Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Diffusion-Weighted Imaging Fluid-Attenuated Inversion Recovery Mismatch on Portable, Low-Field Magnetic Resonance Imaging Among Acute Stroke Patients.

OBJECTIVE: For stroke patients with unknown time of onset, mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) can guide thrombolytic intervention. However, access to MRI for hyperacute stroke is limited. Here, we sought to evaluate whether a portable, low-field (LF)-MRI scanner can identify DWI-FLAIR mismatch in acute ischemic stroke. METHODS: Eligible patients with a diagnosis of acute ischemic stroke underwent LF-MRI acquisition on a 0.064-T scanner within 24 h of last known well. Qualitative and quantitative metrics were evaluated. Two trained assessors determined the visibility of stroke lesions on LF-FLAIR. An image coregistration pipeline was developed, and the LF-FLAIR signal intensity ratio (SIR) was derived. RESULTS: The study included 71 patients aged 71 ± 14 years and a National Institutes of Health Stroke Scale of 6 (interquartile range 3-14). The interobserver agreement for identifying visible FLAIR hyperintensities was high (κ = 0.85, 95% CI 0.70-0.99). Visual DWI-FLAIR mismatch had a 60% sensitivity and 82% specificity for stroke patients <4.5 h, with a negative predictive value of 93%. LF-FLAIR SIR had a mean value of 1.18 ± 0.18 <4.5 h, 1.24 ± 0.39 4.5-6 h, and 1.40 ± 0.23 >6 h of stroke onset. The optimal cut-point for LF-FLAIR SIR was 1.15, with 85% sensitivity and 70% specificity. A cut-point of 6.6 h was established for a FLAIR SIR <1.15, with an 89% sensitivity and 62% specificity. INTERPRETATION: A 0.064-T portable LF-MRI can identify DWI-FLAIR mismatch among patients with acute ischemic stroke. Future research is needed to prospectively validate thresholds and evaluate a role of LF-MRI in guiding thrombolysis among stroke patients with uncertain time of onset. ANN NEUROL 2024.

What Is a Meaningful Difference When Using Infarct Volume as the Primary Outcome?: Results From the HERMES Database.

BACKGROUND: Ischemic stroke lesion volume at follow-up is an important surrogate outcome for acute stroke trials. We aimed to assess which differences in 48-hour lesion volume translate into meaningful clinical differences. METHODS: We used pooled data from 7 trials investigating the efficacy of endovascular treatment for anterior circulation large vessel occlusion in acute ischemic stroke. We assessed 48-hour lesion volume follow-up computed tomography or magnetic resonance imaging. The primary outcome was a good functional outcome, defined as modified Rankin Scale (mRS) scores of 0 to 2. We performed multivariable logistic regression to predict the probability of achieving mRS scores of 0 to 2 and determined the differences in 48-hour lesion volume that correspond to a change of 1%, 5%, and 10% in the adjusted probability of achieving mRS scores of 0 to 2. RESULTS: In total, 1665/1766 (94.2%) patients (median age, 68 [interquartile range, 57-76] years, 781 [46.9%] female) had information on follow-up ischemic lesion volume. Computed tomography was used for follow-up imaging in 83% of patients. The median 48-hour lesion volume was 41 (interquartile range, 14-120) mL. We observed a linear relationship between 48-hour lesion volume and mRS scores of 0 to 2 for adjusted probabilities between 65% and 20%/volumes <80 mL, although the curve sloped off for lower mRS scores of 0-2 probabilities/higher volumes. The median differences in 48-hour lesion volume associated with a 1%, 5%, and 10% increase in the probability of mRS scores of 0 to 2 for volumes <80 mL were 2 (interquartile range, 2-3), 10 (9-11), and 20 (18-23) mL, respectively. We found comparable associations when assessing computed tomography and magnetic resonance imaging separately. CONCLUSIONS: A difference of 2, 10, and 20 mL in 48-hour lesion volume, respectively, is associated with a 1%, 5%, and 10% absolute increase in the probability of achieving good functional outcome. These results can inform the design of future stroke trials that use 48-hour lesion volume as the primary outcome.

Evaluating artificial intelligence software for delineating hemorrhage extent on CT brain imaging in stroke: AI delineation of ICH on CT.

BACKGROUND: The extent and distribution of intracranial hemorrhage (ICH) directly affects clinical management. Artificial intelligence (AI) software can detect and may delineate ICH extent on brain CT. We evaluated e-ASPECTS software (Brainomix Ltd.) performance for ICH delineation. METHODS: We qualitatively assessed software delineation of ICH on CT using patients from six stroke trials. We assessed hemorrhage delineation in five compartments: lobar, deep, posterior fossa, intraventricular, extra-axial. We categorized delineation as excellent, good, moderate, or poor. We assessed quality of software delineation with number of affected compartments in univariate analysis (Kruskall-Wallis test) and ICH location using logistic regression (dependent variable: dichotomous delineation categories 'excellent-good' versus 'moderate-poor'), and report odds ratios (OR) and 95 % confidence intervals (95 %CI). RESULTS: From 651 patients with ICH (median age 75 years, 53 % male), we included 628 with assessable CTs. Software delineation of ICH extent was 'excellent' in 189/628 (30 %), 'good' in 255/628 (41 %), 'moderate' in 127/628 (20 %), and 'poor' in 57/628 cases (9 %). The quality of software delineation of ICH was better when fewer compartments were affected (Z = 3.61-6.27; p = 0.0063). Software delineation of ICH extent was more likely to be 'excellent-good' quality when lobar alone (OR = 1.56, 95 %CI = 0.97-2.53) but 'moderate-poor' with any intraventricular (OR = 0.56, 95 %CI = 0.39-0.81, p = 0.002) or any extra-axial (OR = 0.41, 95 %CI = 0.27-0.62, p<0.001) extension. CONCLUSIONS: Delineation of ICH extent on stroke CT scans by AI software was excellent or good in 71 % of cases but was more likely to over- or under-estimate extent when ICH was either more extensive, intraventricular, or extra-axial.

Reversibility of Diffusion-Weighted Imaging Lesions in Patients With Ischemic Stroke in the WAKE-UP Trial.

BACKGROUND: Reversibility of the diffusion-weighted imaging (DWI) lesion means that not all of the DWI lesion represents permanently injured tissue. We investigated DWI reversibility and the association with thrombolysis, reperfusion and functional outcome in patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke). METHODS: In this retrospective analysis of WAKE-UP, a randomized controlled trial (RCT) between September 2012 and June 2017 in Belgium, Denmark, France, Germany, Spain and United Kingdom, a convolutional neural network segmented the DWI lesions (b=1000 s/mm2) at baseline and follow-up (24 hours). We calculated absolute and relative DWI reversibility in 2 ways: first, a volumetric (baseline volume-24-hour volume >0) and second, a voxel-based (part of baseline lesion not overlapping with 24-hour lesion) approach. We additionally defined relative voxel-based DWI-reversibility >50% to account for coregistration inaccuracies. We calculated the odds ratio for reversibility according to treatment arm. We analyzed the association of reversibility with excellent functional outcome (modified Rankin Scale score of 0-1), in a multivariable model. RESULTS: In 363 patients, the median DWI volume was 3 (1-10) mL at baseline and 6 (2-20) mL at follow-up. Volumetric DWI reversibility was present in 19% (69/363) with a median absolute reversible volume of 1 mL (0-2) or 28% (14-50) relatively. Voxel-based DWI reversibility was present in 358/363 (99%) with a median absolute volume of 1 mL (0-2), or 22% (9-38) relatively. In 18% of the patients (67/363), relative voxel-based DWI reversibility >50% was present. Volumetric DWI reversibility and relative voxel-based DWI reversibility >50% was more frequent in patients treated with alteplase versus placebo (OR, 1.86 [95% CI, 1.09-3.17] and OR, 2.03 [95% CI, 1.18-3.50], respectively). Relative voxel-based DWI reversibility >50% was associated with excellent functional outcome (OR, 2.30 [95% CI, 1.17-4.51]). CONCLUSIONS: Small absolute volumes of DWI reversibility were present in a large proportion of randomized patients in the WAKE-UP trial. Reversibility was more often present after thrombolysis.

Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke. METHODS: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models. RESULTS: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57-0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60-1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome (P=0.443) or any hemorrhagic transformation (P=0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19-4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80-4.81]). CONCLUSIONS: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01525290.

External Validation of e-ASPECTS Software for Interpreting Brain CT in Stroke.

OBJECTIVE: The purpose of this study was to test e-ASPECTS software in patients with stroke. Marketed as a decision-support tool, e-ASPECTS may detect features of ischemia or hemorrhage on computed tomography (CT) imaging and quantify ischemic extent using Alberta Stroke Program Early CT Score (ASPECTS). METHODS: Using CT from 9 stroke studies, we compared software with masked experts. As per indications for software use, we assessed e-ASPECTS results for patients with/without middle cerebral artery (MCA) ischemia but no other cause of stroke. In an analysis outside the intended use of the software, we enriched our dataset with non-MCA ischemia, hemorrhage, and mimics to simulate a representative "front door" hospital population. With final diagnosis as the reference standard, we tested the diagnostic accuracy of e-ASPECTS for identifying stroke features (ischemia, hyperattenuated arteries, and hemorrhage) in the representative population. RESULTS: We included 4,100 patients (51% women, median age = 78 years, National Institutes of Health Stroke Scale [NIHSS] = 10, onset to scan = 2.5 hours). Final diagnosis was ischemia (78%), hemorrhage (14%), or mimic (8%). From 3,035 CTs with expert-rated ASPECTS, most (2084/3035, 69%) e-ASPECTS results were within one point of experts. In the representative population, the diagnostic accuracy of e-ASPECTS was 71% (95% confidence interval [CI] = 70-72%) for detecting ischemic features, 85% (83-86%) for hemorrhage. Software identified more false positive ischemia (12% vs 2%) and hemorrhage (14% vs <1%) than experts. INTERPRETATION: On independent testing, e-ASPECTS provided moderate agreement with experts and overcalled stroke features. Therefore, future prospective trials testing impacts of artificial intelligence (AI) software on patient care and outcome are required before widespread implementation of stroke decision-support software. ANN NEUROL 2022;92:943-957.

Sex differences in imaging and clinical characteristics of patients from the WAKE-UP trial.

BACKGROUND AND PURPOSE: Sex-based differences in acute ischemic stroke are a well-known phenomenon. We aimed to explore these differences between women and men in the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial. METHODS: We compared baseline demographic and imaging characteristics (visual fluid-attenuated inversion recovery [FLAIR] positivity, relative FLAIR signal intensity, collateral status) between women and men in all screened patients. In randomized patients (i.e., those with diffusion-weighted imaging (DWI)-FLAIR mismatch), we evaluated a modifying role of sex on the treatment effect of alteplase in multivariable logistic regression, with treatment adjusted for National Institute of Health Stroke Scale (NIHSS) score and age. Dependent variables were modified Rankin Scale (mRS) score of 0-1 at 90 days and distribution of mRS scores at 90 days. RESULTS: Of 1362 screened patients, 529 (38.8%) were women. Women were older than men, had higher baseline NIHSS scores and smoked less frequently. FLAIR positivity of the DWI lesion was equally present in women (174/529, 33.1%) and men (273/833, 33.3%; p = 1.00) and other imaging variables also did not differ between the sexes. In a total of 503 randomized patients, of whom 178 were women (35.4%), sex did not modify the treatment effect of alteplase on mRS score 0-1 or on the total distribution of mRS scores. CONCLUSION: As in many other stroke trials, more men than women were included in the WAKE-UP trial, but the presence of a visual DWI-FLAIR mismatch and the relative FLAIR signal intensity did not differ between the sexes. The treatment effect of alteplase was not modified by sex.

Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study.

INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Functional Outcomes of Patients ≥85 Years With Acute Ischemic Stroke Following EVT: A HERMES Substudy.

BACKGROUND: Observational studies have shown endovascular treatment (EVT) for acute ischemic stroke to be effective in the elderly, despite resulting in poorer outcomes and higher rates of mortality compared with younger patients. Randomized data on the effect of advanced age on outcomes following EVT are, however, lacking. Our aim was to assess the EVT effect for ischemic stroke in patients aged ≥85 years and the influence of age on outcome in a large, randomized trial dataset. METHODS: Data were from the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration, a meta-analysis of 7 randomized trials published between January 1, 2010, and May 31, 2017, that tested the efficacy of EVT. A possible multiplicative interaction effect of age on the relationship between treatment and outcome was investigated. Ordinal logistic regression tested the association between EVT and 90-day functional outcome (modified Rankin Scale, primary outcome) in patients ≥85 years. Multivariable binary logistic regression was performed to compare primary and secondary outcomes (modified Rankin Scale score of 0-2/5-6) of patients ≥85 years versus those <85 years. RESULTS: We included 1764 patients in the analysis, of whom 77 (4.4%) were ≥85 years old. A significant interaction of age and treatment on poor outcome (modified Rankin Scale score of 5-6, P=0.020) and mortality (P=0.031) was observed, with older adults having worse functional outcomes at 90 days compared with younger patients (adjusted common odds ratio, 0.20 [95% CI, 0.13-0.33]). However, a benefit of EVT was observed in the ≥85-year-old patient subgroup (common odds ratio, 4.20 [95% CI, 1.56-11.32]). Age ≥85 years was not significantly associated with differing rates of symptomatic intracerebral hemorrhage or reperfusion (adjusted odds ratio, 1.92 [95% CI, 0.71-5.15] and adjusted odds ratio, 0.91 [95% CI, 0.40-2.06], respectively). CONCLUSIONS: Patients ≥85 years old with independent premorbid function more often achieve good functional outcomes and have lower rates of mortality when treated with EVT compared with conservative management, with an observed treatment effect modification of age on outcome. EVT should therefore not be withheld in this subgroup.

Diffusion-Weighted Imaging and Fluid-Attenuated Inversion Recovery Quantification to Predict Diffusion-Weighted Imaging-Fluid-Attenuated Inversion Recovery Mismatch Status in Ischemic Stroke With Unknown Onset.

BACKGROUND: Visual rating of diffusion-weighted imaging (DWI)-fluid-attenuated inversion recovery (FLAIR) mismatch can be challenging. We evaluated quantification of DWI and FLAIR to predict DWI-FLAIR mismatch status in ischemic stroke. METHODS: In screened patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke), we retrospectively studied relative DWI (rDWI SI) and FLAIR signal intensity (rFLAIR SI). We defined the optimal mean rFLAIR SI and interquartile range of the rDWI SI in the DWI lesion to predict DWI-FLAIR mismatch status. We investigated agreement between each quantitative parameter and the DWI-FLAIR mismatch and the association between both quantitative parameters. We evaluated the predictive value of the quantitative parameters for excellent functional outcome by logistic regression, adjusted for DWI lesion volume, treatment, age, and National Institutes of Health Stroke Scale score. RESULTS: In the rFLAIR and rDWI SI analysis, 213/369 and 241/421 subjects respectively had a DWI-FLAIR mismatch. A mean rFLAIR SI cutoff of 1.09 and interquartile range rDWI SI cutoff of 0.47 were optimal to predict the DWI-FLAIR mismatch with a sensitivity and specificity of 77% (95% CI, 71%-83%) and 67% (95% CI, 59%-74%), and 76% (95% CI, 70%-81%) and 72% (95% CI, 65%-79%), respectively. For both quantitative parameters, agreement with the DWI-FLAIR mismatch was fair (73%, κ=0.44 [95% CI, 0.35-0.54] for rFLAIR and 74%, κ=0.48 [95% CI, 0.39-0.56] for rDWI). Both quantitative parameters correlated moderately (Pearson R=0.54 [95% CI, 0.46-0.61]; P<0.001, n=367). The interquartile range rDWI SI (n=188), but not the mean rFLAIR SI (n=172), was an independent predictor of excellent functional outcome (odds ratio, 0.67 per 0.1 unit increase of interquartile range rDWI SI, 95% CI, 0.51-0.89, P=0.01). CONCLUSIONS: Agreement between the quantitative and qualitative approach may be insufficient to advocate DWI or FLAIR quantification as alternative for visual rating.

Thrombectomy With and Without Computed Tomography Perfusion Imaging in the Early Time Window: A Pooled Analysis of Patient-Level Data.

BACKGROUND: The optimal imaging paradigm for endovascular thrombectomy (EVT) patient selection in early time window (0-6 hours) treated acute ischemic stroke patients remains uncertain. We aimed to compare post-EVT outcomes between patients who underwent prerandomization basic (noncontrast computed tomography [CT], CT angiography only) versus additional advanced imaging (computed tomography perfusion [CTP] imaging) and to determine the association of performance of prerandomization CTP imaging with clinical outcomes. METHODS: The HERMES collaboration (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) pooled patient-level data from randomized controlled trials comparing EVT with usual care for acute ischemic stroke due to anterior circulation large vessel occlusion. Good functional outcome, defined as modified Rankin Scale score 0 to 2 at 90 days, was compared between randomized patients with and without CTP baseline imaging. Univariable and multivariable binary logistic regression analysis was performed to determine the association of baseline CTP imaging and good functional outcome. RESULTS: We analyzed 1348 patients 610 (45.3%) of whom underwent CTP prerandomization. The benefit of EVT compared with best medical management was maintained irrespective of the baseline imaging paradigm (90-day modified Rankin Scale score 0-2 in EVT versus control patients: with CTP: 46.0% (137/298) versus 28.9% (88/305), without CTP: 44.1% (162/367) versus 27.3% (100/366). Performance of CTP baseline imaging compared with baseline noncontrast CT and CT angiography only yielded similar rates of good outcome (odds ratio, 1.05 [95% CI, 0.82-1.33], adjusted odds ratio, 1.04, [95% CI, 0.80-1.35]). CONCLUSIONS: Rates of good functional outcome were similar among patients in whom CTP was or was not performed, and EVT treatment effect in the 0- to 6-hour time window was similar in patients with and without baseline CTP imaging.

Significance of Baseline Ischemic Core Volume on Stroke Outcome After Endovascular Therapy in Patients Age ≥75 Years: A Pooled Analysis of Individual Patient Data From 7 Trials.

BACKGROUND: Age and infarct volume are strong predictors of outcome in patients with ischemic stroke who underwent endovascular therapy (EVT). We aimed to investigate the impact of ischemic core volume (ICV) on stroke outcome after EVT in elderly. METHODS: Using the HERMES (Highly Effective Reperfusion Using Multiple Endovascular Devices) collaboration, a patient-level meta-analysis of 7 randomized trials in which patients were enrolled from December 2010 to April 2015) dataset, we categorized patients into those aged <75 and ≥75 years. ICV was calculated on computed tomography perfusion or magnetic resonance diffusion-weighted imaging. The association between ICV and the benefit of EVT over best medical treatment on outcome (modified Rankin Scale [mRS] at 90 days) and an ICV threshold for high likelihood (≥90%) of very poor outcome (mRS score ≥5) after EVT were investigated. RESULTS: A total of 899 patients who had baseline ICV data, 247 patients aged ≥75 years, of which 118 were randomized in the EVT arm. Patients aged ≥75 years required smaller ICV to achieve mRS score ≤3 than those aged <75 years in the EVT arm (median 10.7 mL versus 23.9 mL, P<0.001). In patients aged ≥75 years, modeling of outcome in both treatment arms revealed potential loss of effect for EVT at ICV of ≥50 mL or ≥85 mL for achieving mRS score ≤3 or ≤4, respectively. Treatment effect of EVT was significant in ICV <50 mL for mRS ≤3 (odds ratio 2.38, 95% confidence interval 1.35-4.22). ICV ≥132 mL was a threshold for high likelihood of very poor outcome after EVT. However, EVT still predicted at least 30% rate of mRS ≤3 at 150 mL ICV if near-complete or complete reperfusion was achieved. CONCLUSIONS: Baseline ICV has an impact on stroke outcome after EVT in the elderly, but elderly patients with large ICV may still benefit from EVT if near-complete or complete reperfusion is achieved. Young patients seem to benefit from EVT regardless of ICV status.

Correlation Between Computed Tomography-Based Tissue Net Water Uptake and Volumetric Measures of Cerebral Edema After Reperfusion Therapy.

BACKGROUND: Cerebral edema after large hemispheric infarction is associated with poor functional outcome and mortality. Net water uptake (NWU) quantifies the degree of hypoattenuation on unenhanced-computed tomography (CT) and is increasingly used to measure cerebral edema in stroke research. Hemorrhagic transformation and parenchymal contrast staining after thrombectomy may confound NWU measurements. We investigated the correlation of NWU measured postthrombectomy with volumetric markers of cerebral edema and association with functional outcomes. METHODS: In a pooled individual patient level analysis of patients presenting with anterior circulation large hemispheric infarction (core 80-300 mL or Alberta Stroke Program Early CT Score ≤5) in the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set, cerebral edema was defined as the volumetric expansion of the ischemic hemisphere expressed as a ratio to the contralateral hemisphere(rHV). NWU and midline-shift were compared with rHV as the reference standard on 24-hour follow-up CT, adjusted for hemorrhagic transformation and the use of thrombectomy. Association between edema markers and day 90 functional outcomes (modified Rankin Scale) was assessed using ordinal logistic regression. RESULTS: Overall (n=144), there was no correlation between NWU and rHV (rs=0.055, P=0.51). In sub-group analyses, a weak correlation between NWU with rHV was observed after excluding patients with any degree of hemorrhagic transformation (rs=0.211, P=0.015), which further improved after excluding thrombectomy patients (rs=0.453, P=0.001). Midline-shift correlated strongly with rHV in all sub-group analyses (rs>0.753, P=0.001). Functional outcome at 90 days was negatively associated with rHV (adjusted common odds ratio, 0.46 [95% CI, 0.32-0.65]; P<0.001) and midline-shift (adjusted common odds ratio, 0.85 [95% CI, 0.78-0.92]; P<0.001) but not NWU (adjusted common odds ratio, 1.00 [95% CI, 0.97-1.03]; P=0.84), adjusted for age, baseline National Institutes of Health Stroke Scale, and thrombectomy. Prognostic performance of NWU improved after excluding patients with hemorrhagic transformation and thrombectomy (adjusted odds ratio, 0.90 [95% CI, 0.80-1.02]; P=0.10). CONCLUSIONS: NWU correlated poorly with conventional markers of cerebral edema and was not associated with clinical outcome in the presence of hemorrhagic transformation and thrombectomy. Measuring NWU postthrombectomy requires validation before implementation into clinical research. At present, the use of NWU should be limited to baseline CT, or follow-up CT only in patients without hemorrhagic transformation or treatment with thrombectomy.

Comparison of Three Scores of Collateral Status for Their Association With Clinical Outcome: The HERMES Collaboration.

BACKGROUND: Leptomeningeal collateral status on baseline computed tomographic angiography (CTA) is associated with clinical outcome after acute ischemic stroke treatment. However, assessment of collateral status is not uniform. To compare 3 different CTA collateral scores (CS) and imaging techniques about their association with clinical outcome. METHODS: Pooled analysis of patient-level data from the Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration. Patients with large vessel occlusion from 7 randomized controlled trials that compared endovascular thrombectomy with standard medical care were included. Three different CS (Tan CS, regional CS [rCS], and regional Alberta Stroke Program Early CT Score CS) and 2 imaging techniques (single-phase [sCTA] and multiphase/dynamic CTA) were evaluated. Functional independence (modified Rankin Scale score 0-2) at 3 months poststroke was the primary outcome. Furthermore, we assessed the effect of sCTA image acquisition time on collateral status assessment using an adjusted ordinal logistic regression model to obtain predicted values for the trichotomized rCS. RESULTS: Among 1147 pooled patients, 948 (82.7%) had sCTA and 199 (17.3%) multiphase/dynamic CTA as baseline angiography. With all 3 collateral scales, better CSs were associated with better 3-month functional outcome. With sCTA images, the rCS (area under the curve [AUC] 0.63) and regional Alberta Stroke Program Early CT Score CS (AUC 0.62) better predicted functional outcome than the Tan CS (AUC 0.60, respectively; P<0.001 and P=0.02). With multiphase/dynamic CTA images, all collateral scales performed similarly in predicting functional outcome (rCS [AUC 0.61]; regional Alberta Stroke Program Early CT Score CS [AUC 0.61] versus Tan CS [AUC 0.61], respectively; P=0.93 and P=0.91). Overall, no endovascular thrombectomy treatment effect modification by collateral status (rCS) was demonstrated (P=0.41). sCTA timing independently influenced CS assessment. On earlier timed sCTA, the predicted proportions of scans with poor collaterals was higher and vice versa. CONCLUSIONS: In this data set of highly selected patients with stroke, using a regional CS on sCTA likely allows for the most accurate prediction of functional outcome while on time-resolved CTA, the type of CS did not matter. Patients across all collateral grades benefit from endovascular thrombectomy. sCTA timing independently influenced CS assessment.

Early effect of thrombolysis on structural brain network organisation after anterior-circulation stroke in the randomized WAKE-UP trial.

The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE-UP trial, comparing 127 imaging-selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio-topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network-informed imaging biomarkers and improved prognostication in ischemic stroke.

Value of infarct location in the prediction of functional outcome in patients with an anterior large vessel occlusion: results from the HERMES study.

PURPOSE: Follow-up infarct volume (FIV) is moderately associated with functional outcome. We hypothesized that accounting for infarct location would strengthen the association of FIV with functional outcome. METHODS: We included 252 patients from the HERMES collaboration with follow-up diffusion weighted imaging. Patients received endovascular treatment combined with best medical management (n = 52%) versus best medical management alone (n = 48%). FIV was quantified in low, moderate and high modified Rankin Scale (mRS)-relevant regions. We used binary logistic regression to study the relation between the total, high, moderate or low mRS-relevant FIVs and favorable outcome (mRS < 2) after 90 days. The strength of association was evaluated using the c-statistic. RESULTS: Small lesions only occupied high mRS-relevant brain regions. Lesions additionally occupied lower mRS-relevant brain regions if FIV expanded. Higher FIV was associated with a higher risk of unfavorable outcome, as were volumes of tissue with low, moderate and high mRS relevance. In multivariable modeling, only the volume of high mRS-relevant infarct was significantly associated with favorable outcome. The c-statistic was highest (0.76) for the models that included high mRS-relevant FIV or the combination of high, moderate and low mRS-relevant FIV but was not significantly different from the model that included only total FIV (0.75). CONCLUSION: This study confirms the association of FIV and unfavorable functional outcome but showed no strengthened association if lesion location was taken into account.

Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.

BACKGROUND AND PURPOSE: During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke). METHODS: We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE. RESULTS: Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21-0.61], P<0.001). Higher age (P=0.04) and male sex (P=0.01) were predictors for the occurrence of SAE. CONCLUSIONS: SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra. Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function. Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26). Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

Small Vessel Disease and Ischemic Stroke Risk During Anticoagulation for Atrial Fibrillation After Cerebral Ischemia.

BACKGROUND AND PURPOSE: The causes of recurrent ischemic stroke despite anticoagulation for atrial fibrillation are uncertain but might include small vessel occlusion. We investigated whether magnetic resonance imaging markers of cerebral small vessel disease (SVD) are associated with ischemic stroke risk during follow-up in patients anticoagulated for atrial fibrillation after recent ischemic stroke or transient ischemic attack. METHODS: We analyzed data from a prospective multicenter inception cohort study of ischemic stroke or transient ischemic attack anticoagulated for atrial fibrillation (CROMIS-2 [Clinical Relevance of Microbleeds in Stroke Study]). We rated markers of SVD on baseline brain magnetic resonance imaging: basal ganglia perivascular spaces (number ≥11); cerebral microbleeds (number ≥1); lacunes (number ≥1); and white matter hyperintensities (periventricular Fazekas grade 3 or deep white matter Fazekas grade ≥2). We investigated the associations of SVD presence (defined as presence of ≥1 SVD marker) and severity (composite SVD score) with the risk of ischemic stroke during follow-up using a Cox proportional hazards model adjusted for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65-74, female score. RESULTS: We included 1419 patients (mean age: 75.8 years [SD, 10.4]; 42.1% female). The ischemic stroke rate during follow-up in patients with any SVD was 2.20 per 100-patient years (95% CI, 1.60-3.02), compared with 0.98 per 100 patient-years (95% CI, 0.59-1.62) in those without SVD (P=0.008). After adjusting for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65-74, female score, SVD presence remained significantly associated with ischemic stroke during follow-up (hazard ratio, 1.89 [95% CI, 1.01-3.53]; P=0.046); the risk of recurrent ischemic stroke increased with SVD score (hazard ratio per point increase, 1.33 [95% CI, 1.04-1.70]; P=0.023). CONCLUSIONS: In patients anticoagulated for atrial fibrillation after ischemic stroke or transient ischemic attack, magnetic resonance imaging markers of SVD are associated with an increased risk of ischemic stroke during follow-up; improved stroke prevention treatments are required in this population. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02513316.