Development and Validation of a Postprocedural Model to Predict Outcome After Endovascular Treatment for Ischemic Stroke.

Importance: Outcome prediction after endovascular treatment (EVT) for ischemic stroke is important to patients, family members, and physicians. Objective: To develop and validate a model based on preprocedural and postprocedural characteristics to predict functional outcome for individual patients after EVT. Design, Setting, and Participants: A prediction model was developed using individual patient data from 7 randomized clinical trials, performed between December 2010 and December 2014. The model was developed within the Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration and external validation in data from the Dutch Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry of patients treated in clinical practice between March 2014 and November 2017. Participants included patients from multiple centers throughout different countries in Europe, North America, East Asia, and Oceania (derivation cohort), and multiple centers in the Netherlands (validation cohort). Included were adult patients with a history of ischemic stroke from an intracranial large vessel occlusion in the anterior circulation who underwent EVT within 12 hours of symptom onset or last seen well. Data were last analyzed in July 2022. Main Outcome(s) and Measure(s): A total of 19 variables were assessed by multivariable ordinal regression to predict functional outcome (modified Rankin Scale [mRS] score) 90 days after EVT. Variables were routinely available 1 day after EVT. Akaike information criterion (AIC) was used to optimize model fit vs model complexity. Probabilities for functional independence (mRS 0-2) and survival (mRS 0-5) were derived from the ordinal model. Model performance was expressed with discrimination (C statistic) and calibration. Results: A total of 781 patients (median [IQR] age, 67 [57-76] years; 414 men [53%]) constituted the derivation cohort, and 3260 patients (median [IQR] age, 72 [61-80] years; 1684 men [52%]) composed the validation cohort. Nine variables were included in the model: age, baseline National Institutes of Health Stroke Scale (NIHSS) score, prestroke mRS score, history of diabetes, occlusion location, collateral score, reperfusion grade, NIHSS score at 24 hours, and symptomatic intracranial hemorrhage 24 hours after EVT. External validation in the MR CLEAN Registry showed excellent discriminative ability for functional independence (C statistic, 0.91; 95% CI, 0.90-0.92) and survival (0.89; 95% CI, 0.88-0.90). The proportion of functional independence in the MR CLEAN Registry was systematically higher than predicted by the model (41% vs 34%), whereas observed and predicted survival were similar (72% vs 75%). The model was updated and implemented for clinical use. Conclusion and relevance: The prognostic tool MR PREDICTS@24H can be applied 1 day after EVT to accurately predict functional outcome for individual patients at 90 days and to provide reliable outcome expectations and personalize follow-up and rehabilitation plans. It will need further validation and updating for contemporary patients.

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

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

Timing of symptomatic intracranial hemorrhage after endovascular stroke treatment.

Introduction: Little is known about the timing of occurrence of symptomatic intracranial hemorrhage (sICH) after endovascular therapy (EVT) for acute ischemic stroke. A better understanding could optimize in-hospital surveillance time points and duration. The aim of this study was to delineate the probability of sICH over time and to identify factors associated with its timing. Patients and methods: We retrospectively analyzed data from the Dutch MR CLEAN trial and MR CLEAN Registry. We included adult patients who underwent EVT for an anterior circulation large vessel occlusion within 6.5 h of stroke onset. In patients with sICH (defined as ICH causing an increase of ⩾4 points on the National Institutes of Health Stroke Scale [NIHSS]), univariable and multivariable linear regression analysis was used to identify factors associated with the timing of sICH. This was defined as the time between end of EVT and the time of first CT-scan on which ICH was seen as a proxy. Results: SICH occurred in 205 (6%) of 3391 included patients. Median time from end of EVT procedure to sICH detection on NCCT was 9.0 [IQR 2.9-22.5] hours, with a rapidly decreasing incidence after 24 h. None of the analyzed factors, including baseline NIHSS, intravenous alteplase treatment, and poor reperfusion at the end of the procedure were associated with the timing of sICH. Conclusion: SICHs primarily occur in the first hours after EVT, and less frequently beyond 24 h. Guidelines that recommend to perform frequent neurological assessments for at least 24 h after intravenous alteplase treatment can be applied to ischemic stroke patients treated with EVT.

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

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

Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. METHODS: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. FINDINGS: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13-3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14-3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69-1·21]) and unfractionated heparin (0·81 [0·61-1·08]) led to a non-significant shift towards worse modified Rankin Scale scores. INTERPRETATION: Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. FUNDING: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Predictors of poor outcome despite successful endovascular treatment for ischemic stroke: results from the MR CLEAN Registry.

BACKGROUND: Approximately one-third of patients with ischemic stroke treated with endovascular treatment do not recover to functional independence despite rapid and successful recanalization. We aimed to quantify the importance of predictors of poor functional outcome despite successful reperfusion. METHODS: We analyzed patients from the MR CLEAN Registry between March 2014 and November 2017 with successful reperfusion (extended Thrombolysis In Cerebral Infarction ≥2B). First, predictors were selected based on expert opinion and were clustered according to acquisition over time (ie, baseline patient factors, imaging factors, treatment factors, and postprocedural factors). Second, several models were constructed to predict 90-day functional outcome (modified Rankin Scale (mRS)). The relative importance of individual predictors in the most extensive model was expressed by the proportion of unique added χ2 to the model of that individual predictor. RESULTS: Of 3180 patients, 1913 (60%) had successful reperfusion. Of these 1913 patients, 1046 (55%) were functionally dependent at 90 days (mRS >2). The most important predictors for mRS were baseline patient factors (ie, pre-stroke mRS, added χ2 0.16; National Institutes of Health Stroke Scale score at baseline, added χ2 0.12; age, added χ2 0.10), and postprocedural factors (ie, symptomatic intracranial hemorrhage (sICH), added χ2 0.12; pneumonia, added χ2 0.09). The probability of functional independence for a typical stroke patient with sICH was 54% (95% CI 36% to 72%) lower compared with no sICH, and 21% (95% CI 4% to 38%) for pneumonia compared with no pneumonia. CONCLUSION: Baseline patient factors and postprocedural adverse events are important predictors of poor functional outcome in successfully reperfused patients with ischemic stroke. This implies that prevention of postprocedural adverse events has the greatest potential to further improve outcomes in these patients.

Patient and proxies' attitudes towards deferred consent in randomised trials of acute treatment for stroke: A qualitative survey.

Introduction: Deferral of consent for participation in a clinical study is a relatively novel procedure, in which informed consent is obtained after randomisation and study treatment. Deferred consent can be used in emergency situations, where small therapeutic time windows limit possibilities for patients to provide informed consent. We aimed to investigate patients' or their proxies' experiences and opinions regarding deferred consent in acute stroke randomised trials. Patients and methods: For this qualitative study, Dutch Collaboration for New Treatments of Acute Stroke (CONTRAST) trial participants were selected. Study participants were either patients or their proxies who provided consent and were selected with theoretical sampling based on patient characteristics. Semi-structured interviews were conducted face-to-face or by telephone. Themes and subthemes were iteratively defined. Results: Twenty of the 23 interviewed participants (16 patients and 7 proxies) considered deferred consent acceptable. The received study treatment and consent conversation were remembered by 18 participations, although the concept of randomisation and treatment comparison were generally not well understood. Sixteen participants felt capable of overseeing the decision to give deferred consent. Distress in the first days after stroke, lack of understanding and neurological deficits were reasons for feeling incapable of providing consent. Four participants would have preferred a different timing of the consent conversation, of whom two prior to treatment. Conclusion: Our study found that deferred consent was considered acceptable by most study participants who provided consent for acute stroke randomised trials. Though they felt capable, the recall and comprehension of consent were overall limited.

Prior antiplatelet therapy in patients undergoing endovascular treatment for acute ischemic stroke: Results from the MR CLEAN Registry.

BACKGROUND: Antiplatelet therapy may increase the risk of symptomatic intracranial hemorrhage after endovascular treatment for ischemic stroke but may also have a beneficial effect on functional outcome. The aim of this study is to compare safety and efficacy outcomes after endovascular treatment in patients with and without prior antiplatelet therapy. METHODS: We analyzed patients registered in the MR CLEAN Registry between March 2014 and November 2017, for whom data on antiplatelet therapy were available. We used propensity score nearest-neighbor matching with replacement to balance the probability of receiving prior antiplatelet therapy between the prior antiplatelet therapy and no prior antiplatelet therapy group and adjusted for baseline prognostic factors to compare these groups. Primary outcome was symptomatic intracranial hemorrhage. Secondary outcomes were 90-day functional outcome (modified Rankin Scale), successful reperfusion (extended thrombolysis in cerebral infarction score ≥2B) and 90-day mortality. RESULTS: Thirty percent (n = 937) of the 3154 patients were on prior antiplatelet therapy, who were matched to 477 patients not on prior antiplatelet therapy. Symptomatic intracranial hemorrhage occurred in 74/937 (7.9%) patients on prior antiplatelet therapy and in 27/477 (5.6%) patients without prior antiplatelet therapy adjusted odds ratio 1.47, 95% confidence interval 0.86-2.49. No associations were found between prior antiplatelet therapy and functional outcome (adjusted common odds ratio 0.87, 95% confidence interval 0.65-1.16), successful reperfusion (adjusted odds ratio 1.23, 95% confidence interval 0.77-1.97), or 90-day mortality (adjusted odds ratio 1.15, 95% confidence interval 0.86-1.54). CONCLUSION: We found no evidence of an association of prior antiplatelet therapy with the risk of symptomatic intracranial hemorrhage after endovascular treatment, nor on functional outcome, reperfusion, or mortality. A substantial beneficial or detrimental effect of antiplatelet therapy on clinical outcome cannot be excluded. A randomized clinical trial comparing antiplatelet therapy versus no antiplatelet therapy is needed.

Predicting Poor Outcome Before Endovascular Treatment in Patients With Acute Ischemic Stroke.

Background: Although endovascular treatment (EVT) has greatly improved outcomes in acute ischemic stroke, still one third of patients die or remain severely disabled after stroke. If we could select patients with poor clinical outcome despite EVT, we could prevent futile treatment, avoid treatment complications, and further improve stroke care. We aimed to determine the accuracy of poor functional outcome prediction, defined as 90-day modified Rankin Scale (mRS) score ≥5, despite EVT treatment. Methods: We included 1,526 patients from the MR CLEAN Registry, a prospective, observational, multicenter registry of ischemic stroke patients treated with EVT. We developed machine learning prediction models using all variables available at baseline before treatment. We optimized the models for both maximizing the area under the curve (AUC), reducing the number of false positives. Results: From 1,526 patients included, 480 (31%) of patients showed poor outcome. The highest AUC was 0.81 for random forest. The highest area under the precision recall curve was 0.69 for the support vector machine. The highest achieved specificity was 95% with a sensitivity of 34% for neural networks, indicating that all models contained false positives in their predictions. From 921 mRS 0-4 patients, 27-61 (3-6%) were incorrectly classified as poor outcome. From 480 poor outcome patients in the registry, 99-163 (21-34%) were correctly identified by the models. Conclusions: All prediction models showed a high AUC. The best-performing models correctly identified 34% of the poor outcome patients at a cost of misclassifying 4% of non-poor outcome patients. Further studies are necessary to determine whether these accuracies are reproducible before implementation in clinical practice.

Informed consent procedures for emergency interventional research in patients with traumatic brain injury and ischaemic stroke.

Health-care professionals and researchers have a legal and ethical responsibility to inform patients before carrying out diagnostic tests or treatment interventions as part of a clinical study. Interventional research in emergency situations can involve patients with some degree of acute cognitive impairment, as is regularly the case in traumatic brain injury and ischaemic stroke. These patients or their proxies are often unable to provide informed consent within narrow therapeutic time windows. International regulations and national laws are criticised for being inconclusive or restrictive in providing solutions. Currently accepted consent alternatives are deferred consent, exception from consent, or waiver of consent. However, these alternatives appear under-utilised despite being ethically permissible, socially acceptable, and regulatorily compliant. We anticipate that, when the requirements for medical urgency are properly balanced with legal and ethical conduct, the increased use of these alternatives has the potential to improve the efficiency and quality of future emergency interventional studies in patients with an inability to provide informed consent.

Multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke. The effect of periprocedural medication: acetylsalicylic acid, unfractionated heparin, both, or neither (MR CLEAN-MED). Rationale and study design.

BACKGROUND: Despite evidence of a quite large beneficial effect of endovascular treatment (EVT) for ischemic stroke caused by anterior circulation large vessel occlusion, many patients do not recover even after complete recanalization. To some extent, this may be attributable to incomplete microvascular reperfusion, which can possibly be improved by antiplatelet agents and heparin. It is unknown whether periprocedural antithrombotic medication in patients treated with EVT improves functional outcome. The aim of this study is to assess the effect of acetylsalicylic acid (ASA) and unfractionated heparin (UFH), alone, or in combination, given to patients with an ischemic stroke caused by an intracranial large vessel occlusion in the anterior circulation during EVT. METHODS: MR CLEAN-MED is a multicenter phase III trial with a prospective, 2 × 3 factorial randomized, open label, blinded end-point (PROBE) design, which aims to enroll 1500 patients. The trial is designed to evaluate the effect of intravenous ASA (300 mg), UFH (low or moderate dose), both or neither as adjunctive therapy to EVT. We enroll adult patients with a clinical diagnosis of stroke (NIHSS ≥ 2) and with a confirmed intracranial large vessel occlusion in the anterior circulation on CTA or MRA, when EVT within 6 h from symptom onset is indicated and possible. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days. Treatment effect on the mRS will be estimated with ordinal logistic regression analysis, with adjustment for main prognostic variables. Secondary outcomes include stroke severity measured with the NIHSS at 24 h and at 5-7 days, follow-up infarct volume, symptomatic intracranial hemorrhage (sICH), and mortality. DISCUSSION: Clinical equipoise exists whether antithrombotic medication should be administered during EVT for a large vessel occlusion, as ASA and/or UFH may improve functional outcome, but might also lead to an increased risk of sICH. When one or both of the study treatments show the anticipated effect on outcome, we will be able to improve outcome of patients treated with EVT by 5%. This amounts to more than 50 patients annually in the Netherlands, more than 1800 in Europe, and more than 1300 in the USA. TRIAL REGISTRATION: ISRCT, ISRCTN76741621 . Dec 6, 2017.

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

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

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.

Neurological Deficits in Stroke Patients that May Impede the Capacity to Provide Informed Consent for Endovascular Treatment Trials.

BACKGROUND: We assessed the occurrence of neurological deficits that may impede the capacity to provide consent for trial participation in patients with an acute stroke, who are eligible for endovascular treatment (EVT). METHODS: We used data from the Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry, a prospective observational cohort study. We included 1526 patients with an anterior large vessel occlusion, undergoing EVT between March 2014 and June 2016. We based our assessment of decision-making capacity for trial participation on neurological symptoms influencing conditions concerning informed consent as stated in the declaration of Helsinki. We formulated a strict and a mild capacity assessment rule, using 2 different cut points in item scores on the National Institutes of Health Stroke Scale (NIHSS). RESULTS: Applying the strict and mild rule, respectively 1469 (96%) and 1220 (80%) patients deemed not capable of decision-making for trial participation on admission, and 1077 (79%) and 825 (60%) patients at 24-48 hours after admission. Highest frequencies of predefined scores suggesting incapacity based on the strict rule were on the NIHSS items "Level of Consciousness Questions" (59%), "Best Gaze" (68%), and "Best Language" (58%). Patients who were considered incapable were older (median 71 versus 66 years, P = .043), had higher NIHSS scores (median 16 versus 8, P < .001), and had more often left hemisphere strokes (55% versus 28%, P < .001) than patients who were presumably capable. CONCLUSIONS: In the majority of patients with an anterior circulation stroke who are eligible for EVT, neurological deficits are present that may impede the capacity to provide informed consent for trial participation.

Does Sex Modify the Effect of Endovascular Treatment for Ischemic Stroke?

Background and Purpose- Previous studies have reported less favorable outcome and less effect of endovascular treatment (EVT) after ischemic stroke in women than in men. Our aim was to study the influence of sex on outcome and on the effect of EVT for ischemic stroke in recent randomized trials on EVT. Methods- We used data from 7 randomized controlled trials on EVT within the HERMES collaboration. The primary outcome was 90-day functional outcome (modified Rankin Scale). We compared baseline characteristics and outcomes between men and women. With ordinal logistic regression, we evaluated the association between EVT and 90-day functional outcome for men and women separately, adjusted for potential confounders. We tested for interaction between sex and EVT. Results- We included 1762 patients in the analyses, of whom 833 (47%) were women. Women were older (median, 70 versus 66 years; P<0.001), were smoking less often (30% versus 44%; P<0.001), and had higher collateral grades (grade 3: 46% versus 35%; P<0.001) than men. Functional independence (modified Rankin Scale score, 0-2) at 90 days was reached by 318 women (39%) and 364 men (39%). The effect of EVT on the ordinal modified Rankin Scale was similar in women (adjusted common odds ratio [acOR], 2.13; 95% CI, 1.47-3.07) and men (acOR, 2.16; 95% CI, 1.59-2.96), with a P for interaction of 0.926. Conclusions- Sex does not influence clinical outcome after EVT and does not modify treatment effect of EVT. Therefore, sex should not be a consideration in the selection of patients for EVT.

Endovascular Treatment With or Without Prior Intravenous Alteplase for Acute Ischemic Stroke.

Background It is unclear whether intravenous thrombolysis ( IVT ) with alteplase before endovascular treatment ( EVT ) is beneficial for patients with acute ischemic stroke caused by a large vessel occlusion. We compared clinical and procedural outcomes, safety, and workflow between patients treated with both IVT and EVT and those treated with EVT alone in routine clinical practice. Methods and Results Using multivariable regression, we evaluated the association of IVT + EVT with 90-day functional outcome (modified Rankin Scale), mortality, reperfusion, first-pass effect, and symptomatic intracranial hemorrhage in the MR CLEAN (Multicenter Randomised Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands) Registry. Of 1485 patients, 1161 (78%) were treated with IVT + EVT , and 324 (22%) with EVT alone. Patients treated with IVT + EVT had atrial fibrillation less often (16% versus 44%) and had better pre-stroke modified Rankin Scale scores (pre-stroke modified Rankin Scale 0: 73% versus 52%) than those treated with EVT alone. Procedure time was shorter in the IVT + EVT group (median 62 versus 68 minutes). Nontransferred IVT + EVT patients had longer door-to-groin-puncture times (median 105 versus 94 minutes). IVT + EVT was associated with better functional outcome (adjusted common odds ratio 1.47; 95% CI : 1.10-1.96) and lower mortality (adjusted odds ratio 0.58; 95% CI : 0.40-0.82). Successful reperfusion, first-pass effect, and symptomatic intracranial hemorrhage did not differ between groups. Conclusions In this observational study, patients treated with IVT + EVT had better clinical outcomes than patients who received EVT alone. This finding may demonstrate a true benefit of IVT before EVT , but its interpretation is hampered by the possibility of residual confounding and selection bias. Randomized trials are required to properly assess the effect of IVT before EVT .

Effect of Interhospital Transfer on Endovascular Treatment for Acute Ischemic Stroke.

Background and Purpose- To assess the effect of inter-hospital transfer on time to treatment and functional outcome after endovascular treatment (EVT) for acute ischemic stroke, we compared patients transferred from a primary stroke center to patients directly admitted to an intervention center in a large nationwide registry. Methods- MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry is an ongoing, prospective, observational study in all centers that perform EVT in the Netherlands. We included adult patients with an acute anterior circulation stroke who received EVT between March 2014 to June 2016. Primary outcome was time from arrival at the first hospital to arterial groin puncture. Secondary outcomes included the 90-day modified Rankin Scale score and functional independence (modified Rankin Scale score of 0-2). Results- In total 821/1526 patients, (54%) were transferred from a primary stroke center. Transferred patients less often had prestroke disability (227/800 [28%] versus 255/699 [36%]; P=0.02) and more often received intravenous thrombolytics (659/819 [81%] versus 511/704 [73%]; P<0.01). Time from first presentation to groin puncture was longer for transferred patients (164 versus 104 minutes; P<0.01, adjusted delay 57 minutes [95% CI, 51-62]). Transferred patients had worse functional outcome (adjusted common OR, 0.75 [95% CI, 0.62-0.90]) and less often achieved functional independence (244/720 [34%] versus 289/681 [42%], absolute risk difference -8.5% [95% CI, -8.7 to -8.3]). Conclusions- Interhospital transfer of patients with acute ischemic stroke is associated with delay of EVT and worse outcomes in routine clinical practice, even in a country where between-center distances are short. Direct transportation of patients potentially eligible for EVT to an intervention center may improve functional outcome.

Personalized Prehospital Triage in Acute Ischemic Stroke.

Background and Purpose- Direct transportation to a center with facilities for endovascular treatment might be beneficial for patients with acute ischemic stroke, but it can also cause harm by delay of intravenous treatment. Our aim was to determine the optimal prehospital transportation strategy for individual patients and to assess which factors influence this decision. Methods- We constructed a decision tree model to compare outcome of ischemic stroke patients after transportation to a primary stroke center versus a more distant intervention center. The optimal strategy was estimated based on individual patient characteristics, geographic location, and workflow times. In the base case scenario, the primary stroke center was located at 20 minutes and the intervention center at 45 minutes. Additional sensitivity analyses included an urban scenario (10 versus 20 minutes) and a rural scenario (30 versus 90 minutes). Results- Direct transportation to the intervention center led to better outcomes in the base case scenario when the likelihood of a large vessel occlusion as a cause of the ischemic stroke was >33%. With a high likelihood of large vessel occlusion (66%, comparable with a Rapid Arterial Occlusion Evaluation score of 5 or above), the benefit of direct transportation to the intervention center was 0.10 quality-adjusted life years (=36 days in full health). In the urban scenario, direct transportation to an intervention center was beneficial when the risk of large vessel occlusion was 24% or higher. In the rural scenario, this threshold was 49%. Other factors influencing the decision included door-to-needle times, door-to-groin times, and the door-in-door-out time. Conclusions- The preferred prehospital transportation strategy for suspected stroke patients depends mainly on the likelihood of large vessel occlusion, driving times, and in-hospital workflow times. We constructed a robust model that combines these characteristics and can be used to personalize prehospital triage, especially in more remote areas.