Patterns and Implications of Intracranial Atherosclerosis in Anterior and Posterior Circulation Identified by High-Resolution Vessel Wall Imaging.

INTRODUCTION: Anterior and posterior circulation atheroscleroses differ in vascular risk factors and stroke patterns. Posterior circulation stroke has worse clinical outcomes. However, few studies described the differentiation of plaque features between anterior and posterior circulation atheroscleroses via high-resolution vessel wall imaging (HR-VWI). We aimed to compare the plaque imaging features between anterior and posterior circulations to highlight the relevance of plaque imaging features to clinical events of ischemic stroke. METHODS: Prospective data from a HR-VWI cohort of adult patients with acute ischemic stroke or transient ischemic attack were retrospectively analyzed. Quantitative and qualitative measurements of atherosclerotic plaques along the middle cerebral arteries (MCAs), the basilar artery (BA), and the vertebral arteries (VAs) were conducted on HR-VWI. Vessels with stenotic degrees over 30% were identified on the matched time-of-flight magnetic resonance angiography (TOF-MRA) and visually classified into normal, irregular, stenotic, and occluded. The sensitivity, specificity, positive and negative predictive values for TOF-MRA in detecting abnormal vessels were calculated by using quantification on the basis of HR-VWI findings as the reference standard. RESULTS: One hundred and one patients (median age, 64 years old; 62.4% males) were included in this study. A total of 292 plaques were identified, with 152 in the MCAs, 35 in the BA, and 105 in the VAs. The VAs possessed significantly higher enhancement index (EI) (median 38.37 vs. 18.40, p <0.001), more plaques with positive remodeling (76.2% vs. 57.2%, p = 0.002) and intraplaque hypo-intensity (43.8% vs. 12.5%, p <0.001) than the MCAs. The MCAs presented with more intraplaque hemorrhage (IPH) (20.4% vs. 8.6%, p = 0.014) than the VAs. The sensitivity and specificity of TOF-MRA for evaluating luminal stenosis were 89.0 (82.5-93.4) and 66.7 (24.1-94.0) in anterior circulation, respectively, and were 75.2 (66.7-82.2) and 27.3 (7.3-60.7) in posterior circulation, respectively. CONCLUSION: Our findings might elucidate the clinical events and outcomes in anterior and posterior circulation stroke. Posterior circulation atherosclerosis had higher EI and more plaques with hypo-intensity, suggesting a heavier atherosclerosis burden. Positive remodeling pattern in posterior circulation atherosclerosis might create an impression of "wider" vascular lumen, leading to possible underestimation of atherosclerosis burden of posterior circulation on TOF-MRA as compared to HR-VWI. Besides, anterior circulation atherosclerosis with IPH might be associated with plaque rupture and artery-to-artery embolism. Future studies are needed to verify these findings.

Risk of subsequent disabling or fatal stroke in patients with transient ischaemic attack or minor ischaemic stroke: an international, prospective cohort study.

BACKGROUND: Patients who have had a transient ischaemic attack or minor stroke have an increased risk of cardiovascular events for the following 5 years. We aimed to assess 5-year functional outcomes in patients with transient ischaemic attack or minor ischaemic stroke and to determine the factors associated with long-term disability. METHODS: We analysed data from patients in TIAregistry.org, an international, prospective, observational registry of patients with transient ischaemic attack or minor ischaemic stroke from 61 specialised centres in 21 countries. Patients aged 18 years or older who had a transient ischaemic attack or minor stroke within the previous 7 days between May 30, 2009, and Dec 30, 2011, with a baseline modified Rankin scale (mRS) score of 0-1, and who had been followed up for 5 years, were eligible for inclusion in this study. We evaluated whether existing comorbidities and stroke recurrence, categorised as disabling (mRS score of >1, including death) or non-disabling (mRS score of 0-1), at 5 years after baseline, were associated with poor functional outcome (defined as an mRS score of >1). We used multivariable generalised equation models for factors associated with poor functional outcome at 5 years and multivariable cause-specific Cox hazard regression models in case of stroke recurrence. FINDINGS: Between May 30, 2009, and Dec 30, 2011, 3847 eligible patients were included in the study, 3105 (80·7%) of whom had an mRS evaluation at 5 years of follow-up. Median follow-up duration was 5·00 years (IQR 4·78-5·00). 710 (22·9%) of 3105 patients had an mRS score greater than 1 at 5 years. Factors associated with poor functional outcome at 5 years were older age (per 10-year increase, odds ratio [OR] 2·18, 95% CI 1·93-2·46; p<0·0001), diabetes of any type (1·45, 1·18-1·78; p=0·0001), history of stroke or transient ischaemic attack before the qualifying event (1·74, 1·37-2·22; p<0·0001), hypertension (1·38, 1·00-1·92; p=0·050), atrial fibrillation or flutter (1·52, 1·04-1·94; p=0·030), congestive heart failure (1·73, 1·22-2·46; p=0·0024), valvular disease (2·47, 1·70-3·58; p<0·0001), stroke as qualifying event (1·31, 1·09-1·57; p=0·0037), history of peripheral artery disease (1·98, 1·28-3·07; p=0·0023), history of coronary artery disease (1·32, 1·00-1·74; p=0·049), intracranial haemorrhage during follow up (4·94, 1·91-12·78; p=0·0013), and living alone (1·32, 1·10-1·59; p=0·0031). Regular physical activity before the index event was associated with reduced risk of poor functional outcome (OR 0·52, 95% CI 0·42-0·66; p<0·0001). 345 recurrent strokes had occurred at 5 years of follow-up, 141 (40·9%) of which were disabling or fatal. Stroke recurrence increased the risk of having a disability at 5 years (OR 3·52, 95% CI 2·37-5·22; p<0·0001). Recurrent disabling or fatal strokes were independently associated with older age (per 10-year increase, hazard ratio [HR] 1·61, 95% CI 1·35-1·92; p<0·0001), diabetes of any type (2·23, 1·56-3·17; p<0·0001), National Institutes of Health Stroke Scale score of greater than 5 at discharge (5·11, 2·15-12·13; p=0·0013), history of coronary artery disease (1·76, 1·17-2·65; p=0·0063), history of stroke or transient ischaemic attack before the qualifying event (1·54, 1·03-2·29; p=0·035), congestive heart failure (1·86, 1·01-3·47; p=0·044), stroke as qualifying event (1·73, 1·22-2·45; p=0·0024), mRS score of greater than 1 at discharge (2·48, 1·27-4·87; p=0·0083), and intracranial haemorrhage during follow-up (17·15, 9·95-27·43; p<0·0001). Regular physical activity before the index event was associated with reduced risk of recurrent disabling stroke at 5 years (HR 0·56, 95% CI 0·31-0·99; p=0·046), and 5-year disability without recurrent stroke (0·61, 0·47-0·79; p=0·0001). INTERPRETATION: We found a substantial burden of disability (mRS score of >1) at 5 years after transient ischaemic attack or minor ischemic stroke, and most predictors of this disability were modifiable risk factors. Patients who did regular physical exercise before the index event had a significantly reduced risk of disability at 5 years compared with patients who did no exercise. FUNDING: AstraZeneca, Sanofi, Bristol Myers Squibb, SOS Attaque Cérébrale Association.

Time to Loading Dose and Risk of Recurrent Events in the SOCRATES Trial.

Background and Purpose- Recurrent ischemia risk is high in the acute period after cerebral ischemic events. Effects of antiplatelet agents may vary by time to loading dose (TLD). We explored the risk of recurrent events and safety and efficacy of ticagrelor versus aspirin in relation to TLD. Methods- We randomized 13 199 patients with noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to 90-day ticagrelor or aspirin treatment within 24 hours of symptom onset. For this analysis, 13 126 patients were categorized by TLD as <12 hours or ≥12 hours from start of index event. The primary end point was the composite of stroke, myocardial infarction, or death within 90 days. Major bleeding was the primary safety end point. Results- TLD was <12 hours in 4403 (33.5%) and ≥12 hours in 8723 (66.5%). The Kaplan-Meier% for the primary end point for all patients with TLD<12 hours was 7.5% versus 6.9% in TLD≥12 hours. Among patients with TLD<12 hours, the primary end point occurred in 147/2196 (6.8%) randomized to ticagrelor and in 184/2207 (8.3%) randomized to aspirin (hazard ratio, 0.79; 95% CI, 0.64-0.98; P=0.036). Among patients with TLD≥12 hours, the primary end point occurred in 6.7% patients randomized to ticagrelor versus 7.0% to aspirin (hazard ratio, 0.95; 95% CI, 0.81-1.12; P=0.55). There was no significant treatment-by-TLD interaction. Major bleeding rates were comparable on ticagrelor and aspirin, regardless of TLD. Conclusions- The event rate for the primary end point was higher in patients treated early (<12 hours) versus later (≥12 hours). In this exploratory analysis, a larger numerical difference in the primary end point was observed among patients on ticagrelor than on aspirin when TLD was <12 hours compared with ≥12 hours, although the interaction terms for treatment-by-TLD were not significant. For major bleeding, no relation to TLD was observed. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Efficacy and Safety of Ticagrelor in Relation to Aspirin Use Within the Week Before Randomization in the SOCRATES Trial.

BACKGROUND AND PURPOSE: SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), comparing ticagrelor with aspirin in patients with acute cerebral ischemia, found a nonsignificant 11% relative risk reduction for stroke, myocardial infarction, or death (P=0.07). Aspirin intake before randomization could enhance the effect of ticagrelor by conferring dual antiplatelet effect during a high-risk period for subsequent stroke. Therefore, we explored the efficacy and safety of ticagrelor versus aspirin in the patients who received any aspirin the week before randomization. METHODS: A prespecified subgroup analysis in SOCRATES (n=13 199), randomizing patients with acute ischemic stroke (National Institutes of Health Stroke Scale score of ≤5) or transient ischemic attack (ABCD2 score of ≥4) to 90-day treatment with ticagrelor or aspirin. Patients in the prior-aspirin group had received any aspirin within the week before randomization. Primary end point was time to stroke, myocardial infarction, or death. Safety end point was PLATO (Study of Platelet Inhibition and Patient Outcomes) major bleeding. RESULTS: The 4232 patients in the prior-aspirin group were older, had more vascular risk factors, and vascular disease than the other patients. In the prior-aspirin group, the primary end point occurred in 138/2130 (6.5%) of patients on ticagrelor and in 177/2102 (8.3%) on aspirin (hazard ratio, 0.76; 95% confidence interval, 0.61-0.95; P=0.02); in patients with no prior-aspirin usage an event occurred in 304/4459 (6.9%) and 320/4508 (7.1%) on ticagrelor and aspirin, respectively (hazard ratio, 0.96; 95% confidence interval, 0.82-1.12; P=0.59). The treatment-by-prior-aspirin interaction was not statistically significant (P=0.10). In the prior-aspirin group, major bleeding occurred in 0.7% and 0.4% of patients on ticagrelor and aspirin, respectively (hazard ratio, 1.58; 95% confidence interval, 0.68-3.65; P=0.28). CONCLUSIONS: In this secondary analysis from SOCRATES, fewer primary end points occurred on ticagrelor treatment than on aspirin in patients receiving aspirin before randomization, but there was no significant treatment-by-prior-aspirin interaction. A new study will investigate the benefit-risk of combining ticagrelor and aspirin in patients with acute cerebral ischemia (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429). CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01994720.

Effect of a financial incentive on the acceptance of a smoking cessation programme with service charge: a cluster-controlled trial.

INTRODUCTION: Frontline health care professionals in Hong Kong may encounter high refusal rates for the Hospital Authority's Smoking Counselling and Cessation Programme (SCCP) when smokers know it is subject to a service charge. We compared SCCP booking and attendance rates among smokers with or without a financial incentive. METHODS: In this multicentre non-randomised cluster-controlled trial, adult smokers who attended one of six general out-patient clinics between November 2015 and April 2016 were invited to join an SCCP. Attendees in the three intervention-group centres but not the three control-group centres received a supermarket coupon to offset the service charge. RESULTS: A total of 173 smokers aged 18 years or older (92 in the intervention group and 81 in the control group) were recruited into the study. In the intervention group, 47 smokers (51%) agreed via a questionnaire that they would join the SCCP, compared with only 23 smokers in the control group (28%). The booking rates were 83% (n=39) in the intervention group and 83% (n=19) in the control group. Among those who had booked a place, 19 (49%) intervention-group participants and 11 (58%) control-group participants attended an SCCP session. Multivariable logistic regression revealed that offering a coupon was associated with agreeing to join an SCCP (odds ratio=4.963, 95% confidence interval=2.173-11.334; P<0.001) and booking an SCCP place (odds ratio=4.244, 95% confidence interval=1.838-9.799; P<0.001). CONCLUSION: Provision of a financial incentive was positively associated with agreement to join an SCCP and booking an SCCP place. Budget holders should consider providing the SCCP free of charge to increase smokers' access to the service.

Phosphorus flame retardants and Bisphenol A in indoor dust and PM2.5 in kindergartens and primary schools in Hong Kong.

Organophosphate flame retardants (PFRs) and bisphenol A (BPA) were measured in indoor dust and PM2.5 samples from nine kindergartens and two primary schools in Hong Kong. The average levels of PM2.5 ranged from 4.0E+03 ng/m3 to 1.5E+04 ng/m3. Average levels of PFRs (from 1.5 ng/m3 to 20 ng/m3 in PM2.5; from 8.0E-02 µg/g dw to 2.4 µg/g dw in dust) and BPA (from 6.4E-01 ng/m3 to 1.0 ng/m3 in PM2.5; from 1.0E-02 µg/g dw to 2.0E-01 µg/g dw in dust) were detected in most of the sampling sites. Tri-(2-Chloroethyl) phosphate (TCEP), tris(1,3-Dichloro-2-propyl) phosphate (TDCP), tris-(chloroisopropyl) phosphate (TCPP), and triphenyl phosphate (TPHP) were present in low levels in PM2.5 with medians of 16, 14, 8.7, and 3.2 ng/m3, respectively. In dust, the medians were 1.5E-01, 5.5E-02, 5.9E-01, 8.6E-01, and 8.5E-02 µg/g dw for TCEP, TCPP, TDCPP, TPHP, and 2-ethylhexyl diphenyl phosphate, respectively. The medians of BPA were 6.4E-01 ng/m3 and 7.4E-02 µg/g dw for PM2.5 and dust, respectively. A positive correlation was found between indoor PM2.5 and dust in the levels of TCEP (r = 0.85; p = .05). In the individual classroom in this survey, the predominant PFRs were similar, that is, TDCP and TCEP in indoor PM2.5 while TPHP and TDCP in dust. TPHP and TCEP in primary schools were obviously lower than those in kindergartens. The estimated daily intakes via PM2.5 and dust for all selected PFRs ranged from 1.3E-4 µg/kg/d to 2.0E-02 µg/kg/d, and the value of less than the detection limit at 3.5E-4 µg/kg/d was found for BPA. The EDI values of TPHP in dust non-dietary intake fraction were higher than those in the others. Calculated hazard indices (EDI/RfD) ranged from 4.8E-06 and 5.5E-03, showing that PFRs and BPA in PM2.5 and dust presented no health risks to children.

Translesional pressure gradient and leptomeningeal collateral status in symptomatic middle cerebral artery stenosis.

BACKGROUND AND PURPOSE: Leptomeningeal collateral (LMC) status governs the prognosis of large artery occlusive stroke, although factors determining LMC status are not fully elucidated. The aim was to investigate metrics affecting LMC status in such patients by using computational fluid dynamics (CFD) models based on computed tomography angiography (CTA). METHODS: In this cross-sectional study, patients with recent ischaemic stroke or transient ischaemic attack attributed to atherosclerotic M1 middle cerebral artery (MCA) stenosis (50%-99%) were recruited. Demographic, clinical and imaging data of these patients were collected. Ipsilesional LMC status was graded as good or poor by assessing the laterality of anterior and posterior cerebral arteries in CTA. A CFD model based on CTA was constructed to reflect focal hemodynamics in the distal internal carotid artery, M1 MCA and A1 anterior cerebral artery. Pressure gradients were calculated across culprit MCA stenotic lesions in CFD models. Predictors for good LMC status were sought in univariate and multivariate analyses. RESULTS: Amongst the 85 patients enrolled (mean age 61.5 ± 10.9 years), 38 (44.7%) had good ipsilesional LMC status. The mean pressure gradient across MCA lesions was 14.8 ± 18.1 mmHg. Advanced age (P = 0.030) and a larger translesional pressure gradient (P = 0.029) independently predicted good LMCs. A lower fasting blood glucose level also showed a trend for good LMCs (P = 0.058). CONCLUSIONS: Our study suggested a correlation between translesional pressure gradient and maturation of LMCs in intracranial atherosclerotic disease. Further studies with more exquisite and dynamic monitoring of cerebral hemodynamics and LMC evolution are needed to verify the current findings.

Antiplatelet therapy after stroke: should it differ in the acute and chronic phase after stroke.

PURPOSE OF REVIEW: Reviewing existing evidence regarding well tolerated and effective antiplatelet treatment in patients with acute or chronic, noncardioembolic ischemic stroke and transient ischemic attack (TIA). RECENT FINDINGS: For patients with high-risk stroke or TIA, for instance, minor stroke or high-risk TIA, or stroke of atherosclerotic origin with evidence suggesting risk of artery-to-artery embolism or with high-grade, symptomatic arterial stenosis, early initiated, short-term dual antiplatelet (e.g. aspirin and clopidogrel) is effective in reducing the risk of recurrent stroke and other vascular events which does not increase the risk of severe or fatal bleeding, as compared with mono antiplatelet therapy. However, long-term application of aggressive antiplatelet therapies after a noncardioembolic stroke or TIA increases the bleeding risks. Triple antiplatelet therapy is not appropriate for noncardioembolic stroke or TIA, in view of the high bleeding risk. In addition, emerging antiplatelets such as ticagrelor and cilostazol may work better in certain subgroups of stroke patients, which warrants further investigation. SUMMARY: Antiplatelet therapies should differ in the acute and chronic phases among patients with high-risk stroke or TIA when more aggressive antiplatelet treatment is reasonable in the acute phase, but no solid evidence supports different antiplatelet strategies in acute and chronic phases in patients with low-risk noncardioembolic stroke.

Ticagrelor Versus Aspirin in Acute Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Ticagrelor is an effective antiplatelet therapy among patients with atherosclerotic disease and, therefore, could be more effective than aspirin in preventing recurrent stroke and cardiovascular events among patients with embolic stroke of unknown source (ESUS), which includes patients with ipsilateral stenosis <50% and aortic arch atherosclerosis. METHODS: We randomized 13 199 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. In all patients, investigators informed on the presence of ipsilateral stenosis ≥50%, small deep infarct <15 mm, and on cardiac source of embolism detected after enrollment or rare causes, which allowed to construct an ESUS category in all other patients with documented brain infarction. The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. RESULTS: ESUS was identified in 4329 (32.8%) patients. There was no treatment-by-ESUS category interaction (P=0.83). Hazard ratio in ESUS patients was 0.87 (95% confidence interval, 0.68-1.10; P=0.24). However, hazard ratio was 0.51 (95% confidence interval, 0.29-0.90; P=0.02) in ESUS patients with ipsilateral stenosis <50% or aortic arch atherosclerosis (n=961) and 0.98 (95% confidence interval, 0.76-1.27; P=0.89) in the remaining ESUS patients (n=3368; P for heterogeneity =0.04). CONCLUSIONS: In this post hoc, exploratory analysis, we found no treatment-by-ESUS category interaction. ESUS subgroups have heterogeneous response to treatment (Funded by AstraZeneca). CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.

Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes).

BACKGROUND: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)-defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). METHODS: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. RESULTS: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52-1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. CONCLUSIONS: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.

Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial.

BACKGROUND: Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial. METHODS: SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries. We randomly allocated patients (1:1) to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-90, given orally) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90, given orally) within 24 h of symptom onset. Investigators classified all patients into atherosclerotic and non-atherosclerotic groups for the prespecified, exploratory analysis reported in this study. The primary endpoint was the time to occurrence of stroke, myocardial infarction, or death within 90 days. Efficacy analysis was by intention to treat. The SOCRATES trial is registered with ClinicalTrials.gov, number NCT01994720. FINDINGS: Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 [50%] to ticagrelor and 6610 [50%] to aspirin). Potentially symptomatic ipsilateral atherosclerotic stenosis was reported in 3081 (23%) of 13 199 patients. We found a treatment-by-atherosclerotic stenosis interaction (p=0·017). 103 (6·7%) of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9·6%) of 1539 patients with ipsilateral stenosis in the aspirin group had an occurrence of stroke, myocardial infarction, or death within 90 days (hazard ratio 0·68 [95% CI 0·53-0·88]; p=0·003). In 10 118 patients with no ipsilateral stenosis, 339 (6·7%) of 5047 patients in the ticagrelor group had an occurrence of stroke, myocardial infarction, or death within 90 days compared with 350 (6·9%) of 5071 in the aspirin group (0·97 [0·84-1·13]; p=0·72). There were no significant differences in the proportion of life-threatening bleeding or major or minor bleeding events in patients with ipsilateral stenosis in the ticagrelor group compared with the aspirin group. INTERPRETATION: In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention. FUNDING: AstraZeneca.

The prognosis of acute symptomatic seizures after ischaemic stroke.

OBJECTIVE: Acute symptomatic seizure (AS) after ischaemic stroke is defined as a seizure occurring ≤7 days of the stroke. There remains a lack of information on the prognosis of AS after ischaemic stroke and how it should be treated. METHODS: We prospectively recruited patients after their incidents of ischaemic stroke from a population-based stroke registry. Stroke aetiology was defined according to Trial-of-ORG-10172 in acute-stroke treatment (TOAST). Patients were examined for any transient complete-occlusion with recanalisation (TCOR) and haemorrhagic transformation. The seizure outcomes were (1) acute clustering of seizures ≤7 days, (2) seizure recurrence associated with stroke recurrence beyond the 7-day period and (3) unprovoked seizure (US) >7 days. RESULTS: 104 patients (mean age 65 years/55% female) with AS after ischaemic stroke were identified (mean follow-up 6.17 years). Comparison of the group of patients with AS and those without seizures showed that patients with AS had significantly less large-vessel and small-vessel disease but more cardioembolisms (p<0.05) and a higher proportion of TCOR (p<0.01), multiple territory infarcts (p=0.007) and haemorrhagic transformations (p<0.01). Using Kaplan-Meier statistics, the risk of acute clustering of seizures ≤7 days was 22%, with a statistical trend for TCOR as a predictive factor (p=0.06). The risk of seizure recurrence associated with worsening/recurrence of stroke beyond 7 days was 13.5% at 2 years, 16.4% at 4 years and 18% at 8 years. Presence of >2 cardiovascular risk factors (p<0.05) and status epilepticus (P<0.05) are predictive risk factors on Cox regression model. The risk of US was 19% at 2 years, 25% at 4 years and 28% at 8 years with epileptiform EEG as a predictive factor (p<0.05). CONCLUSIONS: Seizure recurrence following AS after ischaemic stroke may appear as acute clustering. Afterwards, seizures may occur as often with a recurrent stroke as without one within 4.2 years. We recommend the use of antiepileptic agents for up to 4 years if the underlying stroke aetiology cannot be fully treated.

Prognostic Factors and Pattern of Long-Term Recovery with MLC601 (NeuroAiD™) in the Chinese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study.

BACKGROUND: The Chinese Medicine NeuroAiD Efficacy on Stroke recovery - Extension (CHIMES-E) study is among the few acute stroke trials with long-term outcome data. We aimed to evaluate the recovery pattern and the influence of prognostic factors on treatment effect of MLC601 over 2 years. METHODS: The CHIMES-E study evaluated the 2 years outcome of subjects aged ≥18 years with acute ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score 6-14, pre-stroke modified Rankin Scale (mRS) score ≤1 included in a multicenter, randomized, double-blind, placebo-controlled trial of MLC601 for 3 months. Standard stroke care and rehabilitation were allowed during follow-up with mRS score being assessed in-person at month (M) 3 and by telephone at M1, M6, M12, M18 and M24. RESULTS: Data from 880 subjects were analyzed. There was no difference in baseline characteristics between treatment groups. The proportion of subjects with mRS score 0-1 increased over time in favor of MLC601 most notably from M3 to M6, thereafter remaining stable up to M24, while the proportion deteriorating to mRS score ≥2 remained low at all time points. Older age (p < 0.01), female sex (p = 0.06), higher baseline NIHSS score (p < 0.01) and longer onset to treatment time (OTT; p < 0.01) were found to be predictors of poorer outcome at M3. Greater treatment effect, with more subjects improving on MLC601 than placebo, was seen among subjects with 2 or more prognostic factors (OR 1.65 at M3, 1.78 at M6, 1.90 at M12, 1.65 at M18, 1.39 at M24), especially in subjects with more severe stroke or longer OTT. CONCLUSIONS: The sustained benefits of MLC601 over 2 years were due to more subjects improving to functional independence at M6 and beyond compared to placebo. Selection of subjects with poorer prognosis, particularly those with more severe NIHSS score and longer OTT delay, as well as a long follow-up period, may improve the power of future trials investigating the treatment effect of neuroprotective or neurorestorative therapies.

Good collateral circulation predicts favorable outcomes in intravenous thrombolysis: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Baseline collateral status has been correlated with outcomes of acute ischaemic stroke patients receiving intravenous thrombolysis (IVT) in previous studies. We carried out the current systematic review and meta-analysis to synthesize currently available evidence regarding such correlations. METHODS: Full-text articles published since 2000 were retrieved and screened. The overall effect sizes of good versus poor collateral status over a series of outcomes and certain baseline features were estimated by random-effects models and presented in risk ratios (RRs) or mean differences. RESULTS: Overall, 28 (3057 patients) and 14 (1584 patients) studies were included in qualitative and quantitative synthesis, respectively. Compared with poor pre-treatment collateral status, good collaterals showed a beneficial effect over the primary outcome of a favorable functional outcome at 3 or 6 months [RR, 2.45; 95% confidence interval, 1.94-3.09; P < 0.001] in acute ischaemic stroke patients receiving IVT treatment. However, such an effect tended to be different between studies with prescribed time windows of 3, 4.5 and > 4.5 h (up to 7 h), with the RRs being 2.21, 2.48 and 5.00, respectively (I2  = 53%). Good pre-treatment collaterals were also associated with a smaller infarct size at baseline, and a lower rate of symptomatic intracranial hemorrhage and a higher rate of neurological improvement early after IVT treatment. CONCLUSIONS: The present study has demonstrated the prognostic value of baseline collateral circulation for outcomes of acute ischaemic stroke patients receiving intravenous reperfusion therapies, studied with different time windows of up to 7 h after ictus for IVT therapy.

The curative effect comparison of two kinds of therapeutic regimens on decreasing the relative intensity of microembolic signal in CLAIR trial.

BACKGROUND: Microembolic signals (MESs) are direct markers of unstable large artery atherosclerotic plaques. In a previous study, we found that the number of MESs is associated with stroke recurrence and that clopidogrel plus aspirin more effectively reduce the number of MESs than does aspirin alone. Stroke recurrence is associated with not only the number of MESs but also the size of the MES, which can theoretically be estimated by monitoring the MES intensity via transcranial doppler (TCD). Thus, we compared the effects of clopidogrel and aspirin with aspirin alone on MES intensity using TCD. METHODS: We recruited 100 patients who experienced acute ischemic stroke or transient ischemic attack (TIA) within 7days of symptom onset. All patients also had large artery stenosis in the cerebral or carotid arteries and the presence of MES as revealed by TCD. The patients were randomized to receive either aspirin or clopidogrel and aspirin for 7days. MES monitoring was performed on days 2 and 7. RESULTS: Intent-to-treat (ITT) analysis (46 patients in the dual therapy group, 52 patients in the monotherapy group) and per-protocol (PP) analysis (25 patients in the dual therapy group, 31 patients in the monotherapy group) were performed on 98 patients. The primary finding was that the MES intensity was dramatically reduced in the dual therapy group. ITT analysis of the dual therapy group revealed that the MES intensity was 8.04 (0-16) dB before treatment, 0.00 (0-17) dB on day 2, and 0.00 (0-12) dB on day 7 (P=0.000). In the monotherapy group, the MES intensity was 9.00 (0-20) dB before treatment, 8.25 (0-17) dB on day 2, and 7.0 (0-18) dB on day 7 (P=0.577). PP analysis revealed similar results. No severe hemorrhagic complications were detected. The two patients in this study who experienced stroke recurrence were in the monotherapy group. CONCLUSIONS: Clopidogrel and aspirin more effectively decrease the MES intensity than aspirin alone in patients with large artery stenotic minor stroke or TIA.

Sex and the treatment effect in the Chinese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) trial.

In the randomized controlled trial of NeuroAiD versus placebo following ischemic stroke, there was a trend for sex influencing the treatment effect of NeuroAiD in improving functional outcome following ischemic stroke (p=0.075).

Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.

BACKGROUND: Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia. METHODS: We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. RESULTS: During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%. CONCLUSIONS: In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01994720.).