Shoji Arihiro

Free radical scavenger, edaravone, in stroke with internal carotid artery occlusion

BACKGROUND Edaravone has potent free radical quenching and antioxidant actions. The agent has been recently in commercial use for acute ischemic stroke patients. In this study, we investigated the therapeutic effect of edaravone on severe carotid-territorial stroke. METHODS Stroke patients with internal carotid artery occlusion and baseline NIH Stroke Scale Score > or =15 were treated for 14 days with drip intravenous infusion of edaravone (n=30) and were compared with a historical control cohort of similar patients (n=31). Glycerol was also administered to all patients in both groups. RESULTS Infarct volume (P<0.02) and midline shift (P<0.02) on CT performed on day 2 of the patients treated with edaravone were smaller than those without edaravone. For patients with edaravone, infarct volume (P<0.0001) and midline shift (P<0.0001) on days 5-7 were greater than those on day 2. Hemorrhagic transformation of infarcts on day 2 was less severe in patients with than without edaravone (P<0.03). Within 14 days after the onset of stroke, 6 patients with edaravone (20%) and 14 without edaravone (45%) died directly of stroke (P<0.03). Among all patients, only two treated with edaravone were independent without any assistance 8 weeks after the onset. CONCLUSIONS Edaravone was associated with delayed evolution of infarcts and edema in patients with severe carotid-territorial stroke and decreased mortality during the acute stage. The agent, however, failed to prevent evolution of infarcts and edema on later days, and did not significantly improve functional outcome among the surviving patients.

Systolic Blood Pressure After Intravenous Antihypertensive Treatment and Clinical Outcomes in Hyperacute Intracerebral Hemorrhage The Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement-Intracerebral Hemorrhage Study

Background and Purpose— Blood pressure (BP) lowering is often conducted as part of general acute management in patients with acute intracerebral hemorrhage. However, the relationship between BP after antihypertensive therapy and clinical outcomes is not fully known. Methods— Hyperacute (<3 hours from onset) intracerebral hemorrhage patients with initial systolic BP (SBP) >180 mm Hg were included. All patients received intravenous antihypertensive treatment, based on predefined protocol to lower and maintain SBP between 120 and 160 mm Hg. BPs were measured every 15 minutes during the initial 2 hours and every 60 minutes in the next 22 hours (a total of 30 measurements). The mean achieved SBP was defined as the mean of 30 SBPs, and associations between the mean achieved SBP and neurological deterioration (≥2 points’ decrease in Glasgow Coma Score or ≥4 points’ increase in 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, mean achieved SBP was independently associated with neurological deterioration (odds ratio, 4.45; 95% confidence interval, 2.03–9.74 per 10 mm Hg increment), hematoma expansion (1.86; 1.09–3.16), and unfavorable outcome (2.03; 1.24–3.33) after adjusting for known predictive factors. Conclusions— High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.

Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan: The SAMURAI-NVAF Study

Background Large clinical trials are lack of data on non-vitamin K antagonist oral anticoagulants for acute stroke patients. Aim To evaluate the choice of oral anticoagulants at acute hospital discharge in stroke patients with nonvalvular atrial fibrillation and clarify the underlying characteristics potentially affecting that choice using the multicenter Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-NVAF registry (ClinicalTrials.gov NCT01581502). Method The study included 1192 acute ischemic stroke/transient ischemic attack patients with nonvalvular atrial fibrillation (527 women, 77·7 ± 9·9 years old) between September 2011 and March 2014, during which three nonvitamin K antagonist oral anticoagulant oral anticoagulants were approved for clinical use. Oral anticoagulant choice at hospital discharge (median 23-day stay) was assessed. Results Warfarin was chosen for 650 patients, dabigatran for 203, rivaroxaban for 238, and apixaban for 25. Over the three 10-month observation periods, patients taking warfarin gradually decreased to 46·5% and those taking nonvitamin K antagonist oral anticoagulants increased to 48·0%. As compared with warfarin users, patients taking nonvitamin K antagonist oral anticoagulants included more men, were younger, more frequently had small infarcts, and had lower scores for poststroke CHADS2, CHA2DS2-VASc, and HAS-BLED, admission National Institutes of Health stroke scale, and discharge modified Rankin Scale. Nonvitamin K antagonist oral anticoagulants were started at a median of four-days after stroke onset without early intracranial hemorrhage. Patients starting nonvitamin K antagonist oral anticoagulants earlier had smaller infarcts and lower scores for the admission National Institutes of Health stroke scale and the discharge modified Rankin Scale than those starting later. Choice of nonvitamin K antagonist oral anticoagulants was independently associated with 20-day or shorter hospitalization (OR 2·46, 95% CI 1·87–3·24). Conclusions Warfarin use at acute hospital discharge was still common in the initial years after approval of nonvitamin K antagonist oral anticoagulants, although nonvitamin K antagonist oral anticoagulant users increased gradually. The index stroke was milder and ischemia-risk indices were lower in nonvitamin K antagonist oral anticoagulant users than in warfarin users. Early initiation of nonvitamin K antagonist oral anticoagulants seemed safe.

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.

Three-month risk-benefit profile of anticoagulation after stroke with atrial fibrillation: The SAMURAI-Nonvalvular Atrial Fibrillation (NVAF) study

Aims This study was performed to determine the short-term risk-benefit profiles of patients treated with oral anticoagulation for acute ischemic stroke or transient ischemic attack using a multicenter, prospective registry. Methods A total of 1137 patients (645 men, 77 ± 10 years old) with acute ischemic stroke/transient ischemic attack taking warfarin (662 patients) or non-vitamin K antagonist oral anticoagulants (dabigatran in 205, rivaroxaban in 245, apixaban in 25 patients) for nonvalvular atrial fibrillation who completed a three-month follow-up survey were studied. Choice of anticoagulants was not randomized. Primary outcome measures were stroke/systemic embolism and major bleeding. Results Both warfarin and non-vitamin K antagonist oral anticoagulants were initiated within four days after stroke/transient ischemic attack onset in the majority of cases. Non-vitamin K antagonist oral anticoagulant users had lower ischemia- and bleeding-risk indices (CHADS2, CHA2DS2-VASc, HAS-BLED) and milder strokes than warfarin users. The three-month cumulative rate of stroke/systemic embolism was 3.06% (95% CI 1.96%–4.74%) in warfarin users and 2.84% (1.65%–4.83%) in non-vitamin K antagonist oral anticoagulant users (adjusted HR 0.96, 95% CI 0.44–2.04). The rate of major bleeding was 2.61% (1.60%–4.22%) and 1.11% (0.14%–1.08%), respectively (HR 0.63, 0.19–1.78); that for intracranial hemorrhage was marginally significantly lower in non-vitamin K antagonist oral anticoagulant users (HR 0.17, 0.01–1.15). Major bleeding did not occur in non-vitamin K antagonist oral anticoagulant users with a CHADS2 score <4 or those with a discharge modified Rankin Scale score ≤2. Conclusions Stroke or systemic embolism during the initial three-month anticoagulation period after stroke/transient ischemic attack was not frequent as compared to previous findings regardless of warfarin or non-vitamin K antagonist oral anticoagulants were used. Intracranial hemorrhage was relatively uncommon in non-vitamin K antagonist oral anticoagulant users, although treatment assignment was not randomized. Early initiation of non-vitamin K antagonist oral anticoagulants during the acute stage of stroke/transient ischemic attack in real-world clinical settings seems safe in bleeding-susceptible Japanese population.

Higher Risk of Ischemic Events in Secondary Prevention for Patients With Persistent Than Those With Paroxysmal Atrial Fibrillation.

Background and Purpose— The discrimination between paroxysmal and sustained (persistent or permanent) atrial fibrillation (AF) has not been considered in the approach to secondary stroke prevention. We aimed to assess the differences in clinical outcomes between mostly anticoagulated patients with sustained and paroxysmal AF who had previous ischemic stroke or transient ischemic attack. Methods— Using data from 1192 nonvalvular AF patients with acute ischemic stroke or transient ischemic attack who were registered in the SAMURAI-NVAF study (Stroke Management With Urgent Risk-Factor Assessment and Improvement-Nonvalvular AF; a prospective, multicenter, observational study), we divided patients into those with paroxysmal AF and those with sustained AF. We compared clinical outcomes between the 2 groups. Results— The median follow-up period was 1.8 (interquartile range, 0.93–2.0) years. Of the 1192 patients, 758 (336 women; 77.9±9.9 years old) and 434 (191 women; 77.3±10.0 years old) were assigned to the sustained AF group and paroxysmal AF groups, respectively. After adjusting for sex, age, previous anticoagulation, and initial National Institutes of Health Stroke Scale score, sustained AF was negatively associated with 3-month independence (multivariable-adjusted odds ratio, 0.61; 95% confidence interval, 0.43–0.87; P=0.006). The annual rate of stroke or systemic embolism was 8.3 and 4.6 per 100 person-years, respectively (multivariable-adjusted hazard ratio, 1.95; 95% confidence interval, 1.26–3.14) and that of major bleeding events was 3.4 and 3.1, respectively (hazard ratio, 1.13; 95% confidence interval, 0.63–2.08). Conclusions— Among patients with previous ischemic stroke or transient ischemic attack, those with sustained AF had a higher risk of stroke or systemic embolism compared with those with paroxysmal AF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01581502.

Intravenous Nicardipine Dosing for Blood Pressure Lowering in Acute Intracerebral Hemorrhage: The Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Intracerebral Hemorrhage Study

BACKGROUND Intravenous nicardipine is commonly used to reduce elevated blood pressure in acute intracerebral hemorrhage (ICH). We determined factors associated with nicardipine dosing and the association of dose with clinical outcomes in hyperacute ICH. METHODS Hyperacute (<3 hours from onset) ICH patients with initial systolic blood pressure (SBP) greater than 180 mm Hg were included. All patients initially received 5 mg/hour of intravenous nicardipine. The dose was adjusted to maintain SBP between 120 and 160 mm Hg. Associations of maximum hourly and total doses with early neurologic deterioration (END), hematoma expansion (>33%), and modified Rankin Scale score 4-6 at 3 months were assessed. RESULTS Two hundred six patients (81 women, 65.8 ± 11.8 years) were studied. Initial SBP was 201.9 ± 15.9 mm Hg. Maximum and total nicardipine doses were 9.1 ± 4.2 mg/hour and 123.7 ± 100.2 mg/day, respectively. Multivariate analyses revealed that men (standardized regression coefficient [β] = .20, P = .0030 for maximum dose; β = .25, P = .0002 for total dose), age (β = -.28, P = .0002; β = -.25, P = .0005), and initial SBP (β = .19, P = .0018; β = .18, P = .0021) were independently associated with both maximum and total doses. Body weight (β = .20, P = .0084) was independently associated with total dose. After multivariate adjustment, maximum dose (per 1 mg/hour; odds ratio [OR], 1.25; 95% confidence interval [CI], 1.09-1.45) was independently, and total dose (per 10 mg/day; OR, 1.06; 95% CI, .998-1.132) tended to be independently, associated with END. Nicardipine dose was not associated with hematoma expansion or 3-month outcome. CONCLUSIONS Nicardipine dose is roughly predictable with sex, age, body weight, and initial SBP in acute ICH. The maximum dose was associated with neurologic deterioration.

Conjugate Eye Deviation in Acute Intracerebral Hemorrhage Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement–ICH (SAMURAI-ICH) Study

Background and Purpose— Conjugate eye deviation (CED) occurs frequently in patients with acute stroke. The purpose of this study was to elucidate the factors that correlate with CED as well as the relationship between CED and outcomes in patients with acute intracerebral hemorrhage. Methods— A total of 211 patients with acute supratentorial intracerebral hemorrhage were recruited in a multicenter, prospective study. CED was assessed with a National Institutes of Health Stroke Scale “best gaze” subscore of ≥1. Hematoma location and volume were assessed on CT. Results— Forty-five percent of the patients had CED. On multivariable analysis, right-sided lesion (OR, 2.36; 95% CI, 1.18–4.93), hematoma volume (OR, 1.07; 95% CI, 1.04–1.10 per 1 mL), and baseline Glasgow Coma Scale score (OR, 0.66; 95% CI, 0.53–0.80 per 1 point) were independently associated with CED. After adjusting for sex, age, intraventricular extension of the hematoma, baseline Glasgow Coma Scale score, and hematoma volume, the presence of CED both on admission and 72 hours later was an independent predictor of death or dependency at 3 months poststroke (OR, 5.77; 95% CI, 2.27–16.94). The optimal cutoff volume of hematoma related to CED was ≥13.5 mL for patients with putaminal hemorrhage (sensitivity, 76%; specificity, 72%) and ≥7.7 mL for patients with thalamic hemorrhage (sensitivity, 82%; specificity, 83%). Conclusions— The persistence of CED was a significant predictor of death or dependency after acute supratentorial intracerebral hemorrhage even after adjusting for initial severity and hematoma volume. CED can be evoked by a relatively smaller thalamic hematoma than a putaminal hematoma.

Blood glucose levels during the initial 72 h and 3-month functional outcomes in acute intracerebral hemorrhage: The SAMURAI–ICH study

PURPOSE Prognostic values of blood glucose levels following admission remain unclear. We investigated associations between blood glucose levels during the initial 72 h and outcomes of acute ICH. METHODS Participants comprised hyperacute ICH patients who received intravenous antihypertensive treatment. Blood glucose levels were measured on admission and at 24 and 72 h after starting treatment, along with hemoglobin (Hb)A1c level on admission. Associations with clinical outcomes of hematoma expansion (>33% increase), none to minimal disability (3-month modified Rankin Scale [mRS] 0-1) and bedridden or death (3-month mRS 5-6) were analyzed. RESULTS Of the 176 patients (70 women; 65 ± 12 years), 30 (18%) showed hematoma expansion, and 33 (19%) had none to minimal disability and 15 (10%) were bedridden or died. On multivariate regression analysis, blood glucose at 24h (per 10mg/dl odds ratio [OR], 0.84; 95% confidence interval [CI], 0.69-0.98) and blood glucose at 72 h (OR, 0.75; 95%CI, 0.59-0.92) were inversely associated with none to minimal disability, and blood glucose at 24h (OR, 1.14; 95%CI, 1.00-1.30) was positively associated with bedridden or death. No parameters were associated with hematoma expansion. CONCLUSIONS High blood glucose levels at 24 and 72 h were independently associated with poor functional outcomes 3 months after ICH. We need to investigate whether blood glucose control during the acute period ameliorates clinical outcomes.

Reduced Estimated Glomerular Filtration Rate Affects Outcomes 3 Months after Intracerebral Hemorrhage: The Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Intracerebral Hemorrhage Study

BACKGROUND The effect of renal dysfunction on intracerebral hemorrhage (ICH) remains unclear. We investigated associations of renal dysfunction assessed by estimated glomerular filtration rate (eGFR) with clinical courses and outcomes in ICH patients. METHODS From a prospective, multicenter, observational study, 203 patients who had supratentorial ICH within 3 hours of onset were included. Patients were classified into 3 groups based on eGFR: Group 1 (eGFR < 60 mL/minute/m(2)), Group 2 (60-89), and Group 3 (≥ 90). Outcomes included neurologic deterioration within 72 hours, hematoma expansion (> 33% in volume) at 24 hours, and favorable (modified Rankin Scale [mRS] ≤ 2) or unfavorable (mRS ≥ 5) outcome at 3 months. RESULTS Thirty-seven patients (16 women, 74.6 ± 13.2 years) were assigned to Group 1, 99 (34 women, 65.2 ± 11.4 years) to Group 2, and 67 (30 women, 61.3 ± 9.4 years) to Group 3. Significant differences were found in age (P < .001) and initial systolic blood pressure among the groups (208.4 ± 18.0, 201.9 ± 15.1, and 198.1 ± 14.2 mm Hg for Group 1, 2, and 3, respectively; P = .006). Similar rates of neurologic deterioration (14%, 6%, and 6%) and hematoma expansion (16%, 14%, and 18%) were observed among the groups. However, in Group 1, favorable outcome was less frequent (17%, 48%, and 42%; P = .002) and unfavorable outcome was more frequent (24%, 7%, and 6%; P = .013) than in the other groups. After adjustment for confounders, eGFR < 60 mL/minute/m(2) was independently associated with both favorable outcome (odds ratio [OR], .21; 95% CI, .07-.54) and unfavorable outcome (OR, 5.64; 95% CI, 1.80-18.58). CONCLUSIONS Renal dysfunction (eGFR < 60 mL/minute/m(2)) was associated with poor clinical outcome after ICH.