A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke

The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODS We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. RESULTS The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P=0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). CONCLUSIONS In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups

Hospital Variation in Time to Endovascular Treatment for Ischemic Stroke: What Is the Optimal Target for Improvement?

BACKGROUND: Time to reperfusion in patients with ischemic stroke is strongly associated with functional outcome and may differ between hospitals and between patients within hospitals. Improvement in time to reperfusion can be guided by between-hospital and within-hospital comparisons and requires insight in specific targets for improvement. We aimed to quantify the variation in door-to-reperfusion time between and within Dutch intervention hospitals and to assess the contribution of different time intervals to this variation. METHODS AND RESULTS: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry. The door-to-reperfusion time was subdivided into time intervals, separately for direct patients (door-to-computed tomography, computed tomography-to-computed tomography angiography [CTA], CTA-to-groin, and groin-to-reperfusion times) and for transferred patients (door-to-groin and groin-to-reperfusion times). We used linear mixed models to distinguish the variation in door-to-reperfusion time between hospitals and between patients. The proportional change in variance was used to estimate the amount of variance explained by each time interval. We included 2855 patients of 17 hospitals providing endovascular treatment. Of these patients, 44% arrived directly at an endovascular treatment hospital. The between-hospital variation in door-to-reperfusion time was 9%, and the within-hospital variation was 91%. The contribution of case-mix variables on the variation in door-to-reperfusion time was marginal (2%– 7%). Of the between-hospital variation, CTA-to-groin time explained 83%, whereas groin-to-reperfusion time explained 15%. Within-hospital variation was mostly explained by CTA-to-groin time (33%) and groin-to-reperfusion time (42%). Similar results were found for transferred patients. CONCLUSIONS: Door-to-reperfusion time varies between, but even more within, hospitals providing endovascular treatment for ischemic stroke. Quality of stroke care improvements should not only be guided by between-hospital comparisons, but also aim to reduce variation between patients within a hospital, and should specifically focus on CTA-to-groin time and groin-to-reperfusion time

Intracranial carotid artery calcification subtype and collaterals in patients undergoing endovascular thrombectomy

Background and aims: Distinct subtypes of intracranial carotid artery calcification (ICAC) have been found (i.e., medial and intimal), which may differentially be associated with the formation of collaterals. We investigated the association of ICAC subtype with collateral status in patients undergoing endovascular thrombectomy (EVT) for ischemic stroke. We further investigated whether ICAC subtype modified the association between collateral status and functional outcome. Methods: We used data from 2701 patients with ischemic stroke undergoing EVT. Presence and subtype of ICAC were assessed on baseline non-contrast CT. Collateral status was assessed on baseline CT angiography using a visual scale from 0 (absent) to 3 (good). We investigated the association of ICAC subtype with collateral status using ordinal and binary logistic regression. Next, we assessed whether ICAC subtype modified the association between collateral status and functional outcome (modified Rankin Scale, 0–6). Results: Compared to patients without ICAC, we found no association of intimal or medial ICAC with collateral status (ordinal variable). When collateral grades were dichotomized (3 versus 0–2), we found that intimal ICAC was significantly associated with good collaterals in comparison to patients without ICAC (aOR, 1.41 [95%CI:1.06–1.89]) or with medial ICAC (aOR, 1.50 [95%CI:1.14–1.97]). The association between higher collateral grade and better functional outcome was significantly modified by ICAC subtype (p for interaction = 0.01). Conclusions: Patients with intimal ICAC are more likely to have good collaterals and benefit more from an extensive collateral circulation in terms of functional outcome after EVT

Cerebrospinal fluid volume improves prediction of malignant edema after endovascular treatment of stroke

Background: The ratio of intracranial cerebrospinal fluid (CSF) volume to intracranial volume (ICV) has been identified as a potential predictor of malignant edema formation in patients with acute ischemic stroke. Aims: We aimed to evaluate the added value of the CSF/ICV ratio in a model to predict malignant edema formation in patients who underwent endovascular treatment. Methods: We included patients from the MR CLEAN Registry, a prospective national multicenter registry of patients who were treated with endovascular treatment between 2014 and 2017 because of acute ischemic stroke caused by large vessel occlusion. The CSF/ICV ratio was automatically measured on baseline thin-slice noncontrast CT. The primary outcome was the occurrence of malignant edema based on clinical and imaging features. The basic model included the following predictors: age, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT score, occlusion of the internal carotid artery, collateral score, time between symptom onset and groin puncture, and unsuccessful reperfusion. The extended model included the basic model and the CSF/ICV ratio. The performance of the basic and the extended model was compared with the likelihood ratio test. Results: Malignant edema occurred in 40 (6%) of 683 patients. In the extended model, a lower CSF/ICV ratio was associated with the occurrence of malignant edema (odds ratio (OR) per percentage point, 1.2; 95% confidence interval (CI) 1.1–1.3, p < 0.001). Age lost predictive value for malignant edema in the extended model (OR 1.1; 95% CI 0.9–1.5, p = 0.372). The performance of the extended model was higher than that of the basic model (p < 0.001). Conclusions: Adding the CSF/ICV ratio improves a multimodal prediction model for the occurrence of malignant edema after endovascular treatment

Cerebrospinal fluid volume improves prediction of malignant edema after endovascular treatment of stroke

Background: The ratio of intracranial cerebrospinal fluid (CSF) volume to intracranial volume (ICV) has been identified as a potential predictor of malignant edema formation in patients with acute ischemic stroke. Aims: We aimed to evaluate the added value of the CSF/ICV ratio in a model to predict malignant edema formation in patients who underwent endovascular treatment. Methods: We included patients from the MR CLEAN Registry, a prospective national multicenter registry of patients who were treated with endovascular treatment between 2014 and 2017 because of acute ischemic stroke caused by large vessel occlusion. The CSF/ICV ratio was automatically measured on baseline thin-slice noncontrast CT. The primary outcome was the occurrence of malignant edema based on clinical and imaging features. The basic model included the following predictors: age, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT score, occlusion of the internal carotid artery, collateral score, time between symptom onset and groin puncture, and unsuccessful reperfusion. The extended model included the basic model and the CSF/ICV ratio. The performance of the basic and the extended model was compared with the likelihood ratio test. Results: Malignant edema occurred in 40 (6%) of 683 patients. In the extended model, a lower CSF/ICV ratio was associated with the occurrence of malignant edema (odds ratio (OR) per percentage point, 1.2; 95% confidence interval (CI) 1.1–1.3, p < 0.001). Age lost predictive value for malignant edema in the extended model (OR 1.1; 95% CI 0.9–1.5, p = 0.372). The performance of the extended model was higher than that of the basic model (p < 0.001). Conclusions: Adding the CSF/ICV ratio improves a multimodal prediction model for the occurrence of malignant edema after endovascular treatment

Intracranial carotid artery calcification subtype and collaterals in patients undergoing endovascular thrombectomy

Background and aims: Distinct subtypes of intracranial carotid artery calcification (ICAC) have been found (i.e., medial and intimal), which may differentially be associated with the formation of collaterals. We investigated the association of ICAC subtype with collateral status in patients undergoing endovascular thrombectomy (EVT) for ischemic stroke. We further investigated whether ICAC subtype modified the association between collateral status and functional outcome. Methods: We used data from 2701 patients with ischemic stroke undergoing EVT. Presence and subtype of ICAC were assessed on baseline non-contrast CT. Collateral status was assessed on baseline CT angiography using a visual scale from 0 (absent) to 3 (good). We investigated the association of ICAC subtype with collateral status using ordinal and binary logistic regression. Next, we assessed whether ICAC subtype modified the association between collateral status and functional outcome (modified Rankin Scale, 0–6). Results: Compared to patients without ICAC, we found no association of intimal or medial ICAC with collateral status (ordinal variable). When collateral grades were dichotomized (3 versus 0–2), we found that intimal ICAC was significantly associated with good collaterals in comparison to patients without ICAC (aOR, 1.41 [95%CI:1.06–1.89]) or with medial ICAC (aOR, 1.50 [95%CI:1.14–1.97]). The association between higher collateral grade and better functional outcome was significantly modified by ICAC subtype (p for interaction = 0.01). Conclusions: Patients with intimal ICAC are more likely to have good collaterals and benefit more from an extensive collateral circulation in terms of functional outcome after EVT.</p

Association between type of intervention center and outcomes after endovascular treatment for acute ischemic stroke: Results from the MR CLEAN Registry

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) is performed in intervention centers that provide the full range of neuro(endo)vascular care (level 1) and centers that only perform EVT for AIS (level 2). We compared outcomes between these center types and assessed whether differences in outcomes could be explained by center volume (CV). Patients and methods: We analyzed patients included in the MR CLEAN Registry (2014–2018), a registry of all EVT-treated patients in the Netherlands. Our primary outcome was the shift on the modified Rankin scale (mRS) after 90 days (ordinal regression). Secondary outcomes were the NIHSS 24–48 h post-EVT, door-to-groin time (DTGT), procedure time (linear regression), and recanalization (binary logistic regression). We compared outcomes between level 1 and 2 centers using multilevel regression models, with center as random intercept. We adjusted for relevant baseline factors, and in case of observed differences, we additionally adjusted for CV. Results: Of the 5144 patients 62% were treated in level 1 centers. We observed no significant differences between center types in mRS (adjusted(a)cOR: 0.79, 95% CI: 0.40 to 1.54), NIHSS (aβ: 0.31, 95% CI: −0.52 to 1.14), procedure duration (aβ: 0.88, 95% CI: −5.21 to 6.97), or DTGT (aβ: 4.24, 95% CI: −7.09 to 15.57). The probability for recanalization was higher in level 1 centers compared to level 2 centers (aOR 1.60, 95% CI: 1.10 to 2.33), and this difference probably depended on CV. Conclusions: We found no significant differences, that were independent of CV, in the outcomes of EVT for AIS between level 1 and level 2 intervention centers

Diagnostic performance of an algorithm for automated large vessel occlusion detection on CT angiography

BACKGROUND: Machine learning algorithms hold the potential to contribute to fast and accurate detection of large vessel occlusion (LVO) in patients with suspected acute ischemic stroke. We assessed the diagnostic performance of an automated LVO detection algorithm on CT angiography (CTA). METHODS: Data from the MR CLEAN Registry and PRESTO were used including patients with and without LVO. CTA data were analyzed by the algorithm for detection and localization of LVO (intracranial internal carotid artery (ICA)/ICA terminus (ICA-T), M1, or M2). Assessments done by expert neuroradiologists were used as reference. Diagnostic performance was assessed for detection of LVO and per occlusion location by means of sensitivity, specificity, and area under the curve (AUC). RESULTS: We analyzed CTAs of 1110 patients from the MR CLEAN Registry (median age (IQR) 71 years (60-80); 584 men; 1110 with LVO) and of 646 patients from PRESTO (median age (IQR) 73 years (62-82); 358 men; 141 with and 505 without LVO). For detection of LVO, the algorithm yielded a sensitivity of 89% in the MR CLEAN Registry and a sensitivity of 72%, specificity of 78%, and AUC of 0.75 in PRESTO. Sensitivity per occlusion location was 88% for ICA/ICA-T, 94% for M1, and 72% for M2 occlusion in the MR CLEAN Registry, and 80% for ICA/ICA-T, 95% for M1, and 49% for M2 occlusion in PRESTO. CONCLUSION: The algorithm provided a high detection rate for proximal LVO, but performance varied significantly by occlusion location. Detection of M2 occlusion needs further improvement

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 (β = 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.</p