Fukuoka Stroke Registry Research Articles

Registry Studies of Stroke in Japan.

Recently, the Cerebrovascular and Cardiovascular Disease Control Act was enacted, for which it was necessary to establish a comprehensive and accurate nationwide database and promote rational and economical stroke countermeasures in Japan, thus serving the public interest. Among the many studies on stroke registries, the Fukuoka Stroke Registry, a regional cohort, provides highly accurate information, and the Japanese Stroke Data Bank, a nationwide cohort, is highly comprehensive. The findings of these studies have contributed to the construction of evidence and the establishment of guidelines for stroke management. In the Nationwide survey of Acute Stroke care capacity for Proper dEsignation of Comprehensive stroke CenTer in Japan, research on improving the quality of medical care to close the gap between guidelines and clinical practice was performed using electronic medical records. This has enabled the recommendation of medical policies in Japan by visualizing medical care. In the era of healthcare big data and the Internet of Things, plenty of healthcare information is automatically recorded electronically and incorporated into databases. Thus, the establishment of stroke registries with the effective utilization of these electronic records can contribute to the development of stroke care.

Sex Differences in Long-Term Functional Decline after Ischemic Stroke: A Longitudinal Observational Study from the Fukuoka Stroke Registry

Introduction: Data on sex differences in poststroke functional status for a period longer than 1 year based on large cohorts are sparse. This study aimed to determine whether there are sex differences in long-term functional decline after ischemic stroke. Methods: We tracked functional status for 5 years among 3-month survivors of acute ischemic stroke and compared outcomes between women and men using a large-scale hospital-based stroke registry in Fukuoka, Japan. Functional status was assessed using the modified Rankin Scale (mRS). Functional dependency was defined as an mRS score of 3, 4, or 5. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals of outcomes after adjusting for possible confounders. Results: A total of 8,446 patients (71.9 ± 12.5 years, 3,377 (40.0%) female patients) were enrolled in this study. Female sex was associated with a higher risk of functional dependency at 5 years poststroke even when adjusting for age, 3-month mRS score, and other confounding factors (multivariable-adjusted OR vs. men, 1.56 [95% confidence interval, 1.26–1.93]). This significant association of female sex with higher dependency at 5 years was also found among patients who were independent at 3 months poststroke. Subgroup analysis showed that increased risk of functional dependency in female patients was more marked in patients aged ≥75 years than in those aged <75 years (p for heterogeneity = 0.02). Conversely, female sex was associated with a lower risk of death. No sex difference was observed in stroke recurrence during 5 years poststroke. Discussion/Conclusion: This longitudinal observational study suggests that female sex was independently associated with an increased risk of functional decline in the chronic phase of stroke, especially in older patients. There was no sex difference in 5-year stroke recurrence, and thus, other factors might be involved in more significant deterioration of functional status in female survivors of ischemic stroke. Further studies are needed to elucidate underlying causes of sex differences in long-term functional decline after stroke.

Pre-Stroke Cholinesterase Inhibitor Treatment Is Beneficially Associated with Functional Outcome in Patients with Acute Ischemic Stroke and Pre-Stroke Dementia: The Fukuoka Stroke Registry

Introduction: Pre-stroke dementia is significantly associated with poor stroke outcome. Cholinesterase inhibitors (ChEIs) might reduce the risk of stroke in patients with dementia. However, the association between pre-stroke ChEI treatment and stroke outcome remains unresolved. Therefore, we aimed to determine this association in patients with acute ischemic stroke and pre-stroke dementia. Methods: We enrolled 805 patients with pre-stroke dementia among 13,167 with ischemic stroke within 7 days of onset who were registered in the Fukuoka Stroke Registry between June 2007 and May 2019 and were independent in basic activities of daily living (ADLs) before admission. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale [mRS] score: 3–6) at 3 months after stroke onset and neurological deterioration (≥2-point increase in the NIH Stroke Scale [NIHSS] during hospitalization), respectively. Logistic regression analysis was used to evaluate associations between pre-stroke ChEI treatment and study outcomes. To improve covariate imbalance, we further conducted a propensity score (PS)-matched cohort study. Results: Among the participants, 212 (26.3%) had pre-stroke ChEI treatment. Treatment was negatively associated with poor functional outcome (odds ratio: 0.68 [95% confidence interval: 0.46–0.99]) and neurological deterioration (0.52 [0.31–0.88]) after adjusting for potential confounding factors. In the PS-matched cohort study, the same trends were observed between pre-stroke ChEI treatment and poor functional outcome (0.61 [0.40–0.92]) and between the treatment and neurological deterioration (0.47 [0.25–0.86]). Conclusions: Our findings suggest that pre-stroke ChEI treatment is associated with reduced risks for poor functional outcome and neurological deterioration after acute ischemic stroke in patients with pre-stroke dementia who are independent in basic ADLs before the onset of stroke.

Anticoagulation and Risk of Stroke Recurrence in Patients with Embolic Stroke of Undetermined Source Having No Potential Source of Embolism

Background: This study aimed to determine whether use of oral anticoagulants (OACs) was associated with a reduced risk of recurrent stroke compared with use of antiplatelets (APs) in patients with embolic stroke of undetermined source (ESUS) having no potential source of embolism. Methods: Of 8,790 patients with acute ischemic stroke registered at 7 centers in the Fukuoka Stroke Registry from June 2007 to May 2017, we included 681 patients (mean age 69.7 [SD 14.1] years, 48.3% men) who experienced ESUS without a potential source of embolism and received OAC alone or AP alone. We estimated hazard ratios (HRs) and 95% confidential intervals (CIs) of recurrent ischemic stroke or any stroke after discharge using a Cox proportional hazards model and Fine and Gray model. Results: During a mean follow-up of 3.4 (SD 1.7) years, event rates of recurrent ischemic stroke were 4.4 per 100 person-years in 489 patients treated with AP and 2.0 per 100 person-years in 192 patients treated with OAC. OAC use was associated with a reduced risk of recurrent ischemic stroke, even after adjusting for potential confounding factors (multivariable-adjusted HR [95% CI], 0.42 [0.23–0.80]) and when additionally considering death as a competing risk (0.45 [0.24–0.85]). The reduced risk of recurrent ischemic stroke was still observed in patients treated with OAC (0.32 [0.15–0.67]) in reference to propensity score-matched patients treated with AP. These associations were maintained for all types of stroke, including ischemic and hemorrhagic stroke. Conclusions: This nonrandomized observational study suggests that anticoagulation therapy might be associated with a reduced risk of recurrent stroke compared with antiplatelet therapy in patients with ESUS in whom no potential source of embolism was identified. Further study should be performed in consideration of a potential source of embolism even in patients with ESUS.

Association of Embolic Sources With Cause-Specific Functional Outcomes Among Adults With Cryptogenic Stroke

It is unknown whether poststroke outcome varies between different potential causes in patients with cryptogenic stroke. To investigate whether functional outcome differs according to potential embolic sources after cryptogenic stroke. This multicenter, hospital-based, prospective stroke registry cohort study investigated potential embolic sources on admission and assessed 3-month outcome in patients with ischemic stroke hospitalized at 7 stroke centers in the Fukuoka Stroke Registry. This registry enlisted 9866 consecutive patients with acute ischemic stroke who were enrolled from June 11, 2007, to May 31, 2016, in Fukuoka, Japan. Patients with small vessel occlusion (n = 3130), extracranial and intracranial atherosclerosis causing at least 50% luminal stenosis in arteries supplying the area of ischemia (n = 2011), and other specific uncommon causes of stroke identified (n = 301) were excluded. Potential embolic sources were diagnosed in patients with embolic stroke of undetermined source (ESUS) based on the following criteria proposed by the Cryptogenic Stroke/ESUS International Working Group: minor-risk potential cardioembolic sources (MCS) (n = 209), covert paroxysmal atrial fibrillation (CPAF) (n = 43), cancer associated (CA) (n = 79), arteriogenic emboli (AE) (n = 522), paradoxical embolism (PE) (n = 190), and undetermined embolism (unidentified or ≥2 potential embolic sources) (UE) (n = 1120). The association between potential causes and functional outcome was evaluated in reference to cardioembolic stroke (CE) caused by major-risk cardioembolic sources after adjusting for age, sex, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy using logistic regression analysis. Functional dependency (modified Rankin Scale score, 3-5) was evaluated at 3 months after onset. The study enrolled 2261 patients with CE (mean [SD] age, 78.4 [10.7] years, 51.8% male) and 2163 patients with ESUS (mean [SD] age, 72.4 [12.6] years, 57.1% male). Compared with CE (median National Institutes of Health Stroke Scale score, 8 [interquartile range {IQR}, 3-17]), baseline neurological deficits did not differ in MCS (median, 7 [IQR, 2-18]), CPAF (median, 6 [IQR, 2-18]), and CA (median, 5 [IQR, 2-13]) but were less severe in AE (median, 2 [IQR, 1-4]), PE (median, 2 [IQR, 1-4]), and UE (median, 3 [IQR, 1-7]). Multivariable-adjusted odds ratios of functional dependency significantly increased in CA (3.61; 95% CI, 1.52-8.54 vs CE) but decreased in PE (0.33; 95% CI, 0.16-0.71 vs CE). Potential causes are associated with poststroke outcome in patients with cryptogenic stroke. Embolic sources potentially underlying cryptogenic stroke should be considered significant variables associated with outcome.

Safety of antithrombotic therapy for patients with acute ischemic stroke harboring unruptured intracranial aneurysm.

Background The safety of antithrombotic therapy for patients with acute ischemic stroke harboring unruptured intracranial aneurysms remains unclear. Aims This study was performed to determine whether treatment with antiplatelets, anticoagulants, or intravenous thrombolytic agents is safe for patients with acute ischemic stroke and unruptured intracranial aneurysms. Methods Among 9149 patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to December 2014, 8857 patients with data on cerebrovascular imaging and three-month outcomes were included in this study. The frequency of adverse events, including intracranial hemorrhage, symptomatic intracranial hemorrhage, and in-hospital mortality, was compared between patients with and without unruptured intracranial aneurysms. The risk of a poor functional outcome (modified Rankin scale score of ≥3) at three months after stroke onset was estimated after adjusting for confounding factors by logistic regression analysis. Results Unruptured intracranial aneurysms were identified in 412 (4.7%) patients, and the mean diameter was 4.1 ± 3.2 mm. There was no significant difference in the frequency of any adverse events between patients with and without unruptured intracranial aneurysms among the overall patients or patients receiving antiplatelets, anticoagulants, or intravenous thrombolytic agents. The odds ratios of a poor functional outcome were not significantly higher in the presence of unruptured intracranial aneurysms, even in patients undergoing antiplatelet therapy, anticoagulation therapy, or intravenous thrombolysis. Conclusions These findings suggest that unruptured intracranial aneurysms are not associated with increased risks of adverse events or poor functional outcomes even after antithrombotic therapy for acute ischemic stroke. However, accumulation of cases is required to verify these findings.

Abstract TP75: Prognosis in Mild or Rapidly Improving Ischemic Stroke Not Treated With Recombinant Tissue Plasminogen Activator: Fukuoka Stroke Registry

Background and Aims: Recombinant tissue plasminogen activator (rt-PA) is often withheld for mild or rapidly improving acute ischemic stroke. The aim of this study is to determine risk factors for poor outcomes in such cases. Method: This study included 772 consecutive acute ischemic stroke patients from the Fukuoka Stroke Registry who did not receive rt-PA therapy because of mild or rapidly improving symptoms. Logistic regression analysis was performed to determine the predictors of poor outcomes (modified Rankin Scale 3-6 at 3 months after onset). Results: Eighty-six patients (11.1%) showed a poor outcome. Compared to patients with a good outcome (n=686), those with a poor outcome were older (78±10 vs. 68±13 years, p&lt;0.0001) and had higher initial NIH Stroke Scale (quartile value 3-4 vs. 1-2, p&lt;0.0001). A poor outcome was more frequent among patients with chronic kidney disease (10.4% vs. 4.8%, p=0.0293), atrial fibrillation (24.4% vs. 15.0%, p=0.0252), cortical symptoms (20.9% vs. 8.6%, p=0.0003), limb paralysis (34.8% vs. 23.3%, p=0.0190), and branch atheromatous disease (15.1% vs. 3.6%, p&lt;0.0001). In multivariate analysis, age (every 1 year, odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10, p&lt;0.0001), chronic kidney disease (OR 1.78, 95% CI 1.11-2.83, p=0.0151), cortical symptoms (OR 2.27, 95% CI 1.19-4.21, p=0.0125), and limb paralysis (OR 1.67, 95% CI 1.04-2.66, p=0.0312) were positively associated with a poor outcome. Conclusion: In patients with older age, chronic kidney disease, cortical symptoms, or limb paralysis, rt-PA administration should be considered even for mild or rapidly improving stroke.

Thrombolytic therapy for acute ischemic stroke following intracranial artery dissection: Fukuoka stroke registry

Background: The use of thrombolytic therapy for acute ischemic stroke caused by intracranial artery dissection (IAD) remains controversial.

Abstract TP253: A Novel Prehospital Scale to Predict Candidates for Acute Stroke Thrombectomy : The Fukuoka Acute Stroke ThrombEctomy pRediction (FASTER) Scale

Background: We aimed to design a prehospital scale to predict candidates for endovascular thrombectomy (CET) in patients with acute ischemic stroke (AIS). Materials and methods: In the Fukuoka Stroke Registry, we identified 3,470 patients with AIS who were transferred by emergency medical service within 24 hours of stroke onset and underwent intracranial vessel evaluation on admission from September 2007 to December 2015. CET were defined as patients with causative occlusion of internal carotid artery, middle cerebral artery, or basilar artery, and National Institute of Health Stroke Scale (NIHSS) score ≥ 6. The Fukuoka Acute Stroke ThrombEctomy pRediction (FASTER) scale was developed with NIHSS items based on the predictive importance derived from random forest analysis to predict CET. The discriminative performance was compared with other published scales for large vessel occlusion. Results: The FASTER scale was designed comprising of 4 NIHSS items : one point each was given for extinction and inattention (NIHSS subscore ≥ 1), best gaze (≥ 1), best language (≥ 1), and motor arm (≥ 2). Receiver operator curves demonstrated that the area under the curve of the FASTER scale was significantly larger than that of the Cincinnati Prehospital Stroke Severity Scale (0.907 vs 0.881, p&lt;0.001), and not significantly different from that of the Rapid Arterial oCclusion Evaluation scale (vs 0.910, p= 0.68). The FASTER scale score ≥2 showed sensitivity of 88.4%, specificity 82.3%, positive predictive value 51.3%, and negative predictive value 97.1% for detecting CET. Conclusion: The FASTER scale is a simple and promising tool that can identify CET in the prehospital setting.

Adverse Influence of Pre-Stroke Dementia on Short-Term Functional Outcomes in Patients with Acute Ischemic Stroke: The Fukuoka Stroke Registry

Background: Dementia and stroke are major causes of disability in the elderly. However, the association between pre-stroke dementia and functional outcome after stoke remains unresolved. We aimed to determine this association in patients with acute ischemic stroke. Methods: Among patients registered in the Fukuoka Stroke Registry from June 2007 to May 2015, 4,237 patients with ischemic stroke within 24 h of onset, who were functionally independent before the onset, were enrolled in this study. Pre-stroke dementia was defined as any type of dementia that was present prior to the index stroke. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale 3-6) at 3 months after the stroke onset and neurological deterioration (≥2-point increases on the National Institutes of Health Stroke Scale score during hospitalization), respectively. For propensity score (PS)-matched cohort study to control confounding variables for pre-stroke dementia, 318 pairs of patients with and without pre-stroke dementia were also selected on the basis of 1:1 matching. Multivariable logistic regression models and conditional logistic regression analysis were used to quantify associations between pre-stroke dementia and study outcomes. Results: Of all 4,237 participants, 347 (8.2%) had pre-stroke dementia. The frequencies of neurological deterioration and poor functional outcome were significantly higher in patients with pre-stroke dementia than in those without pre-stroke dementia (neurological deterioration, 16.1 vs. 7.1%, p < 0.01; poor functional outcome, 63.7 vs. 27.1%, p < 0.01). Multivariable analysis showed that pre-stroke dementia was significantly associated with neurological deterioration (OR 1.67; 95% CI 1.14-2.41; p < 0.01) and poor functional outcome (OR 2.91; 95% CI 2.17-3.91; p < 0.01). In the PS-matched cohort study, the same trends were observed between the pre-stroke dementia and neurological deterioration (OR 2.60; 95% CI 1.17-5.78; p < 0.01) and between the dementia and poor functional outcome (OR 3.62; 95% CI 1.89-6.95; p < 0.01). Conclusions: Pre-stroke dementia was significantly associated with higher risks for poor functional outcome at 3 months after stroke onset as well as for neurological deterioration during hospitalization in patients with acute ischemic stroke.

Influence of Statin Pretreatment on Initial Neurological Severity and Short-Term Functional Outcome in Acute Ischemic Stroke Patients: The Fukuoka Stroke Registry

Background: Statins have neuroprotective effects against ischemic stroke. However, associations between pre-stroke statin treatment and initial stroke severity and between the treatment and functional outcome remain controversial. This study aimed at determining these associations in ischemic stroke patients. Methods: Among patients registered in the Fukuoka Stroke Registry from June 2007 to October 2014, 3,848 patients with ischemic stroke within 24 h of onset, who had been functionally independent before onset, were enrolled in this study. Ischemic stroke was classified as cardioembolic or non-cardioembolic infarction. Primary and secondary study outcomes were mild neurological symptoms defined as a National Institutes of Health Stroke Scale score of ≤4 on admission and favorable functional outcome defined as a modified Rankin Scale score of ≤2 at discharge, respectively. Multivariable logistic regression models were used to quantify associations between pre-stroke statin treatment and study outcomes. Results: Of all 3,848 participants, 697 (18.1%) were taking statins prior to the stroke. The frequency of mild neurological symptoms was significantly higher in patients with pre-stroke statin treatment (64.1%) than in those without the treatment (58.3%, p < 0.01). Multivariable analysis showed that pre-stroke statin treatment was significantly associated with mild neurological symptoms (OR 1.31; 95% CI 1.04-1.65; p < 0.01). Sensitivity analysis in patients with dyslipidemia (n = 1,998) also showed the same trend between pre-stroke statin treatment and mild neurological symptoms (multivariable-adjusted OR 1.26; 95% CI 0.99-1.62; p = 0.06). In contrast, the frequency of favorable functional outcome was not different between patients with (67.0%) and without (65.3%) the treatment (p = 0.40). Multivariable analysis also showed no significant association between pre-stroke statin treatment and favorable functional outcome (OR 1.21; 95% CI 0.91-1.60; p = 0.19). Continuation of statin treatment, however, was significantly associated with favorable functional outcome among patients with pre-stroke statin treatment (multivariable-adjusted OR 2.17; 95% CI 1.16-4.00; p = 0.02). Conclusions: Pre-stroke statin treatment in ischemic stroke patients was significantly associated with mild neurological symptoms within 24 h of onset. Pre-stroke statin treatment per se did not significantly influence the short-term functional outcome; however, continuation of statin treatment during the acute stage of stroke seems to relate with favorable functional outcome for patients with pre-stroke statin treatment.

Causes of Ischemic Stroke in Patients with Non-Valvular Atrial Fibrillation

Background: Oral anticoagulants (OACs) reduce the incidence of embolic events associated with non-valvular atrial fibrillation (NVAF); however, ischemic stroke can still occur in such patients. Although there are various causes of ischemic stroke in patients with NVAF, their medication status at onset has scarcely been studied. This retrospective study aimed to determine the underlying causes of ischemic stroke in patients with NVAF in relation to pre-stroke anticoagulation. Methods: Among Japanese patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to May 2013, 1,302 patients with NVAF who had been hospitalized within 24 h of onset were included in this study, and their backgrounds, pre-stroke use of OACs and prothrombin time-international normalized ratio (PT-INR) on admission were investigated. Strokes were regarded as being non-cardioembolic (CE) type when causes other than NVAF had been identified. The sub-therapeutic range (TR) for warfarin was defined according to Japanese guidelines for pharmacotherapy of atrial fibrillation. Results: Atrial fibrillation had been diagnosed prior to onset of stroke in 704 of 1,302 patients (54%). However, it had not been detected before or on admission, but identified later during hospitalization in 270 patients (21%). Of the patients who had atrial fibrillation on admission but had not been diagnosed as having it, 108 (8%) had not received any medication before onset of stroke and 220 (17%) had received medications other than OACs. OACs had been administered to 415 (59%) of the patients with known atrial fibrillation. The proportion of pre-stroke CHADS₂ or CHA₂DS₂-VASc scores ≥1 ranged from 93 to 99% depending on whether atrial fibrillation had been diagnosed or anticoagulation therapy administered before stroke onset. The PT-INR was in the sub-TR on admission in 283 of 399 patients (71%) receiving warfarin. Male sex, smoking and previous stroke were more prevalent in patients with values within or over the TR of PT-INR than in those in the sub-TR. Non-CE stroke was more prevalent in patients with values above the lower therapeutic limit of the recommended PT-INR than in those in the sub-TR (p < 0.001). The number of CE strokes was much smaller in patients with high admission PT-INR values; this was not observed for non-CE ischemic strokes (p < 0.001). Conclusions: In the clinical setting, under-diagnosis, underuse and sub-therapeutic doses of OACs are major causes of ischemic stroke in patients with NVAF. However, non-CE ischemic strokes may develop in patients receiving therapeutic doses of warfarin.

Abstract TP207: Pre-stroke Dementia is Associated With Poor Functional Outcome After Acute Ischemic Stroke: The Fukuoka Stroke Registry

Introduction: With an aging population, an increased number of acute stroke patients with pre-stroke dementia is expected. Although both stroke and dementia are major cause of disability, the effect of pre-stroke dementia on functional outcome after stroke has been still on debate. Hypothesis: Pre-stroke dementia is associated with poor functional outcome after acute ischemic stroke. Methods: Of 9198 stroke patients registered in the Fukuoka Stroke Registry in Japan from June 2007 to May 2014, 3843 patients with first-ever ischemic stroke within 24h of onset, who had been functionally independent before the onset, were enrolled in this study (cardioembolism [n=926], large artery atherosclerosis [n=583], small vessel occlusion [n=1045], others [n=1289]). Pre-stroke dementia was defined as any type of dementia that was present prior to the stroke. For propensity score (PS)-matched analysis, 320 pairs of patients with and without pre-stroke dementia were also selected. Study outcome was poor functional outcome (modified Rankin Scale 3-6) at discharge. Results: In the total cohort, 330 (8.6%) had pre-stroke dementia. The age (80±8 vs 69±13, year, mean±SD, p&lt;0.01), frequencies of female (46 vs 36, %, p&lt;0.01) and cardioembolism (41 vs 23, %, p&lt;0.01), and NIHSS score on admission (6 [3 - 12] vs 3 [1 - 6], median [interquartile], p&lt;0.01) were higher in patients with pre-stroke dementia than those without the dementia. Poor functional outcome (62 vs 25, %, p&lt;0.01) were more prevalent in patients with pre-stroke dementia than those without the dementia. Multivariable-adjusted analysis showed that pre-stroke dementia was significantly associated with increased risk for poor functional outcome (OR 2.3, 95% CI 1.7-3.2). There were no interactions between pre-stroke dementia and 4 variables (age, sex, stroke subtype, and initial stroke severity [NIHSS≤7 or NIHSS≥8]). In the PS-matched analysis, pre-stroke dementia was still associated with poor functional outcome (OR 4.3, 95%CI 2.1-8.8). Conclusions: Pre-stroke dementia was significantly associated with poor functional outcome at discharge in patients with acute ischemic stroke.

CKD 患者における脳梗塞の特徴

高齢化が進むわが国において，慢性腎臓病（chronic kidney disease: CKD）を合併した脳梗塞患者は今後も増加することが見込まれる．登録研究（Fukuoka Stroke Registry）を用いた解析では，CKDを合併した脳梗塞患者では，高齢，貧血，凝固亢進，炎症などの特徴が見られ，臨床病型では心原性脳塞栓が多かった．また，CKD 合併患者では脳梗塞発症後の機能予後および生命予後は不良であった．CKD は種々の病態を介して脳梗塞後の予後に関連していると考えられる．我々が過去に行った検討では，CKD 患者における蛋白尿は脳梗塞後の予後予測因子の可能性が示唆されており，その機序について考察する．

バイオマーカー探索研究REBIOS による脳梗塞病態解明の試み

我々は脳卒中コホート研究（Fukuoka Stroke Registry; FSR）のサブスタディーとして脳梗塞のバイオマーカー探索研究（Research for Biomarkers in Ischemic Stroke; REBIOS）を行っている．これまでの解析の結果，脳梗塞の病態に関連するバイオマーカーとして有用な複数のタンパク質を発見している．さらに，動物実験や培養細胞を用いた基礎研究によって，REBIOS で発見されたバイオマーカーの機能を解析することで脳梗塞の病態解明につながる知見を得ている．脳梗塞のバイオマーカーの探索は基礎研究を組み合わせることで脳梗塞の病態解明と新規治療法の確立につながる可能性がある．

Day-by-Day Blood Pressure Variability and Functional Outcome After Acute Ischemic Stroke: Fukuoka Stroke Registry.

The relationship between blood pressure (BP) variability and functional outcome in patients with acute ischemic stroke remains unclear. This study aimed to elucidate whether in-hospital day-by-day BP variability is associated with functional outcome after acute ischemic stroke. Using the Fukuoka Stroke Registry, we included 2566 patients with a first-ever ischemic stroke who had been functionally independent before the onset and were hospitalized within 24 hours. BP was measured daily, and its variability was assessed by SD, coefficients of variance, and variations independent of mean. Poor functional outcome was assessed by modified Rankin Scale scores ≥3 at 3 months. After adjustment for multiple confounding factors including age, sex, risk factors, stroke features, baseline severity, thrombolytic therapy, antihypertensive agents, and mean BP, day-by-day BP variability during the subacute stage (4-10 days after onset) was independently associated with a poor functional outcome (multivariable-adjusted odds ratios [95% confidence interval] in the top versus bottom quartile of systolic BP variability, 1.51 [1.09-2.08] for SD; 1.63 [1.20-2.22] for coefficients of variance; 1.64 [1.21-2.24] for variations independent of mean). Similar trends were also observed for diastolic BP variability. These trends were unchanged in patients who were not treated with antihypertensive drugs. In contrast, no association was found between indices of BP variability during the acute stage and functional outcome after adjusting for potential confounders. These data suggest that intraindividual day-by-day BP variability during the subacute stage is associated with the 3-month functional outcome after acute ischemic stroke.

Sex differences in short-term outcomes after acute ischemic stroke: the fukuoka stroke registry.

Variable sex differences in clinical outcomes after stroke have been reported worldwide. This study aimed to elucidate whether sex is an independent risk factor of poor functional outcome after acute ischemic stroke. Using the database of patients with acute stroke registered in the Fukuoka Stroke Registry in Japan from 1999 to 2013, 6236 previously independent patients with first-ever ischemic stroke who were admitted within 24 hours of onset were included in this study. Baseline characteristics were assessed on admission. Study outcomes included neurological improvement, neurological deterioration, and poor functional outcome (modified Rankin Scale score, 3-6 at discharge). Logistic regression analyses were performed to evaluate the association between sex and clinical outcomes. Overall, 2398 patients (38.5%) were women. Severe stroke (National Institutes of Health Stroke Scale score, ≥8) on admission was more prevalent in women than in men. The frequency of neurological improvement or deterioration during hospitalization was not different between the sexes. After adjusting for possible confounders, including age, stroke subtype and severity, risk factors, and poststroke treatments, it was found that female sex was independently associated with poor functional outcome at discharge (odds ratio, 1.30; 95% confidence interval, 1.08-1.57). There was heterogeneity of the association between sex and poor outcome according to age: women had higher risk of poor outcome than men among patients aged ≥70 years, but no clear sex difference was found in patients aged <70 years. Female sex was associated with the risk of poor functional outcome at discharge after acute ischemic stroke.

Intravenous thrombolysis with recombinant tissue plasminogen activator for ischemic stroke patients over 80 years old: the Fukuoka Stroke Registry.

ObjectivesThe benefit of intravenous recombinant tissue plasminogen activator (rt-PA) therapy for very old patients with acute ischemic stroke remains unclear. The aim of this study was to elucidate the efficacy and safety of intravenous rt-PA therapy for patients over 80 years old.MethodsOf 13,521 stroke patients registered in the Fukuoka Stroke Registry in Japan from June 1999 to February 2013, 953 ischemic stroke patients who were over 80 years old, hospitalized within 3 h of onset, and not treated with endovascular therapy were included in this study. Among them, 153 patients were treated with intravenous rt-PA (0.6 mg/kg). For propensity score (PS)-matched case-control analysis, 148 patients treated with rt-PA and 148 PS-matched patients without rt-PA therapy were selected by 1∶1 matching with propensity for using rt-PA. Clinical outcomes were neurological improvement, good functional outcome at discharge, in-hospital mortality, and hemorrhagic complications (any intracranial hemorrhage [ICH], symptomatic ICH, and gastrointestinal bleeding).ResultsIn the full cohort of 953 patients, rt-PA use was associated positively with neurological improvement and good functional outcome, and negatively with in-hospital mortality after adjustment for multiple confounding factors. In PS-matched case-control analysis, patients treated with rt-PA were still at lower risk for unfavorable clinical outcomes than non-treated patients (neurological improvement, odds ratio 2.67, 95% confidence interval 1.61–4.40; good functional outcome, odds ratio 2.23, 95% confidence interval 1.16–4.29; in-hospital mortality, odds ratio 0.30, 95% confidence interval 0.13–0.65). There was no significant association between rt-PA use and risk of hemorrhagic complications in the full and PS-matched cohorts.ConclusionsIntravenous rt-PA therapy was associated with improved clinical outcomes without significant increase in risk of hemorrhagic complications in very old patients (aged>80 years) with acute ischemic stroke.

Gastrointestinal Bleeding in Acute Ischemic Stroke: Recent Trends from the Fukuoka Stroke Registry

Background: Gastrointestinal (GI) hemorrhage is a potentially serious complication of acute stroke, but its incidence appears to be decreasing. The aim of this study was to elucidate the etiology of GI bleeding and its impact on clinical outcomes in patients with acute ischemic stroke in recent years. Methods: Using the database of the Fukuoka Stroke Registry, 6,529 patients with acute ischemic stroke registered between June 2007 and December 2012 were included in this study. We recorded clinical data including any previous history of peptic ulcer, prestroke drug history including the use of antiplatelets, anticoagulants, steroids and nonsteroidal anti-inflammatory drugs (NSAIDs), and poststroke treatment with suppressing gastric acidity. GI bleeding was defined as any episode of hematemesis or melena on admission or during hospitalization. The cause and origin of bleeding were diagnosed endoscopically. Logistic regression analysis was used to identify risk factors for GI bleeding and its influence on deteriorating neurologic function, death, and poor outcome. Results: GI bleeding occurred in 89 patients (1.4%) under the condition that 66% of the total patients received acid-suppressing agents after admission. Multivariate analysis revealed that GI bleeding was associated with the absence of dyslipidemia (p = 0.03), a previous history of peptic ulcer (p < 0.001), and the severity of baseline neurologic deficit (p = 0.002) but not with antiplatelet drugs, anticoagulants, and NSAIDs. The source was the upper GI tract in 51% of the cases; causes included peptic ulceration (28%) and malignancies (12%), and other or unidentified causes accounted for 60%. GI bleeding mostly occurred within 1 week after stroke onset. Hemoglobin concentration fell by a median value of 2.5 g/dl in patients with GI bleeding. Among them, 28 patients underwent blood transfusion (31.5%). After adjustment for confounding factors, GI bleeding was independently associated with neurologic deterioration (OR 3.9, 95% CI 2.3-6.6, p < 0.001), in-hospital death (OR 6.1, 95% CI 3.1-12.1, p < 0.001), and poor outcome at 3 months (OR 6.8, 95% CI 3.7-12.7, p < 0.001). These associations were significant irrespective of whether patients underwent red blood cell transfusion. Conclusions: GI bleeding infrequently occurred in patients with acute ischemic stroke, which was mostly due to etiologies other than peptic ulcer. GI bleeding was associated with poor clinical outcomes including neurologic deterioration, in-hospital mortality, and poor functional outcome.

Impact of the 1425G/A Polymorphism of PRKCH on the Recurrence of Ischemic Stroke: Fukuoka Stroke Registry

Epidemiologic studies have elucidated that the 1425G/A single-nucleotide polymorphism (rs2230500 single-nucleotide polymorphism) in exon 9 of the protein kinase C eta (PRKCH) gene is an independent risk factor for ischemic stroke: stroke incidence is significantly higher in the subjects with AA than those with AG or GG genotype. However, its impact on stroke recurrence remains unknown. The aim of the present study was to clarify whether the polymorphism is also a risk factor for recurrent stroke in patients with acute ischemic stroke. We enrolled 2418 consecutive patients with acute and first-ever ischemic stroke and investigated the 1425G/A polymorphism of PRKCH. Patients were followed up for a median of 733 days. The association between the polymorphism and stroke recurrence was investigated using the Cox proportional hazard model. In the enrolled patients, the GG genotype was the most prevalent (63%), followed by AG (32%) and AA genotypes (5%). Recurrent stroke occurred in 302 patients during the follow-up period. Kaplan-Meier analyses revealed no difference in the rate of recurrent stroke after first-ever stroke among the 3 genotypes. The incidence of recurrent stroke was not significantly different in patients with AA (hazard ratio [HR] 1.02, 95% confidence interval .59-1.64, P=.94) or AG (HR .89, 95% confidence interval .69-1.14, P=.36) genotypes compared with those with the GG genotype after adjusting for multiple confounders. The 1425G/A polymorphism in PRKCH is not a significant predictor of stroke recurrence in patients with acute ischemic stroke during a 2-year follow-up period.