Interobserver Agreement on Intracranial Hemorrhage on Magnetic Resonance Imaging in Patients With Ischemic Stroke.

BACKGROUND: The Heidelberg Bleeding Classification, developed for computed tomography, is also frequently used to classify intracranial hemorrhage (ICH) on magnetic resonance imaging. Additionally, the presence of any ICH is frequently used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. We assessed the interobserver agreement on the presence of any ICH and the type of ICH according to the Heidelberg Bleeding Classification on magnetic resonance imaging in patients treated with reperfusion therapy. METHODS: We used 300 magnetic resonance imaging scans including susceptibility-weighted imaging or T2*-weighted gradient echo imaging of ischemic stroke patients within 1 week after reperfusion therapy. Six observers, blinded to clinical characteristics except for suspected location of the infarction, independently rated ICH according to the Heidelberg Bleeding Classification in random pairs. Percent agreement and Cohen's kappa (κ) were estimated for the presence of any ICH (yes/no), and for agreement on the Heidelberg Bleeding Classification class 1 and 2. For the Heidelberg Bleeding Classification class 1 and 2, weighted κ was estimated to take the degree of disagreement into account. RESULTS: In 297 of 300 scans, the quality of scans was sufficient to score ICH. Observers agreed on the presence or absence of any ICH in 264 of 297 scans (88.9%; κ 0.78 [95% CI, 0.71-0.85]). There was agreement on the Heidelberg Bleeding Classification class 1 and 2 and no ICH in class 1 and 2 in 226 of 297 scans (76.1%; κ 0.63 [95% CI, 0.56-0.69]; weighted κ 0.90 [95% CI, 0.87-0.93]). CONCLUSIONS: The presence of any ICH can be reliably scored on magnetic resonance imaging and can, therefore, be used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. Agreement of ICH types according to the Heidelberg Bleeding Classification is substantial and disagreements are small.

Symptomatic Intracranial Hemorrhage After Endovascular Stroke Treatment: External Validation of Prediction Models.

BACKGROUND: Symptomatic intracranial hemorrhage (sICH) is a severe complication of reperfusion therapy for ischemic stroke. Multiple models have been developed to predict sICH or intracranial hemorrhage (ICH) after reperfusion therapy. We provide an overview of published models and validate their ability to predict sICH in patients treated with endovascular treatment in daily clinical practice. METHODS: We conducted a systematic search to identify models either developed or validated to predict sICH or ICH after reperfusion therapy (intravenous thrombolysis and/or endovascular treatment) for ischemic stroke. Models were externally validated in the MR CLEAN Registry (n=3180; Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was sICH according to the Heidelberg Bleeding Classification. Model performance was evaluated with discrimination (c-statistic, ideally 1; a c-statistic below 0.7 is considered poor in discrimination) and calibration (slope, ideally 1, and intercept, ideally 0). RESULTS: We included 39 studies describing 40 models. The most frequently used predictors were baseline National Institutes of Health Stroke Scale (NIHSS; n=35), age (n=22), and glucose level (n=22). In the MR CLEAN Registry, sICH occurred in 188/3180 (5.9%) patients. Discrimination ranged from 0.51 (SPAN-100 [Stroke Prognostication Using Age and National Institutes of Health Stroke Scale]) to 0.61 (SITS-SICH [Safe Implementation of Treatments in Stroke Symptomatic Intracerebral Hemorrhage] and STARTING-SICH [STARTING Symptomatic Intracerebral Hemorrhage]). Best calibrated models were IST-3 (intercept, -0.15 [95% CI, -0.01 to -0.31]; slope, 0.80 [95% CI, 0.50-1.09]), SITS-SICH (intercept, 0.15 [95% CI, -0.01 to 0.30]; slope, 0.62 [95% CI, 0.38-0.87]), and STARTING-SICH (intercept, -0.03 [95% CI, -0.19 to 0.12]; slope, 0.56 [95% CI, 0.35-0.76]). CONCLUSIONS: The investigated models to predict sICH or ICH discriminate poorly between patients with a low and high risk of sICH after endovascular treatment in daily clinical practice and are, therefore, not clinically useful for this patient population.

Comparison of diffusion weighted imaging b0 with T2*-weighted gradient echo or susceptibility weighted imaging for intracranial hemorrhage detection after reperfusion therapy for ischemic stroke.

PURPOSE: Diffusion-weighted imaging (DWI) b0 may be able to substitute T2*-weighted gradient echo (GRE) or susceptibility-weighted imaging (SWI) in case of comparable detection of intracranial hemorrhage (ICH), thereby reducing MRI examination time. We evaluated the diagnostic accuracy of DWI b0 compared to T2*GRE or SWI for detection of ICH after reperfusion therapy for ischemic stroke. METHODS: We pooled 300 follow-up MRI scans acquired within 1 week after reperfusion therapy. Six neuroradiologists each rated DWI images (b0 and b1000; b0 as index test) of 100 patients and, after a minimum of 4 weeks, T2*GRE or SWI images (reference standard) paired with DWI images of the same patients. Readers assessed the presence of ICH (yes/no) and type of ICH according to the Heidelberg Bleeding Classification. We determined the sensitivity and specificity of DWI b0 for detection of any ICH, and the sensitivity for detection of hemorrhagic infarction (HI1 & HI2) and parenchymal hematoma (PH1 & PH2). RESULTS: We analyzed 277 scans of ischemic stroke patients with complete image series and sufficient image quality (median age 65 years [interquartile range, 54-75], 158 [57%] men). For detection of any ICH on DWI b0, the sensitivity was 62% (95% CI: 50-76) and specificity 96% (95% CI: 93-99). The sensitivity of DWI b0 was 52% (95% CI: 28-68) for detection of hemorrhagic infarction and 84% (95% CI: 70-92) for parenchymal hematoma. CONCLUSION: DWI b0 is inferior for detection of ICH compared to T2*GRE/SWI, especially for smaller and more subtle hemorrhages. Follow-up MRI protocols should include T2*GRE/SWI for detection of ICH after reperfusion therapy.

Infarct volume after ischemic stroke as a mediator of the effect of endovascular thrombectomy on early postprocedural neurologic deficit.

OBJECTIVES: The beneficial effect of endovascular thrombectomy (EVT) on clinical outcome is assumed to be caused by reduced follow-up infarct volume (FIV), which could serve as an early imaging endpoint. However, the effect of EVT on the modified Rankin Scale (mRS) was poorly explained by FIV. NIHSS at 5-7 days could be a more specific measure of the effect of reperfusion therapy, as opposed to the mRS at 3 months. Therefore, we aimed to assess to what extent the effect of EVT on NIHSS is explained by FIV. MATERIALS AND METHODS: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; n = 500) trial to evaluate the mediating role of FIV within 1 week in the relationship between EVT and baseline adjusted NIHSS at 5-7 days. RESULTS: Larger FIVs were associated with higher NIHSS after treatment (adjusted beta-coefficient (aß) 0.47;95%CI 0.39-0.55). EVT was associated with smaller FIVs (ß -0.35;95%CI-0.64 to -0.06) and lower NIHSS (ß -0.63;95%CI-0.90 to -0.35). After adjustment for FIV, the effect of EVT on NIHSS decreased (aß -0.47;95%CI-0.72 to -0.23), indicating that effect of EVT on neurologic deficit is partially mediated by FIV. Reduction of FIV explained 34% (95%CI;5%-93%) of the effect of EVT on the NIHSS at 5-7 days. CONCLUSIONS: Larger FIV was significantly associated with larger neurological deficits after treatment. Reduced infarct volume after EVT explains one third of treatment benefit in terms of neurological deficit. This suggests that FIV is of interest as an imaging biomarker of stroke treatment effect.

Added Value of a Blinded Outcome Adjudication Committee in an Open-Label Randomized Stroke Trial.

BACKGROUND AND PURPOSE: Blinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased treatment effect estimates. An outcome adjudication committee assures blinded outcome assessment, but the added value for trials with prospective randomized open blinded end point design and subjective outcomes is unknown. We aimed to assess the degree of misclassification of modified Rankin Scale (mRS) scores by a central assessor and its impact on treatment effect estimates in a stroke trial with prospective randomized open blinded end point design. METHODS: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was the mRS at 90 days. Standardized, algorithm-based telephone interviews to assess the mRS were conducted from a central location by an experienced research nurse, unaware but not formally blinded to treatment allocation (central assessor). Masked reports of these interviews were adjudicated by a blinded outcome committee. Misclassification was defined as an incorrect classification of the mRS by the central assessor. The effect of endovascular treatment on the mRS was assessed with multivariable ordinal logistic regression. RESULTS: In MR CLEAN, 53/500 (10.6%) of the mRS scores were misclassified. The degree and direction of misclassification did not differ between treatment arms (P=0.59). Benefit of endovascular treatment was shown on the mRS when scored by the central assessor (adjusted common odds ratio, 1.60 [95% CI, 1.16-2.21]) and the outcome adjudication committee (adjusted common odds ratio, 1.67 [95% CI, 1.21-2.20]). CONCLUSIONS: Misclassification by the central assessor was small, randomly distributed over treatment arms, and did not affect treatment effect estimates. This study suggests that the added value of a blinded outcome adjudication committee is limited in a stroke trial with prospective randomized open blinded end point design applying standardized, algorithm-based outcome assessment by a central assessor, who is unaware but not formally blinded to treatment allocation. Registration: URL: https://www.isrctn.com; Unique identifier: ISRCTN10888758.

Determinants of Symptomatic Intracranial Hemorrhage After Endovascular Stroke Treatment: A Retrospective Cohort Study.

BACKGROUND: Symptomatic intracranial hemorrhage (sICH) is a serious complication after endovascular treatment for ischemic stroke. We aimed to identify determinants of its occurrence and location. METHODS: We retrospectively analyzed data from the Dutch MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) and MR CLEAN registry. We included adult patients with a large vessel occlusion in the anterior circulation who underwent endovascular treatment within 6.5 hours of stroke onset. We used univariable and multivariable logistic regression analyses to identify determinants of overall sICH occurrence, sICH within infarcted brain tissue, and sICH outside infarcted brain tissue. RESULTS: SICH occurred in 203 (6%) of 3313 included patients and was located within infarcted brain tissue in 50 (25%), outside infarcted brain tissue in 23 (11%), and both within and outside infarcted brain tissue in 116 (57%) patients. In 14 patients (7%), data on location were missing. Prior antiplatelet use, baseline systolic blood pressure, baseline plasma glucose levels, post-endovascular treatment modified treatment in cerebral ischemia score, and duration of procedure were associated with all outcome parameters. In addition, determinants of sICH within infarcted brain tissue included history of myocardial infarction (adjusted odds ratio, 1.65 [95% CI, 1.06-2.56]) and poor collateral score (adjusted odds ratio, 1.42 [95% CI, 1.02-1.95]), whereas determinants of sICH outside infarcted brain tissue included level of occlusion on computed tomography angiography (internal carotid artery or internal carotid artery terminus compared with M1: adjusted odds ratio, 1.79 [95% CI, 1.16-2.78]). CONCLUSIONS: Several factors, some potentially modifiable, are associated with sICH occurrence. Further studies should investigate whether modification of baseline systolic blood pressure or plasma glucose level could reduce the risk of sICH. In addition, determinants differ per location of sICH, supporting the hypothesis of varying underlying mechanisms. REGISTRATION: URL: https://www.isrctn.com/; Unique identifier: ISRCTN10888758.

National Institutes of Health Stroke Scale: An Alternative Primary Outcome Measure for Trials of Acute Treatment for Ischemic Stroke.

Background and Purpose- The modified Rankin Scale (mRS) at 3 months is the most commonly used primary outcome measure in stroke treatment trials, but it lacks specificity and requires long-term follow-up interviews, which consume time and resources. An alternative may be the National Institutes of Health Stroke Scale (NIHSS), early after stroke. Our aim was to evaluate whether the NIHSS assessed within 1 week after treatment could serve as a primary outcome measure for trials of acute treatment for ischemic stroke. Methods- We used data from 2 randomized controlled trials of endovascular treatment for ischemic stroke: the positive MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; N=500) and the neutral IMS (Interventional Management of Stroke) III trial (N=656). We used a causal mediation model, with linear and ordinal logistic regression adjusted for confounders, to evaluate the NIHSS 24 hours and 5 to 7 days after endovascular treatment as primary outcome measures (instead of the mRS at 3 months) in both trials. Patients who had died before the NIHSS was assessed received the maximum score of 42. NIHSS+1 was then log10-transformed. Results- In both trials, there was a significant correlation between the NIHSS at 24 hours and 5 to 7 days and the mRS. In MR CLEAN, we found a significant effect of endovascular treatment on the mRS and on the NIHSS at 24 hours and 5 to 7 days. After adjustment for NIHSS at 24 hours and 5 to 7 days, the effect of endovascular treatment on the mRS decreased from common odds ratio 1.68 (95% CI, 1.22-2.32) to respectively 1.36 (95% CI, 0.97-1.91) and 1.24 (95% CI, 0.87-1.79), indicating that treatment effect on the mRS is in large part mediated by the NIHSS. In the IMS III trial there was no treatment effect on the NIHSS at 24 hours and 5 to 7 days, corresponding with the absence of a treatment effect on the mRS. Conclusions- The NIHSS within 1 week satisfies the requirements for a surrogate end point and may be used as a primary outcome measure in trials of acute treatment for ischemic stroke, particularly in phase II(b) trials. This could reduce stroke-outcome assessment to its essentials (ie, neurological deficit), and reduce trial duration and costs. Whether and under which conditions it could be used in phase III trials requires a debate in the field with all parties. Clinical Trial Registration- URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758; https://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Disentangling the Association Between Neurologic Deficits, Patient-Reported Impairments, and Quality of Life After Ischemic Stroke.

BACKGROUND AND OBJECTIVES: The EuroQol Group 5-Dimension Self-Reported Questionnaire (EQ-5D) is a well-established instrument to assess quality of life and generates generic utility values for health states reported by patients, derived from assessments by the general public. We hypothesized that language problems and other nonmotor deficits are not captured as well as motor deficits by this system. We aimed to quantify the association between disabling neurologic deficits and the EQ-5D dimension scores and the utility score in patients with ischemic stroke. METHODS: We used data of the Interventional Management of Stroke III trial. Missing data were imputed by multiple imputation. The association between neurologic deficits (individual NIH Stroke Scale [NIHSS] item scores) and the EQ-5D-3L (5 three-level dimension scores and utility score) at 90 days was assessed with ordinal logistic regression and Tobit regression, respectively. The explained variance of each model was estimated with Nagelkerke pseudo-R2 or R2. RESULTS: In total, 525 surviving patients were included. Complete data on both the NIHSS and EQ-5D were available for 481/525 (91.6%) patients. At 90 days, 161/491 (32.8%) patients had aphasia and 226/491 (46.0%) patients had paresis of at least 1 limb. Limb paresis, facial palsy, sensory loss, and dysarthria explained most of the variance in all EQ-5D dimension scores and the utility score. In the utility score, 8.9% of the variance was explained by neglect, 10.0% by aphasia, 10.8% by hemianopia, and 17.5%-24.1% by limb paresis. DISCUSSION: The impact of neurologic deficits on the EQ-5D in patients with ischemic stroke is mostly due to limb paresis, while the EQ-5D is less sensitive to other nonmotor deficits such as hemianopia, aphasia, and neglect. This may lead to overestimation of quality of life and, consequently, underestimation of the (cost-)effectiveness of treatments and interventions. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov. Unique identifier: NCT00359424.

Type of intracranial hemorrhage after endovascular stroke treatment: association with functional outcome.

BACKGROUND: Intracranial hemorrhage (ICH) is a frequent complication after endovascular stroke treatment. OBJECTIVE: To assess the association of the occurrence and type of ICH after endovascular treatment (EVT) with functional outcome. METHODS: We analyzed data from the MR CLEAN-NO IV and MR CLEAN-MED trials. Both trials included adult patients with ischemic stroke with a large vessel occlusion in the anterior circulation, who were eligible for EVT. ICH was classified (1) as asymptomatic or symptomatic (concomitant neurological deterioration of ≥4 points on the NIHSS, or ≥2 points on 1 NIHSS item), and (2) according to the Heidelberg Bleeding Classification. We used multivariable ordinal logistic regression analyses to assess the association of the occurrence and type of ICH with the modified Rankin Scale score at 90 days. RESULTS: Of 1017 included patients, 331 (33%) had an asymptomatic ICH, and 90 (9%) had a symptomatic ICH. Compared with no ICH, both asymptomatic (adjusted common OR (acOR)=0.76; 95% CI 0.58 to 0.98) and symptomatic (acOR=0.07; 95% CI 0.04 to 0.14) ICH were associated with worse functional outcome. In particular, isolated parenchymal hematoma type 2 (acOR=0.37; 95% CI 0.14 to 0.95), combined parenchymal hematoma with hemorrhage outside infarcted brain tissue (acOR=0.17; 95% CI 0.10 to 0.30), and combined hemorrhages outside infarcted brain tissue (acOR=0.14; 95% CI 0.03 to 0.74) were associated with worse functional outcome than no ICH.Strength of the association of ICH with functional outcome depends on the type of ICH. Although the association is stronger for symptomatic ICH, asymptomatic ICH after EVT is also associated with worse functional outcome.

Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial.

Importance: Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen. Objective: To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase. Design, Setting, and Participants: This controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled. Interventions: Patients were randomized (1:1) to receive a bolus of 5 mg of intravenous alteplase and 40 mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9 mg/kg of intravenous alteplase (control). Main Outcomes and Measures: The primary outcome was any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors. Results: A total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (ß = 65 mg/dL; 95% CI, 26-105 mg/dL). Conclusions and Relevance: In this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone. Trial Registration: ClinicalTrials.gov Identifier: NCT04256473.

Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): study protocol for a multicenter randomized controlled phase II trial.

BACKGROUND: The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke. METHODS: DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5-7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure. DISCUSSION: When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke. TRIAL REGISTRATION: NL7409 (November 26, 2018)/NCT04256473 (February 5, 2020).