Endovascular Treatment of Medium Vessel Occlusion Stroke.

Approximately one-third of acute ischemic strokes with an identifiable vessel occlusion are caused by medium vessel occlusion (MeVO), that is, nonlarge vessel occlusions that are potentially amenable to endovascular treatment (EVT). Management of patients with MeVO is challenging in many ways: detecting MeVOs can be challenging, particularly for inexperienced physicians, and in busy clinical routine, MeVOs, therefore, remain sometimes undiagnosed. While the clinical course of MeVO stroke with medical management, including intravenous thrombolysis, is by no means, benign, it is more favorable compared with large vessel occlusion. At the same time, EVT complication rates are higher, and thus, the marginal benefit of EVT beyond best medical management is expected to be smaller and more challenging to detect if it were present. Several randomized controlled trials are currently underway to investigate whether and to what degree patients with MeVO may benefit from EVT and will soon provide robust data for evidence-based MeVO EVT decision-making. In this review, we discuss different ways of defining MeVOs, strategies to optimize MeVO detection on imaging, and considerations for EVT decision-making in the setting of MeVO stroke. We discuss the technical challenges related to MeVO EVT and conclude with an overview of currently ongoing MeVO EVT trials.

An Introduction to Bayesian Approaches to Trial Design and Statistics for Stroke Researchers.

While the majority of stroke researchers use frequentist statistics to analyze and present their data, Bayesian statistics are becoming more and more prevalent in stroke research. As opposed to frequentist approaches, which are based on the probability that data equal specific values given underlying unknown parameters, Bayesian approaches are based on the probability that parameters equal specific values given observed data and prior beliefs. The Bayesian paradigm allows researchers to update their beliefs with observed data to provide probabilistic interpretations of key parameters, for example, the probability that a treatment is effective. In this review, we outline the basic concepts of Bayesian statistics as they apply to stroke trials, compare them to the frequentist approach using exemplary data from a randomized trial, and explain how a Bayesian analysis is conducted and interpreted.

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.

Optimizing Patient-Centered Stroke Care and Research in the Prehospital Setting.

Over the past decades, continuous technological advances and the availability of novel therapies have enabled treatment of more acute medical conditions than ever before. Many of these treatments, such as intravenous thrombolysis and mechanical thrombectomy for acute ischemic stroke, are highly time sensitive. This has raised interest in shifting advanced acute care from hospitals to the prehospital setting. Key objectives of advanced prehospital stroke care may include (1) early targeted treatments in the prehospital setting, for example, intravenous thrombolysis for acute stroke, and (2) advanced prehospital diagnostics such as prehospital large vessel occlusion and intracranial hemorrhage detection, to help inform patient triage and potentially reduce subsequent workload in emergency departments. Major challenges that may hamper a swift transition to more advanced prehospital care are related to conducting clinical trials in the prehospital setting to provide sufficient evidence for emergency interventions, as well as ambulance design, infrastructure, emergency medical service personnel training and workload, and cost barriers. Utilizing new technologies such as telemedicine, mobile stroke units and portable diagnostic devices, customized software applications, and smart storage space management may help surmount these challenges and establish efficient, targeted care strategies that are achievable in the prehospital setting. In this article, we delineate the paradigm of shifting advanced stroke care to the prehospital setting and outline future directions in providing evidence-based, patient-centered prehospital care. While we use acute stroke as an illustrative example, these principles are not limited to stroke patients and can be applied to prehospital triage for any time-critical disease.

Cost-Effectiveness of Endovascular Treatment in Large Vessel Occlusion Stroke With Mild Prestroke Disability: Results From the HERMES Collaboration.

BACKGROUND: The clinical and economic benefit of endovascular treatment (EVT) in addition to best medical management in patients with stroke with mild preexisting symptoms/disability is not well studied. We aimed to investigate cost-effectiveness of EVT in patients with large vessel occlusion and mild prestroke symptoms/disability, defined as a modified Rankin Scale score of 1 or 2. METHODS: Data are from the HERMES collaboration (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials), which pooled patient-level data from 7 large, randomized EVT trials. We used a decision model consisting of a short-run model to analyze costs and functional outcomes within 90 days after the index stroke and a long-run Markov state transition model (cycle length of 12 months) to estimate expected lifetime costs and outcomes from a health care and a societal perspective. Incremental cost-effectiveness ratio and net monetary benefits were calculated, and a probabilistic sensitivity analysis was performed. RESULTS: EVT in addition to best medical management resulted in lifetime cost savings of $2821 (health care perspective) or $5378 (societal perspective) and an increment of 1.27 quality-adjusted life years compared with best medical management alone, indicating dominance of additional EVT as a treatment strategy. The net monetary benefits were higher for EVT in addition to best medical management compared with best medical management alone both at the higher (100 000$/quality-adjusted life years) and lower (50 000$/quality-adjusted life years) willingness to pay thresholds. Probabilistic sensitivity analysis showed decreased costs and an increase in quality-adjusted life years for additional EVT compared with best medical management only. CONCLUSIONS: From a health-economic standpoint, EVT in addition to best medical management should be the preferred strategy in patients with acute ischemic stroke with large vessel occlusion and mild prestroke symptoms/disability.

Distal Embolization in Relation to Radiological Thrombus Characteristics, Treatment Details, and Functional Outcome.

BACKGROUND: Distal embolization (DE) is a common complication of endovascular treatment (EVT). We investigated the association of radiological thrombus characteristics and treatment details with DE. METHODS: Patients with thin-slice (≤2.5 mm) baseline noncontrast computed tomography and computed tomography angiography from the ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke) were included. Thrombus annotation was performed manually on coregistered scans by experienced readers. We assessed thrombus location, distance from internal carotid artery terminus, length, perviousness, absolute attenuation, and hyperdense artery sign. In addition, we evaluated balloon guide catheter use during EVT, first-line EVT approach, the number of thrombectomy passes, and prior intravenous thrombolysis administration. DE was defined as the occurrence of emboli distal to the target artery or in new territories during EVT. The association between thrombus characteristics, treatment details, and DE was evaluated using descriptive statistics and multivariable mixed-effects logistic regression, resulting in adjusted odds ratios (aOR) with 95% CI. Interaction between IVT and radiological thrombus characteristics was assessed by adding interaction terms in separate models. RESULTS: In total, 496 out of 1105 (44.9%) ESCAPE-NA1 patients were included. DE was detected in 251 out of 496 patients (50.6%). Patients with DE had longer thrombi (median, 28.5 [interquartile range, 20.8-42.3] mm versus 24.4 [interquartile range, 17.1-32.4] mm; P<0.01). There were no statistically significant differences in the other thrombus characteristics. Factors associated with DE were thrombus length (aOR, 1.02 [95% CI, 1.01-1.04]), balloon guide catheter use (aOR, 0.49 [95% CI, 0.29-0.85]), and number of passes (aOR, 1.24 [95% CI, 1.04-1.47]). In patients with hyperdense artery sign, IVT was associated with reduced odds of DE (aOR, 0.55 [95% CI, 0.31-0.97]), P for interaction=0.04. CONCLUSIONS: DE was associated with longer thrombi, no balloon guide catheter use, and more EVT passes. IVT was associated with a reduced risk of DE in patients with hyperdense artery sign. These findings may support treatment decisions on IVT and EVT approaches.

No Sex Differences in Mechanical Thrombectomy Time Metrics and Outcomes in Saskatchewan.

BACKGROUND AND PURPOSE: Numerous studies have shown longer pre-hospital and in-hospital workflow times and poorer outcomes in women after acute ischemic stroke (AIS) in general and after endovascular treatment (EVT) in particular. We investigated sex differences in acute stroke care of EVT patients over 5 years in a comprehensive Canadian provincial registry. METHODS: Clinical data of all AIS patients who underwent EVT between January 2017 and December 2022 in the province of Saskatchewan were captured in the Canadian OPTIMISE registry and supplemented with patient data from administrative data sources. Patient baseline characteristics, transport time metrics, and technical EVT outcomes between female and male EVT patients were compared. RESULTS: Three-hundred-three patients underwent EVT between 2017 and 2022: 144 (47.5%) women and 159 (52.5%) men. Women were significantly older (median age 77.5 [interquartile range: 66-85] vs.71 [59-78], p < 0.001), while men had more intracranial internal carotid artery occlusions (48/159 [30.2%] vs. 26/142 [18.3%], p = 0.03). Last-known-well to comprehensive stroke center (CSC)-arrival time (median 232 min [interquartile range 90-432] in women vs. 230 min [90-352] in men), CSC-arrival-to-reperfusion time (median 108 min [88-149] in women vs. 102 min [77-141] in men), reperfusion status (successful reperfusion 106/142 [74.7%] in women vs. 117/158 [74.1%] in men) as well as modified Rankin score at 90 days did not differ significantly. This held true after adjusting for baseline variables in multivariable analyses. CONCLUSION: While women undergoing EVT in the province of Saskatchewan were on average older than men, they were treated just as fast and achieved similar technical and clinical outcomes compared to men.

Toward a Better Understanding of Sex- and Gender-Related Differences in Endovascular Stroke Treatment: A Scientific Statement From the American Heart Association/American Stroke Association.

There are many unknowns when it comes to the role of sex in the pathophysiology and management of acute ischemic stroke. This is particularly true for endovascular treatment (EVT). It has only recently been established as standard of care; therefore, data are even more scarce and conflicting compared with other areas of acute stroke. Assessing the role of sex and gender as isolated variables is challenging because they are closely intertwined with each other, as well as with patients' cultural, ethnic, and social backgrounds. Nevertheless, a better understanding of sex- and gender-related differences in EVT is important to develop strategies that can ultimately improve individualized outcome for both men and women. Disregarding patient sex and gender and pursuing a one-size-fits-all strategy may lead to suboptimal or even harmful treatment practices. This scientific statement is meant to outline knowledge gaps and unmet needs for future research on the role of sex and gender in EVT for acute ischemic stroke. It also provides a pragmatic road map for researchers who aim to investigate sex- and gender-related differences in EVT and for clinicians who wish to improve clinical care of their patients undergoing EVT by accounting for sex- and gender-specific factors. Although most EVT studies, including those that form the basis of this scientific statement, report patient sex rather than gender, open questions on gender-specific EVT differences are also discussed.

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

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

Evaluating the Diagnostic Performance of Prehospital Stroke Scales Across the Range of Deficit Severity: Analysis of the Prehospital Triage of Patients With Suspected Stroke Study.

BACKGROUND: The usefulness of prehospital scales for identifying anterior circulation large vessel occlusion (aLVO) in patients with suspected stroke may vary depending on the severity of their presentation. The performance of these scales across the spectrum of deficit severity is unclear. The aim of this study was to evaluate the diagnostic performance of 8 prehospital scales for identifying aLVO across the spectrum of deficit severity. METHODS: We used data from the PRESTO study (Prehospital Triage of Patients With Suspected Stroke Symptoms), a prospective observational study comparing prehospital stroke scales in detecting aLVO in suspected stroke patients. We used the National Institutes of Health Stroke Scale (NIHSS) score, assessed in-hospital, as a proxy for the Clinical Global Impression of stroke severity during prehospital assessment by paramedics. We calculated the sensitivity, specificity, positive predictive value, negative predictive value, and the difference in aLVO probabilities with a positive or negative prehospital scale test (ΔPaLVO) for each scale for mild (NIHSS 0-4), intermediate (NIHSS 5-9), moderate (NIHSS 10-14), and severe deficits (NIHSS≥15). RESULTS: Among 1033 patients with suspected stroke, 119 (11.5%) had an aLVO, of whom 19 (16.0%) had mild, 25 (21.0%) had intermediate, 30 (25.2%) had moderate, and 45 (37.8%) had severe deficits. The scales had low sensitivity and positive predictive value in patients with mild-intermediate deficits, and poor specificity, negative predictive value, and accuracy with moderate-severe deficits. Positive results achieved the highest ΔPaLVO in patients with mild deficits. Negative results achieved the highest ΔPaLVO with severe deficits, but the probability of aLVO with a negative result in the severe range was higher than with a positive test in the mild range. CONCLUSIONS: Commonly-used prehospital stroke scales show variable performance across the range of deficit severity. Probability of aLVO remains high with a negative test in severely affected patients. Studies reporting prehospital stroke scale performance should be appraised in the context of the NIHSS distribution of their samples.

Variability assessment of manual segmentations of ischemic lesion volume on 24-h non-contrast CT.

PURPOSE: Infarct lesion volume (ILV) may serve as an imaging biomarker for clinical outcomes in the early post-treatment stage in patients with acute ischemic stroke. The aim of this study was to evaluate the inter- and intra-rater reliability of manual segmentation of ILV on follow-up non-contrast CT (NCCT) scans. METHODS: Fifty patients from the Prove-IT study were randomly selected for this analysis. Three raters manually segmented ILV on 24-h NCCT scans, slice by slice, three times. The reference standard for ILV was generated by the Simultaneous Truth And Performance Level estimation (STAPLE) algorithm. Intra- and inter-rater reliability was evaluated, using metrics of intraclass correlation coefficient (ICC) regarding lesion volume and the Dice similarity coefficient (DSC). RESULTS: Median age of the 50 subjects included was 74.5 years (interquartile range [IQR] 67-80), 54% were women, median baseline National Institutes of Health Stroke Scale was 18 (IQR 11-22), median baseline ASPECTS was 9 (IQR 6-10). The mean reference standard ILV was 92.5 ml (standard deviation (SD) ± 100.9 ml). The manually segmented ILV ranged from 88.2 ± 91.5 to 135.5 ± 119.9 ml (means referring to the variation between readers, SD within readers). Inter-rater ICC was 0.83 (95%CI: 0.76-0.88); intra-rater ICC ranged from 0.85 (95%CI: 0.72-0.92) to 0.95 (95%CI: 0.91-0.97). The mean DSC among the three readers ranged from 65.5 ± 22.9 to 76.4 ± 17.1% and the mean overall DSC was 72.8 ± 23.0%. CONCLUSION: Manual ILV measurements on follow-up CT scans are reliable to measure the radiological outcome despite some variability.

Multiphase CTA-derived tissue maps aid in detection of medium vessel occlusions.

PURPOSE: Medium vessel occlusions (MeVOs) can be challenging to detect on imaging. Multiphase computed tomography angiography (mCTA) has been shown to improve large vessel occlusion (LVO) detection and endovascular treatment (EVT) selection. The aims of this study were to determine if mCTA-derived tissue maps can (1) accurately detect MeVOs and (2) predict infarction on 24-h follow-up imaging with comparable accuracy to CT perfusion (CTP). METHODS: Two readers assessed mCTA tissue maps of 116 ischemic stroke patients (58 MeVOs, 58 non-MeVOs) and determined by consensus: (1) MeVO (yes/no) and (2) occlusion site, blinded to clinical or imaging data. Sensitivity, specificity, and area under the curve (AUC) for MeVO detection were estimated in comparison to reference standards of (1) expert readings of baseline mCTA and (2) CTP maps. Volumetric and spatial agreement between mCTA- and CTP-predicted infarcts was assessed using concordance/intraclass correlation and Dice coefficients. Interrater agreement for MeVO detection on mCTA tissue maps was estimated with Cohen's kappa. RESULTS: MeVO detection from mCTA-derived tissue maps had a sensitivity of 91% (95% CI: 80-97), specificity of 82% (95% CI: 70-90), and AUC of 0.87 (95% CI: 0.80-0.93) compared to expert reads of baseline mCTA. Interrater reliability was good (0.72, 95% CI: 0.60-0.85). Compared to CTP maps, sensitivity was 87% (95% CI: 75-95), specificity was 78% (95%CI: 65-88), and AUC was 0.83 (95% CI: 0.76-0.90). The mean difference between mCTA- and CTP-predicted final infarct volume was 4.8 mL (limits of agreement: - 58.5 to 68.1) with a Dice coefficient of 33.5%. CONCLUSION: mCTA tissue maps can be used to reliably detect MeVO stroke and predict tissue fate.

Validation of a machine learning software tool for automated large vessel occlusion detection in patients with suspected acute stroke.

PURPOSE: CT angiography (CTA) is the imaging standard for large vessel occlusion (LVO) detection in patients with acute ischemic stroke. StrokeSENS LVO is an automated tool that utilizes a machine learning algorithm to identify anterior large vessel occlusions (LVO) on CTA. The aim of this study was to test the algorithm's performance in LVO detection in an independent dataset. METHODS: A total of 400 studies (217 LVO, 183 other/no occlusion) read by expert consensus were used for retrospective analysis. The LVO was defined as intracranial internal carotid artery (ICA) occlusion and M1 middle cerebral artery (MCA) occlusion. Software performance in detecting anterior LVO was evaluated using receiver operator characteristics (ROC) analysis, reporting area under the curve (AUC), sensitivity, and specificity. Subgroup analyses were performed to evaluate if performance in detecting LVO differed by subgroups, namely M1 MCA and ICA occlusion sites, and in data stratified by patient age, sex, and CTA acquisition characteristics (slice thickness, kilovoltage tube peak, and scanner manufacturer). RESULTS: AUC, sensitivity, and specificity overall were as follows: 0.939, 0.894, and 0.874, respectively, in the full cohort; 0.927, 0.857, and 0.874, respectively, in the ICA occlusion cohort; 0.945, 0.914, and 0.874, respectively, in the M1 MCA occlusion cohort. Performance did not differ significantly by patient age, sex, or CTA acquisition characteristics. CONCLUSION: The StrokeSENS LVO machine learning algorithm detects anterior LVO with high accuracy from a range of scans in a large dataset.

Which Acute Ischemic Stroke Patients Are Fast Progressors?: Results From the ESCAPE Trial Control Arm.

BACKGROUND AND PURPOSE: Fast infarct progression in acute ischemic stroke has a severe impact on patient prognosis and benefit of endovascular thrombectomy. In this post hoc analysis of the ESCAPE trial (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke), we identified acute ischemic stroke patients with rapid infarct growth and investigated their baseline clinical and imaging characteristics. METHODS: Control arm patients were included if they had follow-up imaging at 2-8 hours without substantial recanalization, and if their baseline Alberta Stroke Program Early CT Score was ≥9. Fast infarct progression was defined as Alberta Stroke Program Early CT Score decay ≥3 points from baseline to 2- to 8-hour follow-up imaging. Clinical and imaging baseline characteristics were compared between fast progressors and other patients, and occlusion site and collateral flow patterns were assessed in detail. RESULTS: Fast infarct progression occurred in 15 of 43 included patients (34.9%). Fast progressors had worse collaterals (poor in 3/15 [20%] versus 0/28 patients, P=0.021) and more carotid-T or -L occlusions (8/15 [53.4%] versus 3/28[10.7%], P=0.021). In 8 out of 15 (53.3%), occlusion site and circle of Willis configuration prevented collateral flow via the anterior or posterior cerebral artery. CONCLUSIONS: Most patients with fast infarct progression had terminal carotid occlusions and impaired collateral flow via the anterior or posterior cerebral artery, indicating that occlusion location and intracranial vascular anatomy are relevant for infarct progression.

Early Recanalization With Alteplase in Stroke Because of Large Vessel Occlusion in the ESCAPE Trial.

BACKGROUND AND PURPOSE: Quantitating the effect of intravenous alteplase on the technical outcome of early recanalization of large vessel occlusions aids understanding. We report the prevalence of early recanalization in patients with stroke because of large vessel occlusion treated with and without intravenous alteplase and endovascular thrombectomy, and its association with clinical outcome. METHODS: Patients with acute ischemic stroke with large vessel occlusion from the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times Trial) were included in this post hoc analysis. Outcomes of interest were the prevalence of early recanalization (1) and good outcome (2), defined as modified Rankin Scale score of 0 to 2 at 90 days. RESULTS: Among 147 patients who did not receive endovascular thrombectomy, early recanalization occurred in 4/30 (13.3%) patients without and 48/117 (41.0%) patients with intravenous alteplase (adjusted risk ratios, 3.2 [95% CI, 1.2-8.1]). Good outcome was achieved by 34/116 (29.3%) of patients who received intravenous alteplase versus 10/29 (34.5%) who did not receive alteplase (adjusted risk ratios, 1.0 [95% CI, 0.6-1.5) and by 20/52 (38.5%) patients with versus 24/93 (25.8%) without early recanalization (adjusted risk ratios, 1.9 [95% CI, 1.2-2.9]). CONCLUSIONS: Early recanalization was confirmed as a strong predictor of good outcome in patients who did not undergo endovascular thrombectomy and was improved with intravenous alteplase, yet a majority of patients (59.0%) did not achieve early reperfusion. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Radiologic Patterns of Intracranial Hemorrhage and Clinical Outcome after Endovascular Treatment in Acute Ischemic Stroke: Results from the ESCAPE-NA1 Trial.

Background Intracranial hemorrhage is a known complication after endovascular treatment in patients with acute ischemic stroke due to large vessel occlusion, but the association between radiologic hemorrhage severity and outcome is controversial. Purpose To investigate the prevalence and impact on outcome of intracranial hemorrhage and hemorrhage severity after endovascular stroke treatment. Materials and Methods The Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke (ESCAPE-NA1) trial enrolled participants with acute large vessel occlusion stroke who underwent endovascular treatment from March 1, 2017, to August 12, 2019. Evidence of any intracranial hemorrhage, hemorrhage multiplicity, and radiologic severity, according to the Heidelberg classification (hemorrhagic infarction type 1 [HI1], hemorrhagic infarction type 2 [HI2], parenchymal hematoma type 1 [PH1], and parenchymal hematoma type 2 [PH2]) was assessed at CT or MRI 24 hours after endovascular treatment. Good functional outcome, defined as a modified Rankin score of 0-2 at 90 days, was compared between participants with intracranial hemorrhage and those without intracranial hemorrhage at follow-up imaging and between hemorrhage subtypes. Poisson regression was performed to obtain adjusted effect size estimates for the presence of any intracranial hemorrhage and hemorrhage subtypes at good functional outcome. Results Of 1097 evaluated participants (mean age, 69 years ± 14 [standard deviation]; 551 men), any degree of intracranial hemorrhage was observed in 372 (34%). Good outcomes were less often achieved among participants with hemorrhage than among those without hemorrhage at follow-up imaging (164 of 372 participants [44%] vs 500 of 720 [69%], respectively; P < .01). After adjusting for baseline variables and infarct volume, intracranial hemorrhage was not associated with decreased chances of good outcome (adjusted risk ratio [RR] = 0.91 [95% CI: 0.82, 1.02], P = .10), but there was a graded relationship of radiologic hemorrhage severity and outcomes, whereby PH1 (RR = 0.77 [95% CI: 0.61, 0.97], P = .03) and PH2 (RR = 0.41 [95% CI: 0.21, 0.81], P = .01) were associated with decreased chances of good outcome. Conclusion Any degree of intracranial hemorrhage after endovascular treatment was seen in one-third of participants. A graded association existed between radiologic hemorrhage severity and outcome. Hemorrhagic infarction was not associated with outcome, whereas parenchymal hematoma was strongly associated with poor outcome, independent of infarct volume. © RSNA, 2021 Clinical trial registration no. NCT01778335 Online supplemental material is available for this article.

A Detailed Analysis of Infarct Patterns and Volumes at 24-hour Noncontrast CT and Diffusion-weighted MRI in Acute Ischemic Stroke Due to Large Vessel Occlusion: Results from the ESCAPE-NA1 Trial.

Background The effect of infarct pattern on functional outcome in acute ischemic stroke is incompletely understood. Purpose To investigate the association of qualitative and quantitative infarct variables at 24-hour follow-up noncontrast CT and diffusion-weighted MRI with 90-day clinical outcome. Materials and Methods The Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke, or ESCAPE-NA1, randomized controlled trial enrolled patients with large-vessel-occlusion stroke undergoing mechanical thrombectomy from March 1, 2017, to August 12, 2019. In this post hoc analysis of the trial, qualitative infarct variables (predominantly gray [vs gray and white] matter involvement, corticospinal tract involvement, infarct structure [scattered vs territorial]) and total infarct volume were assessed at 24-hour follow-up noncontrast CT or diffusion-weighted MRI. White and gray matter infarct volumes were assessed in patients by using follow-up diffusion-weighted MRI. Infarct variables were compared between patients with and those without good outcome, defined as a modified Rankin Scale score of 0-2 at 90 days. The association of infarct variables with good outcome was determined with use of multivariable logistic regression. Separate regression models were used to report effect size estimates with adjustment for total infarct volume. Results Qualitative infarct variables were assessed in 1026 patients (mean age ± standard deviation, 69 years ± 13; 522 men) and quantitative infarct variables were assessed in a subgroup of 358 of 1026 patients (mean age, 67 years ± 13; 190 women). Patients with gray and white matter involvement (odds ratio [OR] after multivariable adjustment, 0.19; 95% CI: 0.14, 0.25; P < .001), corticospinal tract involvement (OR after multivariable adjustment, 0.06; 95% CI: 0.04, 0.10; P < .001), and territorial infarcts (OR after multivariable adjustment, 0.22; 95% CI: 0.14, 0.32; P < .001) were less likely to achieve good outcome, independent of total infarct volume. Conclusion Infarct confinement to the gray matter, corticospinal tract sparing, and scattered infarct structure at 24-hour noncontrast CT and diffusion-weighted MRI were highly predictive of good 90-day clinical outcome, independent of total infarct volume. Clinical trial registration no. NCT02930018 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Mossa-Basha in this issue.

Balloon guide catheters: use, reject, or randomize?

Thrombectomy devices played an important role in the success of endovascular treatment trials over the past five years. A balloon guide catheter (BGC) is an adjunctive device used to arrest and reverse flow by inflating the balloon at its tip, which allows for flow reversal in intracranial arteries during retrieval of thrombectomy devices by applying concomitant aspiration through its lumen. Thereby, it can decrease the risk of clot fragmentation and distal embolization. Despite the numerous benchtop and clinical observational studies showing the superiority of BGC to conventional guide catheters in improving reperfusion quality and clinical outcome, its use is still low in clinical practice. The reasons behind this reluctance might be related to technical and cost issues. Therefore, high level evidence data, i.e., a randomized clinical trial, are needed to increase its implementation in thrombectomy procedures. Nonetheless, several obstacles and challenges can prevent the completion of such a trial, and efforts are needed to overcome them. We provide an overview of the current opinions about BGCs in the neurointerventional community and discuss the feasibility and challenges of a possible randomized trial to answer the question "should a BGC be routinely used in endovascular treatment of acute ischemic stroke?"