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

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

Anti-Xa Activity and Event Risk in Patients With Direct Factor Xa Inhibitors Initiated Early After Stroke.

BACKGROUND: Measuring anti-Xa activity (AXA) has been reported as useful for predicting future risk of hemorrhagic and ischemic events in stroke patients taking direct factor Xa inhibitors. We evaluated AXA levels of rivaroxaban or apixaban in acute stroke patients with non-valvular atrial fibrillation. Methods and Results: This was a single-center, prospective, observational study. Consecutive patients with acute ischemic stroke or transient ischemic attack who were admitted within 7 days of onset and started taking rivaroxaban or apixaban for NVAF between January 2012 and April 2017 were enrolled. AXA was measured at 2 time points: just before (AXAtrough) and 4 h after (AXApeak) taking rivaroxaban or apixaban on the 2nd day or later of administration. Of 156 patients taking rivaroxaban, hemorrhagic events occurred in 13. Patients with hemorrhagic events had higher AXApeak than those without [median (interquartile range): 1.93 (1.11-3.75) vs. 1.35 (0.80-2.00) IU/mL; P<0.01]. Multivariable-adjusted Cox models showed that AXApeak was independently related to the incidence of hemorrhagic events. Of 169 patients taking apixaban, hemorrhagic events occurred in 11. Patients with hemorrhagic events had higher AXAtrough [2.78 (1.90-3.53) vs. 1.42 (0.93-2.08) IU/mL, P<0.01] and AXApeak [4.05 (3.44-4.72) vs. 2.43 (1.79-3.35) IU/mL, P<0.01] than those without. Both AXAtrough and AXApeak were independently related to the incidence of hemorrhagic events. CONCLUSIONS: In these patients who started rivaroxaban or apixaban early after stroke, AXA levels in the early period were related to future hemorrhagic events.

Subacute Methotrexate Encephalopathy Mimicking Ischemic Stroke With Dynamic Changes on Magnetic Resonance Imaging.

We report a 35-year-old woman who suddenly developed left hemiparesis and dysarthria at 13days after treatment with intrathecal and intravenous methotrexate for intravascular large B cell lymphoma with possible central nervous system infiltration. Seven hours after onset, she developed further right hemiparesis and aphasia. However, the majority of neurologic symptoms disappeared spontaneously and completely by 34hours. We also recorded the dynamic progression and regression of abnormal signals in the bilateral corona radiata on diffusion-weighted imaging, in parallel with neurologic symptoms. The rapid reversal of MR abnormalities and neurologic symptoms allowed us to diagnose methotrexate encephalopathy, and exclude intravascular large B cell lymphoma recurrence and regular brain infarction. The case provides new data on the dynamic changes of abnormal signals on magnetic resonance imaging in methotrexate encephalopathy over a short recovery time.

Spontaneous heparin-induced thrombocytopenia syndrome without any proximate heparin exposure, infection, or inflammatory condition: Atypical clinical features with heparin-dependent platelet activating antibodies.

Recent studies suggest that a thromboembolic disorder resembling heparin-induced thrombocytopenia (HIT), so-called spontaneous HIT syndrome, can occur in patients without any history of heparin exposure. It is likely due to anti-platelet factor 4 (PF4)/polyanion antibodies induced by other polyanions, such as bacterial surfaces and nucleic acids. We describe an atypical case of spontaneous HIT syndrome. A 70-year-old man suddenly presented with acute cerebral sinus thrombosis (CST). Soon after the initiation of unfractionated heparin (UFH) for the treatment of CST, his platelet count fell precipitously and he developed deep vein thrombosis, a clinical picture consistent with rapid-onset HIT but without any proximate episodes of heparin exposure, infection, trauma, surgery, or other acute illness. Antigen assays and a washed platelet activation assay indicated that the patient already possessed anti-PF4/heparin IgG antibodies with heparin-dependent platelet activation properties on admission. Cessation of UFH and initiation of argatroban resulted in prompt recovery of his platelet count without further thromboembolic events. We identified two similar cases in the literature. However, these patients do not meet the recently proposed criteria for spontaneous HIT syndrome. Even in atypical cases, however, inappropriate or delayed diagnosis of HIT appears to be associated with worse outcomes. We propose that these atypical cases should be included in the category of spontaneous HIT syndrome.

Continuous antihypertensive therapy throughout the initial 24 hours of intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study.

BACKGROUND AND PURPOSE: A short duration (<24 hours) of antihypertensive therapy (AHT) after acute intracerebral hemorrhage (ICH) may be sufficient because active bleeding generally ceases within several hours. We aimed to determine the association between sequential systolic blood pressure (SBP) levels during AHT and outcomes in ICH patients. METHODS: In 211 hyperacute ICH patients who underwent AHT based on predefined protocol, the mean of hourly SBP (mSBP) measurements was calculated over 1 to 8 hours (first mSBP), 9 to 16 hours (second mSBP), and 17 to 24 hours (third mSBP) after the initiation of AHT. Outcomes included neurological deterioration (72-hour Glasgow Coma Scale decrease ≥2 or National Instititutes of Health Stroke Scale increase ≥4), hematoma expansion (>33%), and unfavorable outcome (3-month modified Rankin Scale score 4-6). RESULTS: The median first, second, and third mSBPs were 132, 131, and 137 mm Hg, respectively. A higher first mSBP (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.34-4.69 per 10 mm Hg) or second mSBP (OR, 2.08; 95% CI, 1.20-3.80) was independently associated with neurological deterioration, and a higher second mSBP (OR, 1.40; 95% CI, 1.02-2.00) or third mSBP (OR, 1.45; 95% CI, 1.05-2.05) was associated with unfavorable outcome. None of the mSBPs was associated with hematoma expansion. CONCLUSIONS: The continuation of AHT throughout the initial 24 hours after ICH may improve outcomes.

Blood pressure variability on antihypertensive therapy in acute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-intracerebral hemorrhage study.

BACKGROUND AND PURPOSE: The associations between early blood pressure (BP) variability and clinical outcomes in patients with intracerebral hemorrhage after antihypertensive therapy, recently clarified by a post hoc analysis of Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2), were confirmed using the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI)-intracerebral hemorrhage study cohort. METHODS: Patients with hyperacute (<3 hours from onset) intracerebral hemorrhage with initial systolic BP (SBP) >180 mm Hg were registered in a prospective, multicenter, observational study. All patients received antihypertensive therapy based on a predefined standardized protocol to lower and maintain SBP between 120 and 160 mm Hg using intravenous nicardipine. BPs were measured hourly during the initial 24 hours. BP variability was determined as SD and successive variation. The associations between BP variability and hematoma expansion (>33%), neurological deterioration within 72 hours, and unfavorable outcome (modified Rankin Scale, 4-6) at 3 months were assessed. RESULTS: Of the 205 patients, 33 (16%) showed hematoma expansion, 14 (7%) showed neurological deterioration, and 81 (39%) had unfavorable outcomes. The SD and successive variation of SBP were 13.8 (interquartile range, 11.5-16.8) and 14.9 (11.7-17.7) mm Hg, respectively, and those of diastolic BP were 9.4 (7.5-11.2) and 13.1 (11.2-15.9) mm Hg, respectively. On multivariate regression analyses, neurological deterioration was associated with the SD of SBP (odds ratio, 2.75; 95% confidence interval, 1.45-6.12 per quartile) and the successive variation of SBP (2.37; 1.32-4.83), and unfavorable outcome was associated with successive variation of SBP (1.42; 1.04-1.97). Hematoma expansion was not associated with any BP variability. CONCLUSIONS: SBP variability during the initial 24 hours of acute intracerebral hemorrhage was independently associated with neurological deterioration and unfavorable outcomes. Stability of antihypertensive therapy may improve clinical outcomes.

[A case of recurrent stroke with carotid-web despite dabigatran treatment successfully treated by carotid endarterectomy].

We present a case of a 41-year-old female presenting with recurrence of ischemic stroke on subtherapeutic doses of dabigatran. She had a history of embolic stroke of undetermined sources at the age of 40, and underwent implantable cardiac monitor implantation and had started dabigatran. One year after the first ischemic stroke, she presented with sudden dysarthria and left hemiparesis and was admitted to our hospital. An MRI of the head revealed acute cerebral infarction in the right corona radiata, and an MR angiography revealed right M2 occlusion. Cervical 3D-CTA revealed a protruding structure on the posterior wall of the carotid artery bulb, which was diagnosed as carotid web. She underwent carotid endarterectomy, and the specimen was pathologically confirmed to be vascular malformation due to fibromuscular dysplasia.

Filamin A Variant as a Possible Second-Hit Gene Promoting Moyamoya Disease-like Vascular Formation Associated With RNF213 p.R4810K Variant.

Background and Objective: The objective of this case report was to identify a second-hit gene that may promote Moyamoya disease (MMD)-like vascular formation in an individual having the RNF213 p.R4810K variant. Methods: We performed magnetic resonance imaging and genetic analyses of RNF213 and FLNA in a 21-year-old woman, who showed Ehlers-Danlos-like symptoms and developed a first-ever unprovoked seizure, and of her healthy parents. Results: We identified bilateral periventricular nodular heterotopia (PNH) as the cause of seizures and MMD-like vascular formation in the patient. The patient had the RNF213 p.R4810K variant. Exome analysis identified c.4868delG in the X-linked FLNA gene encoding filamin A p.G1623V fs*41, which could explain PNH and Ehlers-Danlos-like symptoms. Her mother had the same FLNA variant and had asymptomatic bilateral PNH, whereas her father had the RNF213 variant and had normal cerebrovascular structure. Discussion: The family study suggested that the FLNA variant promoted MMD-like vascular formation in a patient having the RNF213 variant, while the RNF213 variant amplified the phenotypic changes elicited by the FLNA abnormality. Collectively, we identified a gene abnormality in filamin A, a target of RNF213-mediated proteasomal degradation, that may promote MMD-like vascular formation as a possible second-hit gene in individuals having the RNF213 p.R4810K variant.

PON1 Q192R is associated with high platelet reactivity with clopidogrel in patients undergoing elective neurointervention: A prospective single-center cohort study.

BACKGROUND AND PURPOSE: The impact of the paraoxonase-1 (PON1) polymorphism, Q192R, on platelet inhibition in response to clopidogrel remains controversial. We aimed to investigate the association between carrier status of PON1 Q192R and high platelet reactivity (HPR) with clopidogrel in patients undergoing elective neurointervention. METHODS: Post-clopidogrel platelet reactivity was measured using a VerifyNow® P2Y12 assay in P2Y12 reaction units (PRU) for consecutive patients before the treatment. Genotype testing was performed for PON1 Q192R and CYP2C19*2 and *3 (no function alleles), and *17. PRU was corrected on the basis of hematocrit. We investigated associations between factors including carrying ≥1 PON1 192R allele and HPR defined as original and corrected PRU ≥208. RESULTS: Of 475 patients (232 men, median age, 68 years), HPR by original and corrected PRU was observed in 259 and 199 patients (54.5% and 41.9%), respectively. Carriers of ≥1 PON1 192R allele more frequently had HPR by original and corrected PRU compared with non-carriers (91.5% vs 85.2%, P = 0.031 and 92.5% vs 85.9%, P = 0.026, respectively). In multivariate analyses, carrying ≥1 PON1 192R allele was associated with HPR by original (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.03-3.76) and corrected PRU (OR 2.34, 95% CI 1.21-4.74) after adjustment for age, sex, treatment with antihypertensive medications, hematocrit, platelet count, total cholesterol, and carrying ≥1 CYP2C19 no function allele. CONCLUSIONS: Carrying ≥1 PON1 192R allele is associated with HPR by original and corrected PRU with clopidogrel in patients undergoing elective neurointervention, although alternative results related to other genetic polymorphisms cannot be excluded.

Concentrations of dabigatran administered after acute ischemic stroke.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the anticoagulation intensity of dabigatran for acute ischemic stroke patients and hemorrhagic/ischemic events after early initiation of dabigatran. METHODS: Acute ischemic stroke/transient ischemic attack (TIA) patients admitted to our hospital who started dabigatran from January 2012 to December 2017 were studied. Blood samples were drawn just before (0 h) and 4 h after dabigatran at a median of 5 days after starting dabigatran to measure dabigatran concentrations (C0h, C4h) based on the thrombin clotting time assay (Hemoclot®). RESULTS: Of the 70 patients (54 men, 69 ± 9 y), 14 started dabigatran after a TIA, and 56 started it after an ischemic stroke a median of 5 days after onset. C0h, C4h was 82.5 ± 58.0, 143.1 ± 98.2 ng/dl (150 mg BID, 35 patients) and 50.6 ± 40.9, 91.2 ± 64.7 ng/ml (110 mg BID, 35 patients). During a median follow-up of 382 (IQR 109-688) days of all 70 patients, five had clinical events. Three patients had bleeding events, two with nasal bleeding (C0h, C4h: 50, 80 ng/ml, C0h, C4h: 91, 173 ng/ml) and one with GI bleeding (C0h, C4h: 5, 5 ng/ml). Two patients had ischemic events, one with ischemic stroke (C0h, C4h: 10, 50 ng/ml) and another with acute myocardial infarction (C0h, C4h: 40, 40 ng/ml). CONCLUSIONS: There was no obvious relationship between dabigatran concentration and hemorrhagic/ischemic events in this study. Larger sample study will be needed to examine the relationship between the concentration and events in clinical practice.

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.

Platelet reactivity and hemorrhage risk in neurointerventional procedures under dual antiplatelet therapy.

BACKGROUND AND PURPOSE: Hemorrhagic complications during neurointerventional procedures have various etiologies and can result in severe morbidity and mortality. This study investigated the possible association between low platelet reactivity measured by the VerifyNow assay and increased hemorrhagic complications during elective neurointervention under dual antiplatelet therapy. METHODS: From May 2010 to April 2013 we recorded baseline characteristics, P2Y12 reaction units (PRU), and aspirin reaction units using VerifyNow. The primary endpoint was post-procedural hemorrhagic complications. RESULTS: A total of 279 patients were enrolled and 31 major hemorrhagic complications (11.1%) were identified. From receiver-operating characteristic curve analysis, PRU values could discriminate between patients with and without major hemorrhagic complications (area under the curve 0.63). Aspirin reaction unit values had no association with the primary outcome. The optimal cut-off for the primary outcome (PRU ≤175) was used to identify the low platelet reactivity group. The incidence of hemorrhagic complications was 20.0% in this group and 8.9% in the non-low platelet reactivity group. Multivariate analysis identified low platelet reactivity as an independent predictor for hemorrhagic complications. CONCLUSIONS: The risk of hemorrhagic complications during elective neurointervention including cerebral aneurysm coil embolization and carotid artery stenting under dual antiplatelet therapy is associated with the response to clopidogrel but not to aspirin. A PRU value of ≤175 discriminates between patients with and without hemorrhagic complications. Future prospective studies are required to validate whether a specific PRU value around 170-180 is predictive of hemorrhagic complications.

Relative systolic blood pressure reduction and clinical outcomes in hyperacute intracerebral hemorrhage: the SAMURAI-ICH observational study.

BACKGROUND AND PURPOSE: Blood pressure lowering is often performed as a part of general acute management in acute intracerebral hemorrhage (ICH) patients. The relationship between relative blood pressure reduction and clinical outcomes is not fully known. METHODS: Hyperacute (<3 h from onset) ICH patients with initial SBP more than 180 mmHg were included in the observational study. All patients received intravenous antihypertensive treatment based on a predefined protocol to lower and maintain SBP between 120 and 160 mmHg. The relative SBP reduction was defined as the ratio of SBP reduction to the admission SBP in the first 24 h, and associations between the relative SBP reduction and neurological deterioration (≥2 points decrease in the Glasgow Coma Scale score or ≥4 increase in the National Institutes of Health Stroke Scale score), hematoma expansion (>33% increase), and unfavorable outcome (modified Rankin scale score 4-6 at 3 months) were assessed with multivariate logistic regression analyses. RESULTS: Of the 211 patients [81 women, median age 65 (interquartile range 58-74) years, and median initial National Institutes of Health Stroke Scale score 13 (8-17)] enrolled, 17 (8%) showed neurological deterioration, 36 (17%) showed hematoma expansion, and 87 (41%) had an unfavorable outcome. On multivariate regression analyses, relative SBP reduction was independently and inversely associated with neurological deterioration (odds ratio 0.053, 95% confidence interval 0.011-0.254 per 10% increment), hematoma expansion (0.289, 0.099-0.841), and unfavorable outcome (0.254, 0.095-0.680) after adjusting for known predictive factors. CONCLUSION: Insufficient relative SBP reduction after standardized antihypertensive therapy in hyperacute ICH was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may improve clinical outcomes.

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.

Low DWI-ASPECTS is associated with atrial fibrillation in acute stroke with the middle cerebral artery trunk occlusion.

BACKGROUND AND PURPOSE: For optimal acute stroke management and secondary prevention, discrimination of stroke etiology is crucial. We hypothesized that a low Alberta Stroke Program Early CT Score (ASPECTS) on diffusion-weighted imaging (DWI) immediately after stroke onset was associated with the presence of atrial fibrillation (AF). METHODS: Consecutive patients admitted within 24h from stroke onset with an occlusion at the horizontal segment of the middle cerebral artery (M1) on initial MRA were retrospectively enrolled. AF was diagnosed based on continuous electrocardiogram monitoring during acute hospitalization or its confirmed history. RESULTS: Of the 206 patients (95 women, median age 77 [IQR 69-85] years, NIHSS score 18 [13-23]) enrolled, AF was identified in 138 patients (AF group): chronic AF in 89, known paroxysmal AF (pAF) in 13, and masked pAF on admission in 36. The ASPECTS score on the initial DWI, performed a median of 2.5h after onset, was lower in the AF group than in the others (4 [2-6] vs. 7 [4-8], p<0.001). With the optimal cut-off value of ≤ 6 (sensitivity, 78%; specificity, 57%; area under the ROC curve, 0.682), DWI-ASPECTS was independently associated with the presence of any AF (OR 5.05, 95%CI 2.36 to 10.8), as well as the presence of any pAF (OR 8.64, 95%CI 3.00 to 24.9) and that of masked pAF on admission (OR 10.0, 95%CI 3.06 to 32.9). CONCLUSION: Extensive early ischemic change assessed by DWI-ASPECTS predicts the presence of AF, even initially masked pAF, in acute stroke patients with M1 occlusion.