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.

Endovascular treatment versus no endovascular treatment after 6-24 h in patients with ischaemic stroke and collateral flow on CT angiography (MR CLEAN-LATE) in the Netherlands: a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial.

BACKGROUND: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA). METHODS: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20-2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44-1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49-14·10]). INTERPRETATION: In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow. FUNDING: Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

Endovascular Therapy for Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effectiveness of endovascular therapy in patients with stroke caused by basilar-artery occlusion has not been well studied. METHODS: We randomly assigned patients within 6 hours after the estimated time of onset of a stroke due to basilar-artery occlusion, in a 1:1 ratio, to receive endovascular therapy or standard medical care. The primary outcome was a favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 to 6, with 0 indicating no disability, 3 indicating moderate disability, and 6 indicating death) at 90 days. The primary safety outcomes were symptomatic intracranial hemorrhage within 3 days after the initiation of treatment and mortality at 90 days. RESULTS: A total of 300 patients were enrolled (154 in the endovascular therapy group and 146 in the medical care group). Intravenous thrombolysis was used in 78.6% of the patients in the endovascular group and in 79.5% of those in the medical group. Endovascular treatment was initiated at a median of 4.4 hours after stroke onset. A favorable functional outcome occurred in 68 of 154 patients (44.2%) in the endovascular group and 55 of 146 patients (37.7%) in the medical care group (risk ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.50). Symptomatic intracranial hemorrhage occurred in 4.5% of the patients after endovascular therapy and in 0.7% of those after medical therapy (risk ratio, 6.9; 95% CI, 0.9 to 53.0); mortality at 90 days was 38.3% and 43.2%, respectively (risk ratio, 0.87; 95% CI, 0.68 to 1.12). CONCLUSIONS: Among patients with stroke from basilar-artery occlusion, endovascular therapy and medical therapy did not differ significantly with respect to a favorable functional outcome, but, as reflected by the wide confidence interval for the primary outcome, the results of this trial may not exclude a substantial benefit of endovascular therapy. Larger trials are needed to determine the efficacy and safety of endovascular therapy for basilar-artery occlusion. (Funded by the Dutch Heart Foundation and others; BASICS ClinicalTrials.gov number, NCT01717755; Netherlands Trial Register number, NL2500.).

A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke.

BACKGROUND: 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. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.).

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

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

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.

Association between thrombus composition and stroke etiology in the MR CLEAN Registry biobank.

PURPOSE: The composition of thrombi retrieved during endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) due to large vessel occlusion (LVO) may differ depending on their origin. In this study, we investigated the association between thrombus composition and stroke etiology in a large population of patients from the Dutch MR CLEAN Registry treated with EVT in daily clinical practice. METHODS: The thrombi of 332 patients with AIS were histologically analyzed for red blood cells (RBC), fibrin/platelets (F/P), and white blood cells (leukocytes) using a machine learning algorithm. Stroke etiology was assessed using the Trial of Org 10,172 in acute stroke treatment (TOAST) classification. RESULTS: The thrombi of cardioembolic origin contained less RBC and more F/P than those of non-cardioembolic origin (25.8% vs 41.2% RBC [p = 0.003] and 67.1% vs 54.5% F/P [p = 0.004]). The likelihood of a non-cardioembolic source of stroke increased with increasing thrombus RBC content (OR 1.02; [95% CI 1.00-1.06] for each percent increase) and decreased with a higher F/P content (OR 1.02; [95% CI 1.00-1.06]). Thrombus composition in patients with a cardioembolic origin and undetermined origin was similar. CONCLUSION: Thrombus composition is significantly associated with stroke etiology, with an increase in RBC and a decrease in F/P raising the odds for a non-cardioembolic cause. No difference between composition of cardioembolic thrombi and of undetermined origin was seen. This emphasizes the need for more extensive monitoring for arrhythmias and/or extended cardiac analysis in case of an undetermined origin.

Effect of Intravenous Alteplase Treatment on First-Line Stent Retriever Versus Aspiration Alone During Endovascular Treatment.

BACKGROUND: We aimed to assess whether the effect of intravenous alteplase treatment (IVT) before endovascular treatment (EVT) on outcome is modified by first-line technique during EVT in IVT eligible patients. METHODS: This was a post hoc analysis from MR CLEAN-NO IV (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands - Intravenous Treatment Followed by Intra-Arterial Treatment Versus Direct Intra-Arterial Treatment for Acute Ischemic Stroke Caused by a Proximal Intracranial Occlusion), a randomized trial of IVT followed by EVT versus EVT alone in patients presenting directly to EVT-capable centers. We included data from all patients who underwent EVT with a thrombectomy attempt. We compared patients treated with stent retriever (with or without aspiration) to aspiration alone as first-line EVT technique and assessed the interaction of first-line EVT technique with IVT treatment. Primary outcome was the 90-day modified Rankin Scale score, analyzed with mixed model ordinal regression for a shift towards better outcome. Secondary outcomes included successful reperfusion (extended Thrombolysis in Cerebral Infarction score 2b-3). RESULTS: Of 473 included patients, 102 (21.6%) were treated with aspiration alone as first-line technique. In the full population, functional outcome was similar for patients treated with stent retriever versus aspiration only (adjusted common odds ratio [acOR]' 1.07 [95% CI, 0.69-1.66]). We observed a significant interaction between IVT and first-line EVT technique (P=0.03). In the aspiration-only group, patients treated with EVT alone had worse functional outcome compared to those treated with IVT and EVT (acOR, 0.44 [95% CI, 0.21-0.90]). In the stent retriever group, functional outcome did not differ between patients treated with or without IVT (acOR, 1.08 [95% CI, 0.74-1.57]). There was no statistically significant interaction for successful reperfusion. CONCLUSIONS: In MR CLEAN-NO IV, the treatment effect of IVT was modified by first-line EVT technique. Patients treated with aspiration only as first-line technique had worse clinical outcomes if they did not receive IVT. No such difference was observed in patients treated with stent retrievers. Confirmation by pooling with results from other trials is needed to confirm these findings.

Improvements in Endovascular Treatment for Acute Ischemic Stroke: A Longitudinal Study in the MR CLEAN Registry.

BACKGROUND: We evaluated data from all patients in the Netherlands who underwent endovascular treatment for acute ischemic stroke in the past 3.5 years, to identify nationwide trends in time to treatment and procedural success, and assess their effect on clinical outcomes. METHODS: We included patients with proximal occlusions of the anterior circulation from the second and first cohorts of the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry (March 2014 to June 2016; June 2016 to November 2017, respectively). We compared workflow times and rates of successful reperfusion (defined as an extended Thrombolysis in Cerebral Infarction score of 2B-3) between cohorts and chronological quartiles (all included patients stratified in chronological quartiles of intervention dates to create equally sized groups over the study period). Multivariable ordinal logistic regression was used to assess differences in the primary outcome (ordinal modified Rankin Scale at 90 days). RESULTS: Baseline characteristics were similar between cohorts (second cohort n=1692, first cohort n=1488) except for higher age, poorer collaterals, and less signs of early ischemia on computed tomography in the second cohort. Time from stroke onset to groin puncture and reperfusion were shorter in the second cohort (median 185 versus 210 minutes; P<0.001 and 236 versus 270 minutes; P<0.001, respectively). Successful reperfusion was achieved more often in the second than in the first cohort (72% versus 66%; P<0.001). Functional outcome significantly improved (adjusted common odds ratio 1.23 [95% CI, 1.07-1.40]). This effect was attenuated by adjustment for time from onset to reperfusion (adjusted common odds ratio, 1.12 [95% CI, 0.98-1.28]) and successful reperfusion (adjusted common odds ratio, 1.13 [95% CI, 0.99-1.30]). Outcomes were consistent in the analysis per chronological quartile. CONCLUSIONS: Clinical outcomes after endovascular treatment for acute ischemic stroke in routine clinical practice have improved over the past years, likely resulting from improved workflow times and higher successful reperfusion rates.

Quantitative thrombus characteristics on thin-slice computed tomography improve prediction of thrombus histopathology: results of the MR CLEAN Registry.

OBJECTIVES: Thrombus computed tomography (CT) characteristics might be used to assess histopathologic thrombus composition in patients treated with endovascular thrombectomy (EVT) for acute ischemic stroke (AIS). We aimed to assess the variability in thrombus composition that could be predicted with combined thrombus CT characteristics. METHODS: Thrombi of patients enrolled in the MR CLEAN Registry between March 2014 and June 2016 were histologically analyzed with hematoxylin-eosin staining and quantified for percentages of red blood cells (RBCs) and fibrin/platelets. We estimated the association between general qualitative characteristics (hyperdense artery sign [HAS], occlusion location, clot burden score [CBS]) and thrombus composition with linear regression, and quantified RBC variability that could be explained with individual and combined characteristics with R2. For patients with available thin-slice (≤ 2.5 mm) imaging, we performed similar analyses for general and quantitative characteristics (HAS, occlusion location, CBS, [relative] thrombus density, thrombus length, perviousness, distance from ICA-terminus). RESULTS: In 332 included patients, the presence of HAS (aß 7.8 [95% CI 3.9-11.7]) and shift towards a more proximal occlusion location (aß 3.9 [95% CI 0.6-7.1]) were independently associated with increased RBC and decreased fibrin/platelet content. With general characteristics, 12% of RBC variability could be explained; HAS was the strongest predictor. In 94 patients with available thin-slice imaging, 30% of RBC variability could be explained; thrombus density and thrombus length were the strongest predictors. CONCLUSIONS: Quantitative thrombus CT characteristics on thin-slice admission CT improve prediction of thrombus composition and might be used to further guide clinical decision-making in patients treated with EVT for AIS in the future. KEY POINTS: • With hyperdense artery sign and occlusion location, 12% of variability in thrombus RBC content can be explained. • With hyperdense artery sign, occlusion location, and quantitative thrombus characteristics on thin-slice (≤ 2.5 mm) non-contrast CT and CTA, 30% of variability in thrombus RBC content can be explained. • Absolute thrombus density and thrombus length were the strongest predictors for thrombus composition.

Impact of the lockdown on acute stroke treatments during the first surge of the COVID-19 outbreak in the Netherlands.

INTRODUCTION: We investigated the impact of the Corona Virus Disease 2019 (COVID-19) pandemic and the resulting lockdown on reperfusion treatments and door-to-treatment times during the first surge in Dutch comprehensive stroke centers. Furthermore, we studied the association between COVID-19-status and treatment times. METHODS: We included all patients receiving reperfusion treatment in 17 Dutch stroke centers from May 11th, 2017, until May 11th, 2020. We collected baseline characteristics, National Institutes of Health Stroke Scale (NIHSS) at admission, onset-to-door time (ODT), door-to-needle time (DNT), door-to-groin time (DGT) and COVID-19-status at admission. Parameters during the lockdown (March 15th, 2020 until May 11th, 2020) were compared with those in the same period in 2019, and between groups stratified by COVID-19-status. We used nationwide data and extrapolated our findings to the increasing trend of EVT numbers since May 2017. RESULTS: A decline of 14% was seen in reperfusion treatments during lockdown, with a decline in both IVT and EVT delivery. DGT increased by 12 min (50 to 62 min, p-value of < 0.001). Furthermore, median NIHSS-scores were higher in COVID-19 - suspected or positive patients (7 to 11, p-value of 0.004), door-to-treatment times did not differ significantly when stratified for COVID-19-status. CONCLUSIONS: During the first surge of the COVID-19 pandemic, a decline in acute reperfusion treatments and a delay in DGT was seen, which indicates a target for attention. It also appeared that COVID-19-positive or -suspected patients had more severe neurologic symptoms, whereas their EVT-workflow was not affected.

Prediction of Outcome and Endovascular Treatment Benefit: Validation and Update of the MR PREDICTS Decision Tool.

Background and Purpose: Benefit of early endovascular treatment (EVT) for ischemic stroke varies considerably among patients. The MR PREDICTS decision tool, derived from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), predicts outcome and treatment benefit based on baseline characteristics. Our aim was to externally validate and update MR PREDICTS with data from international trials and daily clinical practice. Methods: We used individual patient data from 6 randomized controlled trials within the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration to validate the original model. Then, we updated the model and performed a second validation with data from the observational MR CLEAN Registry. Primary outcome was functional independence (defined as modified Rankin Scale score 0­2) 3 months after stroke. Treatment benefit was defined as the difference between the probability of functional independence with and without EVT. Discriminative performance was evaluated using a concordance (C) statistic. Results: We included 1242 patients from HERMES (633 assigned to EVT, 609 assigned to control) and 3156 patients from the MR CLEAN Registry (all of whom underwent EVT within 6.5 hours). The C-statistic for functional independence was 0.74 (95% CI, 0.72­0.77) in HERMES and, after model updating, 0.80 (0.78­0.82) in the Registry. Median predicted treatment benefit of routinely treated patients (Registry) was 10.3% (interquartile range, 5.8%­14.4%). Patients with low (<1%) predicted treatment benefit (n=135/3156 [4.3%]) had low rates of functional independence, irrespective of reperfusion status, suggesting potential absence of treatment benefit. The updated model was made available online for clinicians and researchers at www.mrpredicts.com. Conclusions: Because of the substantial treatment effect and small potential harm of EVT, most patients arriving within 6 hours at an endovascular-capable center should be treated regardless of their clinical characteristics. MR PREDICTS can be used to support clinical judgement when there is uncertainty about the treatment indication, when resources are limited, or before a patient is to be transferred to an endovascular-capable center.

High Admission Glucose Is Associated With Poor Outcome After Endovascular Treatment for Ischemic Stroke.

BACKGROUND AND PURPOSE: High-serum glucose on admission is a predictor of poor outcome after stroke. We assessed the association between glucose concentrations and clinical outcomes in patients who underwent endovascular treatment. METHODS: From the MR CLEAN Registry, we selected consecutive adult patients with a large vessel occlusion of the anterior circulation who underwent endovascular treatment and for whom admission glucose levels were available. We assessed the association between admission glucose and the modified Rankin Scale score at 90 days, symptomatic intracranial hemorrhage and successful reperfusion rates. Hyperglycemia was defined as admission glucose ≥7.8 mmol/L. We evaluated the association between glucose and modified Rankin Scale using multivariable ordinal logistic regression and assessed whether successful reperfusion (extended Thrombolysis in Cerebral Infarction 2b-3) modified this association. RESULTS: Of 3637 patients in the MR CLEAN Registry, 2908 were included. Median admission glucose concentration was 6.8 mmol/L (interquartile range, 5.9-8.1) and 882 patients (30%) had hyperglycemia. Hyperglycemia on admission was associated with a shift toward worse functional outcome (median modified Rankin Scale score 4 versus 3; adjusted common odds ratio, 1.69 [95% CI, 1.44-1.99]), increased mortality (40% versus 23%; adjusted odds ratio, 1.95 [95% CI, 1.60-2.38]), and an increased risk of symptomatic intracranial hemorrhage (9% versus 5%; adjusted odds ratio, 1.94 [95% CI, 1.41-2.66]) compared with nonhyperglycemic patients. The association between admission glucose levels and poor outcome (modified Rankin Scale score 3-6) was J-shaped. Hyperglycemia was not associated with the rate of successful reperfusion nor did successful reperfusion modify the association between glucose and functional outcome. CONCLUSIONS: Increased admission glucose is associated with poor functional outcome and an increased risk of symptomatic intracranial hemorrhage after endovascular treatment.

Stroke Etiology and Thrombus Computed Tomography Characteristics in Patients With Acute Ischemic Stroke: A MR CLEAN Registry Substudy.

Background and Purpose- If a relationship between stroke etiology and thrombus computed tomography characteristics exists, assessing these characteristics in clinical practice could serve as a useful additional diagnostic tool for the identification of stroke subtype. Our purpose was to study the association of stroke etiology and thrombus computed tomography characteristics in patients with acute ischemic stroke due to a large vessel occlusion. Methods- For 1429 consecutive patients enrolled in the MR CLEAN Registry, we determined stroke cause as defined by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. The association of stroke etiology with the hyperdense artery sign, clot burden score, and thrombus location was estimated with univariable and multivariable binary and ordinal logistic regression. Additionally, for 367 patients with available thin-section imaging, we assessed the association of stroke etiology with absolute and relative thrombus attenuation, distance from internal carotid artery-terminus to thrombus, thrombus length, and thrombus attenuation increase with univariable and multivariable linear regression. Results- Compared with cardioembolic strokes, noncardioembolic strokes were associated with presence of hyperdense artery sign (odds ratio, 2.2 [95% CI, 1.6-3.0]), lower clot burden score (common odds ratio, 0.4 [95% CI, 0.3-0.6]), shift towards a more proximal thrombus location (common odds ratio, 0.2 [95% CI, 0.2-0.3]), higher absolute thrombus attenuation (ß, 3.6 [95% CI, 0.9-6.4]), decrease in distance from the ICA-terminus (ß, -5.7 [95% CI, -8.3 to -3.0]), and longer thrombi (ß, 8.6 [95% CI, 6.5-10.7]), based on univariable analysis. Thrombus characteristics of strokes with undetermined cause were similar to those of cardioembolic strokes. Conclusions- Thrombus computed tomography characteristics of cardioembolic stroke are distinct from those of noncardioembolic stroke. Additionally, our study supports the general hypothesis that many cryptogenic strokes have a cardioembolic cause. Further research should focus on the use of thrombus computed tomography characteristics as a diagnostic tool for stroke cause in clinical practice.

Path From Clinical Research to Implementation: Endovascular Treatment of Ischemic Stroke in the Netherlands.

Before 2015, endovascular treatment (EVT) for acute ischemic stroke was considered a promising treatment option. Based on limited evidence, it was performed in several dedicated stroke centers worldwide on selected patients. Since 2015, EVT for patients with intracranial large vessel occlusion has quickly been implemented as standard treatment in many countries worldwide, supported by the revised international guidelines based on solid evidence from multiple clinical trials. We describe the development in use of EVT in the Netherlands before, during, and after the pivotal EVT trials. We used data from all patients who were treated with EVT in the Netherlands from January 2002 until December 2018. We undertook a time-series analysis to examine trends in the use of EVT using Poisson regression analysis. Incidence rate ratios per year with 95% CIs were obtained to demonstrate the impact and implementation after the publication of the EVT trial results. We made regional observation plots, adjusted for stroke incidence, to assess the availability and use of the treatment in the country. In the buildup to the MR CLEAN (Multicenter Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands), a slow increase of EVT patients was observed, with 0.2% of all ischemic stroke patients receiving EVT. Before the trial results were formally announced, a statistically significant increase in EVT-treated patients per year was observed (incidence rate ratio, 1.72 [95% CI, 1.46-2.04]), and after the trial publication, an immediate steep increase was seen, followed by a more gradual increase (incidence rate ratio, 2.14 [95% CI, 1.77-2.59]). In 2018, the percentage of ischemic stroke patients receiving EVT increased to 5.8%. A well-developed infrastructure, a pragmatic approach toward the use of EVT in clinical practice, in combination with a strict adherence by the regulatory authorities to national evidence-based guidelines has led to successful implementation of EVT in the Netherlands. Ongoing efforts are directed at further increasing the proportion of stroke patients with EVT in all regions of the country.

Intravenous Thrombolysis Is Not Associated with Increased Time to Endovascular Treatment.

BACKGROUND: Endovascular treatment (EVT) with or without intravenous thrombolysis (IVT) is effective and safe in is-chemic stroke caused by large vessel occlusion, but IVT might delay time to EVT or increase risk of intracranial hemorrhage (ICH). We assessed the influence of prior IVT on time to treatment and risk of ICH in patients treated with EVT. METHODS: We analyzed data from the MR CLEAN Registry and included patients with an anterior circulation occlusion treated with EVT who presented directly to an intervention center, between 2014 and 2017. Primary endpoint was the door to groin time. Secondary outcomes were workflow time intervals and safety outcomes. We compared patients who received EVT only with patients who received IVT prior to EVT. RESULTS: We included 1,427 patients directly referred to an intervention center of whom 1,023 (72%) received IVT + EVT. Adjusted door to CT imaging and door to groin time were shorter in IVT + EVT patients (difference 5.7 min [95% CI: 4.6-6.8] and 7.0 min [95% CI: 2.4-12], respectively) while CT imaging to groin time was similar between the groups. Early recanalization on digital subtraction angiography before EVT was seen more often after prior IVT (11 vs. 5.2%, aOR 2.4 [95% CI: 1.4-4.2]). Rates of symptomatic ICH were similar. CONCLUSION: Prior IVT did not delay door to groin times and was associated with higher rates of early recanalization, without increasing the risk of ICH. Our results do not warrant withholding IVT prior to EVT.

Correction to: Disc inflammation and Modic changes show an interaction effect on recovery after surgery for lumbar disc herniation.

In Tables 3 and 4: In the first column and row, the text reads "Mixed model test (patients with Modic changes)". This should have been just "Mixed model". The complete correct Tables 3 and 4 are given below.

Workflow Intervals of Endovascular Acute Stroke Therapy During On- Versus Off-Hours: The MR CLEAN Registry.

Background and Purpose- Endovascular treatment (EVT) of patients with acute ischemic stroke because of large vessel occlusion involves complicated logistics, which may cause a delay in treatment initiation during off-hours. This might lead to a worse functional outcome. We compared workflow intervals between endovascular treatment-treated patients presenting during off- and on-hours. Methods- We retrospectively analyzed data from the MR CLEAN Registry, a prospective, multicenter, observational study in the Netherlands and included patients with an anterior circulation large vessel occlusion who presented between March 2014 and June 2016. Off-hours were defined as presentation on Monday to Friday between 17:00 and 08:00 hours, weekends (Friday 17:00 to Monday 8:00) and national holidays. Primary end point was first door to groin time. Secondary end points were functional outcome at 90 days (modified Rankin Scale) and workflow time intervals. We stratified for transfer status, adjusted for prognostic factors, and used linear and ordinal regression models. Results- We included 1488 patients of which 936 (62.9%) presented during off-hours. Median first door to groin time was 140 minutes (95% CI, 110-182) during off-hours and 121 minutes (95% CI, 85-157) during on-hours. Adjusted first door to groin time was 14.6 minutes (95% CI, 9.3-20.0) longer during off-hours. Door to needle times for intravenous therapy were slightly longer (3.5 minutes, 95% CI, 0.7-6.3) during off-hours. Groin puncture to reperfusion times did not differ between groups. For transferred patients, the delay within the intervention center was 5.0 minutes (95% CI, 0.5-9.6) longer. There was no significant difference in functional outcome between patients presenting during off- and on-hours (adjusted odds ratio, 0.92; 95% CI, 0.74-1.14). Reperfusion rates and complication rates were similar. Conclusions- Presentation during off-hours is associated with a slight delay in start of endovascular treatment in patients with acute ischemic stroke. This treatment delay did not translate into worse functional outcome or increased complication rates.

Periprocedural Intravenous Heparin During Endovascular Treatment for Ischemic Stroke: Results From the MR CLEAN Registry.

Background and Purpose- Intravenous administration of heparin during endovascular treatment for ischemic stroke may improve outcomes. However, risks and benefits of this adjunctive therapy remain uncertain. We aimed to evaluate periprocedural intravenous heparin use in Dutch stroke intervention centers and to assess its efficacy and safety. Methods- Patients registered between March 2014 and June 2016 in the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke), including all patients treated with endovascular treatment in the Netherlands, were analyzed. The primary outcome was functional outcome (modified Rankin Scale) at 90 days. Secondary outcomes were successful recanalization (extended Thrombolysis in Cerebral Infarction ≥2B), symptomatic intracranial hemorrhage, and mortality at 90 days. We used multilevel regression analysis to evaluate the association of periprocedural intravenous heparin on outcomes, adjusted for center effects and prognostic factors. To account for possible unobserved confounding by indication, we analyzed the effect of center preference to administer intravenous heparin, defined as percentage of patients treated with intravenous heparin in a center, on functional outcome. Results- One thousand four hundred eighty-eight patients from 16 centers were analyzed, of whom 398 (27%) received intravenous heparin (median dose 5000 international units). There was substantial between-center variability in the proportion of patients treated with intravenous heparin (range, 0%-94%). There was no significant difference in functional outcome between patients treated with intravenous heparin and those without (adjusted common odds ratio, 1.17; 95% CI, 0.87-1.56), successful recanalization (adjusted odds ratio, 1.24; 95% CI, 0.89-1.71), symptomatic intracranial hemorrhage (adjusted odds ratio, 1.13; 95% CI, 0.65-1.99), or mortality (adjusted odds ratio, 0.95; 95% CI, 0.66-1.38). Analysis at center level showed that functional outcomes were better in centers with higher percentages of heparin administration (adjusted common odds ratio, 1.07 per 10% more heparin, 95% CI, 1.01-1.13). Conclusions- Substantial between-center variability exists in periprocedural intravenous heparin use during endovascular treatment, but the treatment is safe. Centers using heparin more often had better outcomes. A randomized trial is needed to further study these effects.

Thrombus Migration Paradox in Patients With Acute Ischemic Stroke.

Background and Purpose- The location of the thrombus as observed on first digital subtraction angiography during endovascular treatment may differ from the initial observation on initial noninvasive imaging. We studied the incidence of thrombus dynamics, its impact on patient outcomes, and its association with intravenous thrombolytics. Methods- We included patients from the MR CLEAN registry (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke) with an initial target occlusion on computed tomography angiography located in the intracranial internal carotid artery, M1, or M2. The conventional angiography target occlusion was defined during endovascular treatment. Thrombus dynamics were classified as growth, stability, migration, and resolution. The primary outcome was functional outcome at 90 days (modified Rankin Scale). The secondary outcomes were successful and complete reperfusion (extended treatment in cerebral infarction scores of 2b-3 and 3, respectively). Results- The analysis included 1349 patients. Thrombus migration occurred in 302 (22%) patients, thrombus growth in 87 (6%), and thrombus resolution in 39 (3%). Intravenous treatment with alteplase was associated with more thrombus migration (adjusted odds ratio, 2.01; CI, 1.29-3.11) and thrombus resolution (adjusted odds ratio, 1.85; CI, 1.22-2.80). Thrombus migration was associated with a lower chance of complete reperfusion (adjusted odds ratio, 0.57; CI, 0.42-0.78) and successful reperfusion (adjusted odds ratio, 0.74; CI, 0.55-0.99). In the subgroup of patients with M1 initial target occlusion, thrombus migration was associated with better functional outcome (adjusted common odds ratio, 1.49; CI, 1.02-2.17), and there was a trend towards better functional outcome in patients with thrombus resolution (adjusted common odds ratio, 2.23; CI, 0.93-5.37). Conclusions- In patients with acute ischemic stroke, thrombus location regularly changes between computed tomography angiography and digital subtraction angiography. Administration of intravenous alteplase increases the chance of thrombus migration and resolution. Thrombus migration is associated with better functional outcome but reduces the rate of complete reperfusion.