Clinical impact of body mass index on outcomes of ischemic and hemorrhagic strokes.

BACKGROUND AND AIM: To investigate the prognostic implication of body mass index (BMI) on clinical outcomes after acute ischemic and hemorrhagic stroke. METHODS: The subjects of the study included adult patients with available baseline body weight and height data who had suffered an acute stroke and were registered in the Japan Stroke Data Bank-a hospital-based, multicenter stroke registration database-between January 2006 and December 2020. The outcome measures included unfavorable outcomes defined as a modified Rankin Scale (mRS) score of 5-6 and favorable outcomes (mRS 0-2) at discharge, and in-hospital mortality. Mixed effects logistic regression analysis was conducted to determine the relationship between BMI categories (underweight, normal weight, overweight, class I obesity, class II obesity; <18.5, 18.5-23.0, 23.0-25.0, 25-30, ⩾30 kg/m2) and the outcomes, after adjustment for covariates. RESULTS: A total of 56,230 patients were assigned to one of the following groups: ischemic stroke (IS, n = 43,668), intracerebral hemorrhage (ICH, n = 9741), and subarachnoid hemorrhage (SAH, n = 2821). In the IS group, being underweight was associated with an increased likelihood of unfavorable outcomes (odds ratio, 1.47 (95% confidence interval (CI):1.31-1.65)) and in-hospital mortality (1.55 (1.31-1.83)) compared to outcomes in those with normal weight. Being overweight was associated with an increased likelihood of favorable outcomes (1.09 (1.01-1.18)). Similar associations were observed between underweight and these outcomes in specific IS subtypes (cardioembolic stroke, large artery stroke, and small-vessel occlusion). Patients with a BMI ⩾30.0 kg/m2 was associated with an increased likelihood of unfavorable outcomes (1.44 (1.01-2.17)) and in-hospital mortality (2.42 (1.26-4.65)) in large artery stroke. In patients with ICH, but not those with SAH, being underweight was associated with an increased likelihood of unfavorable outcomes (1.41 (1.01-1.99)). CONCLUSIONS: BMI substantially impacts functional outcomes following IS and ICH. Lower BMI consistently affected post-stroke disability and mortality, while higher BMI values similarly affected these outcomes after large artery stroke.

Favorable prognosis in posterior circulation ischemic stroke: Insights from a nationwide stroke databank.

INTRODUCTION: Clinical trials have historically underrepresented patients with posterior circulation ischemic stroke (PCIS). This study aimed to comprehensively assess the clinical characteristics and outcomes of PCIS patients compared to those with anterior circulation ischemic stroke (ACIS). METHODS: A retrospective analysis was conducted using data from the Japan Stroke Data Bank, encompassing 20 years across 130 stroke centers. The study focused on patients diagnosed with PCIS or ACIS. RESULTS: Among 37,069 patients reviewed, 7425 had PCIS, whereas 29,644 had ACIS. PCIS patients were younger and had a lower female representation than ACIS patients. Notably, PCIS patients had more favorable outcomes: 71% achieved a modified Rankin Scale of 0-2 or showed no deterioration at discharge (17 days at the median after admission), compared to 60% for ACIS patients (p < 0.001). Factors associated with an unfavorable outcome in the PCIS subgroup were older age, female sex (assigned at birth), history of hypertension, and higher National Institute of Health Stroke Scale (NIHSS) scores at admission. In both sexes, older age and higher NIHSS scores were negatively associated with favorable outcomes. CONCLUSIONS: PCIS patients demonstrated a more favorable prognosis than ACIS patients. Factors like older age, female sex, and higher NIHSS scores at admission were identified as independent predictors of unfavorable outcomes in PCIS patients. Older age and higher NIHSS scores at admission were common independent negative factors for a favorable outcome regardless of sex.

Presenting Symptoms and Diffusion-Weighted MRI Positivity by Time After Transient Neurologic Events: A Pooled Analysis of 3 Cohort Studies

BACKGROUND AND OBJECTIVE: The association between focal vs nonfocal presenting symptom and diffusion-weighted imaging (DWI) positivity in relation to onset-to-imaging time in patients with transient neurologic events remains unclear. We hypothesize that episodes consisting of focal symptoms would have proportionally higher DWI-positive imaging at later onset-to-imaging times. METHODS: Patients with transient neurologic symptoms and a normal neurologic examination who had DWI in the combined data set of 3 cohort studies were included. We used logistic regression models to evaluate the association between each type of presenting symptom (motor weakness, speech impairment, sensory symptoms, vision loss, diplopia, gait instability, dizziness, headache, presyncope, and amnesia) and DWI positivity after adjusting for clinical variables (age, sex, history of stroke, dyslipidemia, coronary artery disease, atrial fibrillation, symptoms duration [<10, 10-59, ≥60 minutes, or unclear], and study source). We stratified the results by onset-to-imaging time categories (<6 hours, 6-23 hours, and ≥24 hours). RESULTS: Of the total 2,411 patients (1,345 male, median age 68 years), DWI-positive lesions were detected in 598 patients (24.8%). The prevalence of DWI positivity was highest in those with motor weakness (34.7%), followed by speech impairment (33.5%). In a multivariable analysis, the presence of motor weakness, speech impairment, and sensory symptoms was associated with DWI positivity, while vision loss and headache were associated with lower odds of DWI positivity, but nevertheless had 13.6% and 15.3% frequency of DWI positive. The odds of being DWI positive varied by onset-to-imaging time categories for motor weakness, with greater odds of being DWI positive at later imaging time (<6 hours: odds ratio [OR] 1.25, 95% confidence interval [CI] 0.84-1.87; 6-23 hours: OR 2.24, 95% CI 1.47-3.42; and ≥24 hours: OR 2.42, 95% CI 1.74-3.36; interaction p = 0.033). Associations of other symptoms with DWI positivity did not vary significantly by time categories. DISCUSSION: We found that onset-to-imaging time influences the relationship between motor weakness and DWI positivity in patients with transient neurologic events. Compared with motor, speech, and sensory symptoms, visual or nonfocal symptoms carry a lower but still a substantive association with DWI positivity.

Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial.

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. Design, Setting, and Participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. Main Outcomes and Measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. Conclusions and Relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

Magnetic Resonance Imaging-Guided Intravenous Thrombolysis in Cardioembolic Stroke Patients With Unknown Time of Onset　- Subanalysis of the THAWS Randomized Control Trial.

BACKGROUND: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset.Methods and Results: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0-1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50-9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12-1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis. CONCLUSIONS: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.

Improvement of Functional Outcomes in Patients with Stroke who Received Alteplase for Over 15 Years: Japan Stroke Data Bank.

AIM: The nationwide verification of intravenous thrombolysis (IVT) was rarely performed after the extension of the therapeutic time window of alteplase or after the expansion of mechanical thrombectomy (MT). We aimed to examine the long-term change in accurate real-world outcomes of IVT in patients with acute ischemic stroke (AIS) using the Japan Stroke Databank, a representative Japan-wide stroke database. METHODS: We extracted all patients with AIS who received IVT with alteplase between October 11, 2005, the approval date for alteplase use for AIS in Japan, and December 31, 2020. Patients were categorized into three groups using two critical dates in Japan as cutoffs: the official extension date of the therapeutic time window for IVT to within 4.5 h of symptom onset and the publication date of the revised guideline, where the evidence level of MT was heightened. We assessed the yearly trend of IVT implementation rates and the secular changes and three-group changes in clinical outcomes at discharge. RESULTS: Of 124,382 patients with AIS, 9,569 (7.7%) received IVT (females, 41%; median age, 75 years). The IVT implementation rate has generally increased over time and plateaued in recent years. The proportion of favorable outcomes (modified Rankin Scale score of 0-2) increased yearly over 15 years. The results of the changes in the outcomes of the three groups were similar to those of the annual changes. CONCLUSIONS: We revealed that IVT implementation rates in patients with AIS increased, and the functional outcome in these patients improved over 15 years. Therefore, the Japanese IVT dissemination strategy is considered appropriate and effective.

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.

Characteristics and outcomes of unknown onset stroke: The Japan Stroke Data Bank.

BACKGROUND: Clinical outcomes of unknown onset stroke (UOS) are influenced by the enlargement of the therapeutic time window for reperfusion therapy. This study aimed to investigate and describe the characteristics and clinical outcomes of patients with UOS. METHODS: Patients with acute ischemic stroke (AIS) who were admitted within 24 h of their last known well time, from January 2017 to December 2020, were included. Data were obtained from a long-lasting nationwide hospital-based multicenter prospective registry: the Japan Stroke Data Bank. The co-primary outcomes were the National Institutes of Stroke Scale (NIHSS) scores on admission and unfavorable outcomes at discharge, corresponding to modified Rankin Scale (mRS) scores of 3-6. RESULTS: Overall, 26,976 patients with AIS were investigated. Patients with UOS (N = 5783, 78 ± 12 years of age) were older than patients with known onset stroke (KOS) (N = 21,193, 75 ± 13 years of age). Age, female sex, higher premorbid mRS scores, atrial fibrillation, and congestive heart failure were associated with UOS in multivariate analysis. UOS was associated with higher NIHSS scores (median = 8 [interquartile range [IQR]: 3-19] vs. 4 [1-10], adjusted incidence rate ratio = 1.37 [95% CI: 1.35-1.38]) and unfavorable outcomes (52.1 vs. 33.6%, adjusted odds ratio = 1.27 [1.14-1.40]). Intergroup differences in unfavorable outcomes were attenuated among females (1.12 [0.95-1.32] vs. males 1.38 [1.21-1.56], P = 0.040) and in the subgroup that received reperfusion therapy (1.10 [0.92-1.33] vs. those who did not receive therapy 1.23 [1.08-1.39], P = 0.012). CONCLUSIONS: UOS was associated with unfavorable outcomes but to a lesser degree among females and patients receiving reperfusion therapy.

Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke: Subanalysis of the CSPS.com Trial.

BACKGROUND: The effectiveness of long-term dual antiplatelet therapy (DAPT) to prevent recurrent strokes in patients with lacunar stroke remains unclarified. Therefore, this study aimed to compare and to elucidate the safety and effectiveness of DAPT and single antiplatelet therapy (SAPT) in preventing recurrence in chronic lacunar stroke. METHODS: CSPS.com (Cilostazol Stroke Prevention Study for Antiplatelet Combination) was a prospective, multicenter, randomized controlled trial. In this prespecified subanalysis, 925 patients (mean age, 69.5 years; 69.4% men) with lacunar stroke were selected from 1884 patients with high-risk noncardioembolic stroke, enrolled in the CSPS.com trial after 8 to 180 days following stroke. Patients were randomly assigned to receive either SAPT or DAPT using cilostazol and were followed for 0.5 to 3.5 years. The primary efficacy outcome was the first recurrence of ischemic stroke. The safety outcomes were severe or life-threatening bleeding. RESULTS: The DAPT group receiving cilostazol and either aspirin or clopidogrel and SAPT group receiving aspirin or clopidogrel alone comprised 464 (50.2%) and 461 (49.8%) patients, respectively. Ischemic stroke occurred in 12 of 464 patients (1.84 per 100 patient-years) in the DAPT group and 31 of 461 patients (4.42 per 100 patient-years) in the SAPT group, during follow-up. After adjusting for multiple potential confounding factors, ischemic stroke risk was significantly lower in the DAPT group than in the SAPT group (hazard ratio, 0.43 [95% CI, 0.22-0.84]). The rate of severe or life-threatening hemorrhage did not differ significantly between the groups (2 patients [0.31 per 100 patient-years] versus 6 patients [0.86 per 100 patient-years] in the DAPT and SAPT groups, respectively; hazard ratio, 0.36 [95% CI, 0.07-1.81]). CONCLUSIONS: In patients with lacunar stroke, DAPT using cilostazol had significant benefits in reducing recurrent ischemic stroke incidence compared with SAPT without increasing the risk of severe or life-threatening bleeding. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000012180.

Japanese Postmarket Surveillance of Percutaneous Transluminal Angioplasty and Wingspan Stenting for Intracranial Atherosclerotic Disease.

BACKGROUND: The Wingspan stent system was approved as a rescue device for angioplasty of intracranial atherosclerotic disease (ICAD) in 2012. We conducted the government-recommended Japanese Postmarket Surveillance of Percutaneous Transluminal Angioplasty and Wingspan Stenting for Intracranial Atherosclerotic Disease to monitor Wingspan safety and performance. METHODS: In this open-label, single-arm study at 76 centers in Japan, ICAD subjects were treated with the Wingspan stent between 2014 and 2016. Efficacy end points were successful stent deployment and technical success, defined as stenosis improvement to <50%. Safety end points were ischemic stroke, modified Rankin Scale and National Institutes of Health Stroke Scale scores, adverse events, and mortality. Subjects were considered treated outside of current recommendations if not already receiving antithrombotics or if percutaneous transluminal angioplasty and stenting occurred within 7 days of onset. RESULTS: The safety cohort included 305 subjects (mean age: 68.7 + 9.6; 83.3% male). Four subjects were removed due to being out of contract. Therefore, 301 subjects were included (mean age: 68.7 ± 9.7; 84.1% male). Successful stent placement was 96.7%. Technical success was observed in 86.8% of lesions. At 1 year, the rate of restenosis was 15.7%, ischemic stroke was 3.9%, and any stroke was 7.9%. Functionally independent outcome (modified Rankin Scale: 0-2) was 88.9% and mortality 3.0%. Significantly more serious adverse events occurred in subjects treated outside of current recommendations (17.9%) versus subjects treated per current recommendations (8.8%) (P = 0.045). CONCLUSIONS: Endovascular treatment using the Wingspan stent for ICAD is safe and effective in the Japanese population.

Dual antiplatelet therapy with cilostazol in stroke patients with extracranial arterial stenosis or without arterial stenosis: A subgroup analysis of the CSPS.com trial.

BACKGROUND: We previously reported that dual antiplatelet therapy (DAPT) with cilostazol was superior to aspirin or clopidogrel for the prevention of recurrent stroke and vascular events in a subgroup analysis of intracranial arterial stenosis in the Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com), a randomized controlled trial. AIMS: We conducted another subgroup analysis to investigate the benefit of DAPT with cilostazol in patients with extracranial arterial stenosis (ECAS) and those without arterial stenosis. METHODS: We compared the risk of recurrent ischemic stroke, vascular events, and major bleeding between DAPT with cilostazol plus aspirin or clopidogrel and aspirin or clopidogrel alone in patients with ischemic stroke between 8 and 180 days before starting trial treatment and ECAS or without arterial stenosis. RESULTS: The median follow-up period was 1.4 years. The risk of recurrent ischemic stroke (hazard ratio (HR): 1.04, 95% confidence interval (CI): 0.42-2.57) and vascular events (HR: 0.97, 95% CI: 0.42-2.24) did not differ between the two groups for the 253 patients with ECAS, whereas they were lower (HR: 0.36, 95% CI: 0.18-0.74 and HR: 0.47, 95% CI: 0.26-0.85, respectively) in the DAPT group for the 944 patients without arterial stenosis. The risk of major bleeding did not differ between the groups in patients with ECAS (HR: 0.58, 95% CI: 0.05-6.39) or without arterial stenosis (HR: 0.79, 95% CI: 0.27-2.26). CONCLUSION: DAPT with cilostazol might be beneficial for prevention of recurrent stroke and vascular events in patients without arterial stenosis but not in those with ECAS. DATA ACCESS STATEMENT: We will make the deidentified participant data from this research available to the scientific community with as few restrictions as feasible, while retaining exclusive use until the publication of major output.

Intravenous Alteplase at 0.6 mg/kg for Unknown Onset Stroke with Prior Antithrombotic Medication: THAWS Randomized Clinical Trial.

AIM: This study aimed to assess the potential effect of prior antithrombotic medication for thrombolysis in an unknown onset stroke. METHODS: This was a predefined sub-analysis of the THAWS trial. Stroke patients with a time last known well ＞4.5 h who had a DWI-fluid-attenuated inversion recovery mismatch were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg (alteplase group) or standard medical treatment (control group). Patients were dichotomized by prior antithrombotic medication. RESULTS: Of 126 patients (intention-to-treat population), 40 took antithrombotic medication (24 with antiplatelets alone, 13 with anticoagulants alone, and 3 with both), and the remaining 86 did not before stroke onset. Of these, 17 and 52 patients, respectively, received alteplase, and 23 and 34, respectively, had standard medical treatment. Antithrombotic therapy was initiated within 24 h after randomization less frequently in the alteplase group (12% vs. 86%, p＜0.01). Both any intracranial hemorrhage within 22-36 h (26% vs. 14%) and a modified Rankin Scale score of 0-1 at 90 days (good outcome) (47% vs. 48%) were comparable between the two groups. A good outcome was more common in the alteplase group than in the control group in patients with prior antithrombotic medication [relative risk (RR) 2.25, 95% confidence interval (CI) 1.02-4.99], but it tended to be less common in the alteplase group in those without (RR 0.69, 95% CI 0.46-1.03) (p＜0.01 for interaction). The frequency of any intracranial hemorrhage did not significantly differ between the two groups in any patients dichotomized by prior antithrombotic medication. CONCLUSION: Alteplase appears more beneficial in patients with prior antithrombotic medication.

Sex Difference in the Impact of Dual Antiplatelet Therapy using Cilostazol for Secondary Stroke Prevention: A Sub-Analysis of CSPS.com.

AIM: Although some sex differences in stroke have been reported, differences in the effects of antiplatelet therapy for secondary stroke prevention have not been clarified. METHODS: In the Cilostazol Stroke Prevention Study combination trial, patients with high-risk, non-cardioembolic ischemic stroke between 8 and 180 days after onset treated with aspirin or clopidogrel alone were recruited and randomly assigned to receive either monotherapy or dual antiplatelet therapy (DAPT) using cilostazol and followed up for 0.5-3.5 years. The primary efficacy outcome was recurrence of ischemic stroke. The safety outcome was severe or life-threatening hemorrhage. Outcomes were analyzed by sex. RESULTS: A total of 1,320 male patients and 558 female patients were included. The male patients had more risk factors than the female patients. In male patients, the primary endpoint occurred at a rate of 2.0 per 100 patient-years in the DAPT group and 5.1 per 100 patient-years in the monotherapy group (hazard ratio (HR), 0.40; 95% confidence interval (CI), 0.23-0.68). In male patients, DAPT prolonged the time to recurrent stroke by 4.02-fold (95% CI, 1.63-9.96) compared with monotherapy. In female patients, the average annual event rates were 2.7 per 100 patient-years in the DAPT group and 3.3 per 100 patient-years in the monotherapy group (HR, 0.82; 95% CI, 0.37-1.84). Safety outcomes did not differ significantly in both male and female patients. CONCLUSIONS: Long-term DAPT using cilostazol reduced the recurrence of ischemic stroke and prolonged the recurrence-free time in male patients, but not in female patients.

Impact of three major risk factors on clinical outcomes in patients with nonvalvular atrial fibrillation receiving rivaroxaban: Sub-analysis from the XAPASS study.

Background: To evaluate the impact of three risk factors (age [≥75 years], renal impairment [creatinine clearance <50 ml/min], and low body weight [≤50 kg]) on the risk of any bleeding events, all-cause mortality, and stroke, non-central nervous system (non-CNS) systemic embolism (SE), and myocardial infarction (MI) in patients with nonvalvular atrial fibrillation (NVAF) treated with rivaroxaban in a real-world clinical setting. Methods: The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) is a prospective, single-arm, observational study. Enrolled patients were divided into four subgroups by the number of risk factors. Results: Overall, 9823 patients were included: 4299 with low risk, 2816 with moderate risk, 1574 with high risk, and 1134 with very high risk. The hazard ratios (95% confidence interval) (reference: low risk) for the moderate-, high-, and very-high-risk groups were 1.62 (1.19, 2.21) (p = 0.002), 2.15 (1.47, 3.15) (p < 0.001), and 2.49 (1.60, 3.87) (p <0.001) for major bleeding, and 1.98 (1.47, 2.66), 2.29 (1.59, 3.29), and 2.74 (1.81, 4.16) (p <0.001 for all) for stroke/non-CNS SE/MI, respectively. Conclusions: Age ≥75 years and renal impairment, but not low body weight, were determinants for major bleeding. The accrual of three risk factors was associated with increased risk for major bleeding and stroke/non-CNS SE/MI in patients with NVAF receiving rivaroxaban; there was no increase in the cumulative risk for these with an increasing number of risk factors.

Early initiation of rivaroxaban after reperfusion therapy for stroke patients with nonvalvular atrial fibrillation.

BACKGROUND: The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated. METHODS: From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months. RESULTS: Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54). CONCLUSIONS: Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.

Etiology and Outcome of Ischemic Stroke in Patients With Renal Impairment Including Chronic Kidney Disease: Japan Stroke Data Bank.

BACKGROUND AND OBJECTIVES: Chronic kidney disease is a worldwide public health problem that is recognized as an established risk factor for stroke. It remains unclear whether its distribution and clinical impact are consistent across ischemic stroke subtypes in patients with renal impairment. We examined whether renal impairment was associated with the proportion of each stroke subtype vs ischemic stroke overall and with functional outcomes after each stroke subtype. METHODS: Study participants were 10,392 adult patients with an acute stroke from the register of the Japan Stroke Data Bank, a hospital-based multicenter stroke registration database, between October 2016 and December 2019, whose baseline serum creatinine levels or a dipstick proteinuria result were available. All ischemic strokes were classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Unfavorable functional outcome was defined as modified Rankin Scale (mRS) score 3-6 at discharge. Mixed effect logistic regression was used to determine the relationship between the outcomes and the estimated glomerular filtration rate (eGFR), eGFR strata (<45, 45-59, ≥60 mL/min/1.73 m2), or dipstick proteinuria ≥1 adjusted for covariates. RESULTS: Overall, 2,419 (23%) patients had eGFR 45-59 mL/min/1.73 m2 and 1,976 (19%) had eGFR <45 mL/min/1.73 m2, including 185 patients (1.8%) receiving hemodialysis. Both eGFR 45-59 and eGFR <45 mL/min/1.73 m2 were associated with a higher proportion of cardioembolic stroke (odds ratio [OR], 1.21 [95% CI, 1.05-1.39] and 1.55 [1.34-1.79], respectively) and a lower proportion of small vessel occlusion (0.79 [0.69-0.90] and 0.68 [0.59-0.79], respectively). A similar association with the proportion of these 2 subtypes was proven in the analyses using decreased eGFR as continuous values. Both eGFR <45 mL/min/1.73 m2 and proteinuria were associated with unfavorable functional outcomes in patients with cardioembolic stroke (OR, 1.30 [95% CI, 1.01-1.69] and 3.18 [2.03-4.98], respectively) and small vessel occlusion (OR, 1.44 [1.01-2.07] and 2.08 [1.08-3.98], respectively). DISCUSSION: Renal impairment contributes to the different distributions and clinical effects across specific stroke subtypes, particularly evident in cardioembolic stroke and small vessel occlusion. This possibly indicates shared mechanisms of susceptibility and potentially enhancing pathways.

Practical "1-2-3-4-Day" Rule for Starting Direct Oral Anticoagulants After Ischemic Stroke With Atrial Fibrillation: Combined Hospital-Based Cohort Study.

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

Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke: A CSPS.com Trial Post Hoc Analysis.

BACKGROUND AND OBJECTIVES: Long-term treatment with the combination of cilostazol with aspirin or clopidogrel showed a lower risk of stroke recurrence compared to aspirin or clopidogrel alone after high-risk noncardioembolic ischemic stroke in a randomized trial. We aimed to determine whether the effect of the dual medication compared to monotherapy on risk of recurrent ischemic stroke differs according to timing of starting medication after stroke onset. METHODS: In a subanalysis of the randomized controlled trial, patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone or a combination of cilostazol with aspirin or clopidogrel. They were divided into 3 groups according to the timing of starting trial treatment: between 8 and 14 days after stroke onset (8-14 days group), between 15 and 28 days after stroke onset (15-28 days group), and between 29 and 180 days after stroke onset (29-180 days group). The primary efficacy outcome was the first recurrence of ischemic stroke. Safety outcomes included severe or life-threatening bleeding. RESULTS: Of 1,879 patients, 498 belonged to the 8-14 days group, 467 to the 15-28 days group, and 914 to the 29-180 days group. There was a significant treatment-by-subgroup interaction for the recurrence of ischemic stroke between trial treatment and trichotomized groups. The recurrence of ischemic stroke was less common with dual therapy than with monotherapy in the 15-28 days group (annualized rate 1.5% vs 4.9%, respectively; adjusted hazard ratio 0.34 [95% CI 0.12-0.95]) and the 29-180 days group (1.9% vs 4.4%, respectively; 0.27 [0.12-0.63]) and similarly common in the 8-14 days group (4.5% for both; 1.02 [0.51-2.04]). Severe or life-threatening bleeding occurred similarly between patients on dual therapy and those on monotherapy in any of the trichotomized groups (crude hazard ratio 0.22 [95% CI 0.03-1.88] in the 8-14 days group, 1.07 [0.15-7.60] in the 15-28 days group, and 0.76 [0.24-2.39] in the 29-180 days group). DISCUSSION: Long-term dual antiplatelet therapy using cilostazol starting 15-180 days after stroke onset, compared to therapy started 8-14 days after onset, was more effective for secondary stroke prevention than monotherapy without increasing hemorrhage risk. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT01995370; UMIN Clinical Trials Registry 000012180. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute noncardioembolic stroke taking either aspirin or clopidogrel, the addition of cilostazol 15-180 days after stroke onset decreases the risk of recurrent ischemic stroke.

Intensive blood pressure lowering with nicardipine and outcomes after intracerebral hemorrhage: An individual participant data systematic review.

BACKGROUND AND AIMS: Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure levels achieved with intravenous nicardipine after onset of intracerebral hemorrhage on clinical outcomes were determined. METHODS: A systematic review and individual participant data analysis of articles before 1 October 2020 identified on PubMed were performed (PROSPERO: CRD42020213857). Prospective studies involving hyperacute intracerebral hemorrhage adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale were eligible. Outcomes included death or disability at 90 days, defined as the modified Rankin Scale score of 4-6, and hematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. SUMMARY OF REVIEW: Three studies met the eligibility criteria. For 1265 patients enrolled (age 62.6 ± 13.0 years, 484 women), death or disability occurred in 38.2% and hematoma expansion occurred in 17.4%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio (aOR) 1.12, 95% confidence interval (CI) 1.00-1.26 per 10 mmHg) and hematoma expansion (1.16, 1.02-1.32). Mean hourly systolic blood pressure from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Later achievement of systolic blood pressure to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00-1.05 per hour). CONCLUSIONS: Rapid lowering of systolic blood pressure by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute intracerebral hemorrhage was associated with lower risks of hematoma expansion and 90-day death or disability without increasing serious adverse events.

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.