological deterioration (END) in the first 24‐h period, even after intravenous alteplase. Three cases treated with cilostazol, a phosphodiesterase 3‐inhibitor, prior to intravenous alteplase with the aim of mitigating END are described. All three patients had no bleeding complications and good outcomes at 3 months, although two patients showed END within 24 h after intravenous alteplase.

BACKGROUND AND PURPOSE: Susceptibility vessel sign (SVS), a hypointense signal on MR T2-weighted gradient-recalled echo images, is associated with erythrocyte-predominant thrombi, which are often present in cardioembolism (CE). In contrast, cancer-associated hypercoagulability (CAH)-related stroke, which is presumably caused by fibrin-predominant thrombi, is associated with the absence of SVS. We hypothesized that the prevalence of SVS may be of help in distinguishing CAH-related stroke from CE. This study attempted to validate this hypothesis and investigated the usefulness of SVS in differentiating CAH-related stroke from CE. MATERIALS AND METHODS: We retrospectively studied both CAH-related stroke patients (CAH group) and CE patients (CE group), who had major cerebral artery occlusion on MR angiography that was performed within 6 hours of stroke onset. All patients visited our department from 2015 to 2021. CAH-related stroke was defined as 1) complication of active cancer, 2) pre-treatment D-dimer value >3 μg/mL, 3) multiple vascular territories infarctions, and 4) lack of any other specifically identified causes of stroke. We compared SVS positivity rates within each group. Multivariable logistic regression analysis was used to assess the association between the absence of SVS and CAH-related stroke. RESULTS: Of 691 patients with CAH-related stroke or CE, major cerebral artery occlusion was observed in 10 patients in the CAH group and 198 patients in the CE group. The absence of SVS was identified in 55 of 208 patients and was significantly more frequent in the CAH versus the CE group (90% versus 24%, p < 0.05). For predicting CAH-related stroke, absence of SVS demonstrated a sensitivity of 90% (95% confidence interval [95%CI] 59-99), specificity of 78% (95%CI 71-83), positive predictive value of 18 (95%CI 10- 31), negative predictive value of 99% (95%CI 96-99), and a likelihood ratio of 4.06. Multivariable logistic regression analysis revealed that the absent of SVS was independently associated with CAH-related stroke (odds ratio 43, 95% [CI] 6.8-863; p < 0.01). CONCLUSIONS: The absence of SVS was more frequent in CAH-related stroke versus that found for CE. These findings could potentially be helpful for clinical management and differentiating between CE and CAH-related stroke. ABBREVIATIONS: CAH, cancer-associated hypercoagulability; CE, cardioembolism; SVS, susceptibility vessel sign; GRE, gradient recalled echo.

Purpose To develop an imaging prediction model for patients with embolic stroke of undetermined source (ESUS), we investigated the association of topographic diffusion-weighted imaging (DWI) patterns with potential embolic sources (PES) identified by transesophageal echocardiography. Methods From a total of 992 consecutive patients with embolic stroke, 366 patients with the ESUS group were selected. ESUS was defined as no atrial fibrillation (Af) within 24h from admission and no PES after general examination. Clinical variables include age (> 80years, 70–80 years), sex, vascular risk factors and left atrial diameter > 4 cm. Age, sex and vascular risk factors adjusted odds ratio of each DWI for the different PESs were calculated. DWI was determined based on the arterial territories. Middle cerebral arteries were divided into 4 segments, i.e., M1–M4. Moreover, M2 segments were subdivided into superior and inferior branches. Results The 366 patients consisted of 168 with paroxysmal Af (pAf), 77 with paradoxical embolism, 71 with aortic embolism and 50 with undetermined embolism after transesophageal echocardiography. The variables adjusted odds ratio (OR) of internal carotid artery (OR: 12.1, p = 0.037), M1 (4.2, p = 0.001), inferior M2 (7.5, p = 0.0041) and multiple cortical branches (12.6, p < 0.0001) were significantly higher in patients with pAf. Striatocapsular infarction (12.5, p < 0.0001) and posterior inferior cerebellar artery infarcts (3.6, p = 0.018) were significantly associated with paradoxical embolism. Clinical variables adjusted OR of multiple small scattered infarcts (8.3, p < 0.0001) were significantly higher in patients with aortic embolism. Conclusion The associations of DWI with different PES have their distinctive characteristics and DWI along with clinical variables may help predict PES in patients with ESUS.

Introduction: In patients with cancer-associated hypercoagulability (CAH)-related stroke, D-dimer trends after anticoagulant therapy may offer a biomarker of treatment efficacy. The purpose of this study was to clarify the association between D-dimer trends and recurrent stroke after anticoagulant therapy in patients with CAH-related stroke. Methods: We performed retrospective cohort study of consecutive patients with CAH-related stroke at two stroke centers from 2011 to 2020. The ratio of posttreatment to pretreatment D-dimer levels (post/pre ratio) was used as an indicator of D-dimer trends after anticoagulant therapy. Fine-Gray models were used to evaluate the association between post/pre ratio and recurrent stroke. Results: Among 360 acute ischemic stroke patients with active cancer, 73 patients with CAH-related stroke were included in this study. Recurrent stroke occurred in 13 patients (18%) during a median follow-up time of 28 days (interquartile range, 11–65 days). Multivariate analysis revealed that high post/pre ratio was independently associated with recurrent stroke (per 0.1 increase: hazard ratio 2.20, 95% confidence interval 1.61–3.01, p = 0.012). Conclusion: D-dimer levels after anticoagulant therapy were associated with recurrent stroke in CAH-related stroke patients. Patients with neutral trends in high D-dimer levels after anticoagulant therapy were at high risk of recurrent stroke.