Joung-Ho Rha

The Impact of Recanalization on Ischemic Stroke Outcome A Meta-Analysis

Background and Purpose— For a biomarker to serve as an auxiliary or surrogate outcome measure, it must be tightly correlated with and causally related to functional clinical outcome. Vessel recanalization is a potential surrogate outcome marker for functional outcome in trials of thrombolytic and mechanical recanalization therapies in acute stroke, but the correlation of recanalization and clinical outcome has not been previously systematically reviewed. Methods— Through Medline search, we identified and abstracted recanalization and outcome data from all articles published between 1985 and 2002 that assessed vessel recanalization, either spontaneous or therapeutically induced, in acute ischemic stroke. Results— Fifty-three studies encompassing 2066 patients reported recanalization rates. Recanalization rates categorized according to intervention were: spontaneous (24.1%), intravenous fibrinolytic (46.2%), intra-arterial fibrinolytic (63.2%), combined intravenous–intra-arterial (67.5%), and mechanical (83.6%). Clinical outcome data categorized by success or failure in achieving recanalization was available from 33 articles encompassing 998 patients. Good functional outcomes at 3 months were more frequent in recanalized versus nonrecanalized patients with odds ratio of 4.43 (95% CI, 3.32 to 5.91). Three-month mortality was reduced in recanalized patients (odds ratio, 0.24; 95% CI, 0.16 to 0.35). Rates of symptomatic hemorrhagic transformation did not differ between the 2 groups (odds ratio, 1.11; 95% CI, 0.71 to 1.74). Conclusions— Formal meta-analysis confirms a strong correlation between recanalization and outcome in acute ischemic stroke. Recanalization is strongly associated with improved functional outcomes and reduced mortality. These findings suggest that recanalization is an appropriate biomarker of therapeutic activity in early phase trials of thrombolytic treatment in acute ischemic stroke.

Stroke awareness decreases prehospital delay after acute ischemic stroke in korea

BackgroundDelayed arrival at hospital is one of the major obstacles in enhancing the rate of thrombolysis therapy in patients with acute ischemic stroke. Our study aimed to investigate factors associated with prehospital delay after acute ischemic stroke in Korea.MethodsA prospective, multicenter study was conducted at 14 tertiary hospitals in Korea from March 2009 to July 2009. We interviewed 500 consecutive patients with acute ischemic stroke who arrived within 48 hours. Univariate and multivariate analyses were performed to evaluate factors influencing prehospital delay.ResultsAmong the 500 patients (median 67 years, 62% men), the median time interval from symptom onset to arrival was 474 minutes (interquartile range, 170-1313). Early arrival within 3 hours of symptom onset was significantly associated with the following factors: high National Institutes of Health Stroke Scale (NIHSS) score, previous stroke, atrial fibrillation, use of ambulance, knowledge about thrombolysis and awareness of the patient/bystander that the initial symptom was a stroke. Multivariable logistic regression analysis indicated that awareness of the patient/bystander that the initial symptom was a stroke (OR 4.438, 95% CI 2.669-7.381), knowledge about thrombolysis (OR 2.002, 95% CI 1.104-3.633) and use of ambulance (OR 1.961, 95% CI 1.176-3.270) were significantly associated with early arrival.ConclusionsIn Korea, stroke awareness not only on the part of patients, but also of bystanders, had a great impact on early arrival at hospital. To increase the rate of thrombolysis therapy and the incidence of favorable outcomes, extensive general public education including how to recognize stroke symptoms would be important.

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.

Endovascular Recanalization Therapy in Acute Ischemic Stroke: Updated Meta-analysis of Randomized Controlled Trials

Background and Purpose Recent randomized clinical trials (RCTs) have demonstrated benefits of endovascular recanalization therapy (ERT) contrary to earlier trials. We aimed to estimate the benefits of ERT added to standard therapy in acute ischemic stroke. Methods From a literature search of RCTs testing ERT, we performed a meta-analysis to estimate an overall efficacy and safety of ERT for all trials, stent-retriever trials, and RCTs comparing ERT and intravenous tissue plasminogen activator (IV-TPA). Results We identified 15 relevant RCTs including 2,899 patients. For all trials, ERT was associated with increased good outcomes (odds ratio [OR] 1.79; 95% confidence interval [CI] 1.34, 2.40; P<0.001) compared to the control. ERT also increased no or minimal disability outcomes, good neurological recovery, good activity of daily living, and recanalization. ERT did not significantly increase symptomatic intracranial hemorrhage (SICH) (OR 1.19; 95% CI 0.83, 1.69; P=0.345) or death (OR 0.87; 95% CI 0.71, 1.05; P=0.151). In contrast, ERT significantly reduced extreme disability or death (OR 0.77; 95% CI 0.61, 0.97; P=0.025). Restricting to five stent-retriever trials comparing ERT plus IV-TPA vs. IV-TPA alone, the benefit was even greater for good outcome (OR 2.39; 95% CI 1.88, 3.04; P<0.001) and extreme disability or death (OR 0.57; 95% CI 0.41, 0.78; P=0.001). Restricting to eight RCTs comparing ERT (plus IV-TPA in six trials) with IV-TPA alone showed similar efficacy and safety. Conclusions This updated meta-analysis shows that ERT substantially improves clinical outcomes and reduces extreme disability or death without significantly increasing SICH compared to standard therapy.

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.

Thrombolysis for Acute Ischaemic Stroke with Alteplase in an Asian Population: Results of the Multicenter, Multinational Safe Implementation of Thrombolysis in Stroke-Non-European Union World (SITS-NEW)

Background Safe Implementation of Thrombolysis in Stroke-Non-European Union World was a multinational, prospective, open, monitored, observational study of intravenous alteplase as thrombolytic therapy in clinical practice. Safe Implementation of Thrombolysis in Stroke-Non-European Union World was required to assess the safety of alteplase in an Asian population by comparison with results from the European Safe Implementation of Thrombolysis in Stroke-Monitoring Study and pooled results from randomized controlled trials. Aims and/or hypothesis To evaluate the efficacy and safety of intravenous alteplase (0·9 mg/kg) as thrombolytic therapy within three-hours of onset of acute ischaemic stroke in an Asian population. Methods The 591 patients included were treated at 48 centers in four countries (South Korea, China, India, and Singapore) between 2006 and 2008. Primary outcomes were symptomatic (deterioration in National Institutes of Health Stroke Scale score ≥4 or death within the first 24 h) intracerebral haemorrhage type 2 22–36 h after the thrombolysis and mortality at three-month follow-up. The secondary outcome was functional independence (modified Rankin Scale score 0–2) at three-months. Results were compared with those from Safe Implementation of Thrombolysis in Stroke-Monitoring Study (n = 6483) and pooled results of patients (n = 415) who received intravenous alteplase (0·9 mg/kg) zero- to three-hours from onset of stroke symptoms in four randomized controlled trials (National Institute of Neurological Disorders and Stroke A and B, Altephase Thrombolysis for Acute Noninterventional Therapy in Ischaemic Stroke, and European Cooperative Acute Stroke Study II). Results Results are presented as Safe Implementation of Thrombolysis in Stroke-Non-European Union World vs. Safe Implementation of Thrombolysis in Stroke-Monitoring Study vs. pooled randomized controlled trials. Median age was 64 vs. 68 vs. 70 years, National Institutes of Health Stroke Scale score at baseline was 12 vs. 12 vs. 13, time from stroke onset to treatment was 130 vs. 140 vs. 135 mins, and females were 36·4% vs. 39·8% vs. 41·2%. Main outcomes (proportion of patients and 95% confidence intervals) were symptomatic intracerebral haemorrhage: 1·9% (1·1–3·3) vs. 1·7% (1·4–2·0) vs. 3·1% (1·8–5·3); mortality: 10·2% (8·0–12·9) vs. 11·3% (10·5–12·1) vs. 16·4% (13·1–20·3); and functional independence: 62·5% (58·5–66·4) vs. 54·8% (53·5–56·0) vs. 50·1% (45·3–54·9) at three-months. Adjusted odds ratio (95% confidence intervals) between Safe Implementation of Thrombolysis in Stroke-Non-European Union World and Safe Implementation of Thrombolysis in Stroke-Monitoring Study, and between Safe Implementation of Thrombolysis in Stroke-Non-European Union World and the pooled trials were 1·83 (0·89–3·77; P = 0·1156) and 0·63 (0·19–2·07; P = 0·4470) for symptomatic intracerebral haemorrhage, 0·90 (0·64–1·25; P = 0·5092) and 0·93 (0·52–1·64; P = 0·7915) for mortality at three-months, and 1·57 (1·25–1·96; P < 0·0001) and 1·35 (0·91–2·00; P = 0·1325) for functional independence. Conclusions These data demonstrate the safety and efficacy of the standard dose of intravenous alteplase (0·9 mg/kg) in an Asian population, as previously observed in the European population studied in Safe Implementation of Thrombolysis in Stroke-Monitoring Study and the populations in pooled randomized controlled trials, when used in routine clinical practice within three-hours of stroke onset. The findings should encourage wider use of thrombolytic therapy in Asian countries for suitable patients treated in stroke centers.

Spinal subdural hematoma following tissue plasminogen activator treatment for acute ischemic stroke

A 49-year-old woman with an acute ischemic stroke was treated by the intravenous administration of tissue plasminogen activator within 2 h of symptom onset. She complained of severe upper thoracic back pain the following day. Progressive paraparesis was detected on the third admission day. Spinal MRI demonstrated an acute anterior subdural hematoma from the C7 to T2 level. An urgent laminectomy was performed. Neurologists must be aware of the possibility that neck or back pain after thrombolysis for ischemic stroke may be the first presenting symptom of spinal hematoma.

Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone

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.