Acute Ischemic Stroke In Japan Research Articles

Regional Disparities in Hyperacute Treatment and Functional Outcomes after Acute Ischemic Stroke in Japan.

This study investigated the impact of rurality on acute ischemic stroke (AIS) outcomes, emphasizing the hyperacute phase, in which immediate care is crucial. This retrospective cohort study analyzed data from a large Japanese hospital network covering AIS patients from 2013-2021, was analyzed. The focus was on patients admitted within 4.5 h of the onset, using the Rurality Index for Japan (RIJ) to categorize patients into rural or urban groups. This study examined treatment methods (intravenous thrombolysis [IVT] and mechanical thrombectomy [MT]) and functional outcomes measured using the modified Rankin Scale (mRS), where scores of 3-6 indicated poor outcomes. Multilevel logistic regression was used to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for poor outcomes based on rurality. The study also evaluated the population-attributable fraction (PAF) to estimate potential outcome improvements in urban settings. Of 27,691 patients, 17,516 were included in the total cohort and 4,954 in the hyperacute cohort. Urban patients constituted 73.7% (12,902), with higher IVT (5.2%) and MT (3.6%) rates than rural patients (4.1% IVT, 2.0% MT). Poor mRS outcomes were more common in rural areas than in urban areas, with adjusted ORs of 1.30 (1.18-1.43) in the total cohort and 1.43 (1.19-1.70) in the hyperacute cohort. The PAF for poor outcomes due to rural residency was 14.8% (0.5%-31.0%). This study demonstrated a notable association between rurality and poorer AIS outcomes in Japan, particularly in the hyperacute phase.

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

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

Japan Trevo Registry: Real-world Registry of Stent Retriever Alone or in Combined Therapy with Aspiration Catheter for Acute Ischemic Stroke in Japan.

Endovascular therapy (EVT) for real-world patients after extended time frames is associated with concerns about its efficacy and safety. We conducted a prospective registry at 77 centers between November 2019 and October 2020. The registry criteria included patients treated with Trevo Retriever alone or in combined therapy with an aspiration catheter. The primary outcome was effective reperfusion (thrombolysis in cerebral infarction grade ≥ 2b), the secondary outcome was a modified Rankin scale 0-2 at 90 days, and the safety outcomes were worsening of neurologic symptoms within 24 h postoperatively, intracranial hemorrhage (ICH) within 24 h after EVT and mortality. We also exlpored the difference between patients whose last known well time (LKWT) to a puncture was less than 6 h (0-6 h) and those whose LKWT was 6 h or more but less than 24 h (6-24 h). Among the 1041 patients registered, 1025 patients were analyzed. The mean age was 76.9 years, and 53.6% of the participants were males. The 6-24 h group was 206/998 (20.6%), the median National Institute of Health Stroke Scale (NIHSS) score at admission was 18, and the median Alberta Stroke Program Early CT score was 8. Combined technique as the first pass was used on 817 (79.7%) patients. The primary outcome was 934 (91.1%). The secondary outcome was 433/1021 (42.4%). Symptomatic ICH, any ICH, and mortality were 10/1019 (1.0%), 311/1019 (30.5%), and 75 (7.3%). In the subanalysis, the 6-24 h group was lower in NIHSS (median;18 vs 16), and the secondary outcome was not significantly different in the <6 h group. Even after treatment time expansion, this result was comparable to other Trevo-based trials and nationwide registries.

Abstract WP191: Post Stroke Dysphagia Prediction Score In Acute Ischemic Stroke In Japan

Background and Purpose: Post stroke dysphagia (PSD) is a common complication after stroke. The earlier prediction of PSD is essential for patient stratification for intensive rehabilitation, but there was no scoring system for predicting PSD. We aimed to develop the PSD prediction score. Methods: We examined consecutive patients with acute ischemic stroke between 2018-2020. Patients with in-hospital-death were excluded. Dysphagia state was assessed using food oral intake scale (FOIS) score at hospital discharge. PSD was defined as FOIS 1-3, which represent tube-dependent nutrition. For the assessment of reproducibility of PSD score, patients were divided into derivation and validation cohort. Using the derivation cohort, PSD score was developed from associated factors to discriminate PSD by logistic regression analysis. Discriminative performance was analyzed by receiver operating curve (ROC) analysis. Reproducibility of PSD score was validated using the validation cohort. Results: Among 795 patients (median 77 years; male, 57%), 556 (70%) patients were assigned as derivation cohort and 239 (30%) patients were assigned as validation cohort. In the derivation cohort, older age (≥85 years), low BMI (≦18.5 kg/m 2 for aged &lt;70 years and ≦ 20 kg/m 2 for aged ≥70 years), high NIHSS score (≥16), and low serum albumin (≦3.0 mg/dl) were associated with PSD (Table). PSD score were ranged from 0 to 6 from these factors (Table). Area under the curve (AUC) of PSD score for PSD was 0.83 (95% confidence interval [CI] 0.78-0.88) with an appropriate cut-off value of 2 (sensitivity, 69%; specificity, 88%). In the validation cohort, the AUC of PSD score for PSD was 0.78 (95% CI 0.70-0.86), which was not significantly different in the AUC of the derivation cohort (AUC; 0.83 vs 0.78, p=0.30). Conclusions: In acute ischemic stroke population, the discriminative performance of PSD score had acceptable for diagnosing PSD.

Edaravone, a scavenger for multiple reactive oxygen species, reacts with singlet oxygen to yield 2-oxo-3-(phenylhydrazono)-butanoic acid.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a synthetic antioxidant used as a drug to treat acute ischemic stroke in Japan and amyotrophic lateral sclerosis in Japan and the USA. Its pharmacological mechanism is thought to be scavenging of reactive oxygen species, which are intimately related with these diseases. Recently, the singlet oxygen (‍1O2) has attracted attention among reactive oxygen species. In this study, we investigated the reactivity of edaravone toward 1O2 and identified its reaction products. Edaravone showed a reactivity toward 1O2 greater than those of uric acid, histidine, and tryptophan, which are believed to be ‍1O2 scavengers in vivo. And we confirmed that 2-oxo-3-(phenylhydrazono)-butanoic acid was formed as an oxidation product. We propose a plausible mechanism for 2-oxo-3-(phenylhydrazono)-butanoic acid production by ‍1O2-induced edaravone oxidation. Since 2-oxo-3-(phenylhydrazono)-butanoic acid has already been identified as a radical-initiated oxidation product, free radical-induced oxidation should be seriously reconsidered. We also found that edaravone can react with not only hypochlorous anions but also ‍1O2 that are formed from myeloperoxidase. This result suggests that edaravone treatment can be beneficial against myeloperoxidase-related injuries such as inflammation.

Regional Disparity of Reperfusion Therapy for Acute Ischemic Stroke in Japan: A Retrospective Analysis of Nationwide Claims Data from 2010 to 2015.

BackgroundWe aimed to determine whether a regional disparity exists in usage of reperfusion therapy (intravenous recombinant tissue plasminogen activator [IV rt‐PA] and endovascular thrombectomy [EVT]) and post‐reperfusion 30‐day mortality in patients with acute ischemic stroke, and which regional factors are associated with their usage.Methods and ResultsWe retrospectively investigated 69 948 patients (mean age±SD, 74.9±12.0 years; women, 41.4%) with acute ischemic stroke treated with reperfusion therapy between April 2010 and March 2016 in Japan using nationwide claims data. Regional disparity was evaluated using Gini coefficients for age‐ and sex‐adjusted usage of reperfusion therapy and 30‐day post‐reperfusion in‐hospital death ratio in 47 administrative regions. The association between regional factors and reperfusion therapy usage was evaluated with fixed‐effects regression models. During the study period, Gini coefficients showed low inequality (0.11–0.15) for use of IV rt‐PA monotherapy and IV rt‐PA and/or EVT and extreme inequality (0.49) for EVT usage in 2010, which became moderate inequality (0.25) by 2015. The densities of stroke centers and endovascular specialists, as well as market concentration, were associated with increased usage of reperfusion therapy whereas the proportion of rural residents and delayed ambulance transport were negatively associated with usage. Inequality in the standardized death ratio after EVT was extreme (0.86) in 2010 but became moderate (0.29) by 2015; inequality was low to moderate (0.17–0.23) for IV rt‐PA monotherapy and IV rt‐PA and/or EVT.ConclusionsScrutinizing existing data sources revealed regional disparity in reperfusion therapy for acute ischemic stroke and its associated regional factors in Japan.

Endovascular therapy for acute stroke-An important role of neurologists

Previous randomized clinical trials have revealed significant benefit of the endovascular thrombectomy for the patients with acute ischemic stroke. In this short communication, I would like to introduce the history of endovascular treatment for acute ischemic stroke in Japan, and give a positive message to the neurologists who might contribute to the treatment for acute ischemic stroke.

Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers

PurposeEdaravone is a free-radical scavenger. Edaravone 30 mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30 mg was developed by a Good Manufacturing Practices–compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development. MethodsThis 2-way crossover study was conducted in 10 healthy male volunteers. Eligible subjects were randomized, in a 1:1 ratio, to 1 of 2 dosing sequences: (1) SL edaravone 30 mg, followed by edaravone 30 mg IV infusion given over 30 minutes; or (2) edaravone 30 mg IV infusion given over 30 minutes, followed by SL edaravone 30 mg. The washout period between the 2 dosing periods was at least 24 hours. Serial blood samples were collected in each dosing period. The bioavailability of the SL tablet was assessed using bioavailability analysis. Tolerability was evaluated throughout the study. FindingsThe plasma concentration–time profile of the SL tablet was similar to that with the IV infusion. A mean (SD) Cmax of 2030.2 (517.2) ng/mL was reached within a median Tmax of 0.875 hour, which was statistically significantly longer than the median Tmax with IV administration (0.5 hour). The Cmax with SL administration corresponded to 83.92% (90% CI, 73.22%–96.18%) of the Cmax with the start of IV infusion (2354.0 [336.6] ng/mL). The mean AUC0–t with SL dosing was 5420.07 (1429.75) h · ng/mL, which corresponded to 91.94% (90% CI, 86.81%–97.39%) of the AUC0–t with IV administration (5824.42 [1338.48] h · ng/mL). Two cases of adverse events were reported during the study; both were considered by the investigator to have been possibly not related to the study treatment. ImplicationsThe bioavailability of the SL tablet of edaravone was 91.94%. Compared with IV administration, Cmax with SL administration was ∼17% lower and Tmax was statistically significantly longer. The exposure differences can be addressed by modifying the strength of the SL tablet, and then conducting a second study to demonstrate the pharmacokinetic bioavailability of the sublingually administered new strength versus IV infusion of edaravone.

Outcome of Acute Ischemic Stroke after the Treatment with Edaravone and 0.6 Mg/Kg Alteplase in Japanese Patients with Diabetes

We investigated how diabetes mellitus (DM) affects the outcome of acute ischemic stroke (AIS), comparing with the outcomes in those who had hypertension (HT) and atrial fibrillation (AF). This study was a sub-analysis of PROTECT4.5, which was previously performed as a large-scale, prospective observational study of edaravone with approximately 10,000 patients with AIS in Japan. The study patients treated with edaravone alone or edaravone + alteplase (recombinant tissue plasminogen activator [tPA]) were analyzed for their outcomes and explored for the risk factors of poor outcome, after being divided into 8 groups according to their affected complications of DM, HT, or AF in the groups treated with edaravone alone or edaravone + tPA. Among patients treated with edaravone alone and edaravone + tPA, the mean reduction in the National Institutes of Health Stroke Scale from baseline to 3 months after the onset was 2.0 and 4.4 in DM groups, respectively. The reduction was smaller in these groups compared with other groups (3.3-4.3 and 6.0-7.7, respectively). The logistic regression model revealed that DM was an independent risk factor for highly unfavorable outcome of modified Rankin Scale score 3-6 at 3 months after the onset, among both patients treated with edaravone alone and those treated with edaravone + tPA (odds ratio [OR]: 2.23, 95% confidential interval [CI]: 1.42-3.50 and OR: 2.05, 95% CI: 1.33-3.14, respectively). DM is suggested to adversely affect the outcome of AIS in Japanese patients.

Stabilizers of edaravone aqueous solution and their action mechanisms. 1. Sodium bisulfite.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has been used as a free radical scavenging drug for the treatment of acute ischemic stroke in Japan since 2001. Edaravone is given to patients intravenously; therefore, it is distributed in the form of an aqueous solution. However, aqueous solutions of edaravone are very unstable because it is present as edaravone anion, which is capable of transferring an electron to free radicals including oxygen, and becomes edaravone radical. We observed the formation of hydrogen peroxide and edaravone trimer when aqueous edaravone solution was kept at 60°C for 4 weeks. We proposed the mechanism of edaravone trimer formation from edaravone radicals. Lowering the pH and deoxygenation can effectively increase the stability of aqueous edaravone solution, since the former reduces edaravone anion concentration and the latter inhibits edaravone radical formation. Addition of sodium bisulfite partially stabilized aqueous edaravone solutions and partially inhibited the formation of edaravone trimer. Formation of bisulfite adduct was suggested by 13C NMR and HPLC studies. Therefore, the stabilizing effect of sodium bisulfite is ascribed to the formation of a bisulfite adduct of edaravone and, consequently, reduction in the concentration of edaravone anion.

The Current Status of Endovascular Thrombectomy for Acute Ischemic Stroke in Japan: Results of a Nationwide Questionnaire Survey in 2016

The Current Status of Endovascular Thrombectomy for Acute Ischemic Stroke in Japan: Results of a Nationwide Questionnaire Survey in 2016

Protective Effect of Edaravone in Primary Cerebellar Granule Neurons against Iodoacetic Acid-Induced Cell Injury.

Edaravone (EDA) is clinically used for treatment of acute ischemic stroke in Japan and China due to its potent free radical-scavenging effect. However, it has yet to be determined whether EDA can attenuate iodoacetic acid- (IAA-) induced neuronal death in vitro. In the present study, we investigated the effect of EDA on damage of IAA-induced primary cerebellar granule neurons (CGNs) and its possible underlying mechanisms. We found that EDA attenuated IAA-induced cell injury in CGNs. Moreover, EDA significantly reduced intracellular reactive oxidative stress production, loss of mitochondrial membrane potential, and caspase 3 activity induced by IAA. Taken together, EDA protected CGNs against IAA-induced neuronal damage, which may be attributed to its antiapoptotic and antioxidative activities.

Edaravone Improves Functional and Structural Outcomes in Animal Models of Focal Cerebral Ischemia: A Systematic Review

Edaravone has been used in patients with acute ischemic stroke in Japan for over 10 years but does not have marketing authorization in Europe or America. Either patients in Europe and America are not receiving an effective treatment, or those in Asia are being given a treatment which is not effective. Finding out which of these is true will require further clinical trials, and a better understanding of its efficacy in animal models may help inform the design of those trials so that it might be tested under conditions where there is the greatest prospect of success. We systematically reviewed the efficacy of edaravone in animal models of focal ischemia and summarized data using weighted mean difference DerSimonian and Laird random-effects modeling. We used stratified meta-analysis and metaregression to assess the influence of study design and methodological quality. We identified 49 experiments describing outcome in 814 animals; 30 experiments (519 animals) reported functional and 35 experiments (503 animals) reported structural outcome. Edaravone improved functional and structural outcome by 30·3% (95% confidence interval 23·4-37·2%) and 25·5% (95% confidence interval, 21·1-29·9%), respectively. For functional outcome, there was an inverse relationship between study quality and effect size (P < 0·0017). Effect sizes were larger in studies where randomization or blinded assessment was not reported. There was no evidence of publication bias. Edaravone is a promising treatment for stroke. However, because of the methodological weakness in current animal studies, no sufficient preclinical evidence is available to optimize the study design of clinical trials. Higher quality animal studies are expected to inform further clinical study.

The Efficacy of Edaravone (Radicut), a Free Radical Scavenger, for Cardiovascular Disease

Edaravone was originally developed as a potent free radical scavenger, and has been widely used to treat acute ischemic stroke in Japan since 2001. Free radicals play an important role in the pathogenesis of a variety of diseases, such as cardiovascular diseases and stroke. Therefore, free radicals may be targets for therapeutic intervention in these diseases. Edaravone shows protective effects on ischemic insults and inflammation in the heart, vessel, and brain in experimental studies. As well as scavenging free radicals, edaravone has anti-apoptotic, anti-necrotic, and anti-cytokine effects in cardiovascular diseases and stroke. Edaravone has preventive effects on myocardial injury following ischemia and reperfusion in patients with acute myocardial infarction. Edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, heart failure, diabetes, or hypertension, because these diseases result from oxidative stress and/or cytokine-induced apoptosis. This review evaluates the potential of edaravone for treatment of cardiovascular disease, and covers clinical and experimental studies conducted between 1984 and 2013. We propose that edaravone, which scavenges free radicals, may offer a novel option for treatment of cardiovascular diseases. However, additional clinical studies are necessary to verify the efficacy of edaravone.

Abstract 195: Reducing Frequency of Symptomatic Intracranial Hemorrhage in Patients With Acute Ischemic Stroke Treated by Recombinant Tissue-Plasminogen Activator; Interim Result of a Prospective Observational Cohort Study

[Introduction] Combination therapy with rt-PA and edaravone, a free radical scavenger, has become a prevalent treatment for acute ischemic stroke in Japan. PROTECT4.5 (Post marketing Registry OnTreatment with Edaravone in acute Cerebral infarction by the Time window of 4.5 hours) is a prospective observational cohort study to evaluate the efficacy and safety of the combination therapy. [Hypothesis] We assessed the hypothesis that combination therapy will reduce frequency of symptomatic intracranial hemorrhage in patients with acute ischemic stroke. [Methods] Patients treated by rt-PA and edaravone within 4.5 hours after onset of ischemic stroke were enrolled. The primary endpoints were proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 3 months after onset, and frequency of symptomatic intracranial hemorrhage (sICH) within 36 hours after initiating treatment. Mortality at 3 months after onset was assessed as a secondary endpoint. [Results] Between Apr 2010 and May 2012, 2814 patients from 839 institutes received combination therapy with edaravone and rt-PA. The mean age was 71.9 years old; 62.2% were male. The median score of NIHSS at baseline was 13 and the median time from onset to treatment with rt-PA was 2.25 hours. The most common type of stroke was cardioembolic (57.7%). Concomitant hypertension was present in 58.3% and diabetes mellitus in 17.1%. Estimated glomerular filtration rate &lt; 60 mL/min/1.73m 2 was observed in 34.2% of patients. The proportion of patients with mRS 0-1 was 38.8% [709/1826, 95%Confidence Interval 36.6-41.1%]. Frequency of sICH and mortality were 1.7%[48/2814, 1.3-2.3%] and 8.9%[162/1826, 7.6-10.3%], respectively. [Conclusions] The severity and the proportion of mRS 0-1 in the patients enrolled in PROTECT4.5 were similar to those in the prospective single-arm open-label trial and the previous observational studies of rt-PA [J-ACT (Stroke 2006; 37:1810-1815), CASES (CMAJ 2005; 172:1307-12), STARS (JAMA 2000; 283:1145-50)], but frequency of sICH and mortality were lower.

Effects of Sex Difference on Clinical Features of Acute Ischemic Stroke in Japan

Sex differences in stroke characteristics and outcomes have been inconsistent. The goal of this study was to determine the influence of sex on underlying patient characteristics, stroke subtypes and conditions, and outcomes after ischemic stroke from a nationwide registration study. A total of 33,953 patients with acute ischemic stroke, including 13,323 women, were registered in a multicenter, hospital-based registration study based on a computerized database from 162 Japanese institutes (the Japan Standard Stroke Registry Study) between January 2000 and November 2007. Women were significantly older than men at stroke onset (75.0 ± 11.7 v 69.3 ± 11.4 years; P < .0001). After age adjustment, women more frequently had cardioembolic events (odds ratio [OR] 1.090; 95% confidence interval [95% CI] 1.036-1.146; P = .0009) and other strokes (OR 1.177; 95% CI 1.079-1.284; P = .0003) and were more hypertensive (OR 1.056; 95% CI 1.006-1.108; P = .0267) and more dyslipidemic (OR 1.301; 95% CI 1.234-1.373; P < .0001) than men. After multivariate adjustment, onset-to-arrival time was longer (β = 0.0554; P = .026), the initial National Institutes of Health Stroke Scale score was higher (β = 0.1565; P < .001), and the duration of hospitalization was longer (β = 0.035; P = .010) in women than in men. At hospital discharge, women less commonly had a modified Rankin Scale (mRS) score of 0 to 1 (OR 0.802; 95% CI 0.741-0.868; P < .0001) and more commonly had a mRS score of 4 to 6 (OR 1.410; 95% CI 1.293-1.537; P < .0001) than men. Women developed more severe strokes than men in Japan. After multivariate adjustment for initial severity and other characteristics, acute care hospital stays were longer and stroke outcomes at discharge were worse in women than in men.

Neuroprotective Effect of an Antioxidant in Ischemic Stroke: Involvement of Neuronal Death Signaling and Blood-brain Barrier Disruption

Cerebral ischemia is a major cause of death and disability worldwide, and treatments for it are limited. A new therapeutic strategy of brain protection after acute stroke targets the neurovascular unit, such as endothelial cells, astrocytes, microglia, and neurons, instead of neurons only (Fig. 1). Edaravone, a novel free radical scavenger, has been used to treat acute ischemic stroke in Japan. We have previously reported the antiedema effect of the combination therapy of edaravone and mild hypothermia at 35C following transient focal cerebral ischemia (tFCI). However, the mechanism of the effect remains unclear. In the present study, we tested the hypothesis that this combination therapy can reduce oxidative stress and the activation of matrix metalloproteinase-9 (MMP-9), which is related to blood-brain barrier (BBB) dysfunction, and brain edema formation after tFCI.

Edaravone: A new therapeutic approach for the treatment of acute stroke

Acute stroke, including acute ischemic stroke (AIS) and acute hemorrhagic stroke, (AHS) is a common medical problem with particular relevance to the demographic changes in industrialized societies. In recent years, treatments for AIS have emerged, including thrombolysis with tissue plasminogen activator (t-PA). Although t-PA is the most effective currently available therapy, it is limited by a narrow therapeutic time window and side effects, and only 3% of all AIS patients receive thrombolysis. Edaravone was originally developed as a potent free radical scavenger and, since 2001, has been widely used to treat AIS in Japan. It was shown that edaravone extended the narrow therapeutic time window of t-PA in rats. The therapeutic time window is very important for the treatment of AIS, and early edaravone treatment is more effective. Thus, more AIS patients might be rescued by administering edaravone with t-PA. Meanwhile, edaravone attenuates AHS-induced brain edema, neurologic deficits and oxidative injury in rats. Although edaravone treatment is currently only indicated for AIS, it does offer neuroprotective effects against AHS in rats. Therefore, we hypothesize that early administration of edaravone can rescue AHS patients as well as AIS patients. Taken together, our findings suggest that edaravone should be immediately administered on suspicion of acute stroke, including AIS and AHS.

Effect of Edaravone on the Estimated Glomerular Filtration Rate in Patients With Acute Ischemic Stroke and Chronic Kidney Disease

The oxygen free radical scavenger edaravone is used in patients with acute ischemic stroke in Japan, but adverse reactions, especially decreased renal function, have raised concerns. To examine whether a patient's estimated glomerular filtration rate (eGFR) at admission can predict renal function deterioration after edaravone treatment, we retrospectively evaluated the effect of edaravone on eGFR in Japanese patients with acute ischemic stroke and chronic kidney disease (CKD). The baseline eGFR in the edaravone-treated group (73.5±20.3 mL/min/1.73 m(2); n=408) at admission was significantly (P < .05) higher than that in the non-edaravone-treated group (51.9±25.2 mL/min/1.73 m(2); n=41). The change in eGFR after treatment was categorized into 3 grades: nonexacerbation (≤10%), 10%-30% exacerbation, and >30% exacerbation. There was no significant difference in exacerbation grade between the edaravone-treated and non-edaravone-treated groups (χ(2) =3.134; P=.21). We next subdivided the edaravone-treated group according to eGFR at admission as either CKD (eGFR <60 mL/min/1.73 m(2); n=111) and non-CKD (n=297). No significant decrease in eGFR was seen even in the edaravone-treated CKD group (most of whom were in stage 3 CKD). Decreased eGFR in stroke patients was found to be associated with stroke subtype (cardiogenic stroke), but not with infection. The present study demonstrates that eGFR at admission is not a good predictor of renal deterioration in edavarone-treated acute ischemic stroke patients, including those with stage 3 CKD.

Rt-PA intravenous treatment for acute ischemic stroke in Japan —Role of The Committee for Improvement of Stroke Therapy of The Japan Stroke Society—

我が国における脳梗塞rt-PA静注療法の保険適用承認には，承認への要望の段階から日本脳卒中学会の医療向上委員会が緊密に関与してきた．適正使用講習会を実施することを前提として承認された後も，欧米諸国にも前例のない全国的な都道府県レベルでの適正使用講習会を実施し，rt-PA静注療法の実施担当者等を指導してきた．承認後3年間で講習会は189回，受講者は1万人を超え，結果として，約1万5千例の使用例のうち，非適応例への使用頻度は6% 程度に抑えられている．承認と講習会開催の過程と，3年を経過した時点での普及の現状を記載した．