Clinical and Radiological Differences between Patients Diagnosed with Acute Ischemic Stroke and Chameleons at the Emergency Room: Insights from a Single-Center Observational Study.

INTRODUCTION: Scarce data exist about clinical/radiological differences between acute ischemic strokes diagnosed in the emergency room (AISER) and stroke chameleons (SCs). We aimed at describing the differences observed in a comprehensive stroke center in Chile. METHODS: Prospective observational study of patients with ischemic stroke syndromes admitted to the emergency room (ER) of Clínica Alemana between December 2014 and October 2023. RESULTS: 1,197 patients were included; of these 63 (5.2%, 95% CI: 4.1-6.6) were SC; these were younger (p < 0.001), less frequently hypertensive (p = 0.03), and they also had lower systolic (SBP) (p < 0.001), diastolic blood pressures (DBP) (p = 0.011), and NIHSS (p < 0.001). Clinically, they presented less frequently gaze (p = 0.008) and campimetry alterations (p = 0.03), facial (p < 0.001) and limb weakness (left arm [p = 0.004], right arm (p = 0.041), left leg (p = 0.001), right leg p = 0.0029), sensory abnormalities (p < 0.001), and dysarthria (p < 0.001). Neuroradiological evaluations included less frequently large vessel occlusions (p = 0.01) and other stroke locations (p = 0.005); they also differed in their etiologies (p < 0.001). Brainstem strokes (p < 0.001) and extinction/inattention symptoms (p < 0.001) were only seen in AISER. In multivariate analysis, younger age (OR: 0.945; 95% CI: 0.93-0.96), DBP (OR: 0.97; 95% CI, 0.95-0.99), facial weakness (OR: 0.39; 95% CI: 0.19-0.78), sensory abnormities (OR: 0.16.18; 95% CI, 0.05-0.4), infratentorial location (OR: 0.36; 95% CI, 0.15-0.78), posterior circulation involvement (OR: 3.02; 95% CI, 1.45-6.3), cardioembolic (OR: 3.5; 95% CI, 1.56-7.99), and undetermined (OR: 2.42; 95% CI, 1.22-4.7; 95%) etiologies, remained statistically significant. A stepwise analysis including only clinical elements present on the patient's arrival to the ER, demonstrates that age (OR: 0.95; 95% CI: 0.94-0.97), DBP (OR: 0.97; 95% CI, 0.95-0.99), the presence of atrial fibrillation (OR: 2.22; 95% CI, 1.04-4.75, NIHSS (OR: 0.88; 95% CI, 0.71-0.89) and the presence in NIHSS of 1a level of consciousness (OR: 5.66; CI: 95% 1.8-16.9), 1b level of consciousness questions (OR: 3.023; 95% CI, 1.35-6.8), facial weakness (OR: 0.3; CI: 95% 0.17-0.8), and sensory abnormalities (OR: 0.27; 95% CI, 0.1-0.72) remained statistically significant. CONCLUSION: SC had clinical and radiological differences compared to AISER. An additional relevant finding is that neurological symptoms in a patient with atrial fibrillation, even with a negative diffusion-weighted imaging, should be carefully evaluated as a potential stroke until other causes are satisfactorily ruled out.

Associations of Early Systolic Blood Pressure Control and Outcome After Thrombolysis-Eligible Acute Ischemic Stroke: Results From the ENCHANTED Study.

BACKGROUND AND PURPOSE: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. METHODS: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. RESULTS: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P<0.001 and 0.86 [95% CI, 0.76-0.98]; P=0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P=0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P=0.002 and 1.34 [1.11-1.62]; P=0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P=0.184). CONCLUSIONS: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616.

Did COVID-19 impact stroke services? A multicenter study.

BACKGROUND: It has been reported that acute stroke services were compromised during COVID-19 due to various pandemic-related issues. We aimed to investigate these changes by recruiting centers from different countries. METHODS: Eight countries participated in this cross-sectional, observational, retrospective study by providing data from their stroke data base. We compared 1 year before to 1 year during COVID-19 as regards onset to door (OTD), door to needle (DTN), door to groin (DTG), duration of hospital stay, National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at discharge as well as modified Rankin score (mRS) on discharge and at 3 months follow-up. RESULTS: During the pandemic year, there was a reduction in the number of patients, median age was significantly lower, admission NIHSS was higher, hemorrhagic stroke increased, and OTD and DTG showed no difference, while DTN time was longer, rtPA administration was decreased, thrombectomy was more frequent, and hospital stay was shorter. mRS was less favorable on discharge and at 3 months. CONCLUSION: COVID-19 showed variable effects on stroke services. Some were negatively impacted as the number of patients presenting to hospitals, DTN time, and stroke outcome, while others were marginally affected as the type of management.

Risk Factors and Diet Components Determining Adherence to the Mediterranean Diet in Acute Ischemic Stroke Patients: A Cross-Sectional Analysis of a Prospective Hospital Register Study.

OBJECTIVES: Low adherence to a Mediterranean diet (MeDi) is associated with increased incidence, mortality, and severity of acute ischemic strokes (AIS). Nevertheless, the explanatory factors associated with such results are unclear. Our aim was to investigate stroke risk factors associated with adherence to a MeDi in a prospective cohort of AIS patients. MATERIALS AND METHODS: Patients admitted from February 2017 to February 2020 were included in this study. Adherence was measured using the 14-point Mediterranean Diet Adherence Screener (MEDAS). Demographic and clinical characteristics were compared with adherence with a univariate analysis. A binomial regression was used to investigate the independent association of premorbid factors and MeDi components with adherence. RESULTS: There were 413 patients. Mean age was 68.6 (17.4), 176 (42.6%) women. Median MEDAS score was 6 (IQR 4-7) points. 253 patients (61.2%) had a low adherence (MEDAS ≤ 6). In the univariate analysis, a low MEDAS was associated with lower education, diabetes, sedentary lifestyle, greater body mass index (BMI), lower alcohol consumption, and higher LDLc. In the regression analysis, younger age, lower education, functional disability, hypertension, sedentary lifestyle, and higher BMI were associated with lower MEDAS scores. Six MeDi components had particularly low patient adherence: seafood, legumes, olive oil, nuts, wine, and fruit. DISCUSSION: These data indicate low adherence to MeDi in younger patients who are less educated and have existing cardiovascular risk factors, in particular hypertension, sedentary lifestyle, and higher BMI. Some components of the diet had a particularly low adherence. CONCLUSIONS: Tailoring diet prevention interventions to these specific populations, focusing on components with known less adherence, could improve adherence to a MeDi and the opportunity for secondary stroke prevention.

Stroke symptoms, risk factors awareness and personal decision making in Chile. A national survey.

BACKGROUND: Knowledge about stroke symptoms, correct decision in front of a stroke case and recognition of stroke risk factors are crucial to fight against stroke burden. We aimed to assess the stroke awareness among a sample of the Chilean population. METHODS: A closed-ended questions structured survey was applied in November 2019 using a computer-assisted telephone interviewing system. Probabilistic sample, random selection and stratification for region was used. Multivariate logistic regression model was used to estimate the association between participants' characteristics and responses. RESULTS: Of 706 participants, only 74.4% (95% CI 70.9-77.5) recognized at least one typical stroke symptom. Most (586, 82.4% 95% CI 75.2-89.7) chose to contact the emergency ambulance or directly go to the emergency department in case of a stroke symptom and recognized at least one risk factor (692, 97.9% CI 96.7-98.8). In multivariable analysis, sociodemographic characteristics associated to a worse recognition of at least one stroke symptom were being men (OR 0.67, 95% CI 0.47-0.96), being 55 years old or older (OR 0.59 95% CI 0.37-0.93) and from the lowest socioeconomic level (SES) (OR 0.33 95% CI 0.16-0.67). Female sex was associated with lower stroke risk factor knowledge (OR 0.64 95% IC 0.47-0.87). Participants who recognized at least one typical stroke symptom and would promptly seek care at an emergency department differed significantly between SES (p=0.001) and age groups (p=0.035). CONCLUSIONS: We found insufficient knowledge about stroke symptoms and best decisions making in the Chilean population. We describe gaps that can be targeted in future stroke awareness campaigns. There is a need to strengthen tailored stroke education particularly for underserved populations.

Influence of Including Patients with Premorbid Disability in Acute Stroke Trials: The HeadPoST Experience.

BACKGROUND: Patients with premorbid functional impairment are generally excluded from acute stroke trials. We aimed to determine the impact of including such patients in the Head Positioning in acute Stroke Trial (HeadPoST) and early additional impairment on outcomes. METHODS: Post hoc analyses of HeadPoST, an international, cluster-randomized crossover trial of lying-flat versus sitting-up head positioning in acute stroke. Associations of early additional impairment, defined as change in modified Rankin scale (mRS) scores from premorbid levels (estimated at baseline) to Day 7 ("early ΔmRS"), and poor outcome (mRS score 3-6) at Day 90 were determined with generalized linear mixed model. Heterogeneity of the trial treatment effect was tested according to premorbid mRS scores 0-1 versus 2-5. RESULTS: Of 8,285 patients (38.9% female, mean age 68 ± 13 years) with complete data, there were 1,984 (23.9%) with premorbid functional impairment (mRS 2-5). A significant linear association was evident for early ∆mRS and poor outcome (per 1-point increase in ΔmRS, adjusted odds ratio 1.20, 95% confidence interval 1.14-1.27; p < 0.0001). Patients with greater premorbid functional impairment were less likely to develop additional impairment, but their risk of poor 90-day outcome significantly increased with increasing (worse) premorbid mRS scores (linear trend p < 0.0001). There was no heterogeneity of the trial treatment effect by level of premorbid function. CONCLUSIONS: Early poststroke functional impairment that exceeded premorbid levels was associated with worse 90-day outcome, and this association increased with greater premorbid functional impairment. Yet, including premorbid impaired patients in the HeadPoST did not materially affect the subsequent treatment effect. CLINICAL TRIAL REGISTRATION: HeadPoST is registered at http://www.ClinicalTrials.gov (NCT02162017).

In-Hospital Acute Ischemic Stroke is Associated with Worse Outcome: Experience of a Single Center in Santiago Chile.

OBJECTIVES: In-hospital acute ischemic stroke (HIS) accounts for 2-17% of all acute ischemic strokes (AIS) seen in hospital and they have worse prognosis. In this study we aimed to identify the frequency of HIS and their characteristics in our center. MATERIALS AND METHODS: Retrospective analysis of a prospective register of patients with AIS seen at Clínica Alemana de Santiago, between January 2017 and January 2019. HIS and community onset ischemic strokes patients (CIS) were compared, univariate analysis was performed, covariates with p < 0.25 were selected for multivariate analysis. Differences between, proportion of strokes treated with thrombolytic therapy, door to needle time were compared between HIS and CIS patients, as also mortality rates at 90 days. RESULTS: During the study period 369 patients with AIS were seen; of these 20 (5.4%, 95 CI%, 3.5-8.2) corresponded to HIS. In univariate analysis, HIS compared to patients arriving form the community to the emergency room, suffered more frequently from, heart failure (p = 0.04), and active malignancies (p < 0.001). HIS patients had longer times from symptom onset to non-contrast brain tomography (540 ±150 minutes); they were also less frequently treated with intravenous thrombolysis compared to community AIS: 15% versus 30% respectively (p = 0.08). Mortality rates at 90 days were higher in HIS: 30 versus 5% (p = 0.001). CONCLUSIONS: In this cohort, HIS patients suffered delays in their neuroimaging studies and received less intravenous thrombolysis; this underscores the need for a standardized approach to the recognition and management of inhospital acute ischemic stroke.

Frequency and Predictors of Major Bleeding in Patients With Embolic Strokes of Undetermined Source: NAVIGATE-ESUS Trial.

BACKGROUND AND PURPOSE: Risks, sites, and predictors of major bleeding during antithrombotic therapies have not been well defined for patients with recent embolic stroke of undetermined source. METHODS: Exploratory analysis of major bleeds defined by International Society of Thrombosis and Hemostasis criteria occurring among 7213 participants in international NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial) embolic stroke of undetermined source randomized trial comparing rivaroxaban 15 mg daily with aspirin 100 mg daily. RESULTS: During a median follow-up of 11 months, 85 major bleeds occurred. The most frequent site was gastrointestinal (38%), followed by intracranial (29%). Assignment to rivaroxaban (hazard ratio [HR], 2.7 [95% CI, 1.7-4.3]), East Asia region (HR, 2.5 [95% CI, 1.6-3.9]), systolic blood pressure ≥160 mm Hg (HR, 2.2 [95% CI, 1.2-3.8]), and reduced estimated glomerular filtration rate (HR, 1.2 per 10 mL/min per 1.73 m2 decrease, [95% CI, 1.0-1.3]) were independently associated with presence of major bleeds. Five (6%) were fatal. Among 15 patients with intracerebral hemorrhage, 2 (13%) were fatal. There was no evidence of an early high-risk period following initiation of rivaroxaban. The annualized rate of intracerebral hemorrhage was 6-fold higher among East Asian participants (0.67%) versus all other regions (0.11%; HR, 6.3 [95% CI, 2.2-18.0]). Distribution of bleeding sites was similar for rivaroxaban and aspirin. CONCLUSIONS: Among embolic stroke of undetermined source patients participating in an international randomized trial, independent predictors of major bleeding were assignment to rivaroxaban, East Asia region, increased systolic blood pressure, and impaired renal function. East Asia as a region was strongly associated with risk of intracerebral hemorrhage. Estimated glomerular filtration rate should be a consideration for stratifying bleeding risk. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke.

BACKGROUND: The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion. METHODS: In a pragmatic, cluster-randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death). RESULTS: The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying-flat group were less likely than patients in the sitting-up group to maintain the position for 24 hours (87% vs. 95%, P<0.001). In a proportional-odds model, there was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the lying-flat group and patients in the sitting-up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying-flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P=0.84). Mortality within 90 days was 7.3% among the patients in the lying-flat group and 7.4% among the patients in the sitting-up group (P=0.83). There were no significant between-group differences in the rates of serious adverse events, including pneumonia. CONCLUSIONS: Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for 24 hours and patients assigned to a sitting-up position with the head elevated to at least 30 degrees for 24 hours. (Funded by the National Health and Medical Research Council of Australia; HeadPoST ClinicalTrials.gov number, NCT02162017 .).

Pre-stroke adherence to a Mediterranean diet pattern is associated with lower acute ischemic stroke severity: a cross-sectional analysis of a prospective hospital-register study.

BACKGROUND: High adherence to a Mediterranean Diet is associated with reduced incidence and mortality of acute ischemic stroke (AIS) but may also be associated with severity. Our purpose was to investigate the association of adherence to a Mediterranean diet and severity in a prospective hospital register of AIS patients. METHODS: We included AIS patients admitted from February 2017 to July 2019. All were assessed by a neurologist with a standard stroke protocol, including NIHSS. Adherence to Mediterranean diet was prospectively measured by the 14-point Mediterranean Diet Adherence Screener (MEDAS) and defined as low (0-6 points) or high (7-14 points). Demographic and clinical characteristics were compared by group with univariate analysis. A Generalized Linear Model (GLM) was used to investigate the association of admission NIHSS as a continuous ordinal variable and an ordinal logistic regression (OLR) analysis to determine the independent association of the NIHSS quartiles with adherence to Mediterranean diet. RESULTS: Three hundred sixty-eight patients were included, mean age 68.3 (17.7), 158 (42.9%) females. The median NIHSS score was 3 (IQR 1-9) and the median MEDAS score was 6 (IQR 4.5-8). Patients with high MEDAS scores had significantly lower; admission NIHSS scores, sedentary lifestyle, body mass index, total and LDL cholesterol levels, but higher alcohol consumption. After adjustments, high adherence to Mediterranean diet remained independently associated with lower stroke severity both in the GLM (ß coefficient = - 0.19, p = 0.01) and in the OLR model (OR for lower NIHSS quartiles 0.6 (95% CI 0.37-0.98, p = 0.04). CONCLUSIONS: Higher pre-stroke adherence to a Mediterranean diet is independently associated with lower AIS severity.

[Determinants of door to needle time for intravenous thrombolysis in acute ischemic stroke]. / Determinantes del tiempo puerta-aguja en trombolisis endovenosa en el infarto cerebral, experiencia de un centro.

BACKGROUND: Intravenous thrombolysis (IT) in acute ischemic stroke (AIS) is time dependent. The time elapsed from hospital admission to the thrombolytic bolus is named door to needle time (DNT) and is recommend to be of less than 60 min. AIM: To describe the DNT in our center and determine those factors associated with a DNT longer than 60 min. MATERIAL AND METHODS: Prospective analysis of patients treated with IT at a private hospital between June 2016 and June 2019. The percentage of patients with DNT exceeding 60 min, and the causes for this delay were evaluated. RESULTS: IT was used in 205 patients. DNT was 43.6 ± 23.8 min. Forty patients (19.5% (95% CI, 14.4-25.7), had a DNT longer than 60 min. Uni-varied analysis demonstrated that AIS with infratentorial symptomatology (ITS), was significantly associated with DNTs exceeding 60 min. A history of hypertension, a higher NIH Stroke Scale score, the presence of an hyperdense sign in brain tomography (p = 0.001) and the need for endovascular therapy (p = 0.019), were associated with DNT shorter than 60 min. Multivariate analysis ratified the relationship between ITS and DNT longer than 60 min (Odds ratio: 3.19, 95% confidence intervals 1.26-8). CONCLUSIONS: The individual elements that correlated with a DNT longer than 60 min were the failure to detect the AIS during triage and doubts about its diagnosis.

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke.

BACKGROUND: Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODS: Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTS: The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). CONCLUSIONS: This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).

Interaction of Blood Pressure Lowering and Alteplase Dose in Acute Ischemic Stroke: Results of the Enhanced Control of Hypertension and Thrombolysis Stroke Study.

OBJECTIVE: To determine the extent to which the effects of intensive blood pressure (BP) lowering are modified by doses of alteplase in thrombolysis-eligible acute ischemic stroke (AIS) patients. METHODS: Prespecified analyses of the Enhanced Control of Hypertension and Thrombolysis Stroke Study for patients enrolled in both arms: (i) low-dose (0.6 mg/kg body weight) or standard-dose (0.9 mg/kg) alteplase and (ii) intensive (target systolic BP [SBP] 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) BP management. The primary outcome was functional recovery, measured by a shift in scores on modified Rankin scale at 90 days. The safety outcome was any intracranial hemorrhage (ICH). RESULTS: There were 925 participants (mean age 67 years, 39% female, 77% Asian) randomized to both arms: 242 randomly assigned to guideline/standard-dose (GS); 234 to guideline/low-dose (GL); 227 to intensive/standard-dose (IS); and 222 to intensive/low-dose (IL). Overall, average SBP levels within 24 h were lower in the low-dose compared to standard-dose alteplase group (146 and 144 vs. 151 and 150 mm Hg, for GS and GL vs. IS and IL, respectively, p < 0.0001). There was no heterogeneity of the effects of BP lowering (intensive vs. guideline) on functional recovery between standard-dose (OR 0.81, 95% CI 0.59-1.12) and low-dose alteplase (1.06, 0.77-1.47; p = 0.25 for interaction). Similar results were observed for ICH (p = 0.50 for interaction). CONCLUSIONS: In thrombolysis-treated patients with predominantly mild-to-moderate severity AIS, intensive BP lowering neither improve functional recovery, either with low- or standard-dose intravenous alteplase, nor beneficially interact with low-dose alteplase in reducing ICH. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov (NCT01422616).

Yield of Echocardiography in the Evaluation of Cerebral Ischemic Events: A Single Center Cohort Study.

BACKGROUND: Echocardiography (ECO) is frequently used as a screening test in patients with acute ischemic brain disease. We aimed to evaluate the additional information and therapeutic impact resulting from ECO in these patients. METHODS: We conducted a prospective study performing ECO on consecutive patients with ischemic stroke or transient ischemic attacks, admitted to our centre between February 2013 and May 2017. RESULTS: A total of 696 patients were included (female, 57.3%; mean age, 70 ± 15.3 years). Seven hundred thirty two echocardiographic examinations were performed (696 transthoracic and 36 transesophageal). Echocardiography yielded findings judged of clinical importance in 142 patients (20.4%, 95% CI 17.5-23.5). The most frequent of these were left atrial volume enlargement or a normal evaluation. Echocardiography findings resulted in changes in the management of 76 patients (10.7% 95% CI 8.8-13.4); initiation of anticoagulation therapy, administration of IV antibiotic therapy, cardiac surgeries, or other pharmacological therapies occurring in 42 cases (6%). The presence of coronary heart disease (OR: 2.64 95% CI 1.34-5.25), atrial fibrillation (OR: 0.24; 95% CI, 0.2-0.69), and admission NIHSS (OR: 1.04; 95% CI, 1.01-1.09), were the variables associated with changes in management. CONCLUSIONS: In unselected patients with acute ischemic stroke ECO had a low yield of additional information, and it changed management in a small percentage of patients.

Lipid-Lowering Pretreatment and Outcome Following Intravenous Thrombolysis for Acute Ischaemic Stroke: A Post Hoc Analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study Trial.

BACKGROUND: Debate exists as to whether statin pretreatment confers an increased risk of 90-day mortality and symptomatic intracranial haemorrhage (sICH) in acute ischaemic stroke (AIS) patients treated with intravenous thrombolysis. We assessed the effects of undifferentiated lipid-lowering pretreatment on outcomes and interaction with low-dose versus standard-dose alteplase in a post hoc subgroup -analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study. METHODS: In all, 3,284 thrombolysis-eligible AIS patients (mean age 66.6 years; 38% women), with information on lipid-lowering pretreatment, were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 h of symptom onset. Of the total number of patients, 615 (19%) received statin or other lipid-lowering pretreatment. The primary clinical outcome was combined endpoint of death or disability (modified Rankin Scale scores 2-6) at 90 days. RESULTS: Compared with patients with no lipid-lowering pretreatment, those with lipid-lowering pretreatment were significantly older, more likely to be non-Asian and more likely to have a medical history including vascular co-morbidity. After propensity analysis assessment and adjustment for important baseline variables at the time of randomisation, as well as imbalances in management during the first 7 days of hospital admission, there were no significant differences in mortality (OR 0.85; 95% CI 0.58-1.25, p = 0.42), or in overall -90-day death and disability (OR 0.85, 95% CI 0.67-1.09, p = 0.19), despite a significant decrease in sICH among those with -lipid-lowering pretreatment according to the European Co-operative Acute Stroke Study 2 definition (OR 0.49, 95% CI 0.28-0.83, p = 0.009). No differences in key efficacy or safety outcomes were seen in patients with and without lipid-lowering pretreatment between low- and standard-dose alteplase arms. CONCLUSIONS: Lipid-lowering pretreatment is not associated with adverse outcome in AIS patients treated with intravenous alteplase, whether assessed by 90-day death and disability or death alone.

Influence of Renal Impairment on Outcome for Thrombolysis-Treated Acute Ischemic Stroke: ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) Post Hoc Analysis.

BACKGROUND AND PURPOSE: Renal dysfunction (RD) is associated with poor prognosis after stroke. We assessed the effects of RD on outcomes and interaction with low- versus standard-dose alteplase in a post hoc subgroup analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS: A total of 3220 thrombolysis-eligible patients with acute ischemic stroke (mean age, 66.5 years; 37.8% women) were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset. Six hundred and fifty-nine (19.8%) patients had moderate-to-severe RD (estimated glomerular filtration rate, <60 mL/min per 1.73 m2) at baseline. The impact of RD on death or disability (modified Rankin Scale scores, 2-6) at 90 days, and symptomatic intracerebral hemorrhage, was assessed in logistic regression models. RESULTS: Compared with patients with normal renal function (>90 mL/min per 1.73 m2), those with severe RD (<30 mL/min per 1.73 m2) had increased mortality (adjusted odds ratio, 2.07; 95% confidence interval, 0.89-4.82; P=0.04 for trend); every 10 mL/min per 1.73 m2 lower estimated glomerular filtration rate was associated with an adjusted 9% increased odds of death from thrombolysis-treated acute ischemic stroke. There was no significant association with modified Rankin Scale scores 2 to 6 (adjusted odds ratio, 1.03; 95% confidence interval, 0.62-1.70; P=0.81 for trend), modified Rankin Scale 3 to 6 (adjusted odds ratio, 1.20; 95% confidence interval, 0.72-2.01; P=0.44 for trend), or symptomatic intracerebral hemorrhage, or any heterogeneity in comparative treatment effects between low-dose and standard-dose alteplase by RD grades. CONCLUSIONS: RD is associated with increased mortality but not disability or symptomatic intracerebral hemorrhage in thrombolysis-eligible and treated acute ischemic stroke patients. Uncertainty persists as to whether low-dose alteplase confers benefits over standard-dose alteplase in acute ischemic stroke patients with RD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Low- Versus Standard-Dose Alteplase in Patients on Prior Antiplatelet Therapy: The ENCHANTED Trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study).

BACKGROUND AND PURPOSE: Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS: Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2-6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria. RESULTS: There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81-1.26; P=0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75-1.20; P=0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87-1.21; P=0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00-3.30; P=0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant (P-trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2-6; OR, 0.84; 95% CI, 0.62-1.12 versus OR, 1.16; 95% CI, 0.99-1.36). CONCLUSIONS: Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Reliability of Hand-Held Transcranial Doppler with M-mode Ultrasound in Middle Cerebral Artery Measurement.

PURPOSE: To determine the intra- and interrater agreement of mean flow velocity (MFV) and pulsatility index (PI) measurement in middle cerebral arteries, assessed by transcranial Doppler (TCD) with M-mode. METHODS: Masked experienced neurosonologists performed TCD with M-mode using handheld probe in healthy adult volunteers. The Bland-Altman method for concordance and intraclass correlation coefficient were used. RESULTS: Seventy-seven healthy volunteers and seven raters participated (3 on regular TCD shift and 4 off-shift). The intrarater absolute mean difference between measurements was 5.5 cm/s [95% confidence interval (CI), 4.7-6.3] for MVF and 0.073 (95% CI, 0.063-0.083) for PI. The difference between MFV measurements was significantly higher in off-shift raters (p = 0.015). The interrater absolute mean difference between measurements was 6.5 cm/s (95% CI, 5.5-7.5) for MVF and 0.065 (95% CI, 0.059-0.071) for PI. No influence was found for the middle cerebral artery side, volunteer's sex, or age, and there was no significant difference between raters. The intraclass correlation coefficient was 82.2% (95% CI 77.8-85.6) and 72.9% (95% CI 67.4-77.6) for MFV and PI, respectively. CONCLUSIONS: There exists good intra- and interrater agreement in MFV and PI measurements using M-mode TCD. These results support the use of this noninvasive tool and are important for clinical and investigational purposes.

[Thrombolysis in stroke mimics: Experience in 10 cases]. / Trombolisis intravenosa en cuadros imitadores de isquemia cerebral: experiencia de un centro.

BACKGROUND: The effectiveness of intravenous thrombolysis (IVT) in cerebral ischemia is time dependent. Stroke mimics (SM) are frequent in emergency rooms. The effort to reduce door to needle time, can lead to administer thrombolytics to SM. AIM: To describe the frequency and prognosis of SM treated with IVT. MATERIAL AND METHODS: Prospective analysis of all patients evaluated in a Chilean private clinic between December 2004 and July 2015 with a suspected acute ischemic stroke (AIS). We calculated the number of SM that were treated with IVT. In these patients, we analyzed the presence of symptomatic cerebral hemorrhage defined as the presence of a neurological deterioration of four points or more on the National Institute of Health Stroke Scale, the presence of extracranial bleeding according to Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries criteria and the patient's functional status at three months by modified Rankin scale (MRS). RESULTS: We evaluated 1,417 patients with suspected AIS, of which 240 (16.9%) were finally diagnosed as SM. A total of 197 patients were treated with IVT, of these 10 (5%) corresponded to SM. All SM patients treated with thrombolytic drugs were functionally independent at 3 months and showed no bleeding complications. CONCLUSIONS: Occasionally SM patients were treated with IVT. This treatment was not associated with bleeding complications and the prognosis of these patients at three months was favorable.