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Background and Purpose: This study aimed to investigate the value of d -dimer levels in predicting recurrent stroke in patients with embolic stroke of undetermined source. We also evaluated the underlying causes of recurrent stroke according to d -dimer levels. Methods: A total of 1431 patients with undetermined source were enrolled in this study and divided into quartiles according to their baseline plasma d -dimer levels. The primary outcome measure was the occurrence of recurrent stroke (ischemic or hemorrhagic) in the year following the stroke event. Results: The risk of recurrent stroke increased significantly with the increasing d -dimer quartile (log-rank P =0.001). Patients in the higher d -dimer quartiles had a higher probability of recurrent embolic stroke because of covert atrial fibrillation, hidden malignancy, or undetermined sources. Most recurrent strokes in Q3 and Q4 were embolic but not in Q1 or Q2. Multivariate analysis revealed that patients in Q3 and Q4 had a significantly increased risk of recurrent stroke compared with those in Q1 (hazard ratio, 3.12 [95% CI, 1.07−9.07], P =0.036; hazard ratio, 7.29 [95% CI, 2.59−20.52], P P trend d -dimer level above normal range and the risk of recurrent stroke (hazard ratio, 2.48 [95% CI, 1.31−4.70], P =0.005). In subgroup analyses, a high d -dimer level was associated with a significantly higher risk of recurrent stroke in men than in women ( P =0.039). Conclusions: Our findings suggest that d -dimer levels can be a useful risk assessment biomarker for predicting recurrent stroke, especially embolic ischemic stroke, in patients with undetermined source.

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.

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.

Background and Purpose— The purpose of this study was to investigate the association between adiposity using adipose tissue imaging and stroke outcomes in acute ischemic stroke patients treated with intravenous thrombolysis. Methods— A total of 127 patients with acute ischemic stroke treated with intravenous thrombolysis who underwent abdominal computed tomography on admission were enrolled in this prospective cohort study. Patients were grouped according to their visceral adipose tissue (VAT) proportion tertile. The primary outcome was measured using the modified Rankin Scale 3 months after symptom onset. Favorable and excellent outcomes were defined as modified Rankin Scale scores of 0 to 2 and 0 to 1, respectively. Results— As VAT proportion tertile increased, the number of patients exhibiting a favorable or excellent outcome decreased. In the final multivariable analysis after adjustments for confounders, patients in the highest VAT proportion tertile showed a decreased probability of a favorable and excellent outcome compared with those in the lowest tertile (odds ratio=0.18; 95% CI, 0.05−0.60; P =0.005 and odds ratio=0.13; 95% CI, 0.02−0.64; P =0.012, respectively). Obese patients (body mass index ≥25) also showed an excellent outcome compared with nonobese patients (odds ratio=4.88; 95% CI, 1.47−7.85; P =0.011). Among obese patients, those with an excellent outcome presented a significantly lower VAT proportion than those without (38.2% versus 46.1%, P =0.006). Conclusions— Results of this study indicate that low visceral abdominal fat proportion is associated with a favorable and excellent outcome in acute ischemic stroke patients treated with intravenous thrombolysis. Better clinical outcomes in obese patients were also associated with a lower proportion of VAT.

Background and Purpose— We analyzed the association between cerebral microbleeds (CMBs) and clinical outcome in acute ischemic stroke patients and especially in a subgroup of patients with successful recanalization. Methods— A total of 1532 acute ischemic stroke patients treated with intravenous thrombolysis or mechanical thrombectomy were enrolled in this prospective cohort study. The primary outcome was measured using the modified Rankin Scale at 3 months, according to the CMB status based on magnetic resonance imaging at admission. Favorable outcome was defined as functional independence with modified Rankin Scale scores of 0 to 2. Secondary outcomes included the occurrence of symptomatic intracranial hemorrhage. Results— There was no statistically significant association between the presence of CMB and favorable outcome at 3 months when considering all patients (44.3% versus 37.6%; P =0.121). In patients with recanalization, the number of patients with favorable outcomes was significantly higher in the CMB-negative than in the CMB-positive group (57.0% versus 36.0%; P P =0.038) and symptomatic intracranial hemorrhage (odds ratio=3.21; 95% CI, 1.37−7.49; P =0.007) in patients with recanalization. In the analysis of subgroups, a statistically significant interaction was found between CMB presence and recanalization in predicting functional outcomes at 3 months. Conclusions— These results indicate that the presence of CMBs, and especially high burden and lobar location, are independent predictors of poor 3-month clinical outcomes and may increase symptomatic intracranial hemorrhage risk in acute ischemic stroke patients with recanalization. Our findings suggest that CMBs lead to more unfavorable effects in patients with recanalization after large vessel occlusion than in those without recanalization.

Background and Purpose— We analyzed the relationship between HbA1c (glycated hemoglobin) levels and clinical outcomes in patients with large vessel occlusion treated with mechanical thrombectomy (MT). Methods— A total of 534 patients with acute ischemic stroke (AIS) treated with MT were enrolled in this prospective cohort study. The primary outcome measured was the modified Rankin Scale score at 3 months, according to HbA1c level. High HbA1c levels were defined as a plasma level of HbA1c >6.5%. Favorable outcomes were defined as functional independence, with modified Rankin Scale scores of 0 to 2. Secondary functional outcomes included mortality, early clinical outcomes, and intracranial hemorrhage. Results— The number of patients with a favorable outcome was significantly lower in patients with HbA1c >6.5% than in those with HbA1c ≤6.5% (28.8% versus 42.1%; P =0.006). In multivariate analysis, high HbA1c levels (especially >7.0% HbA1c) were significantly associated with poor functional outcomes 3 months after AIS in patients with large vessel occlusion treated with MT. High HbA1c was also significantly associated with increased mortality and worse early clinical outcomes after AIS in patients treated with MT. Subgroup analyses showed that HbA1c >6.5% was associated with significantly lower odds of functional independence at 3 months after AIS, when comparing the recanalized group with nonrecanalized patients. Conclusions— These results suggest that high HbA1c level is an independent predictor of a poor outcome at 3 months after AIS in patients with large vessel occlusion treated with MT, particularly in those with recanalization, and may augment the risk of mortality and early clinical worsening after AIS.

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.

Background and Purpose: We investigated the impact of the presence, burden, and location of cerebral microbleeds (CMBs) on the risk of major adverse cerebrovascular and cardiovascular events (MACCE) in patients with acute ischemic stroke and atrial fibrillation treated with oral anticoagulants (OACs). We also examined whether the clinical effect of CMBs differs according to the type of OACs. Methods: A total of 1742 patients with acute ischemic stroke and atrial fibrillation treated with OACs were enrolled in this cohort study. The primary composite outcome was the occurrence of MACCE (a composite of stroke, acute myocardial infarction, or vascular death) over a 2-year period according to CMB status. Results: CMB presence was significantly associated with the risk of future MACCE (hazard ratio, 1.89 [95% CI, 1.23–2.88]; P =0.003) after adjustment for confounders in patients with acute ischemic stroke and atrial fibrillation taking OACs. Patients with exactly 1 CMB had a similar rate of MACCE compared with those without CMBs ( P =0.461). However, patients with multiple CMBs (≥2), particularly high burden CMBs (≥5), had a significantly higher proportion of MACCE. Both CMB-positive groups with lobar and deep CMB had more frequent MACCE than the CMB-negative group, and the rate of MACCE was not different according to CMB location. In patients treated with warfarin, CMB was significantly associated with a risk of MACCE ( P =0.002), but not in patients treated with direct OACs ( P =0.517). Conclusions: The study results indicate that the risk of future MACCE increased with increasing CMB burden in patients with AIS and atrial fibrillation taking OACs, while the anatomic location of CMBs did not influence the risk of future MACCE. This risk seemed to be more apparent in patients taking warfarin.

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.

Background and Purpose— Randomized trials comparing the use of multimodal magnetic resonance imaging (MRI) to multimodal computed tomography (CT)/ CT angiography (CTA) for selecting candidates for endovascular therapy (EVT) have not been reported. This study aimed to elucidate whether MRI-based selection for EVT is safe and effective within and after a 6-hour time window compared with conventional CTA-based selection. Methods— Data from a prospective, nationwide, multicenter stroke registry were analyzed. Workflow timelines were compared between patients selected for EVT based on MRI (the MRI group) and CTA (the CTA group). Multivariable ordinal and binary logistic regression analyses were performed to explore the relationships between decision imaging for EVT and clinical outcomes, including good and excellent outcomes (modified Rankin Scale scores of 0–2 and 0–1, respectively) at 3-month, modified Rankin Scale score distributions and safety outcomes (symptomatic intracranial hemorrhage [SICH] and mortality). Results— Ultimately, 1265 patients (age, 69±12 yrs; men, 55%) were enrolled in this study. The median National Institutes of Health Stroke Scale score was 15 (11–19). All workflow time metrics were significantly delayed in the MRI group compared with the CTA group. There was no difference in good 3-month outcomes in patients arriving within 6 hours of onset between the MRI and CTA groups (38.1% versus 38.5%), but SICH and mortality rates were lower in the MRI group than the CTA group (3.8% versus 7.7%, P =0.01 for SICH; 15.4% versus 20.9%, P =0.04 for mortality). In the multivariable analysis, decision imaging was not significantly associated with 3-month functional outcomes (all P >0.1) or mortality ( P =0.051); however, the MRI group was less likely to develop SICH than the CTA group ( P =0.01; odds ratio, 0.34 [95% CI, 0.17–0.77]). Conclusions— Our study found MRI-based selection for EVT was not associated with improving functional outcome compared with CT-based selection, but may be better at reducing the risk of SICH, despite the delays in all workflow time metrics.

Background and Purpose— Since its introduction, controversy has existed about the administration of intravenous heparin for the treatment of acute ischemic stroke. We studied trends in the intravenous heparin use during a 6-year time period and the potential influence of clinical guidelines in national language on intravenous heparin administration in Korea. Methods— On the basis of a prospective nationwide multicenter stroke registry, we collected data on patients with acute ischemic stroke who arrived within 7 days of symptom onset during the time period 2008 to 2013. We studied patient demographics, prestroke medical history, stroke characteristics, and stroke treatment. Data from a total of 23 425 patients from 12 university hospitals or regional stroke centers were analyzed. Results— The administration of intravenous heparin steadily decreased throughout the study period: 9.7% in 2008, 10.9% in 2009, 9.4% in 2010, 6.0% in 2011, 4.7% in 2012, and 4.3% in 2013 ( P for trend P P Conclusions— Use of intravenous heparin for acute ischemic stroke treatment has decreased in Korea, and this change may be attributable to the spread and successful implementation of regional clinical practice guidelines.

Background and Purpose— Most patients with cerebral infarction die of brain edema because of the breakdown of the blood–brain barrier (BBB) in ischemic tissue. Caveolins (a group of proteins) are key modulators of vascular permeability; however, a direct role of caveolin-1 (Cav-1) in the regulation of BBB permeability during ischemic injury has yet to be identified. Methods— Cav-1 expression was measured by immunoblotting after photothrombotic ischemia. A direct functional role of Cav-1 in cerebral edema and BBB permeability during cerebral ischemia was investigated by genetic manipulation (gene disruption and re-expression) of Cav-1 protein expression in mice. Results— There was a significant correlation between the extent of BBB disruption and the Cav-1 expression. In Cav-1–deficient (Cav-1 −/− ) mice, the extent of BBB disruption after cerebral ischemia was increased compared with wild-type (Cav-1 +/+ ) mice, whereas the increase in cerebral edema volume was ameliorated by lentiviral-mediated re-expression of Cav-1. Furthermore, Cav-1 −/− mice had significantly higher degradation of tight junction proteins and proteolytic activity of matrix metalloproteinase than Cav-1 +/+ mice. Conversely, re-expression of Cav-1 in Cav-1 −/− mice restored tight junction protein expression and reduced matrix metalloproteinase proteolytic activity. Conclusions— These results indicate that Cav-1 is a critical determinant of BBB permeability. Strategies for regulating Cav-1 represent a novel therapeutic approach to controlling BBB disruption and subsequent neurological deterioration during cerebral ischemia.

Backgrounds: Previous studies demonstrated the association of resting heart rate with cardiovascular outcomes while there were only few evidence for patients who experienced ischemic stroke. As atrial fibrillation (AF) is characterized by rapidity and irregularity of heart rate, heart rate characteristics might be a predictor for future vascular event in patients with AF acute ischemic stroke. Methods: From a multicenter prospective registry of stroke patients, acute ischemic stroke patients with AF who admitted within 48 hours after stroke onset were included. Heart rate data during the first 24 hours after admission were collected and level and variability of heart rate were assessed by mean and coefficient of variation (CV). Primary outcome was a composite of stroke recurrence, myocardial infarction and all-cause death, which was prospectively captured until 1 year after stroke onset. Results: A total of 2,046 patients were included for the final analysis. There were 102 (5.0%) stroke recurrence, 9 (0.4%) myocardial infarction and 440 (21.5%) death events within 1 year after stroke onset. Proportional hazards regression models were constructed and the non-linearity of effects of heart rate parameters were examined for outcome events. Among all the associations, effects of mean heart rate on primary outcome and all-cause mortality were non-linear ( p’s for quadratic effect = 0.017 and 0.032, respectively). The overall effects were significant only for effects of mean heart rate on primary outcome and all-cause mortality (P =0.013 and P=0.006, respectively). Effects of CV on outcome variables were not significant. Conclusion: This study suggests that mean heart rate during the first day of hospitalization was a predictor of future vascular events in AF patients presenting with acute ischemic stroke and the association seems to be non-linear ‘J shaped’. However, heart rate variability did not affect.

Background and Purpose— Research on the relationship between caffeine-containing medicines (CCMs) and the risk of hemorrhagic stroke (HS) is sparse. The aim of this study is to evaluate the association between CCMs and the risk of HS. Methods— We performed a multicenter case–control study in South Korea, from 2002 to 2004. A total of 940 patients with nontraumatic acute HS, aged 30 to 84 years without a history of stroke, 940 community, and 940 hospital controls, age and sex matched to each case, were included. We obtained information on all medications taken in the 14 days before the date (index date) and time of stroke onset (zero-time) for case subjects or matched zero-time for control subjects. Exposure to CCMs was defined by use on the index date before zero-time or during the preceding 3 days. The adjusted odds ratios and their 95% confidence intervals (CIs) were estimated by conditional logistic regression. Results— The adjusted odds ratio for the association between the use of CCM and risk for HS was 2.23 (95% CI, 1.41–3.69) for all HS, 2.24 (95% CI, 1.08–4.66) for subarachnoid hemorrhage, and 2.49 (95% CI, 1.29–4.80) for intracerebral hemorrhage. Stratified by daily coffee intake, adjusted odds ratio of CCMs for HS was 2.95 (95% CI, 1.45–5.98) for those who did not drink coffee on a daily basis. Conclusions— These results suggest that use of CCMs is associated with increased risk of HS, both subarachnoid hemorrhage and intracerebral hemorrhage.

Background: The widespread use of drip-and-ship strategy in acute ischemic stroke (AIS) is confined by the safety concerns during transfer. However, recent development of endovascular therapy (EVT) might add the advantage of higher recanalization rate to this strategy. We evaluated the effectiveness and safety of drip-and-ship versus conventional (front-door) strategy of preceding intravenous thrombolysis (IVT) in large artery occlusion stroke patients receiving EVT. Method: From a prospective multicenter stroke registry (CRCS-5) database, we identified AIS patients treated with IVT and EVT within 8 h of onset and admitted to the 14 participating centers between 2008 and 2013. Safety outcomes were symptomatic intracranial hemorrhage (sICH), and 3-month mortality. Effectiveness outcome was a 3-month modified Rankin Scale (mRS) score. We performed multivariable logistic regression analysis using generalized estimating equation to estimate adjusted odds ratio (OR) and 95% confidence interval (CI) of the drip-and-ship versus the front-door. Results: Of 16929 AIS patients registered during 64 months, 480 were treated with IVT and EVT within 8 h, and 61 (13%) were categorized into drip-and-ship group. Mean onset to IVT and IVT to EVT times were 117±51 and 187±69 minutes in drip-and-ship strategy and 127±59 and 75±38 minutes in front-door strategy, respectively. Forty-eight drip-and-ship cases were matched to 146 front-door cases by age and initial NIH stroke scale (NIHSS). Compared to the front-door cases, the drip-and-ship cases were more likely to be a habitual smoker, and treated with standard dose alteplase. sICH developed in 5.5% of the front-door strategy and 10.4% of the drip-and-ship strategy (p=0.146). After adjustment for age, initial NIHSS, pre-stroke mRS score, and variables with p Conclusion: The drip-and-ship strategy did not improve functional recovery at 3 months, and the safety issues might still exist in patients receiving EVT. However, there is a possible underestimation of initial stroke severity in drip and ship patients.

Background and Purpose— In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence. Methods— In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding. Results— Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77–1.35; P =0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P =0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group. Conclusions— Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00814268.

Background and Purpose— Selecting among different antiplatelet strategies when patients experience a new ischemic stroke while taking aspirin is a common clinical challenge, currently addressed by a paucity of data. Methods— This study is an analysis of a prospective multicenter stroke registry database from 14 hospitals in South Korea. Patients with acute noncardioembolic stroke, who were taking aspirin for prevention of ischemic events at the time of onset of stroke, were enrolled. Study subjects were divided into 3 groups according to the subsequent antiplatelet therapy strategy pursued; maintaining aspirin monotherapy (MA group), switching aspirin to nonaspirin antiplatelet agents (SA group), and adding another antiplatelet agent to aspirin (AA group). The primary study end point was the composite of stroke (ischemic and hemorrhagic), myocardial infarction, and vascular death up to 1 year after stroke onset. Results— A total of 1172 patients were analyzed for this study. Antiplatelet strategies pursued in study patients were MA group in 212 (18.1%), SA group in 246 (21.0%), and AA group in 714 (60.9%). The Cox proportional hazards regression analysis showed that, compared with the MA group, there was a reduction in the composite vascular event primary end point in the SA group (hazard ratio, 0.50; 95% confidence interval, 0.27–0.92; P =0.03) and in the AA group (hazard ratio, 0.40; 95% confidence interval, 0.24–0.66; P Conclusions— This study showed that, compared with maintaining aspirin, switching to or adding alternative antiplatelet agents may be better in preventing subsequent vascular events in patients who experienced a new ischemic stroke while taking aspirin.

Background and Purpose— Time-dependent changes in individual platelet reactivity have been detected in patients with coronary artery disease. Therefore, we sought to evaluate the time-dependent changes in platelet reactivity to aspirin during the acute stage after ischemic stroke and the clinical implications of variable patient responses to aspirin in acute ischemic stroke. Methods— We conducted a single-center, prospective, observational study. The acute aspirin reaction unit (ARU) was measured after 3 hours of aspirin loading, with higher values indicating increased platelet reactivity despite aspirin therapy. The follow-up ARU was measured on the fifth day of consecutive aspirin intake. The numeric difference between the follow-up ARU and the acute ARU was defined as ΔARU and was stratified into quartiles. Early neurological deterioration was regarded as an early clinical outcome. Results— Both the acute ARU (476±69 IU) and the follow-up ARU (451±68 IU) were measured in 349 patients in this study. Early neurological deterioration was observed in 72 patients (20.6%). Changes in aspirin platelet reactivity over time showed an approximately Gaussian distribution. The highest ΔARU quartile was independently associated with early neurological deterioration (odds ratio, 3.19; 95% confidence interval, 1.43–7.10; P =0.005) by multivariate logistic regression analysis. Conclusions— The results of our study showed that the increase in platelet reactivity to aspirin over time is independently associated with early neurological deterioration in patients with acute ischemic stroke. In addition, during the acute stage of ischemic stroke, serial platelet reactivity assays may be more useful than a single assay for identifying the clinical implications of aspirin platelet reactivity after ischemic stroke.

Background and Purpose— We aimed to generate rigorous graphical and statistical reference data based on volumetric measurements for assessing the relative severity of white matter hyperintensities (WMHs) in patients with stroke. Methods— We prospectively mapped WMHs from 2699 patients with first-ever ischemic stroke (mean age=66.8±13.0 years) enrolled consecutively from 11 nationwide stroke centers, from patient (fluid-attenuated-inversion-recovery) MRIs onto a standard brain template set. Using multivariable analyses, we assessed the impact of major (age/hypertension) and minor risk factors on WMH variability. Results— We have produced a large reference data library showing the location and quantity of WMHs as topographical frequency-volume maps. This easy-to-use graphical reference data set allows the quantitative estimation of the severity of WMH as a percentile rank score. For all patients (median age=69 years), multivariable analysis showed that age, hypertension, atrial fibrillation, and left ventricular hypertrophy were independently associated with increasing WMH (0–9.4%, median=0.6%, of the measured brain volume). For younger (≤69) hypertensives (n=819), age and left ventricular hypertrophy were positively associated with WMH. For older (≥70) hypertensives (n=944), age and cholesterol had positive relationships with WMH, whereas diabetes mellitus, hyperlipidemia, and atrial fibrillation had negative relationships with WMH. For younger nonhypertensives (n=578), age and diabetes mellitus were positively related to WMH. For older nonhypertensives (n=328), only age was positively associated with WMH. Conclusions— We have generated a novel graphical WMH grading (Kim statistical WMH scoring) system, correlated to risk factors and adjusted for age/hypertension. Further studies are required to confirm whether the combined data set allows grading of WMH burden in individual patients and a tailored patient-specific interpretation in ischemic stroke-related clinical practice.

Background: Combination treatment with clopidogrel and aspirin is not currently recommended for secondary prevention of stroke, but its superior effect to aspirin alone has been controversial according to stroke subtype and stage. We sought to compare the effect of aspirin and clopidogrel to aspirin alone for recurrent ischemic lesion in acute stage of atherothrombotic stroke. Methods: Combination of clopidogrel and aspirin for prevention of recurrence in acute atherothrombotic stroke study (COMPRESS) was a prospective, randomized, double-blind, placebo-controlled, multicenter trial. We enrolled 358 patients with acute atherothrombotic stroke within 48 hours after symptom onset, and randomly assigned them to receive clopidogrel (75 mg per day) plus aspirin (100 mg per day) or aspirin alone (100 mg per day) for 30 days. The primary endpoint was proportion of patients with a newly developed ischemic lesion within 30 days, as confirmed with brain MRI. Secondary endpoints were modified Rankin Scale scores at 30 days, occurrence of the composite endpoint of non-fatal stroke, myocardial infarction and cardiovascular death, and incidence of all types of stroke. The clinicaltrials.gov registration number for this trial was NCT00814268. Results: Among 358 patients enrolled, 349 patients who received at least one dose of study medication after randomization were included in the efficacy analysis population (clopidogrel plus aspirin, n=174; aspirin alone, n=175).Recurrent ischemic lesions were observed in 61 patients in the combination group (36.5%) and 60 patients in the aspirin alone group (35.9%; p=0.91). The significant difference was not found between the groups in the secondary endpoints. In the safety analysis, any bleeding incidence was non-significantly higher in the combination group (n=29 vs. n=19; p=0.10), and episodes of life-threatening hemorrhage and major hemorrhage were very low in both groups. Conclusion: Combination treatment of clopidogrel and aspirin is not superior to aspirin alone for prevention of recurrent ischemic lesion in acute atherothrombotic stroke patients. Acknowledgement: This study was co-sponsored by Sanofi-Aventis Korea and BMS Korea.

Background: Some studies have shown that biological aspirin resistance (BAR) could be associated with an increased risk of early neurological deterioration (END). Considering the risk of END and recurrent stroke is greatest during the acute phase, it would be important to investigate the influences of acute BAR on early outcomes in acute ischemic stroke. However, it is still controversial if assays of aspirin resistance might accurate and consistent. Therefore, we sought to find whether the changes of aspirin responsiveness might be associated with END in patients with acute ischemic stroke. Methods: This study was a part 1 study of ongoing, single center, prospective observational study. Patients of part 1 study were consecutively recruited from our tertiary stroke center. These patients were those who (1) presented and were evaluated within the first 24 hours of symptom onset; (2) were no potential risks of cardioembolism; and (3) provided written informed consent. Aspirin reaction unit (ARU) was assessed using the VerifyNow. Acute ARU (aARU) was measured at 3 hours after aspirin loading in emergent department. Follow-up ARU (fuARU) was performed after 5 consecutive days of aspirin medication. An ARU value ≥ 550 was defined as BAR. Differences between fuARU and aARU were defined as “changes of ARU”. To evaluate the association between changes of ARU and END, ‘changes of ARU’ were classified according to 4 equal sized groups. END was defined as an increase in NIHSS scores by 1 or more points between hospital days 0 and 5. Results: Three-hundreds forty nine patients were performed both aARU and fuARU. END occurred in 72 (20.6%) patients. Patients with END had higher values of changes of ARU than those without (-7.1 vs -29.6, p=0.040, respectively). Furthermore, END more frequently occurred in patients in forth quartiles than those in other quatiles of changes of ARU (4 th quartiles: OR, 3.188; 95% CI, 1.431-7.104; p=0.005). Conclusions: Our results showed that increase of fuARU was independently associated with END. The results of our study suggested that in acute stage of ischemic stroke, it may be helpful for serial assay of aspirin responsiveness to evaluate the association between early outcomes and aspirin resistance.

Background: One third of patients with initially mild strokes have unfavorable outcome, and the efficacy of intravenous thrombolysis (IVT) in those patients has not proven. This study aimed to evaluate the comparative effectiveness of IVT over no thrombolysis in patients with mild ischemic stroke presenting within 4.5 hours of onset. Methods: From a multicenter prospective stroke registry database, we identified acute ischemic stroke patients (1) who were aged 18 years or more, (2) whose neuroimaging confirmed relevant acute ischemic lesions, (3) who were presented within 4.5 hours of onset, and (4) whose initial NIHSS scores were 5 points or less. Matching and inverse probability of treatment weighting (IPTW) by propensity score (PS) were used to remove baseline imbalance between the IVT and no treatment groups. Further adjustments for potential confounders were made in the IPTW analysis. The adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) of IVT compared to no treatment were calculated for 3-month modified Rankin Scale (mRS) 0-1 (primary efficacy outcome), the full distribution of mRS scores (sedoncary efficacy outcome, by an ordinal logistic regression analysis), and symptomatic hemorrhagic transformation (sHT, safety outcome). Results: Between April 2008 and May 2012, 13,117 stroke patients were hospitalized to the 12 participating centers. Among them, 1,386 subjects met the eligibility criteria, and 194 (14.0%) were treated with IVT. The proportions of 3-month mRS 0-1 were not different between the IVT and no treatment groups (71% vs. 75%, p=0.18), but those of sHT were different (4.1% vs. 0.5%, p The adjusted ORs (95% CIs, p values) were 1.46 (0.95-2.25, 0.08) by PS-matching and 1.47 (0.77-2.82, 0.24) by IPTW for 3-month mRS 0-1; 1.05 (0.73-1.49, 0.80) by PS-matching and 1.09 (0.65-1.81, 0.75) for an increment of 3-month mRS score; and 7.47 (1.52-36.64, 0.01) by PS-matching and 3.85 (0.82-18.06, 0.09) by IPTW for sHT. Conclusion: This comparative effectiveness analysis based on the large multicenter stroke registry database failed to prove the superiority of intravenous thrombolysis over no treatment in patients with mild ischemic stroke.

Introduction: A considerable body of evidence suggests that oxidative stress is a fundamental mechanism of brain damage in stroke. A recent study suggests that the antioxidant properties of alpha-lipoic acid (aLA) correlate with its ability to promote neuroproliferation. However, there have been no reports of comprehensive studies examining the neurorestorative effects of aLA administered after the onset of ischemia. Hypothesis: The neuroprotective effects of acute treatment with ALA on neuroproliferation and long-term functional recovery following cerebral ischemic injury were examined using an animal model of clinical stroke with middle cerebral artery occlusion (MCAO). Methods: The middle cerebral artery (MCA) of adult male Sprague-Dawley rats was occluded for 2 h and then reperfused. To examine the effect of ALA on brain infarction, ALA (20 mg/kg body weight) was administered after the induction of anesthesia in 71 animals (ALA group) through the left external jugular vein immediately after reperfusion of the left MCAO. An equivalent volume of vehicle was administrated to 71 animals (control group) using the same procedure. A neurologic examination was performed at defined points after MCAO and a neurological deficit score (NDS) was obtained. Motor impairment was assessed by the accelerating rotarod test. Levels of endogenous neural precursor and glial cell were analyzed by immunohistochemistry. Results: Immediate aLA administration group after reperfusion significantly reduced the mortality, infarct size, and NDS than control group (n=71, P=0.005, P=0.002, and P=0.001, respectively). Long-term functional outcomes by Rotarod test were also markedly improved by aLA treatment (P=0.013). After 7 and 14 days of treatment, significantly more cells were labeled with BrdU, nestin, and GFAP in the aLA-treated rats along the infarct and infarct core regions. Significantly more BrdU/GFAP double-labeled cells were observed in the subventricular zone of the aLA group on days 7 and 14. Conclusions: These results indicate that urgent treatment with aLA after ischemic injury may have significant neurorestorative effects through enhanced neuroproliferation. aLA may be a useful intervention for the treatment of acute ischemic stroke.

Background: Despite its clinical importance in the Koreans, the status of recanalization therapy for acute occlusion of the intracranial cerebral arteries has not been reported yet. Methods: Using a nationwide stroke registry, a consecutive series of 642 patients with symptomatic occlusion of intracranial arteries were identified among 3028 who were hospitalized within 12 h of stroke onset at 10 participating centers between 2010 and 2011. Demographics, clinical characteristics, clinical outcomes, and type of recanalization therapy were described. Results: The mean age was 68.6 years (57.2% males, median baseline NIHSS 12). MCA was most commonly affected vessel (65.1%), followed by intracranial ICA (15.3%), PCA (14.2%), basilar artery (11.1%), and ACA (5.1%). Recanalization therapy was applied in 307 patients (47.8%); intravenous thrombolysis only (IVT) in 45.9%, and endovascular treatment (ET) in 54.1%. Intravenous thrombolysis treatment preceded ET in 69.9%. Doses of tPA were 0.6mg/kg in 22.3% and 0.9mg/kg in 77.7%. Recanalization therapy according to occluded vessels and onset-to-arrival time is described in the Table. Recanalization by IAT as seen on angiography was complete (thrombolysis in cerebral infarction [TICI] grade 3) in 29.5% and partial (TICI grade 2A or 2B) in 50.6%. Solitaire were applied to 48.8% of patients with ET and recanalization rate was 86.4%, and Penumbra were applied to 15.1% and recanalization rate (TICI grade 2A~3) was 76.0%. Favorable outcome (modified Rankin Scale, 0-2) was achieved in 39.4% of those with IVT and in 35.4% of those with ET, and symptomatic hemorrhagic transformation occurred in 8.5% and 12.0%, respectively. Conclusion: This study shows that a considerable proportion of patients with symptomatic occlusion of intracranial cerebral arteries are treated by endovascular approach. Efficacy and safety of endovascular approach in this setting should be tested by randomized clinical trials.

Background and Purpose— The aim of this study was to investigate differences in risk factors and stroke mechanisms between intracranial atherosclerosis (ICAS) and extracranial atherosclerosis (ECAS) and between anterior and posterior circulation atherosclerosis. Methods— A multicenter, prospective, Web-based registry was performed on atherosclerotic strokes using diffusionweighted magnetic resonance imaging and magnetic resonance angiography. Stroke mechanisms were categorized as artery-to-artery embolism, in situ thrombo-occlusion, local branch occlusion, or hemodynamic impairment. Results— Onethousand patients were enrolled from 9 university hospitals. Age (odds ratio [OR], 1.033; 95% confidence interval [CI], 1.018–1.049), male gender (OR, 3.399; 95% CI, 2.335–4.949), and hyperlipidemia (OR, 1.502; 95% CI, 1.117–2.018) were factors favoring ECAS (vs ICAS), whereas hypertension (OR, 1.826; 95% CI, 1.274–2.618; P =0.001) and diabetes mellitus (OR, 1.490; 95% CI, 1.105–2.010; P =0.009) were related to posterior (vs anterior) circulation diseases. Metabolic syndrome was a factor related to ICAS (vs ECAS) only in posterior circulation strokes (OR, 2.433; 95% CI, 1.005–5.890; P =0.007). Stroke mechanisms included arterytoartery embolism (59.7%), local branch occlusion (14.9%), in situ thrombo-occlusion (13.7%), hemodynamic impairment (0.9%), and mixed (10.8%). Anterior ICAS was more often associated with artery-to-artery embolism (51.8% vs 34.0%) and less often associated with local branch occlusion (12.3% vs 40.4%) than posterior ICAS ( P Conclusions— The prevalence of risk factors and stroke mechanisms differ between ICAS and ECAS, and between anterior and posterior circulation atherosclerosis. Posterior ICAS seems to be closely associated with metabolic derangement and local branch occlusion. Prevention and management strategies may have to consider these differences.

Background and Purpose— We hypothesized that technetium-99m-ethylene dicysteine-metronidazole ( 99m Tc-EC-MN) localizes to brain tissue that is hypoxic but viable. This study prospectively evaluated the relationship between neurological outcome and uptake of 99m Tc-EC-MN in peri-infarcted regions of the brain. Methods— Eight patients with acute ischemic stroke in the territory of the left middle cerebral artery underwent 99m Tc-EC-MN and 99m Tc-ethyl cysteinate dimer (ECD) brain SPECTs on the same day during the subacute stage (10.3±2.5 days). The infarct volumes from 99m Tc-ECD images (IV ECD ), infarct volumes from diffusion-weighted MRI images (IV DW ), and hypoxic volume (HV) from 99m Tc-EC-MN images were calculated. The net infarct volume (NIV ECD ) was defined as IV ECD minus HV. The National Institutes of Health Stroke Scale scores were measured on admission and days 1, 3, 7, and 30. Results— IV ECD was greater than IV DW . The lesion-to-normal count-density ratios of 99m Tc-EC-MN ranged from 1.80 to 5.96. HV was 60.2±65.2 cm 3 , and the mean percent HV was 24.5±28.1% of IV ECD . NIV ECD was 162.6±133.4 cm 3 and was significantly smaller than IV ECD . NIV ECD was significantly correlated with National Institutes of Health Stroke Scale score at 1 month and was a significant predictor of neurological deficit at 1 month. Conclusions— 99m Tc-EC-MN brain SPECT can detect hypoxic tissue after acute ischemic stroke and, in combination with 99m Tc-ECD brain SPECT, is useful in predicting neurological outcome in ischemic stroke patients.