Jaseong Koo

Cilostazol Prevents the Progression of the Symptomatic Intracranial Arterial Stenosis The Multicenter Double-Blind Placebo-Controlled Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis

Background and Purpose— Cilostazol, a phosphodiesterase inhibitor, has been reported to reduce restenosis rate after coronary angioplasty and stenting. This study was performed to investigate the effect of cilostazol on the progression of intracranial arterial stenosis (IAS). Methods— We randomized 135 patients with acute symptomatic stenosis in the M1 segment of middle cerebral artery or the basilar artery to either cilostazol 200 mg per day or placebo for 6 months. Aspirin 100 mg per day was also given to all patients. Patients with potential embolic sources in the heart or extracranial arteries were excluded. IAS was assessed by magnetic resonance angiogram (MRA) and transcranial Doppler (TCD) at the time of recruitment and 6 months later. The primary outcome was the progression of symptomatic IAS on MRA and secondary outcomes were clinical events and progression on TCD. Results— Thirty-eight patients were prematurely terminated. Dropout rates and reasons for dropouts were similar between the cilostazol and placebo groups. There was no stroke recurrence in either cilostazol or placebo group, but there was 1 death and 2 coronary events in each group. In cilostazol group, 3 (6.7%) of 45 symptomatic IAS progressed and 11 (24.4%) regressed. In placebo group, 15 (28.8%) of symptomatic IAS progressed and 8 (15.4%) regressed. Progression of symptomatic IAS in cilostazol group was significantly lower than that in placebo group (P=0.008) Conclusion— Our study suggests that symptomatic IAS is a dynamic lesion and cilostazol may prevent its progression.

Efficacy and Safety of Combination Antiplatelet Therapies in Patients With Symptomatic Intracranial Atherosclerotic Stenosis

Background and Purpose— An optimal strategy for management of symptomatic intracranial atherosclerotic stenosis (ICAS) has not yet been established. We compared the efficacy of 2 combinations of antiplatelets, aspirin plus cilostazol (cilostazol group) verus aspirin plus clopidogrel (clopidogrel group), on the progression of ICAS, which is known to be associated with clinical stroke recurrence. Methods— In this investigator-initiated double-blind trial, 457 patients with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or the basilar artery were randomly allocated into either a cilostazol group or a clopidogrel group. After 7 months of treatment, follow-up MR angiogram and MRI were performed. The primary end point was the progression of ICAS in comparison with stenosis on the baseline MR angiogram. Secondary end points included the occurrence of new ischemic lesions on MRI, composite of cardiovascular events, and major bleeding complications. Results— Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the clopidogrel group (P=0.312). Cilostazol did not reduce the progression of symptomatic ICAS (20 of 202) compared to clopidogrel (32 of 207) (odds ratio, 0.61; P=0.092), although favorable changes in serum lipoproteins were observed in the cilostazol group. There were no significant differences between the 2 groups with respect to new ischemic lesions (18.7% versus 12.0%; P=0.078) and major hemorrhagic complications (0.9% versus 2.6%; P=0.163). Conclusions— This trial failed to show significant difference in preventing progression of ICAS and new ischemic lesions between the 2 combination antiplatelet therapies in the patients with symptomatic ICAS. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00130039.

Cilostazol in Acute Ischemic Stroke Treatment (CAIST Trial): A Randomized Double-Blind Non-Inferiority Trial

Background: Aspirin is a proven antiplatelet agent in acute ischemic stroke, and there are no current guidelines for other antiplatelet treatments. We aimed to compare the efficacy and safety of cilostazol with aspirin in acute stroke. Methods: Patients with measurable neurological deficits (NIHSS score ≤15) within 48 h of onset were randomly assigned to cilostazol (200 mg/day) or aspirin (300 mg/day) for 90 days. The primary endpoint was a modified Rankin Scale (mRS) score of 0–2 at 90 days. Cardiovascular events, bleeding complications, and other functional outcomes were also assessed. Statistical analysis was carried out by intention-to-treat and per-protocol bases. This trial is registered with ClinicalTrials.gov (NCT00272454). Results: In total, 458 patients were enrolled (mean age of 63 years, median NIHSS of 3), and mRS at 90 days was obtained in 447 patients. The primary endpoint was achieved in 76% (173/228) of those randomized to cilostazol and in 75% (165/219) assigned to aspirin, which supported the pre-specified non-inferiority of cilostazol to aspirin (95% CI of proportion difference: –6.15 to 7.22%, p = 0.0004). These results were also supported by per-protocol analysis (p = 0.045). Cardiovascular events occurred in 6 patients (3%) treated with cilostazol, and in 9 patients (4%) treated with aspirin (p = 0.41). Adverse events were more common in cilostazol-treated patients during the trial (91 vs. 85%, p = 0.055), while the frequencies of bleeding complications (cilostazol 11%, aspirin 13%, p = 0.43) or drug discontinuation (cilostazol 10%, aspirin 7%, p = 0.32) were not different. Conclusion: Cilostazol is feasible in acute ischemic stroke, and comparable to aspirin in its efficacy and safety.

Reperfusion Therapy in Unclear-Onset Stroke Based on MRI Evaluation (RESTORE) A Prospective Multicenter Study

Background and Purpose— Unclear-onset strokes are generally excluded from time-based thrombolytic therapy. We examined the safety and feasibility of magnetic resonance imaging-based reperfusion therapy in unclear-onset stroke. Methods— This prospective, multicenter, single-arm study screened consecutive unclear-onset stroke patients within 6 hours of symptom detection. Patients with perfusion-diffusion mismatch >20% and negative or subtle fluid-attenuated inversion recovery changes were treated with intravenous tissue plasminogen activator, intra-arterial therapy, or a combination. The safety outcome was symptomatic intracranial hemorrhage within 48 hours after treatment. The primary efficacy outcome was a 3-month modified Rankin Scale score of 0 to 2. Controls were untreated unclear-onset stroke patients prospectively captured in stroke registries. Results— Of 430 unclear-onset stroke patients, 83 (19.3%) received reperfusion therapy (mean age, 67.5 ± 10.4 years; males, 66.3%; median baseline National Institutes of Health Stroke Scale, 14). Symptomatic intracranial hemorrhage with any neurological decline developed in 5 patients (6.0%). Symptomatic intracranial hemorrhage with National Institutes of Health Stroke Scale worsening ≥4 developed in 3 patients (3.6%). Thirty-seven patients (44.6%) achieved modified Rankin Scale score of 0 to 2, and 24 (28.9%) had modified Rankin Scale score of 0 to 1. Female, baseline National Institutes of Health Stroke Scale score, no immediate or early recanalization, and more white blood cells were independent predictors of poor outcome. Compared with untreated controls, the treated group was significantly associated with good outcomes of modified Rankin Scale score of 0 to 2 after adjusting for age, sex, and baseline National Institutes of Health Stroke Scale in logistic regression analysis (odds ratio, 2.25; 95% CI, 1.14–4.49). Conclusions— In unclear-onset stroke patients, magnetic resonance imaging-based reperfusion therapy was feasible and safe. Randomized controlled trials are warranted to confirm the benefit of reperfusion therapy for unclear-onset stroke.

Intramural Hematoma Detection by Susceptibility-Weighted Imaging in Intracranial Vertebral Artery Dissection

Background: The radiologic diagnosis of vertebral artery dissection (VAD) depends on characteristic intraluminal findings on angiography and intramural hematoma or a double-lumen sign on high-resolution vessel wall imaging. We aimed to evaluate the accuracy of intramural hematoma sign on susceptibility-weighted imaging (SWI) in VAD. Methods: We retrospectively analyzed SWI, phase map images and brain computed tomography (CT) of the consecutive patients who suffered an ischemic stroke in the vertebral artery territory from August 2010 to July 2012. We divided the patients into 2 groups: the VAD group and the nondissection group. VAD was diagnosed by conventional catheter angiographic findings (aneurysmal dilatation, pearl-and-string or tapered steno-occlusion) and pathognomonic findings such as intramural hematoma or a double-lumen sign on the source images of TOF-MRA, high-resolution T1-weighted MRI or high-resolution T2-weighted MRI. Intramural hematoma sign was considered positive if the patient had an eccentric or concentric hypointense signal lesion in the vertebral artery on SWI, a corresponding hyperintense signal on phase map and no evidence of calcification on the brain CT, suggesting blood products other than calcification. Two experienced neuroradiologists blinded to clinical information and angiographic findings were asked to judge for the presence of intramural hematoma sign on SWI. The accuracy of intramural hematoma sign on SWI was evaluated. Phase value, demographic and clinical data were compared between the VAD and the nondissection groups. Results: Thirty-nine patients were included: 10 in the VAD group and 29 in the non-dissection group. Among the VAD group cases, intramural hematoma sign on SWI was positive in 9 of the 10 VAD cases and in 1 out of the 29 cases in the nondissection group. The intramural hematoma sign on SWI was significantly associated with VAD (p < 0.001), and showed sensitivity of 90% and specificity of 96.6%. Mean phase values of intramural hematomas (n = 9) were all positive and those of calcified lesions (n = 13) were all negative (0.45 radian vs. -0.42 radian, p < 0.001). Conclusions: The intramural hematoma sign on SWI was significantly associated with VAD and the phase map values were higher in intramural hematomas when compared with atherosclerotic calcifications.

Nighttime Blood Pressure and White Matter Hyperintensities in Patients With Parkinson Disease

Increasing evidence indicates that nocturnal blood pressure level and/or loss of nocturnal blood pressure dips are sensitive markers of cardiovascular morbidity and mortality. Several studies have suggested that blunted heart rate variability and nocturnal decline in heart rate are also associated with target organ damage. These phenomena occur relatively commonly in patients with Parkinson disease (PD); however, few studies have assessed the consequences of these abnormalities in patients with PD. We investigated the influence of circadian changes in blood pressure and heart rate on white matter hyperintensities (WMHs) in patients with PD. The presence of nocturnal hypertension was associated with increased WMH score, and nighttime systolic pressure was closely related with white matter changes. Blunted heart rate variability and nocturnal decline in heart rate were also related to increasing WMH scores. The non-dipping phenomenon did not influence WMHs. These findings suggest that white matter changes are related to circadian autonomic dysfunction, particularly nocturnal hypertension in patients with PD. Therefore, it is important to monitor nocturnal blood pressure status, because modifying these circadian regulatory disturbances can be beneficial to protect against vascular brain damage in patients with PD. (Author correspondence: neuronet@catholic.ac.kr)

Cerebral Microbleeds and Early Recurrent Stroke After Transient Ischemic Attack Results From the Korean Transient Ischemic Attack Expression Registry

IMPORTANCE The risk of early recurrent stroke after transient ischemic attack (TIA) may be modifiable by optimal treatment. Although ABCD2 scores, diffusion-weighted imaging lesions, and large artery stenosis are well known to predict early stroke recurrence, other neuroimaging parameters, such as cerebral microbleeds (CMBs), have not been well explored in patients with TIA. OBJECTIVE To determine the rate of early recurrent stroke after TIA and its neuroimaging predictors. DESIGN, SETTING, AND PARTICIPANTS In this hospital-based, multicenter prospective cohort study, consecutive patients with TIA were enrolled from 11 university hospitals from July 1, 2010, through December 31, 2012. Patients who were admitted within 24 hours after symptom onset and underwent diffusion-weighted imaging were included. MAIN OUTCOMES AND MEASURES The primary end point was recurrent stroke within 90 days. Baseline demographics, clinical manifestations, neuroimaging findings, and use of antithrombotics or statins also were analyzed. RESULTS A total of 500 patients (mean age, 64 years; male, 291 [58.2%]; median ABCD2 score, 4) completed 90-day follow-up with guideline-based management: antiplatelets (457 [91.4%]), anticoagulants (74 [14.8%]), and statins (345 [69.0%]). Recurrent stroke occurred in 25 patients (5.0%). Compared with patients without recurrent stroke, those with recurrent stroke were more likely to have crescendo TIA (20 [4.2%] vs 4 [16.0%], P = .03), white matter hyperintensities (146 [30.7%] vs 13 [52.0%], P = .03), and CMBs (36 [7.6%] vs 7 [28.0%], P = .003). On multivariable Cox proportional hazards analysis, CMBs remained as independent predictors for recurrent stroke (hazard ratio, 3.66; 95% CI, 1.47-9.09; P = .005). CONCLUSIONS AND RELEVANCE Immediate and optimal management seems to modify the risk of recurrent stroke after TIA. Cerebral microbleeds may be novel predictors of stroke recurrence, which needs further validation.

Association Between Changes in Lipid Profiles and Progression of Symptomatic Intracranial Atherosclerotic Stenosis A Prospective Multicenter Study

Background and Purpose— Predictors of progression of intracranial atherosclerotic stenosis have not been clearly identified. We investigated whether poststroke changes in lipid profiles would affect the prognosis of symptomatic intracranial atherosclerotic stenosis. Methods— This is a substudy of Trial of cilOstazol in Symptomatic intracranial Stenosis 2 (TOSS-2). From 10 centers we enrolled 230 subjects with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or basilar artery. At baseline and 7 months after stroke, subjects underwent MR angiogram and assessment of cardiovascular risk factors including lipoprotein levels. Progression of intracranial atherosclerotic stenosis was determined by comparing stenosis on the baseline and follow-up MR angiograms. Results— Cilostazol treatment was more frequently seen in the nonprogression group (109 of 198 [55.1%]) than in the progression group (11 of 32 [34.4%]). At 7 months after stroke when compared with baseline, low-density lipoprotein cholesterol and total cholesterol levels decreased in both groups. However, only nonprogressors showed increase in high-density lipoprotein cholesterol levels between baseline and follow-up. Changes in apolipoprotein B/apolipoprotein A-I levels were not different between the groups, although apolipoprotein B/A-I at 7 months was higher in progressors than in nonprogressors. Remnant lipoprotein cholesterol levels decreased in nonprogressors, whereas they did not change in progressors. In multivariable analyses, after adjusting for cilostazol treatment and remnant lipoprotein cholesterol reduction or apolipoprotein B/A-I at 7 months, high-density lipoprotein cholesterol elevation remained as a significant predictor for the nonprogression. Conclusions— This is the first prospective multicenter study to demonstrate that high-density lipoprotein cholesterol elevation, along with remnant lipoprotein cholesterol reduction and low apolipoprotein B/A-I, is associated with prevention of angiographic progression of symptomatic intracranial atherosclerotic stenosis. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00130039.

Burden of Ischemic Stroke in Korea: Analysis of Disability-Adjusted Life Years Lost

Background and Purpose Disability-adjusted life years (DALY), incorporating both disability and mortality, has been widely employed to measure regional and global burdens of stroke. Thus far, the DALY lost to stroke in a population has been estimated using only the crude population-level data; no previous study has incorporated refined data from stroke registries. The aim of this study was to integrate the stroke registry data and the population-level incidence data to project the nationwide DALY lost to ischemic stroke. Methods From the data of two large ischemic stroke registries, we derived an average DALY lost due to ischemic stroke for each of the following age groups: <45, 45-54, 55-64, 65-74, 75-84, and ≥85 years. The nationwide ischemic stroke incidence for each age group was extracted from a cardiovascular and cerebrovascular surveillance study that analyzed the 2004 Korean Health Insurance database. Results The average DALY lost due to ischemic stroke for the age groups <45, 45-54, 55-64, 65-74, 75-84, and ≥85 years was 5.07, 4.63, 4.35, 3.88, 2.88, and 1.73, respectively. By multiplying the incidence and the average DALY lost, the nationwide DALY lost was determined to be 9,952 for those <45 years, 24,608 for 45-54 years, 50,682 for 55-64 years, 88,875 for 65-74 years, 52,089 for 75-84 years, and 8,192 for ≥85 years, respectively. The projected nationwide DALY lost due to 64,688 ischemic strokes in 2004 was 234,399 (121,482 for men and 113,244 for women), and the DALY lost per 100,000 person-years was 483 (500 for men and 469 for women). Conclusions Incidence data from a population study and DALY values derived from stroke registries can be integrated to provide a more refined projection of the nationwide burden of ischemic stroke. In Korea, more than 230,000 years of healthy life are being lost annually due to ischemic stroke, and hence prompt action is imperative.

Predictors of Recurrent Stroke in Patients With Symptomatic Intracranial Arterial Stenosis

Background and Purpose— Our goal was to investigate whether initial ischemic lesion pattern can predict stroke recurrence in patients with symptomatic intracranial arterial stenosis. Methods— Of the Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis (TOSS)-2 trial participants, we included patients who underwent diffusion-weighted imaging and fluid attenuation inversion recovery imaging at baseline with a follow-up fluid attenuation inversion recovery imaging at 7 months. Based on the diffusion-weighted imaging findings, we classified the initial ischemic lesion patterns according to location (subcortical versus cortical versus subcorticocortical) and multiplicity (single versus multiple). We also evaluated the occurrence of new ischemic lesions on follow-up fluid attenuation inversion recovery as well as clinical stroke in the symptomatic intracranial arterial stenosis territory. Results— Of 353 patients included in this study, 44 (12.5%) and 13 (3.7%) patients had new ischemic lesions and clinical recurrent stroke in the initial symptomatic intracranial arterial stenosis territory, respectively. On multivariable analysis, the initial lesion patterns of subcorticocortical and multiple lesions were independent predictors of new ischemic lesions in the symptomatic intracranial arterial stenosis territory (OR, 3.01; 95% CI, 1.33–7.01; P=0.03; OR, 2.81; 95% CI, 1.34–5.9; P=0.006). These patterns also predicted clinical recurrent stroke. Conclusion— Subcorticocortical lesions and multiple lesions are radiological predictors of recurrent ischemic stroke in symptomatic patients with intracranial arterial stenosis. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00130039.