Causes of Death in Elderly Patients With Non-Valvular Atrial Fibrillation　- Results From the ANAFIE Registry.

BACKGROUND: Previous studies on mortality in atrial fibrillation (AF) included a limited number of elderly patients receiving direct oral anticoagulants (DOACs). This subanalysis of the ANAFIE Registry evaluated 2-year mortality according to causes of death of elderly non-valvular AF (NVAF) patients in the DOAC era.Methods and Results: The ANAFIE Registry was a multicenter prospective observational study. Mean patient age was 81.5 years and 57.3% of patients were male. Of the 32,275 patients completing the study, 2,242 died. The most frequent causes of death were cardiovascular (CV) death (32.4%), followed by infection (17.1%) and malignancy (16.1%). Incidence rates of CV-, malignancy-, and infection-related death were 1.20, 0.60, and 0.63 per 100 person-years, respectively. Patients aged ≥85 years showed increased proportions of non-CV and non-malignancy deaths and a decreased proportion of malignancy deaths compared with patients aged <85 years. The incidence of death due to congestive heart failure/cardiogenic shock, infection, and renal disease was higher in patients aged ≥85 than those aged <85 years. Compared with warfarin, DOACs were associated with a significantly lower risk of death by intracranial hemorrhage, ischemic stroke, and renal disease. CONCLUSIONS: This subanalysis described the mortality according to causes of death of Japanese elderly NVAF patients in the DOAC era. Our results imply that a more holistic approach to comorbid conditions and stroke prevention are required in these patients.

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.

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.

Branch atheromatous disease diagnosed as embolic stroke of undetermined source: A sub-analysis of NAVIGATE ESUS.

BACKGROUND: Branch atheromatous disease (BAD) is distinctive from large and small arterial diseases, which is single subcortical infarction larger than lacunar stroke in the territories of deep perforators without relevant arterial stenosis. BAD meets the current criteria of embolic stroke of undetermined source. We performed an exploratory analysis of BAD in patients recruited to NAVIGATE embolic stroke of undetermined source, a randomized controlled trial to compare rivaroxaban and aspirin in embolic stroke of undetermined source patients. METHODS AND RESULTS: Among 3972 stroke patients in cerebral hemispheres with intracranial arterial imaging, 502 (12.6%) patients met the criteria for BAD. BAD was associated with younger age (years; OR: 0.97, 95% CI: 0.96-0.98), race (Asian; OR: 1.78, 95% CI: 1.44-2.21), region (Eastern Europe; OR: 2.49, 95% CI: 1.87-3.32), and higher National Institute of Health Stroke Scale (OR: 1.17, 95% CI: 1.12-1.22) at randomization. During follow-up, stroke or systemic embolism (2.5%/year vs. 6.2%/year, p = 0.0022), stroke (2.1%/year vs. 6.2%/year, p = 0.0008), and ischemic stroke (2.1%/year vs. 5.9%/year, p = 0.0013) occurred less frequently in BAD than non-BAD patients. There were no differences in annual rates of stroke or systemic embolism (2.5%/year vs. 2.5%/year, HR: 1.01, 95% CI: 0.33-3.14) or major bleeding (1.3%/year vs. 0.8%/year, HR: 1.51, 95% CI: 0.25-9.05) between rivaroxaban and aspirin groups among BAD patients. CONCLUSIONS: BAD was relatively common, especially in Asian and from Eastern Europe among embolic stroke of undetermined source patients. Stroke severity was higher at randomization but recurrence of stroke was fewer in BAD than non-BAD patients. The efficacy and safety of rivaroxaban and aspirin did not differ among BAD patients.

Rivaroxaban concentrations in acute stroke patients with different dosage forms.

BACKGROUND: The crushed-tablet rivaroxaban concentration has been previously reported to be lower than the non-crushed concentration. However, the rivaroxaban concentration of fine granules has not yet been investigated. The anticoagulation intensity of rivaroxaban with fine granules, tablets, and crushed tablets was compared in acute stroke patients to assess the efficacy of each form. METHODS AND FINDINGS: Hospitalized patients over 75 years old with acute stroke who started taking rivaroxaban from April 2012 to September 2017 were included. Blood samples were drawn just before and 4 hours after taking rivaroxaban on a median of 5 days after treatment initiation for concentration measurements (C0h, C4h) based on an anti-factor Xa chromogenic assay. Of 114 patients (49 female, 83±5 years old), 97 had ischemic strokes, 9 had transient ischemic attacks, and 8 had intracerebral hemorrhages. Rivaroxaban was administered a median of 7 days after onset. Of these, 38 patients were given the 15 mg dose, and 76 were given the 10 mg dose. In the 15 mg dose group, C0h was significantly higher in the fine granule group than in the crushed tablet group, with no significant difference compared to the tablet group [C0h: 27.6±6.8 vs 4.0±4.1 (P = 0.01) vs. 33.3±25.2 ng/ml, (P = 0.51), respectively], as was C4h [223.0±66.6 vs 103.0±79.5 (P = 0.02) vs. 229.5±121.6 ng/ml (P = 0.88)]. In the 10 mg dose group, C0h was significantly higher in the fine granule group than in the crushed tablet group and comparable to that in the tablet group [23.2±7.9 vs 7.5±6.2 (P<0.01) vs 19.0±15.8 ng/ml, (P = 0.35)], as was C4h [150.7±85.4 vs 85.1±46.8 (P<0.01) vs 189.8±92.7 ng/ml (P = 0.18)]. CONCLUSIONS: The rivaroxaban concentration with fine granules was consistent with that in the tablet group and higher than that in the crushed tablet group.

Development and validation of a score for evaluating comprehensive stroke care capabilities: J-ASPECT Study.

BACKGROUND: Although the Brain Attack Coalition recommended establishing centers of comprehensive care for stroke and cerebrovascular disease patients, a scoring system for such centers was lacking. We created and validated a comprehensive stroke center (CSC) score, adapted to Japanese circumstances. METHODS: Of the selected 1369 certified training institutions in Japan, 749 completed an acute stroke care capabilities survey. Hospital performance was determined using a 25-item score, evaluating 5 subcategories: personnel, diagnostic techniques, specific expertise, infrastructure, and education. Consistency and validity were examined using correlation coefficients and factorial analysis. RESULTS: The CSC score (median, 14; interquartile range, 11-18) varied according to hospital volume. The five subcategories showed moderate consistency (Cronbach's α = 0.765). A strong correlation existed between types of available personnel and specific expertise. Using the 2011 Japanese Diagnosis Procedure Combination database for patients hospitalized with stroke, four constructs were identified by factorial analysis (neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and neurocritical care and rehabilitation) that affected in-hospital mortality from ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The total CSC score was related to in-hospital mortality from ischemic stroke (odds ratio [OR], 0.973; 95% confidence interval [CI], 0.958-0.989), intracerebral hemorrhage (OR, 0.970; 95% CI, 0.950-0.990), and subarachnoid hemorrhage (OR, 0.951; 95% CI, 0.925-0.977), with varying contributions from the four constructs. CONCLUSIONS: The CSC score is a valid measure for assessing CSC capabilities, based on the availability of neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and critical care and rehabilitation services.

Anticoagulation intensity of rivaroxaban for stroke patients at a special low dosage in Japan.

OBJECTIVES: In Japan, low-dose rivaroxaban [15 mg QD/10 mg QD for creatinine clearance of 30-49 mL/min] was approved for clinical use in NVAF patients partly because of its unique pharmacokinetics in Japanese subjects. The aim of the study was to determine the anticoagulation intensity of rivaroxaban and its determinant factors in Japanese stroke patients. METHODS: Consecutive stroke patients with NVAF admitted between July 2012 and December 2013 were studied. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and estimated plasma concentration of rivaroxaban (Criv) based on an anti-factor Xa chromogenic assay were measured just before and 4 and 9 h after administration at the steady state level of rivaroxaban. Determinant factors for Criv were explored using a linear mixed-model approach. RESULTS: Of 110 patients (37 women, 75±9 years old), 59 took 15 mg QD of rivaroxaban and 51 took 10 mg QD. Criv at 4 h was 186 ng/mL for patients taking 15 mg QD and 147 ng/mL for those taking 10 mg QD. Both PT and aPTT were positively correlated with Criv. Criv was 72% lower at 4 h in 15 patients receiving crushed tablets than in the other patients, and tablet crushing was significantly associated with lower Criv (adjusted estimate -0.43, 95% CI -0.60 to -0.26) after multivariate-adjustment. CONCLUSION: The anticoagulation effects of rivaroxaban in the acute stroke setting for Japanese NVAF patients were relatively low as compared with those in the ROCKET-AF and J-ROCKET AF trials. Tablet crushing, common in dysphagic patients, decreased Criv.

The impact of comprehensive stroke care capacity on the hospital volume of stroke interventions: a nationwide study in Japan: J-ASPECT study.

BACKGROUND: The association between comprehensive stroke care capacity and hospital volume of stroke interventions remains uncertain. We performed a nationwide survey in Japan to examine the impact of comprehensive stroke care capacity on the hospital volume of stroke interventions. METHODS: A questionnaire on hospital characteristics, having tissue plasminogen activator (t-PA) protocols, and 25 items regarding personnel, diagnostic, specific expertise, infrastructure, and educational components recommended for comprehensive stroke centers (CSCs) was sent to 1369 professional training institutions. We examined the effect of hospital characteristics, having a t-PA protocol, and the number of fulfilled CSC items (total CSC score) on the hospital volume of t-PA infusion, removal of intracerebral hemorrhage, and coiling and clipping of intracranial aneurysms performed in 2009. RESULTS: Approximately 55% of hospitals responded to the survey. Facilities with t-PA protocols (85%) had a significantly higher likelihood of having 23 CSC items, for example, personnel (eg, neurosurgeons: 97.3% versus 66.1% and neurologists: 51.3% versus 27.7%), diagnostic (eg, digital cerebral angiography: 87.4% versus 43.2%), specific expertise (eg, clipping and coiling: 97.2% and 54% versus 58.9% and 14.3%, respectively), infrastructure (eg, intensive care unit: 63.9% versus 33.9%), and education (eg, professional education: 65.2% versus 20.7%). On multivariate analysis adjusted for hospital characteristics, total CSC score, but not having a t-PA protocol, was associated with the volume of all types of interventions with a clear increasing trend (P for trend < .001). CONCLUSION: We demonstrated a significant association between comprehensive stroke care capacity and the hospital volume of stroke interventions in Japan.

[Cerebellar infarction in a young adult due to traumatic vertebral artery dissection after lateral mass fracture at the sixth cervical vertebrae].

A 23-years-old man fell off stairs and got a blow on the left head and right shoulder. He felt dysesthesia at the right thumb on the following day, and received chiropractic therapy from the forth day after injury. On the sixth day after injury, he developed dizziness and nausea, and was urgently hospitalized in our cerebrovascular center. On admission, he had horizontal nystagmus and truncal ataxia. Diffusion-weighted magnetic resonance imaging showed high intensity lesions in right cerebellum hemisphere of posterior inferior cerebellar artery territory, indicating fresh infarcts. On angiogram, right vertebral artery showed tapering occlusion at C6 level, indicating dissection. Computed tomogram showed fracture of the right lateral mass at C6 which extended into the transverse foramen. Under diagnosis of the traumatic vertebral artery dissection due to cervical fracture, we started anticoagulation therapy, which was followed by oral antiplatelet therapy in the chronic stage. Extracranial vertebral artery dissection due to cervical fracture is an important cause of brain infarction in a young adult. Radiological examinations are necessary to rule out traumatic vertebral artery dissection for patients with prolonged dizziness after head injury.

Recurrent embolic stroke originating from an internal carotid aneurysm in a young adult.

An unruptured intracranial aneurysm is an uncommon but possible embolic source to the brain. We report a young patient who developed recurrent ischemic strokes occurring mainly in the left internal carotid arterial territory within a short interval; the first stroke occurred midway through a long-distance race, and the second stroke occurred immediately following a bowel movement. The angiographical contrast deficit indicated a thrombus in the left anterior cerebral artery as a result of the embolism. A saccular aneurysm of the left distal internal carotid artery was the only detectable potential embolic source. Initially anticoagulant therapy was given, and then surgical clipping of the aneurysm was performed. The patient has been free from stroke recurrence. As a cause of ischemic stroke in young adults, a carotid saccular aneurysm should be considered. Hard exercise and a Valsalva maneuver may be important triggers of thrombus detachment from the aneurysm.

Recurrent small-artery disease in hyperhomocysteinemia: widowers' stroke syndrome?

Hyperhomocysteinemia is thought to cause ischemic strokes. We report two middle-aged widowers with frequent recurrences of small-artery strokes, two capsular infarcts and a thalamic hemorrhage in one patient, and two thalamic and pontine infarcts in the other. Blood tests following the final stroke showed hyperhomocysteinemia and methylenetetrahydrofolate reductase C677T gene mutation, with low concentration of vitamin B6. Multivitamin supplementation normalized plasma homocysteine levels in both patients. Hyperhomocysteinemia is treatable; therefore, serum homocysteine should be measured as a potential risk factor for stroke recurrence in relatively young patients with recurrent small-artery infarctions or hemorrhage, especially those with insufficient lifestyle factors.

[Brain hemorrhage with medical treatment: prediction of early outcome and production of critical paths].

The first purpose of this study was to detect clinical and radiological factors on admission which predict early outcome of patients in brain hemorrhage with medical treatment. For 50 consecutive patients in our Cerebrovascular Center, NIH Stroke Scale score was a useful indicator for prediction of independent daily life, discharge to home, and death in the acute stage; the score < or = 4, < or = 7, and > or = 23 were the most appropriate cut-off values for the above events, respectively. The second purpose of this study was to produce critical paths of medical management for brain hemorrhage based on the above results. We prepared three courses of paths according to clinical severity. As inclusion criteria for each course, we used the above three cut-off values and hematoma volume. Duration of hospitalization of the three courses was 16, 20, and 28 days. When we applied the paths to 200 patients with brain hemorrhage who were enrolled in the research grant supported by the Japanese ministry of health, labor and welfare (12C-10), duration of hospitalization for the majority of the patients were 5 days or more than the planned duration in the paths. It is indispensable to manage acute stroke patients according to critical paths, because standard and efficient strategies of clinical medicine have been stressed these years. We will immediately apply the new paths in this study to patients in our center, and renew them at short intervals. We think that we can contribute to new evidences for standard medical management of brain hemorrhage by our approach to the critical paths.

Hypertensive encephalopathy extending into the whole brainstem and deep structures.

In patients with hypertensive encephalopathy, brain edema is frequently distributed in the parieto-occipital white matter. We report a patient with high arterial blood pressure of over 300/160 mmHg on admission, who had extensive MRI-documented reversible lesions throughout the whole brain, including the brainstem, thalami, basal ganglia, and cerebellum. Extraordinarily severe acceleration of hypertension may be essential for the breakdown of autoregulation in the deep structures, especially in the brainstem including medulla.