Thrombolysis In Wake-up Stroke Research Articles

Thrombolysis in wake-up stroke based on MRI mismatch

ObjectivesWake-up stroke (WUPS) patients can be selected to intravenous thrombolysis (IVT) treatment based on the Magnetic Resonance Imaging (MRI) mismatch concept. However, recent studies suggest the introduction of modified MRI mismatch criteria, allowing IVT in WUPS patients with a partial mismatch. Material and methodsWUPS patients treated with IVT in the NOR-TEST trial and consecutively thereafter at Stavanger University Hospital were included in this study. Patient selection for treatment was performed based on the clinical presentation and the MRI DWI/FLAIR mismatch criteria. MRI examinations were reassessed according to the modified DWI-FLAIR mismatch criteria, allowing partial mismatch. Improvement in NIHSS and mRS at 3 months were used to analyze clinical outcome, and the rate of intracranial hemorrhage (ICH) to analyze safety. Results78 WUPS patients were treated with IVT. Only 68 of these patients were independent pre-stroke and included in the clinical analysis. When reassessing the MRI examinations, 41 (60 %) were rated as DWI/ FLAIR mismatch, 14 (21 %) as partial mismatch and 13 (19 %) as match. The results show that the patient groups had a mRS score 0–1 at 3 months measured as primary outcome to respectively 27 (65.9 %), 11 (78.6 %) and 8 (61.5 %); (P = 0.629). The mismatch group showed the best clinical improvement (3-points NIHSS reduction, p = 0.005). No ICH was seen in any of the groups. ConclusionOur study extended the mismatch concept in clinical praxis to treat WUPS patients with partial mismatch, showing the best clinical outcome in the mismatch group.

Thrombolysis for Wake-Up Stroke Versus Non-Wake-Up Unwitnessed Stroke: EOS Individual Patient Data Meta-Analysis.

Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Abstract WP16: Thrombolysis in Wake-Up Stroke Improves Outcomes, Reduces Cost, and Reverses ADC Lesions

Introduction: Trials using advanced imaging have shown a benefit from intravenous thrombolysis in patients with wake-up stroke, but real-world data is limited. This study presents data on outcomes in patients presenting with wake-up stroke at a comprehensive stroke center comparing those who received thrombolysis to those who did not. Methods: In February 2022, our institution implemented a wake-up stroke protocol utilizing emergent MRI-based evaluation for possible thrombolysis. The protocol combines clinical criteria (suspected ischemic stroke with disabling neurologic deficits; last known normal within 12 hours; time from symptom discovery to arrival within 4.5 hours) and imaging criteria (absence of proximal large vessel occlusion; FLAIR-DWI mismatch; signal intensity ratio < 1.15 in those able to receive perfusion imaging). In this study, we compared discharge outcomes and hospital length of stay for patients with ischemic stroke selected for wake-up protocol with vs. without thrombolytic therapy. In addition, we assessed the proportion of patients with reversibility of diffusion restriction, defined as a decrease in infarct volume on ADC sequence between the pre-treatment to 24-hour post-treatment MRI. Results: Between February 2022 & June 2023, there were 31 wake-up stroke activations (~2 per month). Median admission NIHSS was 6. 30% had medium or distal vessel occlusions. 71% of stroke activations had a final diagnosis of ischemic stroke; 32% of cases were eligible per protocol and treated with thrombolysis. Compared to patients diagnosed with ischemic stroke but not eligible for treatment, those treated with thrombolysis were more likely to be discharged home (70% vs. 17%, p = 0.02) and had a shorter hospital stay by ~1.5 days (mean LOS 3.6 days vs. 4.8 days; median LOS 3 days vs. 4.5 days; p <0.01). ADC reversibility was demonstrated in ~30% of patients who underwent thrombolysis. Conclusions: Intravenous thrombolysis for patients presenting with wake-up stroke was feasible, improved outcomes, and reduced potential cost. It also demonstrated ADC reversibility in 30% of cases. Further steps are needed to increase availability of emergent MRI and optimize door to thrombolysis times in order to streamline access for potential treatment.

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

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. 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. 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. 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.

Editors' Note: Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial

Dr. Schlemm et al. performed a prespecified analysis of the association of cerebral microbleeds (CMBs) with the treatment effect of IV alteplase vs placebo in the randomized controlled WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) trial of patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch on MRI. Among 459 patients available for analysis, there was no evidence of reduced treatment effect of alteplase in the 98 (21.4%) patients who had at least 1 CMB on baseline imaging. However, CMBs were associated with a nonsignificant increased risk of symptomatic intracranial hemorrhage (ICH; 11.2% vs 4.2%; adjusted odds ratio 2.32, 95% CI 0.99–5.43). In response, Drs. Meinel and Seiffge highlight the importance of distinguishing patients with CMBs from cerebral amyloid angiopathy or other cerebral small vessel disease—who have an increased risk of postthrombolysis ICH—from those with other causes of CMBs and other such lesions on susceptibility-weighted imaging, like those seen after valve implantation, extracorporeal membrane oxygenation, or prolonged intensive care unit stay. They also recommend examining the interaction of CMBs and white matter hyperintensities to better elucidate the risk of postthrombolysis hemorrhage. Responding to these comments, the authors note that new CMBs in acute ischemic stroke patients after IV thrombolysis were associated with an increased risk of hemorrhagic complications in prior literature, whereas new CMBs after cardiac surgery were not associated with bleeding risk, suggesting different risk profiles for patients with different causes of acute CMBs—a topic meriting further investigation in histopathology and observational studies. This exchange highlights the challenges of disentangling cause-specific bleeding risks associated with CMBs when examining ICH outcomes in patients undergoing thrombolysis. Dr. Schlemm et al. performed a prespecified analysis of the association of cerebral microbleeds (CMBs) with the treatment effect of IV alteplase vs placebo in the randomized controlled WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) trial of patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch on MRI. Among 459 patients available for analysis, there was no evidence of reduced treatment effect of alteplase in the 98 (21.4%) patients who had at least 1 CMB on baseline imaging. However, CMBs were associated with a nonsignificant increased risk of symptomatic intracranial hemorrhage (ICH; 11.2% vs 4.2%; adjusted odds ratio 2.32, 95% CI 0.99–5.43). In response, Drs. Meinel and Seiffge highlight the importance of distinguishing patients with CMBs from cerebral amyloid angiopathy or other cerebral small vessel disease—who have an increased risk of postthrombolysis ICH—from those with other causes of CMBs and other such lesions on susceptibility-weighted imaging, like those seen after valve implantation, extracorporeal membrane oxygenation, or prolonged intensive care unit stay. They also recommend examining the interaction of CMBs and white matter hyperintensities to better elucidate the risk of postthrombolysis hemorrhage. Responding to these comments, the authors note that new CMBs in acute ischemic stroke patients after IV thrombolysis were associated with an increased risk of hemorrhagic complications in prior literature, whereas new CMBs after cardiac surgery were not associated with bleeding risk, suggesting different risk profiles for patients with different causes of acute CMBs—a topic meriting further investigation in histopathology and observational studies. This exchange highlights the challenges of disentangling cause-specific bleeding risks associated with CMBs when examining ICH outcomes in patients undergoing thrombolysis.

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.

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. 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. 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). Agreement between the quantitative and qualitative approach may be insufficient to advocate DWI or FLAIR quantification as alternative for visual rating.

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

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). 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. 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. 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.

Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial.

Background and ObjectivesCerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown.MethodsWe performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment.ResultsOf 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99–5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59–1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07–2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence (p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution.DiscussionIn the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs.Trial Registration InformationClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32.Classification of EvidenceThis study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.

Hyperintense acute reperfusion marker associated with hemorrhagic transformation in the WAKE-UP trial.

Hyperintense acute reperfusion marker (HARM) is an indicator of early disruption of the blood-brain-barrier. Our aim was to investigate the incidence of HARM in patients with a diffusion weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) mismatch and determine the association between this marker and hemorrhagic complications as well as clinical outcome. We included patients from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial who underwent baseline perfusion weighted imaging (PWI). HARM was defined as a hyperintense signal in the cerebrospinal fluid space on FLAIR imaging at 24 h after baseline imaging. We compared baseline characteristics in patients with and without HARM and investigated the association between HARM and any hemorrhagic transformation (HT) and parenchymal hematoma (PH) in a multivariate logistic regression. We also explored HARM as an independent predictor of poor outcome, defined as a modified Rankin Scale of 3-6 at 90 days. HARM was present in 14 of 223 (6%) patients with a DWI-FLAIR mismatch and baseline characteristics were similar in patients with vs without HARM. HARM showed an independent relationship with any HT (OR 6.67; 95%CI 1.72-26.58) and any PH (OR 6.92; 95%CI 1.34-29.49). The rate of HARM was similar in patients with good and poor outcome (5%, p = 0.90). In the WAKE-UP trial, the incidence of HARM was only 6% at 24 h. An association was present between HARM and hemorrhagic complications, but no relationship with functional outcome was observed.

24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke.

To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke. In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke. BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76-4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43-2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26-7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34-2.10) in in the highest quintile. There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.ClinicalTrials.gov identifier NCT01525290.

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra. 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. 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). 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. URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

Abstract P352: Reversible Relative FLAIR Signal Intensity Changes in the Penumbra Correlate With Severity of Hypoperfusion

In ischemic stroke, the study of edema, measurable as fluid attenuated inversion recovery (FLAIR) signal increase, has mainly focused on the ischemic core and less on the surrounding penumbra. To the naked eye, no FLAIR changes are present in the penumbra. However, changes in perfusion status could induce physiological changes resulting in subtle penumbral FLAIR signal alterations. To investigate penumbral FLAIR changes, we included subjects from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) and Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke (AXIS 2) trial with perfusion- and diffusion-weighted imaging (PWI, DWI) and FLAIR at baseline. We used RAPID software to calculate the core and perfusion lesion on DWI and PWI and selected subjects with a minimal mismatch volume (15 ml) and ratio (1.2). We created voxel-based relative FLAIR signal intensity (rFLAIR SI) maps at baseline and follow up (FU) by calculating the ratio of the FLAIR intensity in one voxel and the median FLAIR intensity in a sphere with 15 mm radius around a contralateral homologues voxel. We studied rFLAIR SI in two regions of interest: the baseline penumbra (baseline perfusion lesion - [core lesion + voxels with apparent diffusion coefficient &lt;620 10 -6 mm 2 /s]) and the non-infarcted penumbra (baseline perfusion lesion - FU FLAIR lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). Severity of hypoperfusion was defined as the time to maximum of the residue function. 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’s r 0.03, p&lt;1.0*10 -4 , n=126). At 24 hours in a subgroup from WAKE-UP, rFLAIR SI in the non-infarcted penumbra further increased (ratio=1.05 at 24h vs 1.03 at baseline, p=7.1*10 -3 , n=43). In a different subgroup from AXIS 2, this increase in rFLAIR SI was reversible (ratio=1.02 at 30d vs 1.04 at baseline, p=1.5*10 -3 n=26) since it was no longer different from 1 at 30 days (ratio=1.01 at 30 days, p=0.099, n=26). Increases in rFLAIR SI, likely representing edema, are not restricted to the ischemic core and correlate with severity of hypoperfusion in the penumbra. They appear early after stroke onset, further increase at 24 hours and are reversible by 30 days.

Symptoms and probabilistic anatomical mapping of lacunar infarcts

BackgroundThe anatomical distribution of acute lacunar infarcts has mainly been studied for supratentorial lesions. In addition, little is known about the association with distinct stroke symptoms, not summarized as classical lacunar syndromes. We aimed to describe the spatial lesion distribution of acute supra- and infratentorial lacunar infarcts and their association with stroke symptoms in patients eligible for thrombolysis.MethodsAll patients enrolled in the WAKE-UP trial (efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in wake-up stroke) were screened for lacunar infarcts on diffusion-weighted imaging (DWI). The relationship between the anatomical distribution of supra- and infratentorial lacunar infarcts, their demographic characteristics and acute stroke symptoms, defined by the National Institutes of Health Stroke Scale (NIHSS) score, were correlated and compared.ResultsMaps of lesion distribution from 224 lacunar infarct patients (76 [33.9%] females, mean age [standard deviation] of 63.4 [11.5] years) were generated using computational image mapping methods. Median infarct volume was 0.73 ml (interquartile range [IQR] 0.37–1.15 ml). Median NIHSS sum score on hospital arrival was 4 (IQR 3–6). 165 (73.7%) patients had lacunar infarcts in the supratentorial deep white or grey matter, while 59 (26.3%) patients had infratentorial lacunar infarcts. Patients with supratentorial lacunar infarcts presented with a significantly lower occurrence of deficits in the NIHSS items gaze (p < 0.001) and dysarthria (p = 0.008), but had more often a paresis of the left arm (p = 0.009) and left leg (p = 0.068) compared to patients with infratentorial infarcts.ConclusionsThe anatomical lesion distribution of lacunar infarcts reveals a distinct pattern and supports an association of localization with different stroke symptoms.Trial registrationNCT01525290.

Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial.

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; P>0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.

Abstract WP86: MRI-Guided Mismatch Imaging to Identify Patients for Thrombolysis in the Unknown Time Window: Insights From the WAKE-UP Trial

Background: Two imaging paradigms, the diffusion-weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) and perfusion-weighted imaging (PWI) - DWI mismatch, used in the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) and Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial respectively, can identify patients eligible for thrombolysis if stroke onset time is unknown. Objectives: We explored presence and influence of the PWI-DWI mismatch on outcome in WAKE-UP. Methods: We included patients screened for DWI-FLAIR mismatch in WAKE-UP who also underwent PWI. We defined PWI-DWI mismatch according to EXTEND as core &lt;70 ml, mismatch ratio &gt;1.2 and mismatch volume &gt;10 ml. Primary efficacy end point was favorable outcome defined as modified Rankin Scale score of 0-1, adjusted for age and symptom severity. Results: The analysis included 343 screened patients of which 162 were randomized and treated. Of 343 screened patients, 162 had a DWI-FLAIR mismatch, 80 had a PWI-DWI mismatch and of those, 36 had both mismatches. Proportions of PWI-DWI mismatch did not differ in those with (22%, 36/162) vs without (24%, 44/181) DWI-FLAIR mismatch (p=0.74). PWI-DWI mismatch status did not modify treatment effect of thrombolysis (p for interaction=.68). In patients with both DWI-FLAIR and PWI-DWI mismatch, favorable outcome was present in 52% of those treated with alteplase (11/21) vs 38% (5/13) in those receiving placebo (adjusted OR 2.02; 95% CI 0.44-9.24, p=0.36). Selection based on the presence of the DWI-FLAIR mismatch identified more thrombolysis eligible patients (47%; 95% CI 42%-53%) compared to the PWI-DWI mismatch (23%; 95% CI 19%-28%, p&lt;.0001). Screening for either one of the mismatch profiles resulted in a yield of 60% (95% CI 55%-65%) candidates for thrombolysis. Conclusion: We did not identify an association between the DWI-FLAIR and PWI-DWI mismatch. PWI-DWI mismatch status did not modify treatment effect in patients with DWI-FLAIR mismatch, but the analysis was underpowered. Screening for the presence of either one of the mismatch profiles with MRI seems the most inclusive approach to identify patients who can still benefit from thrombolysis in the unknown time window after stroke onset.

Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial.

Background: The “smoking paradox” indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce.Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status.Results: Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; p < 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; p = 0.02) or atrial fibrillation (3.8% vs. 15.3%; p < 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; p = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score>10 in 27.1% vs. 19.5%; p = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (p-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451–0.978], p = 0.04).Conclusions: In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase.Clinical Trial registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012.

Post-hoc Analysis of Outcome of Intravenous Thrombolysis in Infarcts of Infratentorial Localization in the WAKE-UP Trial.

Introduction: In WAKE-UP (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke), patients with an acute stroke of unknown onset time were randomized to treatment with intravenous alteplase or placebo, guided by MRI.Methods: In this exploratory post-hoc secondary analysis we compared clinical and imaging data, as well as treatment effects and safety of intravenous thrombolysis between patients with infra- vs. supratentorial stroke.Results: Forty-eight out of 503 randomized patients (9.5%) presented with a stroke involving the cerebellum or brainstem. Patients with infratentorial stroke were younger compared to patients with supratentorial stroke (mean age 60 vs. 66 years), more frequently male (85 vs. 62%), and less severely affected (median NIHSS 4.5 vs. 6.0). There was no heterogeneity for treatment effect between supratentorial (OR 1.67 95% CI 1.11–2.51) and infratentorial (OR 1.31 95% CI 0.41–4.22) sub-groups (test for interaction p = 0.70). In patients with infratentorial stroke, favorable outcome [a score of 0–1 on the modified Rankin scale (mRS) at 90 days] was observed in 12/22 patients (54.5%) in the alteplase group and in 13/25 patients (52.0%) in the placebo group (p = 0.59). The primary safety endpoint (death or mRS 4–6 at day 90) occurred in three patients of the alteplase group (13.6%) and three patients in the placebo group (12.0%); p = 0.74.Discussion: WAKE-UP was underpowered for demonstrating treatment effect in subgroup analyses however, based on our current results, there is no evidence to recommend withholding MRI-guided thrombolysis in patients with unknown onset stroke of infratentorial localization.

Abstract TMP15: Thrombolysis in Stroke With Unknown Onset Based on Non-contrast Ct (TRUST CT). An International, Multicenter, Registry-based Study

Background: Thrombolysis in wake-up stroke (WUS) or stroke with unknown onset (SUO) has been recently proven to be safe and effective using magnetic resonance imaging (MRI). However, in most of the thrombolyzing hospitals worldwide MR imaging is not available. We hypothesize that pragmatic non-contrast CT (NCCT)-based WUS/SUO thrombolysis may be feasible and safe. Methods: TRUST-CT is an international multicenter registry-based study. WUS/SUO patients undergoing NCCT-based thrombolysis with NIHSS ≥ 4 and initial ASPECTS ≥ 7 are included and compared to propensity score matched non-thrombolyzed WUS/SUO controls. Primary endpoint is symptomatic intracranial hemorrhage (ICH); secondary endpoints include 24-hour NIHSS change of ≥ 4 and modified Rankin Score (mRS) at 90 days. Results: Until now 100 patients with NCCT-based WUS/SUO thrombolysis were included. As compared to 100 controls, the median admission NIHSS was 9 and 8, respectively; the median ASPECTS was 10 in both groups. 3 (3 %) patients and 0 controls suffered symptomatic ICH. A decrease of ≥ 4 NIHSS points was observed in 48 % of the thrombolyzed patients as compared to 25% in the control group (p = 0.001); 33% and 28% achieved mRS 0 to 1 at 90 days, respectively (p = 0.4). Conclusions: NCCT-based thrombolysis in WUS/SUO seems feasible, safe and eventually effective. Updated results will be presented and discussed in the context of current evidence.

Modified DWI-FLAIR mismatch guided thrombolysis in unknown onset stroke.

DWI-FLAIR mismatch has been recently proven to identify patients with unknown onset stroke (UOS) eligible for thrombolysis. However, this concept may exclude patients from thrombolysis who may eventually benefit as well. We aimed to examine the feasibility, safety and potential efficacy of thrombolysis in wake-up stroke (WUS) and UOS patients using a modified DWI-FLAIR mismatch allowing for partial FLAIR positivity. WUS/UOS patients fulfilling the modified DWI-FLAIR mismatch and treated with intravenous thrombolysis (IVT) were compared to propensity score matched WUS/UOS patients excluded from IVT due to FLAIR positivity. The primary endpoint was a symptomatic intracranial hemorrhage (SICH), the secondary endpoints were improvement of ≥ 4 in NIHSS score and mRS score at 3months. 64 IVT-treated patients (median NIHSS 9) and 64 controls (median NIHSS 8) entered the analysis (p = 0.2). No significant difference in SICH was found between the IVT group and the controls (3.1% vs. 1.6%, p = 0.9). An improvement of ≥ 4 NIHSS points was more frequent in IVT patients as compared to controls (40.6% vs. 18.8%, p = 0.01). 23.4% of IVT patients achieved a mRS score of 0-1 at 3months as compared to 18.8% of the controls (p = 0.8). SICH, improvement of NIHSS ≥ 4 and mRS 0-1 at 3months were comparable in thrombolyzed patients with negative FLAIR images versus those thrombolyzed with partial positive FLAIR images (3% vs. 3%, p = 0.9; 40% vs. 41%, p = 0.9; 19% vs. 22%, p = 0.8). Our study signalizes that thrombolysis may be feasible in selected WUS/UOS patients with partial FLAIR signal positivity.

Stroke With Unknown Time of Symptom Onset: Baseline Clinical and Magnetic Resonance Imaging Data of the First Thousand Patients in WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial).

We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort. We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery. Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P<0.001), and more often aphasia (72.5% versus 34.0%; P<0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; P=0.30). Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01525290. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-005906-32.