Patient Outcomes in Very Elderly Patients With Non-Valvular Atrial Fibrillation　- ANAFIE Registry.

Background: The All Nippon Atrial Fibrillation In the Elderly Registry provides real-world insights into non-valvular atrial fibrillation (NVAF) in >30,000 elderly Japanese patients (aged ≥75 years), including >2,000 nonagenarians. We aimed to investigate outcomes in these patients by age and oral anticoagulant (OAC) type. Methods and Results: This prospective, multicenter, observational, cohort, 2-year follow-up study included elderly patients with NVAF who were able to attend hospital visits. The incidences of stroke/systemic embolic events (SEE), major bleeding, intracranial hemorrhage (ICH), cardiovascular death, all-cause death, and major adverse cardiovascular or neurological events (MACNE) were evaluated by age. Incidence rates increased significantly with age. Stroke/SEE, major bleeding, and ICH incidences plateaued in patients aged ≥90 years. Direct OACs (DOACs) yielded a numerically lower event incidence vs. warfarin in all age groups and endpoints, except for major bleeding in patients aged ≥90 years. DOACs (vs. warfarin) were significantly associated with a lower risk of stroke/SEE, major bleeding, and ICH in the ≥80-<85 years group, and reduced cardiovascular and all-cause death in the ≥75-<80 years group. In the ≥90 years subgroup, major bleeding history was a risk factor for all-cause death. Conclusions: Although DOAC vs. warfarin offers potential benefits for stroke prevention, limitations occurred in reducing major bleeding among those aged ≥90 years, indicating a potential benefit of very-low-dose DOAC for this demographic.

Effect of Hospital Arrival Time on Functional Prognosis of Stroke Patients: Japan Stroke Data Bank Over 20 Years.

AIMS: The impact of weekend/holiday and nighttime hospitalization on functional outcomes and long-term trends in stroke patients is unclear. We examined functional and life outcomes and changes over time. METHODS: We analyzed the clinical data of 203,176patients for hospital arrival day of week and 76,442patients for arrival times using Japan Stroke Data Bank. The endpoints were favorable outcome (Modified Rankin Scale[mRS]0-2), unfavorable outcome(mRS 5-6), and in-hospital mortality. We calculated odds ratios(OR) and 95% confidence interval(CI) of weekends/holidays and off-hours versus weekdays and on-hours for 2000-2009 and 2010-2020 using a mixed-effect multivariate model adjusted for confounding factors and evaluated interactions. Thereafter, we performed to check for year trends. RESULTS: All endpoints were worse in weekend/holiday admissions for all stroke and in off-hours hospitalization for total stroke(TS), ischemic stroke(IS), and intracerebral hemorrhage(ICH). The adjusted ORs for favorable outcomes of weekend/holiday admissions were TS, 0.90(0.87-0.93); IS, 0.89(0.86-0.93); ICH, 0.91(0.84-0.98) and unfavorable outcome TS, 1.04(1.002-1.08) IS, 1.06(1.01-1.11). Off-hour hospitalization had adjusted ORs for favorable outcome(TS, 0.86 [95% CI: 0.82-0.91]; IS, 0.90 [0.84-0.95]; ICH, 0.85 [0.75-0.96]), unfavorable outcome(TS, 1.14 [1.07-1.22]; IS, 1.13 [1.04-1.23]; ICH, 1.15 [1.01-1.31]), and mortality (TS, 1.15 [1.05-1.26]; IS, 1.17 [1.04-1.32]). For IS, the incidence of unfavorable outcomes during off-hours was significantly lower in 2010-2020 than in 2000-2009; after adjusting for reperfusion therapy, it was no longer significant. CONCLUSION: Stroke patients admitted on weekends/holidays and off-hours had worse functional and life outcomes. Functional outcomes for off-hour admission for IS improved at 10-year intervals, possibly due to improvements in stroke care systems.

Blood pressure during long-term cilostazol-based dual antiplatelet therapy after stroke: a post hoc analysis of the CSPS.com trial.

We determined the associations of follow-up blood pressure (BP) after stroke as a time-dependent covariate with the risk of subsequent ischemic stroke, as well as those of BP levels with the difference in the impact of long-term clopidogrel or aspirin monotherapy versus additional cilostazol medication on secondary stroke prevention. In a sub-analysis of a randomized controlled trial (CSPS.com), 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. The percent changes, differences, and raw values of follow-up BP were examined. The primary efficacy outcome was the first recurrence of ischemic stroke. In a total of 1657 patients (69.5 ± 9.3 years, female 29.1%) with median 1.5-year follow-up, ischemic stroke recurred in 74 patients. The adjusted hazard ratio for ischemic stroke of a 10% systolic BP (SBP) increase from baseline was 1.19 (95% CI 1.03-1.36), that of a 10 mmHg SBP increase was 1.14 (1.03-1.28), and that of SBP as the raw value with the baseline SBP as a fixed (time-independent) covariate was 1.14 (1.00-1.31). Such significant associations were not observed in diastolic BP-derived variables. The estimated adjusted hazard ratio curves for the outcome showed the benefit of dual therapy over a wide SBP range between ≈120 and ≈165 mmHg uniformly. Lower long-term SBP levels after ischemic stroke were associated with a lower risk of subsequent ischemic events. The efficacy of dual antiplatelet therapy including cilostazol for secondary stroke prevention was evident over a wide SBP range.

Optimal endovascular therapy technique for isolated intracranial atherothrombotic stroke-related large vessel occlusion in the acute to subacute stage.

BACKGROUND AND PURPOSE: Reocclusion after treatment is a concern in endovascular therapy (EVT) for isolated intracranial atherothrombotic stroke-related large vessel occlusion (AT-LVO). However, the optimal EVT technique for AT-LVO has not yet been investigated. This study evaluated the optimal EVT technique for AT-LVO in a real-world setting. MATERIALS AND METHODS: We conducted a historical multicenter registry study at 51 centers that enrolled patients with AT-LVO. We divided the patients into three groups based on the EVT technique: mechanical thrombectomy alone (MT-only), percutaneous transluminal angioplasty (PTA), and stent deployment (Stent). MT alone was classified into the MT-only group, PTA and MT-PTA into the PTA group, and MT-Stent, MT-PTA-Stent, PTA-Stent, and Stent-only into the Stent group. The primary outcome was the incidence of reocclusion of the treated vessels within 90 days of EVT completion. RESULTS: We enrolled 770 patients and analyzed 509 patients. The rates in the MT-only, PTA, and Stent groups were 40.7, 44.4, and 14.9%, respectively. The incidence rate of residual stenosis >70% of final angiography was significantly higher in the MT-only group than in the PTA and Stent groups (MT-only vs. PTA vs. Stent: 34.5% vs. 26.3% vs. 13.2%, p=0.002). The reocclusion rate was significantly lower in the PTA group than in the MT-only group (adjusted hazard ratio [95% confidence interval], 0.48 [0.29-0.80]). Of the patients, 83.5% experienced reocclusion within 10 days after EVT. Alarmingly, a substantial subset (approximately 62.0%) of patients underwent reocclusion within 2 days of EVT. The incidence of modified Rankin scale scores of 0-2 90 days after EVT was not significantly different among the three groups. The incidences of symptomatic intracranial hemorrhage (ICH), any other ICH, and death were not significantly different. CONCLUSIONS: The incidence rate of reocclusion was significantly lower in the PTA group than in the MT-only group. We found no significant difference in reocclusion rates between the Stent and MT-only groups. In Japan, GP IIb/IIIa inhibitors are not reimbursed. Therefore, PTA might be the preferred choice for AT-LVOs due to the higher reocclusion risk with MT-only. Reocclusion was likely to occur within 10 days, particularly within 2 days post-EVT. ABBREVIATIONS: EVT = endovascular treatment; LVO = large vessel occlusion; MT = mechanical thrombectomy; PTA = percutaneous transluminal angioplasty; ICH = intracranial hemorrhage; SD = standard deviation; IQR = interquartile range; HRs = hazard ratios; BMI = body mass index; LDL = low-density lipoprotein; HDL = high-density lipoprotein; DAPT = dual antiplatelet therapy; TAPT = triple antiplatelet therapy.

Outcomes of Bridging Intravenous Thrombolysis Versus Endovascular Therapy Alone in Late-Window Acute Ischemic Stroke.

BACKGROUND: Studies comparing bridging intravenous thrombolysis (IVT) with direct endovascular therapy (EVT) in patients with acute ischemic stroke who present late are limited. We aimed to compare the clinical outcomes and safety of bridging IVT in patients with acute ischemic stroke due to anterior circulation large vessel occlusion who underwent EVT 6 to 24 hours after time last known well. METHODS: We enrolled patients with anterior circulation large vessel occlusion stroke and a National Institutes of Health Stroke Scale score of ≥6 from 20 centers across 10 countries in the multicenter retrospective CLEAR study (CT for Late Endovascular Reperfusion) between January 2014 and May 2022. We used inverse probability of treatment weighting modeling adjusted for clinical and imaging confounders to compare functional outcomes, reperfusion success, symptomatic intracranial hemorrhage, and mortality between EVT patients with and without prior IVT. RESULTS: Of 5098 patients screened for eligibility, we included 2749 patients, of whom 549 received bridging IVT before EVT. The timing of IVT was not recorded. Witnessed stroke onset and transfer rates were higher in the bridging IVT group (25% versus 12% and 77% versus 55%, respectively, P value for both <0.0001), and time intervals between stroke onset and treatment were shorter (time last known well-start of EVT median 560 minutes [interquartile range, 432-791] versus 724 minutes [interquartile range, 544-912]; P<0.0001). After adjustment for confounders, there was no difference in functional outcome at 3 months (adjusted common odds ratio for modified Rankin Scale shift, 1.03 [95% CI, 0.89-1.19]; P=0.72) or successful reperfusion (adjusted odds ratio, 1.19 [95% CI, 0.81-1.75]; P=0.39). There were no safety concerns associated with bridging IVT versus direct EVT (symptomatic intracranial hemorrhage: adjusted odds ratio, 0.75 [95% CI, 0.38-1.48]; P=0.40; mortality: adjusted odds ratio, 1.14 [95% CI, 0.89-1.46]; P=0.31). Results were unchanged when the analysis was limited to patients who received IVT >6 hours after last known well. CONCLUSIONS: In patients with an anterior circulation large vessel occlusion stroke who underwent EVT 6 to 24 hours from last known well, bridging IVT was not associated with a difference in outcomes compared with direct EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04096248.

Expanding the Treatable Imaging Profile in Patients With Large Ischemic Stroke: Subanalysis From a Randomized Clinical Trial.

BACKGROUND: We aimed to examine the boundary of the ischemic core volume in patients undergoing endovascular thrombectomy (EVT) versus those receiving medical management to determine the minimum optimal size for favorable treatment outcomes. METHODS: This is a prespecified substudy of the RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial). Patients with large vessel occlusion were enrolled between November 2018 and September 2021 with a National Institutes of Health Stroke Scale score of at least 6 on admission and an Alberta Stroke Program Early Computed Tomography Score value of 3 to 5. We investigated the correlation between optimal quantified ischemic core volume, assessed solely using magnetic resonance diffusion-weighted imaging, and functional outcomes (modified Rankin Scale score, 0-3) at 90 days by predictive marginal plots. Final infarct volume and safety outcomes (symptomatic intracerebral hemorrhage and mortality) were also assessed. RESULTS: Of the 203 cases, 168 patients (85 in the EVT group versus 83 in the medical management group) were included. The median (interquartile range) core volume was 94 (65-160) mL in patients with EVT and 115 (71-141) mL in the medical management group (P=0.72). The predictive marginal probabilities of the 2 groups intersected at 128 mL for estimating functional outcomes. Symptomatic intracerebral hemorrhage and mortality within 90 days had overlay margins through all core volumes in both groups. The median final infarct volume (interquartile range) was smaller in the EVT group (142 [80-223] mL versus 211 [123-289] mL in the medical management group; P<0.001). CONCLUSIONS: In this prespecified analysis of a randomized clinical trial involving patients with large ischemic strokes, patients with an estimated core volume of up to 128 mL on diffusion-weighted imaging benefit from EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03702413.

A Novel Risk Score for Major Bleeding in Japanese Patients with Non-Valvular Atrial Fibrillation: The J-RISK AF Study.

AIM: Oral anticoagulants (OACs) reduce the risk of ischemic stroke but may increase the risk of major bleeding in patients with non-valvular atrial fibrillation (NVAF). Various risk scores, such as HAS-BLED, ATRIA, ORBIT, and DOAC, have been proposed to assess the risk of major bleeding in patients with NVAF receiving OACs. However, limited data are available regarding bleeding risk stratification in Japanese patients with NVAF. METHODS: Of the 16,098 NVAF patients from the J-RISK AF study, the combined data of the five major AF registries in Japan (J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry), we analyzed 11,539 patients receiving OACs (median age, 71 years old; women, 29.6%; median CHA2DS2-VASc score, 3). RESULTS: During the 2-year follow-up period, major bleeding occurred in 274 patients (1.3% per patient-year). In a multivariate Cox proportional hazards analysis, an advanced age, hypertension (systolic blood pressure ≥ 150 mmHg), bleeding history, anemia, thrombocytopenia, and concomitant antiplatelet agents were significantly associated with a higher incidence of major bleeding. We developed a novel risk stratification system, HED-[EPA]2-B3 score, which had a better predictive performance for major bleeding (C-statistics 0.67, [95% confidence interval, 0.63-0.70]) than the HAS-BLED (0.64, [0.60-0.67], P for difference 0.02) and ATRIA (0.63, [0.60-0.66], P for difference ＜0.01) scores. Furthermore, it was non-significantly higher than the ORBIT (0.65, [0.62-0.68], P for difference 0.07) and DOAC (0.65, [0.62-0.68], P for difference 0.17) scores. CONCLUSION: Our novel risk stratification system, the HED-[EPA]2-B3 score, may be useful for identifying Japanese patients receiving OACs at a risk of major bleeding.

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.

Gastrointestinal bleeding in elderly patients with atrial fibrillation: prespecified All Nippon Atrial Fibrillation in the Elderly (ANAFIE) Registry subgroup analysis.

Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m2, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88-1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.

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.

Stroke in Asia.

BACKGROUND: There is a significant burden of stroke in Asia. Asia has the largest population in the world in 2023, estimated at 4.7 billion. Approximately 9.5-10.6 million strokes will be anticipated annually in the backdrop of a diverse group of well-developed and less developed countries with large disparities in stroke care resources. In addition, Asian countries are in varying phases of epidemiological transition. SUMMARY: In this review, we examined recent epidemiological features of ischaemic stroke and intracerebral haemorrhage in Asia with recent developments in hyperacute stroke reperfusion therapy and technical improvements in intracerebral haemorrhage. The article also discussed the spectrum of cerebrovascular diseases in Asia, which include intracranial atherosclerosis, intracerebral haemorrhage, infective aetiologies of stroke, moyamoya disease, vascular dissection, radiation vasculopathy, and cerebral venous thrombosis. KEY MESSAGES: The review of selected literature and recent updates calls for attention to the different requirements for resources within Asia and highlights the breadth of cerebrovascular diseases still requiring further research and more effective therapies.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Thrombolysis for Wake-Up Stroke Versus Non-Wake-Up Unwitnessed Stroke: EOS Individual Patient Data Meta-Analysis.

BACKGROUND: Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. METHODS: Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. RESULTS: Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. CONCLUSIONS: There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.

OBJECTIVES: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation. METHODS: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. RESULTS: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. INTERPRETATION: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040-1054.

Coronary events in elderly patients with non-valvular atrial fibrillation: a prespecified sub-analysis of the ANAFIE registry.

Real-world data on coronary events (CE) in elderly patients with atrial fibrillation (AF) are lacking in the direct oral anticoagulant era. This prespecified sub-analysis of the ANAFIE Registry, a prospective observational study in > 30,000 Japanese patients aged ≥ 75 years with non-valvular AF (NVAF), investigated CE incidence and risk factors. The incidence and risk factors for new-onset CE (a composite of myocardial infarction [MI] and cardiac intervention for coronary heart diseases other than MI), MI, and cardiac intervention for coronary heart diseases other than MI during the 2-year follow-up were assessed. Bleeding events in CE patients were also examined. Among 32,275 patients, the incidence rate per 100 patient-years was 0.48 (95% confidence interval (CI): 0.42-0.53) for CE during the 2-year follow-up, 0.20 (0.16-0.23) for MI, and 0.29 (0.25-0.33) for cardiac intervention for coronary heart diseases other than MI; that of stroke/systemic embolism was 1.62 (1.52-1.73). Patients with CE (n = 287) likely had lower creatinine clearance (CrCL) and higher CHADS2 and HAS-BLED scores than patients without CE (n = 31,988). Significant risk factors associated with new-onset CE were male sex, systolic blood pressure of ≥ 130 mmHg, diabetes mellitus (glycated hemoglobin ≥ 6.0%), CE history, antiplatelet agent use, and CrCL < 50 mL/min. Major bleeding incidence was significantly higher in patients with new-onset CE vs without CE (odds ratio [95% CI], 3.35 [2.06-5.43]). In elderly patients with NVAF, CE incidence was lower than stroke/systemic embolism incidence. New-onset CE (vs no CE) was associated with a higher incidence of major bleeding.Trial registration: UMIN000024006.

Clinical outcomes and anticoagulation therapy in elderly non-valvular atrial fibrillation and heart failure patients.

AIMS: Atrial fibrillation (AF) and heart failure (HF) often coexist. Older age is strongly associated with stroke, HF, and mortality. The association between coexistence of HF and a risk of clinical outcomes and the effectiveness of anticoagulation therapy including direct oral anticoagulants (DOACs) in elderly patients with AF and HF have not been investigated. We aimed to evaluate 2 years of outcomes and to elucidate the efficacy of DOACs or warfarin in elderly AF patients in the All Nippon AF In the Elderly (ANAFIE) Registry with and without a history of HF. METHODS AND RESULTS: The ANAFIE Registry is a multicentre, prospective observational study following elderly non-valvular AF patients aged ≥75 years for 2 years. Hazard ratios (HRs) were calculated based on the presence or absence of an HF diagnosis and DOAC or warfarin use at enrolment. Among 32 275 eligible patients, 12 116 (37.5%) had been diagnosed with HF. Patients with HF had significantly higher rates of HF hospitalization or cardiovascular death (HR 1.94, P < 0.001), cardiovascular events (HR 1.59, P < 0.001), cardiovascular death (HR 1.49, P < 0.001), all-cause death (HR 1.32, P < 0.001), and net clinical outcome including stroke/systemic embolism, major bleeding, and all-cause death (HR 1.23, P < 0.001), compared with those without HF; however, HRs for stroke/systemic embolism (HR 0.96, P = 0.56) and major bleeding (HR 1.14, P = 0.13) were similar. DOAC use was associated with a low risk of stroke/systemic embolism (HR 0.86, P = 0.19 in HF; HR 0.79, P = 0.016 in non-HF; P for interaction = 0.56), major bleeding (HR 0.71, P = 0.008 in HF; HR 0.75, P = 0.016 in non-HF; P for interaction = 0.74), HF hospitalization or cardiovascular death (HR 0.81, P < 0.001 in HF; HR 0.78, P < 0.001 in non-HF; P for interaction = 0.26), cardiovascular events (HR 0.83, P < 0.001 in HF; HR 0.82, P = 0.001 in non-HF; P for interaction = 0.65), cardiovascular death (HR 0.84, P = 0.12 in HF; HR 0.75, P = 0.035 in non-HF; P for interaction = 0.18), all-cause death (HR 0.89, P = 0.082 in HF; HR 0.80, P = 0.001 in non-HF; P for interaction = 0.091), and net clinical outcome (HR 0.88, P = 0.019 in HF; HR 0.81, P < 0.001 in non-HF; P for interaction = 0.21) compared with warfarin, irrespective of the presence or absence of HF. Analysis using the propensity score matching method showed similar associations. CONCLUSIONS: Non-valvular AF patients aged ≥75 years with a history of HF had higher risks of cardiovascular events and mortality. DOACs were favourable to warfarin regardless of the coexistence of HF. These results might encourage the use of DOACs in elderly patients with non-valvular AF with or without HF.

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.