Collateral-based selection for endovascular treatment of acute ischaemic stroke in the late window (MR CLEAN-LATE): 2-year follow-up of a phase 3, multicentre, open-label, randomised controlled trial in the Netherlands.

BACKGROUND: The MR CLEAN-LATE trial provided evidence for the safety and efficacy of endovascular treatment for acute ischaemic stroke within the late window (after 6-24 h) in patients who were preselected based on the presence of collateral flow on CT angiography. We aimed to evaluate clinical outcomes 2 years after randomisation. METHODS: MR CLEAN-LATE was a phase 3, multicentre, open-label, blinded-endpoint, randomised controlled trial conducted at 18 stroke intervention centres in the Netherlands. If endovascular treatment could be initiated within 6-24 h of symptom onset or last seen well, patients (aged 18 years or older) with an acute ischaemic stroke due to a large vessel occlusion in the anterior circulation and at least some collateral flow in the affected middle cerebral artery territory on CT angiography were randomly assigned (1:1) to either endovascular treatment with best medical treatment (endovascular treatment group) or best medical treatment alone (control group). Web-based randomisation, stratified by centre, was performed with the use of permuted blocks (block size eight to 20). The researchers who collected clinical outcomes and analysed the results were masked to treatment allocation; treating physicians, local investigators, and patients were aware of the received treatment. The primary outcome of MR CLEAN-LATE was the modified Rankin Scale (mRS) score at 90 days after randomisation. For this 2-year prespecified analysis, the primary outcome was mRS score at 2 years (minus 3 months to plus 6 months). Primary and safety analyses were performed based on the modified intention-to-treat principle, and included patients who provided (deferred) consent or died before consent could be obtained. Missing data were handled with multiple imputation by chained equations. The trial is completed and is registered at ISRCTN, ISRCTN19922220. FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned in the MR CLEAN-LATE trial, of whom 502 (94%) gave deferred consent and comprised the modified intention-to-treat population (255 in the endovascular treatment group and 247 in the control group). 261 (52%) patients were female and 241 (48%) were male. Data for mRS score at 2 years were available for 226 (89%) patients in the endovascular treatment group and for 202 (82%) patients in the control group. The median mRS score at 2 years was 4 (IQR 2-6) in the endovascular treatment group and 6 (2-6) in the control group. The endovascular treatment group demonstrated a shift towards better functional outcomes on the mRS (adjusted common odds ratio 1·41 [95% CI 1·00-1·99]; p=0·049). All-cause mortality at 2 years was 34% (87 of 255) in the endovascular treatment group and 41% (101 of 247) in the control group (adjusted hazard ratio 0·81 [95% CI 0·60-1·08]; p=0·15). Major vascular events (ie, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, and cardiac events) were reported between 90 days and 2 years in 23 patients in the endovascular treatment group and 13 patients in the control group. INTERPRETATION: Our results show that the effectiveness of late-window (after 6-24 h) endovascular treatment in improving clinical outcomes is sustained for up to 2 years in a population preselected based on the presence of collateral flow on CT angiography. This finding might be important for prompting further evaluations of cost-effectiveness, health-care policy development, and clinical decision making. FUNDING: The Dutch Organization for Health Research and Health Innovation (ZonMW), Collaboration for New Treatments of Acute Stroke Consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Health Holland Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

Ultra-Early and Short-Term Tranexamic Acid Treatment in Patients With Good- and Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: The results of the ULTRA trial showed that ultra-early and short-term treatment with tranexamic acid (TXA) does not improve clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Possibly, the lack of a beneficial effect in all patients with aSAH is masked by antagonistic effects of TXA in certain subgroups. In this post hoc subgroup analysis, we investigated the effect of TXA on clinical outcome in patients with good-grade and poor-grade aSAH. METHODS: The ULTRA trial was a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment. Participants received ultra-early and short-term TXA in addition to usual care or usual care only. This post hoc subgroup analysis included only ULTRA participants with confirmed aSAH and available World Federation of Neurosurgical Societies (WFNS) grade on admission. Patients were categorized into those with good-grade (WFNS 1-3) and poor-grade (WFNS 4-5) aSAH. The primary outcome was clinical outcome assessed by the modified Rankin scale (mRS). Odds ratios (ORs) and adjusted ORs (aORs) with 95% CIs were calculated using ordinal regression analyses. Analyses were performed using the as-treated principle. In all patients with aSAH, no significant effect modification of TXA on clinical outcome was observed for admission WFNS grade (p = 0.10). RESULTS: Of the 812 ULTRA participants, 473 patients had (58%; N = 232 TXA, N = 241 usual care) good-grade and 339 (42%; N = 162 TXA, N = 176 usual care) patients had poor-grade aSAH. In patients with good-grade aSAH, the TXA group had worse clinical outcomes (OR: 0.67, 95% CI 0.48-0.94, aOR 0.68, 95% CI 0.48-0.94) compared with the usual care group. In patients with poor-grade aSAH, clinical outcomes were comparable between treatment groups (OR: 1.04, 95% CI 0.70-1.55, aOR 1.05, 95% CI 0.70-1.56). DISCUSSION: This post hoc subgroup analysis provides another important argument against the use of TXA treatment in patients with aSAH, by showing worse clinical outcomes in patients with good-grade aSAH treated with TXA and no clinical benefit of TXA in patients with poor-grade aSAH, compared with patients treated with usual care. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid, given for <24 hours within the first 24 hours, does not improve the 6-month outcome in good-grade or poor initial-grade aneurysmal SAH.

Value of Automatically Derived Full Thrombus Characteristics: An Explorative Study of Their Associations with Outcomes in Ischemic Stroke Patients.

(1) Background: For acute ischemic strokes caused by large vessel occlusion, manually assessed thrombus volume and perviousness have been associated with treatment outcomes. However, the manual assessment of these characteristics is time-consuming and subject to inter-observer bias. Alternatively, a recently introduced fully automated deep learning-based algorithm can be used to consistently estimate full thrombus characteristics. Here, we exploratively assess the value of these novel biomarkers in terms of their association with stroke outcomes. (2) Methods: We studied two applications of automated full thrombus characterization as follows: one in a randomized trial, MR CLEAN-NO IV (n = 314), and another in a Dutch nationwide registry, MR CLEAN Registry (n = 1839). We used an automatic pipeline to determine the thrombus volume, perviousness, density, and heterogeneity. We assessed their relationship with the functional outcome defined as the modified Rankin Scale (mRS) at 90 days and two technical success measures as follows: successful final reperfusion, which is defined as an eTICI score of 2b-3, and successful first-pass reperfusion (FPS). (3) Results: Higher perviousness was significantly related to a better mRS in both MR CLEAN-NO IV and the MR CLEAN Registry. A lower thrombus volume and lower heterogeneity were only significantly related to better mRS scores in the MR CLEAN Registry. Only lower thrombus heterogeneity was significantly related to technical success; it was significantly related to a higher chance of FPS in the MR CLEAN-NO IV trial (OR = 0.55, 95% CI: 0.31-0.98) and successful reperfusion in the MR CLEAN Registry (OR = 0.88, 95% CI: 0.78-0.99). (4) Conclusions: Thrombus characteristics derived from automatic entire thrombus segmentations are significantly related to stroke outcomes.

Posterior circulation collaterals as predictors of outcome in basilar artery occlusion: a sub-analysis of the BASICS randomized trial.

Introduction and purpose: Basilar artery occlusion (BAO) is still one of the most devastating neurological conditions associated with high morbidity and mortality. In the present study, we aimed to assess the role of posterior circulation collaterals as predictors of outcome in the BASICS trial and to compare two grading systems (BATMAN score and PC-CS) in terms of prognostic value. Methods: We performed a sub-analysis of the BASICS trial. Baseline clinical and imaging variables were analyzed. For the imaging analysis, baseline CT and CTA were analyzed by a central core lab. Only those patients with good or moderate quality of baseline CTA and with confirmed BAO were included. Multivariable binary logistic regression analysis was used to test the independent association of clinical and imaging characteristics with a favorable outcome at 3 months (defined as a modified Rankin Score of ≤3). ROC curve analysis was used to assess and compare accuracy between the two collateral grading systems. Results: The mean age was 67.0 (±12.5) years, 196 (65.3%) patients were males and the median NIHSS was 21.5 (IQR 11-35). Median NCCT pc-ASPECTS was 10 (IQR10-10) and median collateral scores for BATMAN and PC-CS were 8 (IQR 7-9) and 7 (IQR 6-8) respectively. Collateral scores were associated with favorable outcome at 3 months for both BATMAN and PC-CS but only with a modest accuracy on ROC curve analysis (AUC 0.62, 95% CI [0.55-0.69] and 0.67, 95% CI [0.60-0.74] respectively). Age (OR 0.97, 95% CI [0.95-1.00]), NIHSS (OR 0.91, 95% CI [0.89-0.94]) and collateral score (PC-CS - OR 1.2495% CI [1.02-1.51]) were independently associated with clinical outcome. Conclusion: The two collateral grading systems presented modest prognostic accuracy. Only the PC-CS was independently associated with a favorable outcome at 3 months.

Long-Term Clinical Implications of High-Risk Cardiac Computed Tomography Findings in Patients With Acute Ischemic Stroke.

BACKGROUND: Cardiac computed tomography (CT) acquired during the initial acute stroke imaging protocol (acute cardiac CT) is increasingly used to screen for cardioembolism, but information on the long-term clinical implications of its findings is lacking. METHODS AND RESULTS: We performed a prospective, single-center cohort study in which consecutive patients with ischemic stroke underwent ECG-gated acute cardiac CT and were followed up for 2 years. The primary outcome was functional outcome assessed using the modified Rankin Scale. Secondary outcomes were death and occurrence of major adverse cardiovascular events (composite of recurrent ischemic stroke, myocardial infarction, and cardiovascular death). We compared patients with and without a high-risk structural source of embolism on acute cardiac CT. Of 452 included patients, 55 (12.2%) had a high-risk source of embolism, predominantly cardiac thrombi (38 patients) and signs of endocarditis (8 patients). Follow-up at 2 years was complete for 430 (95.1%) patients. Patients with a high-risk source of embolism had a worse functional outcome (median modified Rankin Scale, 6 [IQR, 2-6] versus 2 [IQR, 1-5]; adjusted common odds ratio, 2.92 [95% CI, 1.62-5.25]), increased mortality rate (52.7% versus 23.7%; adjusted hazard ratio [HR], 3.28 [95% CI, 1.94-5.52]), and major adverse cardiovascular events (38.9% versus 17.5%; adjusted HR, 3.20 [95% CI, 1.80-5.69]). A high-risk source of embolism was not associated with recurrent ischemic stroke (11.1% versus 9.6%; adjusted HR, 1.30 [95% CI, 0.49-3.44]). CONCLUSIONS: Structural high-risk sources of embolism on acute cardiac CT in patients with ischemic stroke were associated with poor long-term functional outcome and occurrence of major adverse cardiovascular events but not with recurrent stroke.

Thrombus Imaging Characteristics to Predict Early Recanalization in Anterior Circulation Large Vessel Occlusion Stroke.

The early management of transferred patients with a large vessel occlusion (LVO) stroke could be improved by identifying patients who are likely to recanalize early. We aim to predict early recanalization based on patient clinical and thrombus imaging characteristics. We included 81 transferred anterior-circulation LVO patients with an early recanalization, defined as the resolution of the LVO or the migration to a distal location not reachable with endovascular treatment upon repeated radiological imaging. We compared their clinical and imaging characteristics with all (322) transferred patients with a persistent LVO in the MR CLEAN Registry. We measured distance from carotid terminus to thrombus (DT), thrombus length, density, and perviousness on baseline CT images. We built logistic regression models to predict early recanalization. We validated the predictive ability by computing the median area-under-the-curve (AUC) of the receiver operating characteristics curve for 100 5-fold cross-validations. The administration of intravenous thrombolysis (IVT), longer transfer times, more distal occlusions, and shorter, pervious, less dense thrombi were characteristic of early recanalization. After backward elimination, IVT administration, DT and thrombus density remained in the multivariable model, with an AUC of 0.77 (IQR 0.72-0.83). Baseline thrombus imaging characteristics are valuable in predicting early recanalization and can potentially be used to optimize repeated imaging workflow.

Impact of Intracranial Volume and Brain Volume on the Prognostic Value of Computed Tomography Perfusion Core Volume in Acute Ischemic Stroke.

BACKGROUND: Computed tomography perfusion (CTP)-estimated core volume is associated with functional outcomes in acute ischemic stroke. This relationship might differ among patients, depending on brain volume. MATERIALS AND METHODS: We retrospectively included patients from the MR CLEAN Registry. Cerebrospinal fluid (CSF) and intracranial volume (ICV) were automatically segmented on NCCT. We defined the proportion of the ICV and total brain volume (TBV) affected by the ischemic core as ICVcore and TBVcore. Associations between the core volume, ICVcore, TBVcore, and functional outcome are reported per interquartile range (IQR). We calculated the area under the curve (AUC) to assess diagnostic accuracy. RESULTS: In 200 patients, the median core volume was 13 (5-41) mL. Median ICV and TBV were 1377 (1283-1456) mL and 1108 (1020-1197) mL. Median ICVcore and TBVcore were 0.9 (0.4-2.8)% and 1.7 (0.5-3.6)%. Core volume (acOR per IQR 0.48 [95%CI 0.33-0.69]), ICVcore (acOR per IQR 0.50 [95%CI 0.35-0.69]), and TBVcore (acOR per IQR 0.41 95%CI 0.33-0.67]) showed a lower likelihood of achieving improved functional outcomes after 90 days. The AUC was 0.80 for the prediction of functional independence at 90 days for the CTP-estimated core volume, the ICVcore, and the TBVcore. CONCLUSION: Correcting the CTP-estimated core volume for the intracranial or total brain volume did not improve the association with functional outcomes in patients who underwent EVT.

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.

Time to Treatment With Intravenous Thrombolysis Before Thrombectomy and Functional Outcomes in Acute Ischemic Stroke: A Meta-Analysis.

Importance: The benefit of intravenous thrombolysis (IVT) for acute ischemic stroke declines with longer time from symptom onset, but it is not known whether a similar time dependency exists for IVT followed by thrombectomy. Objective: To determine whether the benefit associated with IVT plus thrombectomy vs thrombectomy alone decreases with treatment time from symptom onset. Design, Setting, and Participants: Individual participant data meta-analysis from 6 randomized clinical trials comparing IVT plus thrombectomy vs thrombectomy alone. Enrollment was between January 2017 and July 2021 at 190 sites in 15 countries. All participants were eligible for IVT and thrombectomy and presented directly at thrombectomy-capable stroke centers (n = 2334). For this meta-analysis, only patients with an anterior circulation large-vessel occlusion were included (n = 2313). Exposure: Interval from stroke symptom onset to expected administration of IVT and treatment with IVT plus thrombectomy vs thrombectomy alone. Main Outcomes and Measures: The primary outcome analysis tested whether the association between the allocated treatment (IVT plus thrombectomy vs thrombectomy alone) and disability at 90 days (7-level modified Rankin Scale [mRS] score range, 0 [no symptoms] to 6 [death]; minimal clinically important difference for the rates of mRS scores of 0-2: 1.3%) varied with times from symptom onset to expected administration of IVT. Results: In 2313 participants (1160 in IVT plus thrombectomy group vs 1153 in thrombectomy alone group; median age, 71 [IQR, 62 to 78] years; 44.3% were female), the median time from symptom onset to expected administration of IVT was 2 hours 28 minutes (IQR, 1 hour 46 minutes to 3 hours 17 minutes). There was a statistically significant interaction between the time from symptom onset to expected administration of IVT and the association of allocated treatment with functional outcomes (ratio of adjusted common odds ratio [OR] per 1-hour delay, 0.84 [95% CI, 0.72 to 0.97], P = .02 for interaction). The benefit of IVT plus thrombectomy decreased with longer times from symptom onset to expected administration of IVT (adjusted common OR for a 1-step mRS score shift toward improvement, 1.49 [95% CI, 1.13 to 1.96] at 1 hour, 1.25 [95% CI, 1.04 to 1.49] at 2 hours, and 1.04 [95% CI, 0.88 to 1.23] at 3 hours). For a mRS score of 0, 1, or 2, the predicted absolute risk difference was 9% (95% CI, 3% to 16%) at 1 hour, 5% (95% CI, 1% to 9%) at 2 hours, and 1% (95% CI, -3% to 5%) at 3 hours. After 2 hours 20 minutes, the benefit associated with IVT plus thrombectomy was not statistically significant and the point estimate crossed the null association at 3 hours 14 minutes. Conclusions and Relevance: In patients presenting at thrombectomy-capable stroke centers, the benefit associated with IVT plus thrombectomy vs thrombectomy alone was time dependent and statistically significant only if the time from symptom onset to expected administration of IVT was short.

Sex differences in clot, vessel and tissue characteristics in patients with a large vessel occlusion treated with endovascular thrombectomy.

INTRODUCTION: To improve our understanding of the relatively poor outcome after endovascular treatment (EVT) in women we assessed possible sex differences in baseline neuroimaging characteristics of acute ischemic stroke patients with large anterior vessel occlusion (LVO). PATIENTS AND METHODS: We included all consecutive patients from the MR CLEAN Registry who underwent EVT between 2014 and 2017. On baseline non-contrast CT and CT angiography, we assessed clot location and clot burden score (CBS), vessel characteristics (presence of atherosclerosis, tortuosity, size, and collateral status), and tissue characteristics with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Radiological outcome was assessed with the extended thrombolysis in cerebral infarction score (eTICI) and functional outcome with the modified Rankin Scale score (mRS) at 90 days. Sex-differences were assessed with multivariable regression analyses with adjustments for possible confounders. RESULTS: 3180 patients were included (median age 72 years, 48% women). Clots in women were less often located in the intracranial internal carotid artery (ICA) (25%vs 28%, odds ratio (OR) 0.85;95% confidence interval: 0.73-1.00). CBS was similar between sexes (median 6, IQR 4-8). Intracranial (aOR 0.73;95% CI:0.62-0.87) and extracranial (aOR 0.64;95% CI:0.43-0.95) atherosclerosis was less prevalent in women. Vessel tortuosity was more frequent in women in the cervical ICA (aOR 1.89;95% CI:1.39-2.57) and women more often had severe elongation of the aortic arch (aOR 1.38;95% CI:1.00-1.91). ICA radius was smaller in women (2.3vs 2.5 mm, mean difference 0.22;95% CI:0.09-0.35) while M1 radius was essentially equal (1.6vs 1.7 mm, mean difference 0.09;95% CI:-0.02-0.21). Women had better collateral status (⩾50% filling in 62%vs 53% in men, aOR 1.48;95% CI:1.29-1.70). Finally, ASPECT scores were equal between women and men (median 9 in both sexes, IQR 8-10vs 9-10). Reperfusion rates were similar between women and men (acOR 0.94;95% CI:0.83-1.07). However, women less often reached functional independence than men (34%vs 46%, aOR 0.68;95% CI:0.53-0.86). DISCUSSION AND CONCLUSION: On baseline imaging of this Dutch Registry, men and women with LVO mainly differ in vessel characteristics such as atherosclerotic burden, extracranial vessel tortuosity, and collateral status. These sex differences do not result in different reperfusion rates and are, therefore, not likely to explain the worse functional outcome in women after EVT.

Deep learning-based white matter lesion volume on CT is associated with outcome after acute ischemic stroke.

BACKGROUND: Intravenous thrombolysis (IVT) before endovascular treatment (EVT) for acute ischemic stroke might induce intracerebral hemorrhages which could negatively affect patient outcomes. Measuring white matter lesions size using deep learning (DL-WML) might help safely guide IVT administration. We aimed to develop, validate, and evaluate a DL-WML volume on CT compared to the Fazekas scale (WML-Faz) as a risk factor and IVT effect modifier in patients receiving EVT directly after IVT. METHODS: We developed a deep-learning model for WML segmentation on CT and validated with internal and external test sets. In a post hoc analysis of the MR CLEAN No-IV trial, we associated DL-WML volume and WML-Faz with symptomatic-intracerebral hemorrhage (sICH) and 90-day functional outcome according to the modified Rankin Scale (mRS). We used multiplicative interaction terms between WML measures and IVT administration to evaluate IVT treatment effect modification. Regression models were used to report unadjusted and adjusted common odds ratios (cOR/acOR). RESULTS: In total, 516 patients from the MR CLEAN No-IV trial (male/female, 291/225; age median, 71 [IQR, 62-79]) were analyzed. Both DL-WML volume and WML-Faz are associated with sICH (DL-WML volume acOR, 1.78 [95%CI, 1.17; 2.70]; WML-Faz acOR, 1.53 95%CI [1.02; 2.31]) and mRS (DL-WML volume acOR, 0.70 [95%CI, 0.55; 0.87], WML-Faz acOR, 0.73 [95%CI 0.60; 0.88]). Only in the unadjusted IVT effect modification analysis WML-Faz was associated with more sICH if IVT was given (p = 0.046). Neither WML measure was associated with worse mRS if IVT was given. CONCLUSION: DL-WML volume and WML-Faz had a similar relationship with functional outcome and sICH. Although more sICH might occur in patients with more severe WML-Faz receiving IVT, no worse functional outcome was observed. CLINICAL RELEVANCE STATEMENT: White matter lesion severity on baseline CT in acute ischemic stroke patients has a similar predictive value if measured with deep learning or the Fazekas scale. Safe administration of intravenous thrombolysis using white matter lesion severity should be further studied. KEY POINTS: White matter damage is a predisposing risk factor for intracranial hemorrhage in patients with acute ischemic stroke but remains difficult to measure on CT. White matter lesion volume on CT measured with deep learning had a similar association with symptomatic intracerebral hemorrhages and worse functional outcome as the Fazekas scale. A patient-level meta-analysis is required to study the benefit of white matter lesion severity-based selection for intravenous thrombolysis before endovascular treatment.

Intravenous Thrombolysis Before Endovascular Treatment in Posterior Circulation Occlusions: A MR CLEAN Registry Study.

BACKGROUND: The effectiveness of intravenous thrombolysis (IVT) before endovascular treatment (EVT) has been investigated in randomized trials and meta-analyses. These studies mainly concerned anterior circulation occlusions. We aimed to investigate clinical, technical, and safety outcomes of IVT before EVT in posterior circulation occlusions in a nationwide registry. METHODS: Patients were included from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), a nationwide, prospective, multicenter registry of patients with acute ischemic stroke due to a large intracranial vessel occlusion receiving EVT between 2014 and 2019. All patients with a posterior circulation occlusion were included. Primary outcome was a shift toward better functional outcome on the modified Rankin Scale at 90 days. Secondary outcomes were favorable functional outcome (modified Rankin Scale scores, 0-3), occurrence of symptomatic intracranial hemorrhages, successful reperfusion (extended Thrombolysis in Cerebral Ischemia ≥2B), first-attempt successful reperfusion, and mortality at 90 days. Regression analyses with adjustments based on univariable analyses and literature were applied. RESULTS: A total of 248 patients were included, who received either IVT (n=125) or no IVT (n=123) before EVT. Results show no differences in a shift on the modified Rankin Scale (adjusted common odds ratio, 1.04 [95% CI, 0.61-1.76]). Although symptomatic intracranial hemorrhages occurred more often in the IVT group (4.8% versus 2.4%), regression analysis did not show a significant difference (adjusted odds ratio, 1.65 [95% CI, 0.33-8.35]). Successful reperfusion, favorable functional outcome, first-attempt successful reperfusion, and mortality did not differ between patients treated with and without IVT. CONCLUSIONS: We found no significant differences in clinical, technical, and safety outcomes between patients with a large vessel occlusion in the posterior circulation treated with or without IVT before EVT. Our results are in line with the literature on the anterior circulation.

Sex differences in outcomes after endovascular treatment in posterior circulation stroke: results from the MR CLEAN Registry.

BACKGROUND: Women with anterior circulation large vessel occlusion (LVO) have been reported to have worse outcomes after endovascular treatment (EVT) than men. Whether these disparities also exist in LVO of the posterior circulation is yet uncertain. We assessed sex differences in clinical, technical, and safety outcomes of EVT in posterior circulation LVO. METHODS: We used data of patients with posterior circulation LVO included in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014-2018). Primary outcome was the modified Rankin Scale (mRS) score at 90 days assessed with multivariable ordinal regression analysis. Secondary outcomes included favorable functional outcome (mRS ≤3), functional independence (mRS ≤2), death within 90 days, National Institutes of Health Stroke Scale (NIHSS) score 24-48 hours postintervention, complications, successful reperfusion (extended Thrombolysis in Cerebral Ischemia 2B-3), and procedure duration analyzed with multivariable logistic and linear regression analyses. RESULTS: We included 264 patients (42% women). Compared with men, women were older (median age 68 vs 63 years), more often had prestroke disability (mRS ≥1: 37% vs 30%), and received intravenous thrombolytics less often (45% vs 56%). Clinical outcomes were similar between sexes (adjusted (common) OR (aOR) 0.82, 95% CI 0.51 to 1.34; favorable functional outcome 50% vs 43%, aOR 1.31, 95% CI 0.77 to 2.25; death 32% vs 29%, aOR 0.98, 95% CI 0.52 to 1.84). In addition, NIHSS score after 24-48 hours (median 7 vs 9), successful reperfusion (77% vs 73%), and complications did not differ between men and women. CONCLUSIONS: Outcomes in women treated with EVT for posterior circulation LVO were similar compared with men despite less favorable baseline characteristics in women. Therefore men and women may benefit equally from EVT.

Standardizing the estimation of ischemic regions can harmonize CT perfusion stroke imaging.

OBJECTIVES: We aimed to evaluate the real-world variation in CT perfusion (CTP) imaging protocols among stroke centers and to explore the potential for standardizing vendor software to harmonize CTP images. METHODS: Stroke centers participating in a nationwide multicenter healthcare evaluation were requested to share their CTP scan and processing protocol. The impact of these protocols on CTP imaging was assessed by analyzing data from an anthropomorphic phantom with center-specific vendor software with default settings from one of three vendors (A-C): IntelliSpace Portal, syngoVIA, and Vitrea. Additionally, standardized infarct maps were obtained using a logistic model. RESULTS: Eighteen scan protocols were studied, all varying in acquisition settings. Of these protocols, seven, eight, and three were analyzed with center-specific vendor software A, B, and C respectively. The perfusion maps were visually dissimilar between the vendor software but were relatively unaffected by the acquisition settings. The median error [interquartile range] of the infarct core volumes (mL) estimated by the vendor software was - 2.5 [6.5] (A)/ - 18.2 [1.2] (B)/ - 8.0 [1.4] (C) when compared to the ground truth of the phantom (where a positive error indicates overestimation). Taken together, the median error [interquartile range] of the infarct core volumes (mL) was - 8.2 [14.6] before standardization and - 3.1 [2.5] after standardization. CONCLUSIONS: CTP imaging protocols varied substantially across different stroke centers, with the perfusion software being the primary source of differences in CTP images. Standardizing the estimation of ischemic regions harmonized these CTP images to a degree. CLINICAL RELEVANCE STATEMENT: The center that a stroke patient is admitted to can influence the patient's diagnosis extensively. Standardizing vendor software for CT perfusion imaging can improve the consistency and accuracy of results, enabling a more reliable diagnosis and treatment decision. KEY POINTS: • CT perfusion imaging is widely used for stroke evaluation, but variation in the acquisition and processing protocols between centers could cause varying patient diagnoses. • Variation in CT perfusion imaging mainly arises from differences in vendor software rather than acquisition settings, but these differences can be reconciled by standardizing the estimation of ischemic regions. • Standardizing the estimation of ischemic regions can improve CT perfusion imaging for stroke evaluation by facilitating reliable evaluations independent of the admission center.

Implications of Post-recanalization Perfusion Deficit After Acute Ischemic Stroke: a Scoping Review of Clinical and Preclinical Imaging Studies.

The goal of reperfusion therapy for acute ischemic stroke (AIS) is to restore cerebral blood flow through recanalization of the occluded vessel. Unfortunately, successful recanalization does not always result in favorable clinical outcome. Post-recanalization perfusion deficits (PRPDs), constituted by cerebral hypo- or hyperperfusion, may contribute to lagging patient recovery rates, but its clinical significance remains unclear. This scoping review provides an overview of clinical and preclinical findings on post-ischemic reperfusion, aiming to elucidate the pattern and consequences of PRPD from a translational perspective. The MEDLINE database was searched for quantitative clinical and preclinical studies of AIS reporting PRPD based on cerebral circulation parameters acquired by translational tomographic imaging methods. PRPD and stroke outcome were mapped on a charting table, creating an overview of PRPD after AIS. Twenty-two clinical and twenty-two preclinical studies were included. Post-recanalization hypoperfusion is rarely reported in clinical studies (4/22) but unequivocally associated with detrimental outcome. Post-recanalization hyperperfusion is more commonly reported (18/22 clinical studies) and may be associated with positive or negative outcome. PRPD has been replicated in animal studies, offering mechanistic insights into causes and consequences of PRPD and allowing delineation of possible courses of PRPD. Complex relationships exist between PRPD and stroke outcome. Diversity in methods and lack of standardized definitions in reperfusion studies complicate the characterization of reperfusion patterns. Recommendations are made to advance the understanding of PRPD mechanisms and to further disentangle the relation between PRPD and disease outcome.

Endovascular treatment of patients with stroke caused by anterior cerebral artery occlusions.

BACKGROUND: Occlusion of the anterior cerebral artery (ACA) is uncommon but may lead to significant disability. The benefit of endovascular treatment (EVT) for ACA occlusions remains uncertain. METHODS: We included patients treated with EVT and compared patients with ACA occlusions with patients who had internal carotid artery (ICA) or proximal (M1/M2) middle cerebral artery (MCA) occlusions from the MR CLEAN Registry. Primary outcome was the modified Rankin Scale score (mRS). Secondary outcomes were functional independence (mRS 0-2), National Institutes of Health Stroke Scale (NIHSS) score, delta-NIHSS (baseline minus NIHSS score at 24-48 h), and successful recanalization (expanded thrombolysis in cerebral infarction (eTICI) score 2b-3). Safety outcomes were symptomatic intracranial hemorrhage (sICH), periprocedural complications, and mortality. RESULTS: Of 5193 patients, 11 (0.2%) had primary ACA occlusions. Median NIHSS at baseline was lower in patients with ACA versus ICA/MCA occlusions (11, IQR 9-14; versus 15, IQR 11-19). Functional outcome did not differ from patients with ICA/MCA occlusions. Functional independence was 4/11 (36%) in patients with ACA versus 1949/4815 (41%) in ICA/MCA occlusions; median delta-NIHSS was - 1 (IQR - 7 to 2) and - 4 (IQR - 9 to 0), respectively. Successful recanalization was 4/9 (44%), versus 3083/4787 (64%) in ICA/MCA occlusions. Mortality was 3/11 (27%) versus 1263/4815 (26%). One patient with ACA occlusion had sICH; no other complications occurred. CONCLUSION: In this cohort ACA occlusions were uncommon. Functional outcome did not differ between patients with ACA occlusions and ICA/MCA occlusions. Prospective research is needed to determine feasibility, safety, and outcomes of EVT for ACA occlusions.

Cost-effectiveness of CT perfusion for the detection of large vessel occlusion acute ischemic stroke followed by endovascular treatment: a model-based health economic evaluation study.

OBJECTIVES: CT perfusion (CTP) has been suggested to increase the rate of large vessel occlusion (LVO) detection in patients suspected of acute ischemic stroke (AIS) if used in addition to a standard diagnostic imaging regime of CT angiography (CTA) and non-contrast CT (NCCT). The aim of this study was to estimate the costs and health effects of additional CTP for endovascular treatment (EVT)-eligible occlusion detection using model-based analyses. METHODS: In this Dutch, nationwide retrospective cohort study with model-based health economic evaluation, data from 701 EVT-treated patients with available CTP results were included (January 2018-March 2022; trialregister.nl:NL7974). We compared a cohort undergoing NCCT, CTA, and CTP (NCCT + CTA + CTP) with a generated counterfactual where NCCT and CTA (NCCT + CTA) was used for LVO detection. The NCCT + CTA strategy was simulated using diagnostic accuracy values and EVT effects from the literature. A Markov model was used to simulate 10-year follow-up. We adopted a healthcare payer perspective for costs in euros and health gains in quality-adjusted life years (QALYs). The primary outcome was the net monetary benefit (NMB) at a willingness to pay of €80,000; secondary outcomes were the difference between LVO detection strategies in QALYs (ΔQALY) and costs (ΔCosts) per LVO patient. RESULTS: We included 701 patients (median age: 72, IQR: [62-81]) years). Per LVO patient, CTP-based occlusion detection resulted in cost savings (ΔCosts median: € - 2671, IQR: [€ - 4721; € - 731]), a health gain (ΔQALY median: 0.073, IQR: [0.044; 0.104]), and a positive NMB (median: €8436, IQR: [5565; 11,876]) per LVO patient. CONCLUSION: CTP-based screening of suspected stroke patients for an endovascular treatment eligible large vessel occlusion was cost-effective. CLINICAL RELEVANCE STATEMENT: Although CTP-based patient selection for endovascular treatment has been recently suggested to result in worse patient outcomes after ischemic stroke, an alternative CTP-based screening for endovascular treatable occlusions is cost-effective. KEY POINTS: • Using CT perfusion to detect an endovascular treatment-eligible occlusions resulted in a health gain and cost savings during 10 years of follow-up. • Depending on the screening costs related to the number of patients needed to image with CT perfusion, cost savings could be considerable (median: € - 3857, IQR: [€ - 5907; € - 1916] per patient). • As the gain in quality adjusted life years was most affected by the sensitivity of CT perfusion-based occlusion detection, additional studies for the diagnostic accuracy of CT perfusion for occlusion detection are required.

Outcome of patients with multivessel occlusion stroke after endovascular treatment.

INTRODUCTION: Little is known about the implications of multivessel occlusions (MVO) in large vessel occlusion stroke patients who undergo endovascular treatment (EVT). PATIENTS AND METHODS: We report data from the MR CLEAN Registry: a prospective, observational study on all stroke patients who underwent EVT in the Netherlands (March 2014-November 2017). We included patients with an intracranial target occlusion in the anterior circulation. An MVO was defined as an MCA occlusion (M1/M2) or intracranial ICA/ICA-T occlusion, with a concurrent second occlusion in the ACA or PCA territory confirmed on baseline CTA. To compare outcomes, we performed a 10:1 propensity score matching analysis with a logistic regression model including potential confounders. Outcome measures included 90-day functional outcome (modified Rankin Scale, mRS) and mortality. RESULTS: Of 2946 included patients, 71 patients (2.4%) had an MVO (87% concurrent ACA occlusion, 10% PCA occlusion, 3% ⩾3 occlusions). These patients were matched to 71 non-MVO patients. Before matching, MVO patients had a higher baseline NIHSS (median 18 vs 16, p = 0.001) and worse collateral status (absent collaterals: 17% vs 6%, p < 0.001) compared to non-MVO patients. After matching, MVO patients had worse functional outcome at 90 days (median mRS 5 vs 3, cOR 0.39; 95%CI 0.25-0.62). Mortality was higher in MVO patients (46% vs 27%, OR 2.11, 95%CI 1.24-3.57). DISCUSSION AND CONCLUSION: MVOs on baseline imaging were uncommon in LVO stroke patients undergoing EVT, but were associated with poor functional outcome.

Costs and health effects of CT perfusion-based selection for endovascular thrombectomy within 6 hours of stroke onset: a model-based health economic evaluation.

BACKGROUND: Although CT perfusion (CTP) is often incorporated in acute stroke workflows, it remains largely unclear what the associated costs and health implications are in the long run of CTP-based patient selection for endovascular treatment (EVT) in patients presenting within 6 hours after symptom onset with a large vessel occlusion. METHODS: Patients with a large vessel occlusion were included from a Dutch nationwide cohort (n=703) if CTP imaging was performed before EVT within 6 hours after stroke onset. Simulated cost and health effects during 5 and 10 years follow-up were compared between CTP based patient selection for EVT and providing EVT to all patients. Outcome measures were the net monetary benefit at a willingness-to-pay of €80 000 per quality-adjusted life year, incremental cost-effectiveness ratio), difference in costs from a healthcare payer perspective (ΔCosts) and quality-adjusted life years (ΔQALY) per 1000 patients for 1000 model iterations as outcomes. RESULTS: Compared with treating all patients, CTP-based selection for EVT at the optimised ischaemic core volume (ICV≥110 mL) or core-penumbra mismatch ratio (MMR≤1.4) thresholds resulted in losses of health (median ΔQALYs for ICV≥110 mL: -3.3 (IQR: -5.9 to -1.1), for MMR≤1.4: 0.0 (IQR: -1.3 to 0.0)) with median ΔCosts for ICV≥110 mL of -€348 966 (IQR: -€712 406 to -€51 158) and for MMR≤1.4 of €266 513 (IQR: €229 403 to €380 110)) per 1000 patients. Sensitivity analyses did not yield any scenarios for CTP-based selection of patients for EVT that were cost-effective for improving health, including patients aged ≥80 years CONCLUSION: In EVT-eligible patients presenting within 6 hours after symptom onset, excluding patients based on CTP parameters was not cost-effective and could potentially harm patients.

Development and validation of a prediction model for failure of the transfemoral approach of endovascular treatment for large vessel occlusion acute ischemic stroke.

INTRODUCTION: Extracranial vascular characteristics determine the accessibility of the large vessel intracranial occlusion for endovascular treatment (EVT) in acute ischemic stroke. We developed and validated a prediction model for failure of the transfemoral approach to aid clinical decision making regarding EVT. METHODS: A prediction model was developed from data of patients included in the Dutch multicenter MR CLEAN Registry (March 18th 2014 until June 15th 2016) with penalized logistic regression. Predictor variables were available prior to the EVT procedure and included age, hypertension and extracranial vascular characteristics assessed on baseline CTA. The prediction model was internally validated, temporally validated within a second MR CLEAN Registry cohort (June 15th 2016 until November 1st 2017) and updated by re-estimating the coefficients using the combined cohort. RESULTS: Failure of the transfemoral approach occurred in 7% of patients, in both cohorts (derivation cohort: n=887, median age 71 years, interquartile range [IQR] 60-80, 52% men; validation cohort: n=1111, median age 73 years, IQR 62-81, 51% men). The prediction model had a c-statistic of 0.81 (95%CI: 0.76-0.86) in the derivation cohort, 0.69 (95%CI: 0.62-0.75) at temporal validation, and 0.75 (95%CI: 0.71-0.79) in the final prediction model, with the following penalized ß-coefficients for predictors age (per decade): 0.26, hypertension: -0.16, severe aortic arch elongation: 1.45, bovine aortic arch: 0.44, elongation of the supra-aortic arteries: 0.72, cervical ICA elongation: 0.44, and high-grade stenosis of the cervical ICA: 0.78. CONCLUSION: Our prediction model showed good performance for prediction of failure to reach the intracranial occlusion by the transfemoral approach.