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Background and Purpose Nelonemdaz (Neu2000) has both selective antagonism against 2B subunit of N-methyl-D-aspartate receptor and antioxidant activity. This drug provides sufficient evidence of neuroprotection in acute cerebral ischemia/reperfusion models. This phase III trial aims to determine this effect in patients.Design The Rescue on Reperfusion Damage in Cerebral Infarction by Nelonemdaz is a multicenter, double-blinded clinical trial. A total of 496 patients will be randomly assigned into the nelonemdaz (a total of 5,250 mg divided by 10 times for 5 days) and placebo groups. Patients will be included if they have an acute ischemic stroke (National Institutes of Health Stroke Scale score ≥8) caused by intracranial large vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score ≥4), and if they are expected to undergo endovascular thrombectomy within 12 hours after stroke onset.Endpoints The primary endpoint is a favorable shift in the modified Rankin Scale (mRS) score at 90 days after the first dose of drug. The data will be analyzed by the Cochran–Mantel–Haenszel shift test. The secondary endpoints include functional independence (mRS 0–2) at 35 and 90 days, the favorable shift of mRS at 35 days, the proportion of mRS 0 at 35 and 90 days, and the occurrence rates of symptomatic intracranial hemorrhage within 7 days.Conclusion This trial will clarify the efficacy and safety of nelonemdaz in patients with acute ischemic stroke and endovascular thrombectomy. This study has been registered at ClinicalTrials. gov (NCT05041010).

Heritability of stroke is assumed not to be low, especially in the young-age stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population.We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGV) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next-generation sequencing panel.Among 1,033 patients, 131 (12.7%) had 28 CRGV, most frequently in RNF213 (n=59), followed by ABCC6 (n=53) and NOTCH3 (n=15). The frequency of CRGV differed by ischemic stroke subtypes (p0.01)-highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51-55 years (17.1% vs. 9.3%, p=0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUS) were found in 15.4% patients.CRGV in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGV did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGV or VUS should be explored. This article is protected by copyright. All rights reserved.

Background: We aimed to evaluate covert brain infarction (CBI), frequently encountered during the diagnostic work-up of acute ischemic stroke, as a risk factor for stroke recurrence in patients with atrial fibrillation (AF). Methods: For this prospective cohort study, from patients with acute ischemic stroke hospitalized at 14 centers between 2017 and 2019, we enrolled AF patients without history of stroke or transient ischemic attack and divided them into the CBI (+) and CBI (−) groups. The 2 groups were compared regarding the 1-year cumulative incidence of recurrent ischemic stroke and all-cause mortality using the Fine and Gray subdistribution hazard model with nonstroke death as a competing risk and the Cox frailty model, respectively. Each CBI lesion was also categorized into either embolic-appearing (EA) or non-EA pattern CBI. Adjusted hazard ratios and 95% CIs of any CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were estimated. Results: Among 1383 first-ever stroke patients with AF, 578 patients (41.8%) had CBI. Of these 578 with CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were 61.8% (n=357), 21.8% (n=126), and 16.4% (n=95), respectively. The estimated 1-year cumulative incidence of recurrent ischemic stroke was 5.2% and 1.9% in the CBI (+) and CBI (−) groups, respectively ( P =0.001 by Gray test). CBI increased the risk of recurrent ischemic stroke (adjusted hazard ratio [95% CI], 2.91 [1.44–5.88]) but did not the risk of all-cause mortality (1.32 [0.97–1.80]). The EA pattern CBI only and both CBIs elevated the risk of recurrent ischemic stroke (2.76 [1.32–5.77] and 5.39 [2.25–12.91], respectively), while the non-EA pattern only did not (1.44 [0.40–5.16]). Conclusions: Our study suggests that AF patients with CBI might have increased risk of recurrent stroke. CBI could be considered when estimating the stroke risk in patients with AF.

Background: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy. Methods: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy Results: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P =0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92–2.60) between the placebo and low-dose groups and 1.61 (0.94–2.76) between the placebo and high-dose groups. No serious adverse events were reported. Conclusions: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0–2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT02831088.

BackgroundThere is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke (AIS). This study investigated whether advances in these treatments improved outcomes in this population.MethodsUsing a prospective multicenter stroke registry in Korea, young adults (aged 18–50 years) with AIS hospitalized between 2008 and 2019 were identified. The observation period was divided into four epochs: 2008–2010, 2011–2013, 2014–2016, and 2017–2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed.ResultsA total of 7,050 eligible patients (mean age 43.1; men 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (Ptrend=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008–2010 to 2017–2019 (9.5% to 13.8% and 3.2% to 9.2%, respectively; Ptrend’strendtrend’strend=0.04), but was not significant after adjusting for warfarin use.ConclusionImprovements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with AIS over the past decade, indicating a need for further improvement.

Background and Purpose Oral anticoagulants are needed in stroke patients with atrial fibrillation (AF) for the prevention of recurrent stroke. However, the risk of major events or bleeding may be greater in stroke patients than in those without, because the presence of cerebral atherosclerosis or small vessel disease may increase these risks. This study aimed to investigate the outcomes of apixaban-treated stroke patients with AF and assess whether these factors are associated with the outcome.Methods This was a sub-analysis of stroke patients with AF enrolled in a prospective, open-label, multicenter, post-marketing surveillance study in South Korea, who were treated with apixaban and underwent magnetic resonance imaging (MRI) (Clinical trial registration: NCT01885598).Results A total of 651 patients (mean age, 72.5±8.7 years) received apixaban for a mean duration of 82.7±37.4 weeks. Fifty-three bleeding events occurred in 39 patients (6.0%), and 10 (1.5%) experienced major bleeding. Seventeen patients (2.6%) had major events (stroke, n=15, 2.3%; all ischemic), systemic embolism (n=1, 0.2%), and death (n=3, 0.5%). MRI data showed no significant association between white matter ischemic changes and microbleeds, and major events or bleeding. Patients with cerebral atherosclerotic lesions had a higher rate of major events than those without (4.6% [n=10/219] vs. 1.7% [n=7/409], P=0.0357), which partly explains the increased prevalence of major outcomes in this group versus patients without stroke (0.7%, P=0.0002).Conclusions Apixaban is generally safe for patients with ischemic stroke. Increased primary outcomes in stroke patients may in part be attributed to the presence of cerebral atherosclerotic lesions, suggesting that further studies are needed to establish therapeutic strategies in this population.

Background and ObjectivesWe evaluated the association between admission glycated hemoglobin (HbA1c) and subsequent risk of composite vascular events, including stroke, myocardial infarction (MI), and vascular death, in patients with acute ischemic stroke and diabetes.MethodsPatients who had a TIA or an acute ischemic stroke within 7 days of symptom onset and diabetes were included in a retrospective cohort design using the stroke registry of the Clinical Research Center for Stroke in Korea. The association between admission HbA1c and composite vascular events, including stroke, MI, and vascular death, during 1-year follow-up was estimated using the Fine-Gray model. The risk of composite vascular events according to the ischemic stroke subtype was explored using fractional polynomial and linear-quadratic models.ResultsOf the 18,567 patients, 1,437 developed composite vascular events during follow-up. In multivariable analysis using HbA1c as a categorical variable, the risk significantly increased at a threshold of 6.8%–7.0%. The influence of admission HbA1c level on the risk of composite vascular events was pronounced particularly among those in whom fasting glucose at admission was ≤130 mg/dL. The optimal ranges of HbA1c associated with minimal risks for composite vascular events were lowest for the small vessel occlusion subtype (6.6 [95% confidence internal [CI], 6.3–6.9]) compared to the large artery atherosclerosis (7.3 [95% CI, 6.8–7.9]) or the cardioembolic subtype (7.4 [95% CI, 6.3–8.5]).DicussionIn patients with ischemic stroke and diabetes, the risks of composite vascular events were significantly associated with admission HbA1c. The optimal range of admission HbA1c was below 6.8%–7.0% and differed according to the ischemic stroke subtype.

BackgroundNo study has thoroughly compared the effectiveness of combined antiplatelet treatments (other than clopidogrel–aspirin) versus clopidogrel–aspirin or aspirin alone for early secondary prevention in acute ischaemic stroke.MethodsWe identified patients with acute, minor, non-cardiogenic ischaemic stroke treated with aspirin alone, clopidogrel–aspirin or other combination treatment. Propensity scores considering the inverse probability of treatment weighting were used to adjust for baseline imbalances. The primary outcome was the composite of all strokes (ischaemic or haemorrhagic), myocardial infarction and all-cause mortality at 3 months.ResultsAmong 12 234 patients (male: 61.9%; age: 65.5±13 years) who met the eligibility criteria, aspirin, clopidogrel–aspirin and other combination treatments were administered in 52.2%, 42.9% and 4.9% of patients, respectively. In the crude analysis, the primary outcome event at 3 months occurred in 14.5% of the other combination group, 14.4% of the aspirin group and 13.0% of the clopidogrel–aspirin group. In the weighted Cox proportional hazards analysis, the 3-month primary outcome event occurred less frequently in the clopidogrel–aspirin group than in the other combination group (weighted HR: 0.82 (0.59–1.13)), while no association was found between the aspirin group (weighted HR: 1.04 (0.76–1.44)) or other combination group and the 3-month primary outcome.ConclusionOther combined antiplatelet treatment, compared with aspirin alone or clopidogrel–aspirin, was not associated with reduced risks of primary composite vascular events or recurrent stroke during the first 3 months after stroke. Therefore, the results suggest that other combination treatments, particularly the cilostazol-based combination, may not be effective alternatives for clopidogrel–aspirin to prevent early vascular events in patients with acute minor stroke. Further exploration in clinical trials will be needed.

This study aimed to elucidate whether low-density lipoprotein cholesterol (LDL-C) levels differentially affect functional outcomes after intravenous thrombolysis (IVT) depending on prestroke statin use. Patients with acute ischemic stroke treated with IVT were categorized into low, intermediate, and high LDL-C groups based on LDL-C levels at admission ( 130 mg/dl, respectively). Multivariable logistic regression analyses were performed to explore the relationships between LDL-C and clinical outcomes (good outcomes at 3 months, modified Rankin Scale scores 0–2). The interaction between LDL-C levels and prestroke statin use regarding functional outcomes was investigated. Among the 4711 patients (age, 67 ± 12 years; males, 62.1%) who met the eligibility criteria, compared with the high LDL-C group, the low and intermediate LDL-C groups were not associated with good outcomes at 3 months according to the multivariable analysis. A potential interaction between the LDL-C group and prestroke statin use on good outcomes at 3 months was observed (Pinteraction = 0.07). Among patients with prestroke statin use, low (aOR 1.84 [1.04–3.26]) and intermediate (aOR 2.31 [1.20–4.47]) LDL-C groups were independently associated with a greater likelihood of having a 3-month good outcome. Our study showed that LDL-C was not associated with a 3-month good outcome, but prestroke statin use could modify the influence of LDL-C levels on functional outcomes after IVT.

The frequency, management, and outcomes of early neurologic deterioration (END) after ischemic stroke specifically due to stroke progression or stroke recurrence have not been well delineated.In a multicenter, nationwide registry, data on END due to stroke progression or recurrence confirmed by imaging were collected prospectively between January 2019 and July 2020. Patient characteristics, management strategies, and clinical outcomes were analyzed.Among 14,828 consecutive ischemic stroke patients, 1717 (11.6%) experienced END, including 1221 (8.2%) with END due to stroke progression (SP) or stroke recurrence (SR). Active management after END was implemented in 64.2% of patients. Active management strategies included volume expansion (29.2%), change in antithrombotic regimen (26.1%), induced hypertension (8.6%), rescue reperfusion therapy (6.8%), intracranial pressure lowering with hyperosmolar agents (1.5%), bypass surgery (0.6%), and hypothermia (0.1%). Active management strategies that varied with patient features included volume expansion and induced hypertension, used more often in large artery atherosclerosis and small vessel occlusion, and rescue endovascular thrombectomy, more common in other (dissection), cardioembolism, and large artery atherosclerosis. Active management was associated with higher rates of freedom from disability (modified Rankin Scale, mRS, 0-1; 24.3% vs. 16.6%) and functional independence (mRS, 0-2; 41.6% vs. 27.7%) at 3 months.END specifically due to stroke progression or recurrence occurs in 1 in 12 acute ischemic stroke patients. In this observational study, active management, undertaken in two-thirds of patients, was most often hemodynamic or antithrombotic and was associated with improved functional outcomes.

The expected growth of stroke burden in Korea in early 2000s led to the initiation of a government-funded clinical research project with the goal of development and implementation of national stroke guidelines. The CRCS-K (Clinical Research Collaboration for Stroke in Korea) began as a part of this project. For stroke epidemiology and quality of care research, the CRCS-K developed a multicenter, prospective, stroke registry and began collection of data in 2008. Now, about 100 000 cases have been registered at 17 university hospitals or regional stroke centers and about 200 articles have been published based on the registry experience. The analysis of the 10-year secular trends showed overall improvement of stroke care and outcomes and areas for improvement. This large-scale, high-quality dataset provides opportunities to explore and compare treatment disparities using the comparative effectiveness research methods, design and conduct a registry-based randomized clinical trial, connect the registry data with other data sources including the national claims data and neuroimaging or genetic data, and collaborate with other international researchers. An international stroke registry consortium may be a viable future direction.

comTransient splenial lesion of the corpus callosum can be observed in various diseases such as cancer, drug use, metabolic disorders, and cerebrovascular disorders, as well as in patients with infectious diseases. During the coronavirus disease 2019 (COVID-19) pandemic, there were increasing reports of these lesions being detected on brain imaging tests performed in patients with neurological symptoms. On brain magnetic resonance imaging, findings suggestive of cytotoxic edema are observed in the splenium; these are known to disappear with improvement of clinical symptoms. Cytokinopathy caused by infection increases the permeability of the blood–brain barrier and activates the glial cells of the brain to induce cytotoxic edema. Most patients have a good prognosis. The causes, mechanism, diagnosis, treatment and prognosis of transient splenial lesions of the corpus callosum will be summarized in this review.

Rationale: The optimal duration of dual antiplatelet therapy (DAPT) with clopidogrel-aspirin for the large artery atherosclerotic (LAA) stroke subtype has been debated. Aims: To determine whether the 1-year risk of recurrent vascular events could be reduced by a longer duration of DAPT in patients with the LAA stroke subtype. Methods and study design: A total of 4806 participants will be recruited to detect a statistically significant relative risk reduction of 22% with 80% power and a two-sided alpha error of 0.05, including a 10% loss to follow-up. This is a registry-based, multicenter, prospective, randomized, open-label, blinded end point study designed to evaluate the efficacy and safety of a 12-month duration of DAPT compared with a 3-month duration of DAPT in the LAA stroke subtype. Patients will be randomized (1:1) to either DAPT for 12 months or DAPT for 3 months, followed by monotherapy (either aspirin or clopidogrel) for the remaining 9 months. Study outcomes: The primary efficacy outcome of the study is a composite of stroke (ischemic or hemorrhagic), myocardial infarction, and all-cause mortality for 1 year after the index stroke. The secondary efficacy outcomes are (1) stroke, (2) ischemic stroke or transient ischemic attack, (3) hemorrhagic stroke, and (4) all-cause mortality. The primary safety outcome is major bleeding. Discussion: This study will help stroke physicians determine the appropriate duration of dual therapy with clopidogrel-aspirin for patients with the LAA stroke subtype. Trial registration: URL: https://cris.nih.go.kr/cris . CRIS Registration Number: KCT0004407

Background and purposeThere is much uncertainty in endovascular treatment (EVT) decisions in patients with acute large vessel occlusion (LVO) and mild neurological deficits.MethodsFrom a prospective, nationwide stroke registry, all patients with LVO and baseline NIHSS ResultsAmong 1,083 patients, 149 (14%) patients received EVT after a median of 5.9 [3.6–12.3] h after LKW. In propensity score-matched analyses, EVT was not associated with mRS 0-1 (matched OR 0.99 [0.63–1.54]) but increased the risk of a significant hemorrhage (matched OR, 4.51 [1.59–12.80]). Extraneous END occurred in 207 (19%) patients after a median of 24.5 h [IQR, 13.5–41.9 h] after LKW (incidence rate, 1.41 [95% CI, 1.23–1.62] per 100 person-hours). END unrelated to EVT showed a tendency to modify the effectiveness of EVT (P-for-interaction, 0.08), which decreased the odds of having mRS 0–1 in mild LVO patients without END (adjusted OR, 0.63 [0.40–0.99]).ConclusionsThe use of EVT in patients with acute LVO and low NIHSS scores may require the assessment of individual risks of early deterioration, hemorrhagic complications and expected benefit.

Background Previous literature about the effect of heart rate on poststroke outcomes is limited. We attempted to elucidate (1) whether heart rate during the acute period of ischemic stroke predicts subsequent major clinical events, (2) which heart rate parameter is best for prediction, and (3) what is the estimated heart rate cutoff point for the primary outcome. Methods and Results Eight thousand thirty‐one patients with acute ischemic stroke who were hospitalized within 48 hours of onset were analyzed retrospectively. Heart rates between the 4th and 7th day after onset were collected and heart rate parameters including mean, time‐weighted average, maximum, and minimum heart rate were evaluated. The primary outcome was the composite of recurrent stroke, myocardial infarction, and mortality up to 1 year after stroke onset. All heart rate parameters were associated with the primary outcome ( P ’s Conclusions These findings suggest that heart rate during the acute period of ischemic stroke is a predictor of major clinical events, and optimal heart rate control might be a target for preventing subsequent cardiovascular events.

Background: Stroke of other determined etiology (OE) includes patients with an uncommon cause of stroke. We described the general characteristics, management, and outcomes of stroke in OE and its subgroups. Methods: This study is a retrospective analysis of a prospective, multicenter, nationwide registry, the Clinical Research Center for Stroke-Korea-National Institutes of Health registry. We classified OE strokes into 10 subgroups according to the literature and their properties. Each OE subgroup was compared according to clinical characteristics, sex, age strata, lesion locations, and management. Moreover, 1-year composites of stroke and all-cause mortality were investigated according to the OE subgroups. Results: In total, 2119 patients with ischemic stroke with OE types (mean age, 55.6±16.2 years; male, 58%) were analyzed. In the Clinical Research Center for Stroke-Korea-National Institutes of Health registry, patients with OE accounted for 2.8% of all patients with stroke. The most common subtypes were arterial dissection (39.1%), cancer-related coagulopathy (17.3%), and intrinsic diseases of the arterial wall (16.7%). Overall, strokes of OE were more common in men than in women (58% versus 42%). Arterial dissection, intrinsic diseases of the arterial wall and stroke associated with migraine and drugs were more likely to occur at a young age, while disorders of platelets and the hemostatic system, cancer-related coagulopathy, infectious diseases, and hypoperfusion syndromes were more frequent at an old age. The composite of stroke and all-cause mortality within 1 year most frequently occurred in cancer-related coagulopathy, with an event rate of 71.8%, but least frequently occurred in stroke associated with migraine and drugs and arterial dissection, with event rates of 0% and 7.2%, respectively. Conclusions: This study presents the different characteristics, demographic findings, lesion locations, and outcomes of OE and its subtypes. It is characterized by a high proportion of arterial dissection, high mortality risk in cancer-related coagulopathy and an increasing annual frequency of cancer-related coagulopathy in patients with stroke of OE.

BackgroundPrehospital delay is an important contributor to poor outcomes in both acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We aimed to compare the prehospital delay and related factors between AIS and AMI.Methods and ResultsWe identified patients with AIS and AMI who were admitted to the 11 Korean Regional Cardiocerebrovascular Centers via the emergency room between July 2016 and December 2018. Delayed arrival was defined as a prehospital delay of >3 hours, and the generalized linear mixed‐effects model was applied to explore the effects of potential predictors on delayed arrival. This study included 17 895 and 8322 patients with AIS and AMI, respectively. The median value of prehospital delay was 6.05 hours in AIS and 3.00 hours in AMI. The use of emergency medical services was the key determinant of delayed arrival in both groups. Previous history, 1‐person household, weekday presentation, and interhospital transfer had higher odds of delayed arrival in both groups. Age and sex had no or minimal effects on delayed arrival in AIS; however, age and female sex were associated with higher odds of delayed arrival in AMI. More severe symptoms had lower odds of delayed arrival in AIS, whereas no significant effect was observed in AMI. Off‐hour presentation had higher and prehospital awareness had lower odds of delayed arrival; however, the magnitude of their effects differed quantitatively between AIS and AMI.ConclusionsThe effects of some nonmodifiable and modifiable factors on prehospital delay differed between AIS and AMI. A differentiated strategy might be required to reduce prehospital delay.

Background: Optimal antithrombotic regimens to prevent recurrent stroke in patients with ischemic stroke due to atrial fibrillation (AF) and atherosclerotic large-vessel stenosis remain unknown. Aims: This study aimed to evaluate the effect of multiple antithrombotic therapies on outcomes at 1 year after ischemic stroke due to two or more causes. Methods: We identified 862 patients with ischemic stroke due to AF and large artery atherosclerosis from the linked data. These patients were categorized into three groups according to antithrombotic therapies at discharge: (1) antiplatelets, (2) oral anticoagulants (OAC), and (3) antiplatelets plus OAC. The study outcomes were recurrent ischemic stroke, composite outcomes for cardiovascular events, and major bleeding after 1 year. Inverse probability of treatment weighting (IPTW) was used to balance the three groups using propensity scores. Results: Among 862 patients, 169 (19.6%) were treated with antiplatelets, 405 (47.0%) were treated with OAC, and 288 (33.4%) were treated with antiplatelets and OAC. After applying IPTW, only OAC had a significant beneficial effect on the 1-year composite outcome (hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.23–0.60, p Conclusion: This study demonstrated that OAC monotherapy was associated with lower risks of composite outcome and death in patients at 1 year after ischemic stroke due to AF and atherosclerotic stenosis. In addition, the combination of an antiplatelet and OAC had a high risk of major bleeding.

Background and purpose Obstructive sleep apnea (OSA) is a modifiable risk factor for stroke, but there are limited data on which stroke subtypes are associated with OSA. The aim of this study was to assess the risk for wake-up stroke (WUS) associated with OSA according to each etiologic subtype to elucidate the pathophysiologic mechanism of OSA-associated stroke. Method We investigated 557 consecutive patients who were admitted with acute ischemic stroke in two regional comprehensive stroke centers using a standardized protocol including the Berlin questionnaire to identify symptoms of OSA prior to stroke. The collected stroke data included the time of onset, risk factors, and etiologic subtype. Stratified analysis according to sex was conducted because sex has been reported to be an effect modifier of OSA on cardiovascular outcomes. The association between preexisting OSA symptoms and WUS depending on etiologic subtypes was assessed using multivariate logistic regression analysis. Results Preexisting OSA symptoms were associated with the risk of overall WUS in men. Snoring was associated with WUS in large artery atherosclerosis [adjusted odds ratio, 2.67 (1.15–6.23)], and apnea was associated with WUS in small vessel occlusion [adjusted odds ratio, 8.21 (1.15–58.53)], whereas OSA symptoms were not significantly associated with WUS in cardioembolism. Associations between OSA and WUS were not found in women. Conclusion This study demonstrated the differential influences of OSA on WUS depending on etiologic subtypes, suggesting more vulnerability in large artery atherosclerosis and small vessel occlusion. Sex is a significant effect modifier of the association between OSA and WUS.

Background Stroke is an important cause of maternal morbidity and mortality during pregnancy and puerperium. Isolated amnesia is a rare clinical symptom caused by ischemic stroke during pregnancy. We present the first documented case of acute amnesia during pregnancy due to bilateral fornix infarction. Case summary A 32-year-old nullipara presented at 35 wk of gestation with acute amnesia and headache. Brain magnetic resonance imaging and angiography revealed acute infarction in the bilateral anterior fornix. There was no evidence of causative abnormality after extensive work-up, including for vascular abnormality, cardiac disease, coagulopathy, and pregnancy-related conditions. The patient was diagnosed with cryptogenic stroke. Aspirin was administered immediately, and the patient recovered fully without recurrence. Conclusion Acute isolated amnesia due to stroke is rare during pregnancy. Early diagnosis of stroke and immediate treatment prevent neurologic sequelae.

Background Although the effect of blood pressure on poststroke outcome is well recognized, the long‐term trajectory of blood pressure after acute ischemic stroke and its influence on outcomes have not been studied well. Methods and Results We analyzed systolic blood pressure (SBP) measurements in 5514 patients with acute ischemic stroke at ≥2 of 7 prespecified time points during the first year after stroke among those enrolled in a multicenter prospective registry. Longitudinal SBPs were categorized using a group‐based trajectory model. The primary outcome was a composite of stroke recurrence, myocardial infarction, and all‐cause mortality up to 1 year after stroke. The study subjects were categorized into 4 SBP trajectory groups: low (27.0%), moderate (59.5%), persistently high (1.2%), and slowly dropping (12.4%). In the first 3 groups, SBP decreased during the first 3 to 7 days and remained steady thereafter. In the slowly dropping SBP group , SBPs decreased from 182 to 135 mm Hg during the first 30 days, then paralleled the trajectory of the moderate SBP group . Compared with the reference, the moderate SBP group , the slowly dropping SBP group was at higher risk for the primary outcome (adjusted hazard ratio [HR], 1.32; 95% CI, 1.05‒1.65) and mortality (adjusted HR, 1.35; 95% CI, 1.03‒1.78). Primary outcome rates were similarly high in the persistently high SBP group . Conclusions Four 1‐year longitudinal SBP trajectories were identified in patients with acute ischemic stroke. Patients in the slowly dropping SBP and persistently high SBP trajectory groups were prone to adverse cardiovascular outcomes after stroke.

Purpose: The usefulness of the existing risk stratification tools for atrial fibrillation (AF) is limited in predicting stroke recurrence in patients with acute ischemic stroke (AIS). Neuroimaging parameters obtained from diagnostic work-up of AIS could offer more elaborate prediction. Methods: A multicenter prospective cohort of AIS patients with AF recruited from 14 university hospitals or regional stroke centers were followed up for recurrent ischemic stroke (RIS) and a composite of all stroke and TIA. Neuroimaging features were derived from acute and chronic infarction patterns, and SVD markers such as lacunes, CMBs, and WMH. Cumulative incidences according to each neuroimaging parameter were estimated and compared using the Kaplan-Meier method with log-rank test and multivariable cause-specific hazard models with death as a competing risk. Results: A total of 2,270 patients were followed up for 431 days (IQR, 365-735), during which 111 RISs and 130 composite outcomes occurred. In unadjusted analysis, lesion multiplicity among acute infarction patterns, the presence of chronic non-lacunar infarction, and the presence of lacunes among SVD markers increased the risk of RIS significantly (Table). Other neuroimaging features such as territory multiplicity and location, confluency, topography, and size of acute lesions, lesion multiplicity, territory multiplicity, confluency, topography, and size of chronic infarction, number of lacunes, presence of CMBs, and WMH did not affect the incidence of RIS. The adjusted hazard ratios of lesion multiplicity of acute infarction, chronic infarction and lacunes were 1.45 (95% CI, 0.99-2.11), 1.57 (1.06-2.34) and 1.97 (1.30-2.98) for RIS, respectively. Similar findings were obtained for the composite outcome. Conclusions: Several neuroimaging markers were associated with recurrent ischemic stroke in AIS with AF. This could pave the way to a new stratification scheme for AF including neuroimaging parameters.

There has been no comparison of the determinants of admission route between acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We examined whether factors associated with direct versus transferred-in admission to regional cardiocerebrovascular centers (RCVCs) differed between AIS and AMI.Using a nationwide RCVC registry, we identified consecutive patients presenting with AMI and AIS between July 2016 and December 2018. We explored factors associated with direct admission to RCVCs in patients with AIS and AMI and examined whether those associations differed between AIS and AMI, including interaction terms between each factor and disease type in multivariable models. To explore the influence of emergency medical service (EMS) paramedics on hospital selection, stratified analyses according to use of EMS were also performed.Among the 17,897 and 8,927 AIS and AMI patients, 66.6% and 48.2% were directly admitted to RCVCs, respectively. Multivariable analysis showed that previous coronary heart disease, prehospital awareness, higher education level, and EMS use increased the odds of direct admission to RCVCs, but the odds ratio (OR) was different between AIS and AMI (for the first 3 factors, AMIAIS; for EMS use, AMIAIS). EMS use was the single most important factor for both AIS and AMI (OR, 4.72 vs. 3.90). Hypertension and hyperlipidemia increased, while living alone decreased the odds of direct admission only in AMI; additionally, age (65-74 years), previous stroke, and presentation during non-working hours increased the odds only in AIS. EMS use weakened the associations between direct admission and most factors in both AIS and AMI.Various patient factors were differentially associated with direct admission to RCVCs between AIS and AMI. Public education for symptom awareness and use of EMS is essential in optimizing the transportation and hospitalization of patients with AMI and AIS.

ObjectiveTo improve epidemiologic knowledge of neurologic deterioration (ND) in patients with acute ischemic stroke (AIS).MethodsIn this prospective observational study, we captured ND prospectively in 29,446 patients with AIS admitted to 15 hospitals in Korea within 7 days of stroke onset. ND was defined as an increase in NIH Stroke Scale (NIHSS) score ≥2 (total), or ≥1 (motor or consciousness), or any new neurologic symptoms. Change in incidence rate after stroke onset, causes, factors associated with ND, modified Rankin Scale (mRS) score at 3 months and 1 year, and a composite of stroke, myocardial infarction, and all-cause death at 1 year were assessed.ResultsND occurred in 4,299 (14.6%) patients. The highest rate, 6.95 per 1,000 person-hours incidence, was within the first 6 hours, which decreased to 2.09 within 24–48 hours, and 0.66 within 72–96 hours after stroke onset. Old age, female sex, diabetes, early arrival, large artery atherosclerosis as a stroke subtype, high NIHSS scores, glucose level, systolic blood pressure, leukocytosis at admission, recanalization therapy, TIA without a relevant lesion, and steno-occlusion of relevant arteries were associated with ND. The causes were stroke progression (71.8%) followed by recurrence (8.5%). Adjusted relative risks (95% CI) for poor outcome (mRS 3–6) at 3 months and 1 year were 1.75 (1.70–1.80) and 1.70 (1.65–1.75), respectively. The adjusted hazard ratio (95% CI) for the composite event was 1.59 (1.45–1.74).ConclusionsND should be taken into consideration as a factor that may influence the outcome in acute ischemic stroke.

ObjectiveStroke is a devastating and costly disease; however, there is a paucity of information on long-term costs and on how they differ according to 3-month modified Rankin scale (mRS) score, which is a primary outcome variable in acute stroke intervention trials.MethodsWe analyzed a prospective multicenter stroke registry (Clinical Research Collaboration for Stroke in Korea) database through linkage with claims data from the National Health Insurance Service with follow-up to December 2016. Healthcare expenditures were converted into daily cost individually, and annual and cumulative costs up to 5 years were estimated and compared according to the 3-month mRS score.ResultsBetween January 2011 and November 2013, 11,136 patients were enrolled in the study. The mean age was 68 years, and 58% were men. The median follow-up period was 3.9 years (range 0–5 years). Mean cumulative cost over 5 years was $117,576 (US dollars [USD]); the cost in the first year after stroke was the highest ($38,152 USD), which increased markedly from the cost a year before stroke ($8,718 USD). The mean 5-year cumulative costs differed significantly according to the 3-month mRS score (p < 0.001); the costs for a 3-month mRS score of 0 or 5 were $53,578 and $257,486 USD, respectively. Three-month mRS score was an independent determinant of long-term costs after stroke.ConclusionsWe show that 3-month mRS score plays an important role in the prediction of long-term costs after stroke. Such estimates relating to 3-month mRS categories may be valuable when undertaking health economic evaluations related to stroke care.

Background and Purpose— There is a paucity of information about the role of resting heart rate in the prediction of outcome events in patients with ischemic stroke with atrial fibrillation. We aimed to investigate the relationships between the level and variability of heart rate in the acute stroke period and stroke recurrence and mortality after acute ischemic stroke in patients with atrial fibrillation. Methods— Acute patients with ischemic stroke who had atrial fibrillation and were hospitalized within 48 hours of stroke onset were identified from a multicenter prospective stroke registry database. The acute stroke period was divided into early (within 24 hours of hospitalization) and late (72 hours to 7 days from onset) stages, and data on heart rate in both stages were collected. Moreover, the level and variability of heart rate were assessed using mean values and coefficients of variation. Outcome events were prospectively monitored up to 1 year after the index stroke. Results— Among 2046 patients eligible for the early acute stage analysis, 102 (5.0%) had a stroke recurrence, and 440 (21.5%) died during the first year after stroke. A statistically significant nonlinear J-shaped association was observed between mean heart rate and mortality ( P P >0.1 for quadratic and overall effect). The nonlinear and overall effects of the coefficients of variation of heart rate were not significant for all outcome variables. The same results were observed in the late acute stage analysis (n=1576). Conclusions— In patients with atrial fibrillation hospitalized for acute ischemic stroke, the mean heart rate during the acute stroke period was not associated with stroke recurrence but was associated with mortality (nonlinear, J-shaped association). The relationships between heart rate and outcomes were not observed with respect to heart rate variability.

Background and Purpose— This study aimed to compare the effectiveness of dual antiplatelet therapy with clopidogrel plus aspirin (DAPT) with that of aspirin monotherapy (AM) in patients with acute, nonminor, and noncardioembolic stroke. Methods— Using a prospective, nationwide, multicenter stroke registry database, acute (within 24 hours of onset), nonminor (baseline National Institutes of Health Stroke Scale score, 4–15), and noncardioembolic stroke patients were identified. Propensity scores using inverse probability of treatment weighting were used to adjust baseline imbalances between the DAPT and AM groups. A primary outcome measure was a composite of all types of stroke (ischemic and hemorrhagic), myocardial infarction, and all-cause mortality within 3 months of stroke onset. Results— Among the 4461 patients meeting the eligibility criteria (age, 69±13 years; men, 57.7%), 52.5% (n=2340) received AM, and 47.5% (n=2121) received DAPT. The primary outcome event was not significantly different between the DAPT group and the AM group (20.9% versus 22.6%, P =0.13). The event rates of all types of stroke were also not different between the 2 groups (19.3% versus 20.1%, P =0.35), while all-cause mortality was significantly lower in the DAPT group than in the AM group (3.4% versus 4.9%, P =0.02). In the propensity-weighted Cox proportional hazards models with robust estimation, DAPT did not reduce the risk of the primary outcome event (hazards ratio, 0.91; 95% CI, 0.79–1.04) but did reduce the risk of all-cause mortality (0.69; 0.49–0.97). There was no treatment heterogeneity among the predefined subgroups, although the potential benefits of DAPT were suggested in subpopulations of moderate-to-severe relevant arterial stenosis and relatively severe deficits (National Institutes of Health Stroke Scale score, 12–15). Conclusions— Compared to AM, clopidogrel plus aspirin did not reduce the risk of the primary outcome event during the first 3 months after a nonminor, noncardioembolic, ischemic stroke.

OBJECTIVE To evaluate whether prestroke glucose control is associated with functional outcomes in patients with acute large vessel occlusive stroke and diabetes who underwent intra-arterial thrombectomy (IAT). RESEARCH DESIGN AND METHODS From the Clinical Research Center for Stroke–Korea registry, we included patients with emergent large vessel occlusive stroke with diabetes who underwent IAT between January 2009 and March 2020. The association between the HbA1c level at admission and functional outcomes (modified Rankin Scale at 3 months after the index stroke) was assessed. RESULTS A total of 1,351 patients were analyzed. Early neurological deterioration was more common in patients with higher levels of HbA1c at admission (P = 0.02 according to HbA1c quintiles, P = 0.003 according to an HbA1c cutoff value of 7.0%) than in those with lower HbA1c levels. Higher HbA1c levels at admission were significantly associated with decreased odds of favorable functional outcomes at a threshold of 7.0–7.1%. The association was consistently observed in subgroups divided according to age, sex, stroke subtype, occlusion site, degree of recanalization, thrombolysis modalities, time from symptom onset to groin puncture, and treatment period. CONCLUSIONS Prestroke glucose control with a target HbA1c of ≤7.0% may be beneficial for neurological recovery in patients with diabetes undergoing IAT for large vessel occlusive stroke, regardless of stroke subtype, bridging intravenous thrombolysis, occlusion site, degree of recanalization, and treatment period.

Although the effect of blood pressure on post-stroke outcome is well-recognized, the long-term trajectory of blood pressure after acute ischemic stroke and its influence on outcomes have not yet been fully elucidated. From a multicenter prospective registry of acute ischemic stroke patients, 5,514 patients with measurements of systolic blood pressure (SBP) at more than 2 of 7 prespecified time-points, up to 1-year after stroke onset, were analyzed. Outcome measures, a composite of stroke recurrence, myocardial infarction and mortality, and each stroke recurrence and mortality, were prospectively collected up to 1-year after stroke onset. The study subjects were categorized into 4 groups according to their SBP trajectories: Low (27.0%), Moderate (59.5%), Persistently high (1.2%), and Slowly dropping (12.4%). After adjustments for pre-determined covariates, the Slowly dropping SBP Group was at higher risk of the composite outcome (hazard ratio, 1.32; 95% confidence interval, 1.05‒1.65), and mortality (1.35; 1.03‒1.78) compared to the Moderate SBP Group. Four main 1-year longitudinal SBP trajectories were identified after acute ischemic stroke. One trajectory, slowly dropping SBP, was particularly prone to adverse outcomes after stroke. These findings provide possible leads for future investigations of SBP control targets after stroke.

Background It remains unclear whether physicians' attitudes toward timely management of elevated blood pressure affect the risk of stroke recurrence. Methods and Results From a multicenter stroke registry database, we identified 2933 patients with acute ischemic stroke who were admitted to participating centers in 2011, survived at the 1‐year follow‐up period, and returned to outpatient clinics ≥2 times after discharge. As a surrogate measure of physicians' attitude, individual treatment intensification (TI) scores were calculated by dividing the difference between the frequencies of observed and expected medication changes by the frequency of clinic visits and categorizing them into 5 groups. The association between TI groups and the recurrence of stroke within 1 year was analyzed using hierarchical frailty models, with adjustment for clustering within each hospital and relevant covariates. Mean±SD of the TI score was −0.13±0.28. The TI score groups were significantly associated with increased risk of recurrent stroke compared with Group 3 (TI score range, −0.25 to 0); Group 1 (range, −1 to −0.5), adjusted hazard ratio (HR) 13.43 (95% CI, 5.95–30.35); Group 2 (range, −0.5 to −0.25), adjusted HR 4.59 (95% CI, 2.01–10.46); and Group 4 (TI score 0), adjusted HR 6.60 (95% CI, 3.02–14.45); but not with Group 5 (range, 0–1), adjusted HR 1.68 (95% CI, 0.62–4.56). This elevated risk in the lowest TI score groups persisted when confining analysis to those with hypertension, history of blood pressure‐lowering medication, no atrial fibrillation, and regular clinic visits and stratifying the subjects by functional capacity at discharge. Conclusions A low TI score, which implies physicians' therapeutic inertia in blood pressure management, was associated with a higher risk of recurrent stroke. The TI score may be a useful performance indicator in the outpatient clinic setting to prevent recurrent stroke.

Intravenous tissue-plasminogen activator (IV-TPA) treatment in acute ischemic stroke (AIS) patients due to small vessel occlusion (SVO) has been debated because of its small expected benefit and symptomatic intracranial hemorrhage (SICH) risk. Furthermore, data on subgroups of SVO patients are limited. From a prospective multicenter stroke registry database, AIS patients due to SVO within 24 h from onset were selected. Efficacy outcomes were 3-month modified Rankin Scale (mRS) score 0-1 proportion and mRS score distribution. Additionally, subgroup analyses were conducted by age, sex, initial National Institute Health Stroke Scale (NIHSS) score, and presenting limb paresis. This study included 2482 patients: 193 in the IV-TPA group and 2289 in the control group. After adjusting covariates, IV-TPA treatment was associated with an increased mRS 0-1 outcome (adjusted OR [95% CI], 1.56 [1.06-2.29]; P = 0.0249), but was not significantly associated with a favorable mRS shift (1.33 [0.98-1.81]; P = 0.0709). SICH and 3-month death occurred in three (1.6%) and none in the IV-TPA group versus one (0.04%) and 16 (0.7%) in the control group. In subgroup analyses, the IV-TPA effect appeared significantly greater in patients aged ≥80 versus80 for mRS score distribution (P

Background and Purpose— Two large-scale randomized controlled trials of recurrent stroke prevention suggest that dual antiplatelet therapy with clopidogrel plus aspirin is beneficial for prevention of subsequent ischemic events. There is a paucity of data, however, on the efficacy or effectiveness of such an approach in the treatment of stroke patients with symptomatic large artery atherosclerotic occlusive disease. Methods— We used a multicenter stroke registry database (Clinical Research Collaboration for Stroke in Korea) to analyze acute ischemic stroke patients due to large artery atherosclerotic occlusive disease who were treated with aspirin alone or combination of clopidogrel and aspirin from May 2008 to May 2015. The results were analyzed by intention-to-treat, per-protocol, and as-treated methodologies. The primary end point was the 1-year composite outcome of stroke recurrence, myocardial infarction, and all-cause death. To balance the differences between groups, a frailty model using propensity scores and inverse probability of treatment weighting was used. Results— A total of 5934 patients with symptomatic large artery atherosclerotic occlusive disease were treated either with clopidogrel plus aspirin (n=2903, 49%) or aspirin (n=3031, 51%). The frequency of the primary outcome was 12% (n=353) in the clopidogrel-aspirin group and 14% (n=410) in the aspirin group. The hazards of the primary outcome with combination over aspirin only were significantly reduced in the per-protocol and as-treated analyses (hazard ratio, 0.71; 95% CI, 0.57–0.88; P =0.002 and hazard ratio, 0.81; 95% CI, 0.69–0.96; P =0.02, respectively), but there was borderline significance in the intention-to-treat analysis (hazard ratio, 0.86; 95% CI, 0.74–1.01; P =0.06). Combination therapy was beneficial for all-cause death in all analyses but did not reduce recurrent stroke. Conclusions— Compared with patients receiving aspirin monotherapy, the primary outcome seemed to occur less frequently in patients receiving dual antiplatelet therapy, which is explained mainly by the decrease of all-cause death. Since this is a nonrandomized, retrospective, observational study, our study should be cautiously interpreted.

Background and Purpose— This study aimed to compare the effectiveness of dual antiplatelet therapy with clopidogrel-aspirin to that of aspirin monotherapy in patients with acute minor cerebral ischemia using a prospective, nationwide, multicenter, stroke registry database in South Korea. Methods— CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events)-like patients who met eligibility criteria modeled on the CHANCE trial eligibility criteria, including (1) acute minor ischemic stroke defined as National Institutes of Health Stroke Scale score ≤3 or lesion positive transient ischemic attack within 24 hours of onset and (2) noncardioembolic stroke mechanism. Propensity scores using the inverse probability of treatment weighting was used to adjust for baseline imbalances. The primary outcome was the composite of all stroke (ischemic and hemorrhagic), myocardial infarction, and vascular death by 3 months. Results— Among 5590 patients meeting the eligibility criteria, age was 64±13 year and 62.6% were male. Aspirin and combination of clopidogrel-aspirin were administered in 66.1% and 33.9% of patients, respectively. In unadjusted analysis, rates of the 3-month primary vascular event outcome were lower with clopidogrel-aspirin versus aspirin, 9.9% versus 12.2% (hazard ratio, 0.79 [0.67–0.95]). In propensity-weighted Cox proportional hazards regression with robust estimation, clopidogrel-aspirin was associated with a lower risk of the primary vascular event outcome (hazard ratio, 0.76 [0.63–0.92]) and all stroke events (hazard ratio, 0.74 [0.61–0.90]). Among 6 predefined subgroup analyses, 3 showed potential modification of treatment effect, with lesser benefit associated with the absence of prior antiplatelet use ( P interaction =0.01) and younger age (P interaction =0.07), and absence of benefit associated with small vessel occlusion subtype ( P interaction =0.08). Conclusions— Dual antiplatelet therapy with aspirin and clopidogrel was associated with reduced stroke, myocardial infarction, and vascular death in the 3 months following a presenting minor, noncardioembolic ischemic stroke. Benefits may be particularly magnified in patients with a history of prior antiplatelet therapy, older age, and nonsmall vessel disease stroke mechanism.

Purpose: The aim of this study is to investigate the effect of gradual dipyridamole titration and the incidence of dipyridamole-induced headache in patients with ischemic stroke or transient ischemic attack (TIA). Methods: A randomized, double-blind, double-placebo, parallel group, phase 4 clinical trial (KCT0005457) was conducted between July 1, 2019, and February 25, 2020, at 15 medical centers in South Korea. The study included patients aged >19 years diagnosed with a noncardioembolic ischemic stroke or TIA within the previous 3 weeks. The participants were randomized 1:1:1 to receive Adinox® (aspirin 25 mg/dipyridamole 200 mg) and aspirin (100 mg) once daily for the first 2 weeks followed by Adinox® twice daily for 2 weeks (titration group), Adinox® twice daily for 4 weeks (standard group), and aspirin 100 mg once daily for 4 weeks (control group). The primary endpoint was incidence of headache over 4 weeks. The key secondary endpoint was mean cumulative headache. Results: Ninety-six patients were randomized into the titration (n = 31), standard (n = 32), and control (n = 33) groups. The titration and standard groups (74.1% vs. 74.2%, respectively) showed no difference in the primary endpoint. However, the mean cumulated headache was significantly lower in the titration group than in the standard group (0.31 ± 0.46 vs. 0.58 ± 0.51, p = 0.023). Further, adverse drug reactions were more common in the standard group than in the titration group (28.1% vs. 9.7%, respectively, p = 0.054), although not significantly different. Conclusion: The titration strategy was effective in lowering the incidence of cumulative dipyridamole-induced headache.

We investigated a multicenter registry to identify estimated event rates according to CHA2DS2-VASc scores in patients with acute ischemic stroke (AIS) and atrial fibrillation (AF). The additional effectiveness of antiplatelets (APs) plus oral anticoagulants (OACs) compared with OACs alone considering the CHA2DS2-VASc scores was also explored. This study retrospectively analyzed a multicenter stroke registry between Jan 2011 and Nov 2017, identifying patients with acute ischemic stroke with AF. The primary outcome event was a composite of recurrent stroke, myocardial infarction, and all-cause mortality within 1 year. A total of 7395 patients (age, 73 ± 10 years; men, 54.2%) were analyzed. The primary outcome events at one year ranged from 5.99% (95% CI 3.21–8.77) for a CHA2DS2-VASc score of 0 points to 30.45% (95% CI 24.93–35.97) for 7 or more points. After adjustments for covariates, 1-point increases in the CHA2DS2-VASc score consistently increased the risk of primary outcome events (aHR 1.10 [1.06–1.15]) at 1-year. Among OAC-treated patients at discharge (n = 5500), those treated with OAC + AP (vs. OAC alone) were more likely to experience vascular events, though among patients with a CHA2DS2-VASc score of 5 or higher, the risk of primary outcome in the OAC + AP group was comparable to that in the OAC alone group (Pint = 0.01). Our study found that there were significant associations of increasing CHA2DS2-VASc scores with the increasing risk of vascular events at 1-year in AIS with AF. Further study would be warranted.

Background The long‐term incidence of acute myocardial infarction (AMI) in patients with acute ischemic stroke (AIS) has not been well defined in large cohort studies of various race‐ethnic groups. Methods and Results A prospective cohort of patients with AIS who were registered in a multicenter nationwide stroke registry (CRCS‐K [Clinical Research Collaboration for Stroke in Korea] registry) was followed up for the occurrence of AMI through a linkage with the National Health Insurance Service claims database. The 5‐year cumulative incidence and annual risk were estimated according to predefined demographic subgroups, stroke subtypes, a history of coronary heart disease (CHD), and known risk factors of CHD. A total of 11 720 patients with AIS were studied. The 5‐year cumulative incidence of AMI was 2.0%. The annual risk was highest in the first year after the index event (1.1%), followed by a much lower annual risk in the second to fifth years (between 0.16% and 0.27%). Among subgroups, annual risk in the first year was highest in those with a history of CHD (4.1%) compared with those without a history of CHD (0.8%). The small‐vessel occlusion subtype had a much lower incidence (0.8%) compared with large‐vessel occlusion (2.2%) or cardioembolism (2.4%) subtypes. In the multivariable analysis, history of CHD (hazard ratio, 2.84; 95% CI, 2.01–3.93) was the strongest independent predictor of AMI after AIS. Conclusions The incidence of AMI after AIS in South Korea was relatively low and unexpectedly highest during the first year after stroke. CHD was the most substantial risk factor for AMI after stroke and conferred an approximate 5‐fold greater risk.

Background: This study compared the effectiveness of dual antiplatelet therapy (DAPT) with clopidogrel-aspirin with that of aspirin monotherapy (AM) in mild-to-moderate acute ischemic stroke considering the risk of recurrent stroke using the Stroke Prognosis Instrument II (SPI-II) score. Methods: This study is a retrospective analysis of data from a prospective, nationwide, multicenter stroke registry database between January 2011 and July 2018. We included patients with mild-to-moderate (National Institutes of Health Stroke Scale score ≤10), acute (within 24 hours of onset), noncardioembolic ischemic stroke. The primary outcome was a 3-month composite of stroke (either hemorrhagic or ischemic), myocardial infarction, and all-cause mortality. Propensity scores using the inverse probability of treatment weighting method were used to mitigate baseline imbalances between the DAPT and AM groups and within each subgroup considering SPI-II scores. Results: Among the 15 430 patients (age, 66±13 years; men, 62.0%), 45.1% (n=6960) received DAPT and 54.9% (n=8470) received AM. Primary outcome events were significantly more frequent in the AM group (16.7%) than in the DAPT group (15.5%; P =0.03). Weighted Cox proportional hazards models showed a reduced risk of 3-month primary vascular events in the DAPT group versus the AM group (hazard ratio, 0.84 [0.78–0.92]; P P interaction =0.44). However, among the high-risk patients with SPI-II scores >7, a substantially larger absolute benefit was observed for 3-month composite vascular events in the DAPT group (weighted absolute risk differences, 5.4%), whereas smaller absolute benefits were observed among patients in the low- or medium-risk SPI-II subgroups (1.7% and 2.4%, respectively). Conclusions: Treatment with clopidogrel-aspirin was associated with a reduction in 3-month vascular events compared with AM in mild-to-moderate acute noncardioembolic ischemic stroke patients. Larger magnitudes of the effects of DAPT with clopidogrel-aspirin were observed in the high-risk subgroup by SPI-II risk scores.

Uncertainty regarding an optimal antiplatelet regimen still exists in patients with breakthrough acute ischemic stroke (AIS) while on aspirin. This study provides an analysis of a prospective multicenter registry between April 2008 and April 2014. Eligible patients were on aspirin at the time of AIS and treated with antiplatelet regimens (aspirin, clopidogrel, or clopidogrel-aspirin). Potential factors associated with the choice of each antiplatelet regimen were explored and included a predictive risk score for future vascular events, the Essen Stroke Risk Score (ESRS). A total of 2348 patients (age, 69 ± 11 years; male, 57.7%) were analyzed, and 55.3%, 25.3% and 19.4% were treated with clopidogrel-aspirin, aspirin and clopidogrel, respectively. While the likelihood of choosing clopidogrel-aspirin increased as the ESRS increased, the likelihood of choosing aspirin decreased as the ESRS increased (Ptrend interaction

Background and Purpose— We evaluated whether hemoglobin concentration at admission was associated with stroke recurrence and composite vascular events (stroke, myocardial infarction, and vascular death) in acute ischemic stroke. Methods— We collected data from patients with acute ischemic stroke or transient ischemic attack from a multicenter stroke registry database in Korea. The association of hemoglobin concentration with 1-year stroke recurrence and composite vascular events was evaluated with respect to age, presence of cerebral artery stenosis, stroke severity, and stroke subtype. Results— Hemoglobin levels were inversely associated with stroke recurrence and composite vascular events. One-year rates of stroke recurrence and composite vascular events were significantly higher in patients with anemia or moderate anemia. In multivariable analyses, moderate anemia remained an independent predictor of stroke recurrence (adjusted hazard ratio, 1.43 [95% CI, 1.16–1.75]) and composite vascular events (adjusted hazard ratio, 1.26 [95% CI, 1.07–1.48]). Moderate anemia increased the risk of composite vascular events in patients with mild-to-moderate stroke severity (National Institutes of Health Stroke Scale score P =0.01 for interaction). Conclusions— Hemoglobin concentration could be an independent predictor of stroke recurrence and composite vascular events.

Introduction: Although the effect of blood pressure in post-stroke outcome is well recognized, the long-term time course of BP following acute ischemic stroke and it’s influence to outcomes have not been well elucidated. Method: From a multicenter prospective registry of acute ischemic stroke patients, a total of 5,514 patients with measurement of systolic blood pressure (SBP) in more than 2 of 7 prespecified time points up to 1 year after symptom onset were analyzed. The patients were grouped according to longitudinal SBPs of each patient using a group-based trajectory model, and number of groups were determined by the optimal delta-Bayesian Information Criterion. Outcome measures, which were stroke recurrence, mortality and composite of each events along with myocardial infarction were prospectively collected up to 1 year after symptom onset. Results: Patients were categorized into four groups according to their SBP trajectories: low (27.0%), moderate (59.5%), persistently high (1.2%), and slowly dropping (12.4%). After adjustment for pre-determined covariates, there were higher risk of stroke recurrence in persistently high SBP group (hazard ratio (HR), 2.28 [95% confidence interval (CI), 1.01-5.12]). Mortality was higher only in the slowly dropping SBP group (HR, 1.50 [95% CI, 1.09-2.05]). Composite events were higher in both persistently high (HR, 1.96 [95% CI, 1.02-3.75]) and slowing dropping (HR, 1.54 [95% CI, 1.18-2.00]) SBP groups. Conclusion: There were a group of patterns in long-term longitudinal SBP changes after acute ischemic stroke. Especially, slow BP droppers might have a distinct nature with higher mortality and would be a target for future investigations.

We investigated the effectiveness of adding antiplatelet (AP) to oral anticoagulant (OAC) treatment versus OAC treatment alone in patients with AIS with atrial fibrillation (AF) and significant large artery steno-occlusion (LASO). This study is a retrospective analysis of a nationwide, prospective, multicenter stroke registry between April 2008 and November 2017. Patients with acute (within 48 h of onset) and mild-to-moderate (NIHSS score ≤ 15) stroke with AF and concomitant LASO were identified. Antithrombotic regimens at discharge were categorized into OAC alone or OAC + AP. The primary outcome event was a composite of recurrent stroke, myocardial infarction, and all-cause mortality within 3 months of stroke. Among the 2553 patients (age, 73 ± 10 years; men, 50.4%), 78.8% were treated with OAC alone, and 21.2% were treated with OAC + AP. The primary outcome events were significantly more common in the OAC + AP group (6.7%) than the OAC alone group (4.3%) (p = 0.02). Weighted Cox proportional hazard analysis showed that OAC + AP increased the risk of 3-month primary outcome events compared with OAC alone (HR, 1.62 [1.06 to 2.46]). A potential interaction between the type of LASO and discharge antithrombotics was suggested (Pinteraction = 0.04); unlike in patients with complete occlusion (OAC + AP; HR, 2.00 [1.27–3.15]), OAC + AP was comparable with OAC alone for 3-month primary outcome in patients with moderate-to-severe stenosis (HR, 0.54 [0.17–1.70]). In conclusion, OAC + AP might increase the risk of 3-month outcome events compared with OAC alone in patients with AIS with AF and concomitant LASO. However, the effect of additional AP to OAC might differ according to LASO type.

Background Off‐hour presentation can affect treatment delay and clinical outcomes in endovascular therapy ( EVT ) for acute ischemic stroke. We aimed to examine the treatment delays and clinical outcomes of EVT between on‐ and off‐hour admission and to evaluate the effect of hospital procedure volume and the number of neurointerventionalists on off‐hour EVT . Methods and Results From a multicenter registry, we identified patients who were treated with EVT within 12 hours of symptom. Annual hospital procedure volume was divided as low (60). The effect of the number of neurointerventionalists and annual hospital procedure volume on clinical outcome was estimated by the generalized estimation equation. Of the 31 133 stroke patients, 1564 patients met the eligibility criteria (mean age: 69±12 years; median baseline National Institutes of Health stroke scale score, 15 [interquartile range, 10–19]). Of 1564 patients, 893 (57.1%) arrived during off‐hour. The off‐hour patients had greater median door‐to‐puncture time (110 versus 95 minutes; P P =0.90). The presence of three neurointerventionalists was significantly associated with favorable outcomes at 3 months during on‐ and off‐hour (2.07 [1.53–2.81]; P Conclusions The number of neurointerventionalists was more crucial to effective around‐the‐clock EVT for acute stroke patients than hospital procedural volume.

When physicians encounter patients with headache or facial pain (preeruptive pain) associated with acute herpes zoster of the head, especially before the appearance of characteristic skin eruptions (preeruptive phase), they typically find it difficult to make clinical impressions and apply appropriate diagnostic or therapeutic procedures. The objectives of this study were to describe the clinical characteristics of headache or facial pain associated with acute herpes zoster of the head and to elucidate the association between the manifestation of these symptoms in the preeruptive phase and incoming herpes zoster.We retrospectively analyzed the clinical features of 152 patients with acute herpes zoster involving only the head who presented within 10days of rash onset at Chungbuk National University Hospital, a tertiary hospital in Chungcheongbuk-do in South Korea, between January 2011 and December 2015.The mean age of the patients was 54.3±19.8years. One hundred patients had herpes zoster in the trigeminal nerve, 34 in the nervus intermedius, and 18 in the upper cervical nerves. Preeruptive pain was present in 112 (73.7%) patients and had a mean duration of 3.0±1.3days (range, 1-6days). Severity of pain was associated with the presence of preeruptive pain (p=0.040). Headache or facial pain was limited to the ipsilateral side of the face and head in all patients, except for two who had with severe symptoms of meningitis, and was of moderate to severe intensity (90.1%). Pain of a stabbing nature was observed in 128 (84.2%) patients, and 146 (96.1%) reported experiencing this type of pain for the first time. Pain awakened 94 (61.8%) patients from sleep. Sixty-one (54.5%) of the 112 patients with preeruptive pain visited a hospital during the preeruptive phase; their preeruptive phase was significantly longer (p0.001) and more frequently awakened them from sleep (p=0.008). Their presumptive diagnoses were as follows: tension-type headache (n=20, 32.8%); no decision (n=18, 29.5%); herpes zoster (n=5, 8.2%); migraine (n=3, 4.9%); pain associated with upper respiratory tract infection (n=3, 4.9%); parotitis (n=2, 3.3%); dry eye (n=2, 3.3%); and other (n=1 each: trigeminal neuralgia, glaucoma, pharyngitis, vestibular neuronitis, tonsillitis, teeth problems, otitis media, and occipital neuralgia).These results suggest that the typical pain of acute herpes zoster of the head has a stabbing quality, is felt unilaterally, is moderate to severe, often awakens patients from sleep, and has not been previously experienced by most patients. When encountering patients with these features accompanied by pain onset of less than one week, acute herpes zoster of the head should be considered, even without characteristic vesicles, after excluding other secondary causes by appropriate diagnostic workup.

Background and Purpose— We compared baseline characteristics and outcomes at 3 months between patients with minor anterior circulation infarction (ACI) versus minor posterior circulation infarction (PCI), including the influence of large vessel disease on outcomes. Methods— This study is an analysis of a prospective multicenter registry database in South Korea. Eligibility criteria were patients with ischemic stroke admitted within 7 days of stroke onset, lesions in either anterior or posterior circulation, and National Institutes of Health Stroke Scale score of ≤4 at baseline. Patients were divided into 4 groups for further analysis: minor ACI with and without internal carotid artery/middle cerebral artery large vessel disease and minor PCI with and without vertebrobasilar large vessel disease. Results— A total of 7178 patients (65.2±12.6 years) were analyzed in this study, and 2233 patients (31.1%) had disability (modified Rankin Scale score 2–6) at 3 months. Disability was 32.3% in minor PCI and 30.3% in minor ACI ( P =0.07), and death was 1.3% and 1.5%, respectively ( P =0.82). In a multivariable logistic regression analysis, minor PCI was significantly associated with disability at 3 months when compared with minor ACI (odds ratio, 1.23; 95% confidence interval, 1.09–1.37; P Conclusions— Our study showed that minor PCI exhibited more frequent disability at 3 months than minor ACI. Especially, the presence of vertebrobasilar large vessel disease in minor PCI had a substantially higher risk of disability. Our results suggest that minor PCI with vertebrobasilar large vessel disease could require more meticulous care and are important targets for further study.

ObjectiveIt is uncertain whether patients with cardioembolic stroke and without a guidance-based indication for statin therapy should be administered a statin for prevention of subsequent vascular events. This study was performed to determine whether the statin therapy is beneficial in preventing major vascular events in this population.MethodsUsing a prospective multicenter stroke registry database, we identified patients with acute cardioembolic stroke who were hospitalized between 2008 and 2015. Patients who had other established indications for statin therapy according to current guidelines were excluded. Major vascular event was defined as a composite of stroke recurrence, myocardial infarction, and vascular death. We performed frailty model analysis with the robust sandwich variance estimator using the stabilized inverse probability of treatment weighting method to estimate hazard ratios of statin therapy on outcomes.ResultsOf 6,124 patients with cardioembolic stroke, 2,888 (male 44.6%, mean age 75.3 years, 95% confidence interval [CI] 74.8–75.8) were eligible, and 1,863 (64.5%) were on statin therapy during hospitalization. After a median follow-up of 359 days, cumulative incidences of major vascular events were 9.3% in the statin users and 20.5% in the nonusers (p < 0.001 by log-rank test). The adjusted hazard ratios of statin therapy were 0.39 (95% CI 0.31–0.48) for major vascular events, 0.81 (95% CI 0.57–1.16) for stroke recurrence, 0.28 (95% CI 0.21–0.36) for vascular death, and 0.53 (95% CI 0.45–0.61) for all-cause death.ConclusionStarting statin during the acute stage of ischemic stroke may reduce the risk of major vascular events, vascular death, and all-cause death in patients with cardioembolic stroke with no guidance-based indication for statin.

Background and Purpose- Two large-scale randomized controlled trials of recurrent stroke prevention suggest that dual antiplatelet therapy with clopidogrel plus aspirin is beneficial for prevention of subsequent ischemic events. There is a paucity of data, however, on the efficacy or effectiveness of such an approach in the treatment of stroke patients with symptomatic large artery atherosclerotic occlusive disease. Methods- We used a multicenter stroke registry database (Clinical Research Collaboration for Stroke in Korea) to analyze acute ischemic stroke patients due to large artery atherosclerotic occlusive disease who were treated with aspirin alone or combination of clopidogrel and aspirin from May 2008 to May 2015. The results were analyzed by intention-to-treat, per-protocol, and as-treated methodologies. The primary end point was the 1-year composite outcome of stroke recurrence, myocardial infarction, and all-cause death. To balance the differences between groups, a frailty model using propensity scores and inverse probability of treatment weighting was used. Results- A total of 5934 patients with symptomatic large artery atherosclerotic occlusive disease were treated either with clopidogrel plus aspirin (n=2903, 49%) or aspirin (n=3031, 51%). The frequency of the primary outcome was 12% (n=353) in the clopidogrel-aspirin group and 14% (n=410) in the aspirin group. The hazards of the primary outcome with combination over aspirin only were significantly reduced in the per-protocol and as-treated analyses (hazard ratio, 0.71; 95% CI, 0.57-0.88; P=0.002 and hazard ratio, 0.81; 95% CI, 0.69-0.96; P=0.02, respectively), but there was borderline significance in the intention-to-treat analysis (hazard ratio, 0.86; 95% CI, 0.74-1.01; P=0.06). Combination therapy was beneficial for all-cause death in all analyses but did not reduce recurrent stroke. Conclusions- Compared with patients receiving aspirin monotherapy, the primary outcome seemed to occur less frequently in patients receiving dual antiplatelet therapy, which is explained mainly by the decrease of all-cause death. Since this is a nonrandomized, retrospective, observational study, our study should be cautiously interpreted.

Background and Purpose: Stroke is one of the most devastating and costly health problems of today. However, there is lack of knowledge about how costly it is in a long-term perspective and how much the long-term cost differs according to 3-month functional outcome, a major primary outcome variable of acute stroke intervention trials. Methods: Acute ischemic stroke patients who were registered into the multi-center stroke registry (Clinical Research Collaboration for Stroke in Korea, CRCS-K) in South Korea between 2011 and 2013 were matched to the National Health Insurance Service claim database. All the healthcare expenditure was extracted from the claim database and converted into daily cost of each individual. Yearly expenditures and cumulative expenditure up to 5 yeas were obtained and expressed in US dollars and were compared according to 3-month functional outcome (modified Rankin disability scale, mRS).Results: A total of 11,136 acute ischemic stroke patients (mean age, 68 years; men 58%) were analyzed. The median follow-up period was 1,418 days. The mean cumulative healthcare expenditure over 5 years was $74,295 (SD, $91,049) and showed a dramatic increment during the first month followed by a constant increase without a considerable change. The mean 5-year cumulative expenditure differed significantly according to 3-month functional outcome; $32,261 in those with 3-month mRS 0 and $163,244 in those with 3-month mRS 5. After adjusting for the selected potential confounders, the yearly expenditures and the cumulative one at each time point differed significantly according to 3-month mRS scores. Figure given below is showing the median 5-year cumulative daily expenditure by 3-month mRS. Conclusions: This study shows that the impact of 3-month functional outcome on the long-term healthcare expenditure following acute ischemic stroke may be more than expected. The efforts for improving functional outcomes are urgent.