Symptomatic Intracranial Hemorrhage After Endovascular Stroke Treatment: External Validation of Prediction Models.

BACKGROUND: Symptomatic intracranial hemorrhage (sICH) is a severe complication of reperfusion therapy for ischemic stroke. Multiple models have been developed to predict sICH or intracranial hemorrhage (ICH) after reperfusion therapy. We provide an overview of published models and validate their ability to predict sICH in patients treated with endovascular treatment in daily clinical practice. METHODS: We conducted a systematic search to identify models either developed or validated to predict sICH or ICH after reperfusion therapy (intravenous thrombolysis and/or endovascular treatment) for ischemic stroke. Models were externally validated in the MR CLEAN Registry (n=3180; Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was sICH according to the Heidelberg Bleeding Classification. Model performance was evaluated with discrimination (c-statistic, ideally 1; a c-statistic below 0.7 is considered poor in discrimination) and calibration (slope, ideally 1, and intercept, ideally 0). RESULTS: We included 39 studies describing 40 models. The most frequently used predictors were baseline National Institutes of Health Stroke Scale (NIHSS; n=35), age (n=22), and glucose level (n=22). In the MR CLEAN Registry, sICH occurred in 188/3180 (5.9%) patients. Discrimination ranged from 0.51 (SPAN-100 [Stroke Prognostication Using Age and National Institutes of Health Stroke Scale]) to 0.61 (SITS-SICH [Safe Implementation of Treatments in Stroke Symptomatic Intracerebral Hemorrhage] and STARTING-SICH [STARTING Symptomatic Intracerebral Hemorrhage]). Best calibrated models were IST-3 (intercept, -0.15 [95% CI, -0.01 to -0.31]; slope, 0.80 [95% CI, 0.50-1.09]), SITS-SICH (intercept, 0.15 [95% CI, -0.01 to 0.30]; slope, 0.62 [95% CI, 0.38-0.87]), and STARTING-SICH (intercept, -0.03 [95% CI, -0.19 to 0.12]; slope, 0.56 [95% CI, 0.35-0.76]). CONCLUSIONS: The investigated models to predict sICH or ICH discriminate poorly between patients with a low and high risk of sICH after endovascular treatment in daily clinical practice and are, therefore, not clinically useful for this patient population.

Comparison of Prehospital Assessment by Paramedics and In-Hospital Assessment by Physicians in Suspected Stroke Patients: Results From 2 Prospective Cohort Studies.

BACKGROUND: It is unknown if ambulance paramedics adequately assess neurological deficits used for prehospital stroke scales to detect anterior large-vessel occlusions. We aimed to compare prehospital assessment of these stroke-related deficits by paramedics with in-hospital assessment by physicians. METHODS: We used data from 2 prospective cohort studies: the LPSS (Leiden Prehospital Stroke Study) and PRESTO study (Prehospital Triage of Patients With Suspected Stroke). In both studies, paramedics scored 9 neurological deficits in stroke code patients in the field. Trained physicians scored the National Institutes of Health Stroke Scale (NIHSS) at hospital presentation. Patients with transient ischemic attack were excluded because of the transient nature of symptoms. Spearman rank correlation coefficient (rs) was used to assess correlation between the total prehospital assessment score, defined as the sum of all prehospital items, and the total NIHSS score. Correlation, sensitivity and specificity were calculated for each prehospital item with the corresponding NIHSS item as reference. RESULTS: We included 2850 stroke code patients. Of these, 1528 had ischemic stroke, 243 intracranial hemorrhage, and 1079 stroke mimics. Correlation between the total prehospital assessment score and NIHSS score was strong (rs=0.70 [95% CI, 0.68-0.72]). Concerning individual items, prehospital assessment of arm (rs=0.68) and leg (rs=0.64) motor function correlated strongest with corresponding NIHSS items, and had highest sensitivity (arm 95%, leg 93%) and moderate specificity (arm 71%, leg 70%). Neglect (rs=0.31), abnormal speech (rs=0.50), and gaze deviation (rs=0.51) had weakest correlations. Neglect and gaze deviation had lowest sensitivity (52% and 66%) but high specificity (84% and 89%), while abnormal speech had high sensitivity (85%) but lowest specificity (65%). CONCLUSIONS: The overall prehospital assessment of stroke code patients correlates strongly with in-hospital assessment. Prehospital assessment of neglect, abnormal speech, and gaze deviation differed most from in-hospital assessment. Focused training on these deficits may improve prehospital triage.

Prehospital Stroke Triage: A Modeling Study on the Impact of Triage Tools in Different Regions.

BACKGROUND AND PURPOSE: Direct transportation to a thrombectomy-capable intervention center is beneficial for patients with ischemic stroke due to large vessel occlusion (LVO), but can delay intravenous thrombolytics (IVT). The aim of this modeling study was to estimate the effect of prehospital triage strategies on treatment delays and overtriage in different regions. METHODS: We used data from two prospective cohort studies in the Netherlands: the Leiden Prehospital Stroke Study and the PRESTO study. We included stroke code patients within 6 h from symptom onset. We modeled outcomes of Rapid Arterial oCclusion Evaluation (RACE) scale triage and triage with a personalized decision tool, using drip-and-ship as reference. Main outcomes were overtriage (stroke code patients incorrectly triaged to an intervention center), reduced delay to endovascular thrombectomy (EVT), and delay to IVT. RESULTS: We included 1798 stroke code patients from four ambulance regions. Per region, overtriage ranged from 1-13% (RACE triage) and 3-15% (personalized tool). Reduction of delay to EVT varied by region between 24 ± 5 min (n = 6) to 78 ± 3 (n = 2), while IVT delay increased with 5 (n = 5) to 15 min (n = 21) for non-LVO patients. The personalized tool reduced delay to EVT for more patients (25 ± 4 min [n = 8] to 49 ± 13 [n = 5]), while delaying IVT with 3-14 min (8-24 patients). In region C, most EVT patients were treated faster (reduction of delay to EVT 31 ± 6 min (n = 35), with RACE triage and the personalized tool. CONCLUSIONS: In this modeling study, we showed that prehospital triage reduced time to EVT without disproportionate IVT delay, compared to a drip-and-ship strategy. The effect of triage strategies and the associated overtriage varied between regions. Implementation of prehospital triage should therefore be considered on a regional level.

Biphasic Allergic Reactions at a Dutch Emergency Department: A 5-Year Retrospective Cohort Study.

BACKGROUND: A biphasic allergic reaction develops in 0.4-20% of patients with an allergic reaction, but the incidence of severe biphasic reactions is unknown OBJECTIVE: Our objective was to assess the incidence and time of onset of clinically relevant biphasic reactions in a Dutch emergency department (ED) cohort. Furthermore, the characteristics of patients with a biphasic reaction and the mean observation time after an allergy-related ED visit were assessed. METHODS: This was a single-center retrospective cohort study. We collected data from clinical records of adult patients presenting with an allergic reaction to the ED between January 2015 and December 2019. We defined clinically relevant biphasic reactions as biphasic reactions in which the criteria for anaphylaxis were met. RESULTS: Five hundred fifty-seven patients were included. Eight patients (1.4%) developed a biphasic reaction, of which 1 (0.2% of the total inclusions) was clinically relevant. In the subgroup of patients with an anaphylactic reaction (n = 258), those percentages were 2.3% and 0.4%, respectively. The mean time between the initial allergic reaction and the biphasic allergic reaction was 25.4 h (95% CI 13.2-37.6 h). The single clinically relevant biphasic reaction occurred 30 h after the initial reaction. CONCLUSIONS: The incidence of clinically relevant biphasic reactions in our cohort was low, with a mean time between the initial allergic reaction and the biphasic reaction of > 24 h. Based on these single-center retrospective data, routine inpatient monitoring for several hours does not seem warranted for all patients.

Outcome Prediction Models for Endovascular Treatment of Ischemic Stroke: Systematic Review and External Validation.

BACKGROUND AND PURPOSE: Prediction models for outcome of patients with acute ischemic stroke who will undergo endovascular treatment have been developed to improve patient management. The aim of the current study is to provide an overview of preintervention models for functional outcome after endovascular treatment and to validate these models with data from daily clinical practice. METHODS: We systematically searched within Medline, Embase, Cochrane, Web of Science, to include prediction models. Models identified from the search were validated in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) registry, which includes all patients treated with endovascular treatment within 6.5 hours after stroke onset in the Netherlands between March 2014 and November 2017. Predictive performance was evaluated according to discrimination (area under the curve) and calibration (slope and intercept of the calibration curve). Good functional outcome was defined as a score of 0-2 or 0-3 on the modified Rankin Scale depending on the model. RESULTS: After screening 3468 publications, 19 models were included in this validation. Variables included in the models mainly addressed clinical and imaging characteristics at baseline. In the validation cohort of 3156 patients, discriminative performance ranged from 0.61 (SPAN-100 [Stroke Prognostication Using Age and NIH Stroke Scale]) to 0.80 (MR PREDICTS). Best-calibrated models were THRIVE (The Totaled Health Risks in Vascular Events; intercept -0.06 [95% CI, -0.14 to 0.02]; slope 0.84 [95% CI, 0.75-0.95]), THRIVE-c (intercept 0.08 [95% CI, -0.02 to 0.17]; slope 0.71 [95% CI, 0.65-0.77]), Stroke Checkerboard score (intercept -0.05 [95% CI, -0.13 to 0.03]; slope 0.97 [95% CI, 0.88-1.08]), and MR PREDICTS (intercept 0.43 [95% CI, 0.33-0.52]; slope 0.93 [95% CI, 0.85-1.01]). CONCLUSIONS: The THRIVE-c score and MR PREDICTS both showed a good combination of discrimination and calibration and were, therefore, superior in predicting functional outcome for patients with ischemic stroke after endovascular treatment within 6.5 hours. Since models used different predictors and several models had relatively good predictive performance, the decision on which model to use in practice may also depend on simplicity of the model, data availability, and the comparability of the population and setting.

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.

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.

Prehospital Triage Strategies for the Transportation of Suspected Stroke Patients in the United States.

BACKGROUND AND PURPOSE: Ischemic stroke patients with large vessel occlusion (LVO) could benefit from direct transportation to an intervention center for endovascular treatment, but non-LVO patients need rapid IV thrombolysis in the nearest center. Our aim was to evaluate prehospital triage strategies for suspected stroke patients in the United States. METHODS: We used a decision tree model and geographic information system to estimate outcome of suspected stroke patients transported by ambulance within 4.5 hours after symptom onset. We compared the following strategies: (1) Always to nearest center, (2) American Heart Association algorithm (ie, directly to intervention center if a prehospital stroke scale suggests LVO and total driving time from scene to intervention center is <30 minutes, provided that the delay would not exclude from thrombolysis), (3) modified algorithms with a maximum additional driving time to the intervention center of <30 minutes, <60 minutes, or without time limit, and (4) always to intervention center. Primary outcome was the annual number of good outcomes, defined as modified Rankin Scale score of 0-2. The preferred strategy was the one that resulted in the best outcomes with an incremental number needed to transport to intervention center (NNTI) <100 to prevent one death or severe disability (modified Rankin Scale score of >2). RESULTS: Nationwide implementation of the American Heart Association algorithm increased the number of good outcomes by 594 (+1.0%) compared with transportation to the nearest center. The associated number of non-LVO patients transported to the intervention center was 16 714 (NNTI 28). The modified algorithms yielded an increase of 1013 (+1.8%) to 1369 (+2.4%) good outcomes, with a NNTI varying between 28 and 32. The algorithm without time limit was preferred in the majority of states (n=32 [65%]), followed by the algorithm with <60 minutes delay (n=10 [20%]). Tailoring policies at county-level slightly reduced the total number of transportations to the intervention center (NNTI 31). CONCLUSIONS: Prehospital triage strategies can greatly improve outcomes of the ischemic stroke population in the United States, but increase the number of non-LVO stroke patients transported to an intervention center. The current American Heart Association algorithm is suboptimal as a nationwide policy and should be modified to allow more delay when directly transporting LVO-suspected patients to an intervention center.

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.

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.

Clinical and Imaging Determinants of Collateral Status in Patients With Acute Ischemic Stroke in MR CLEAN Trial and Registry.

Background and Purpose- Collateral circulation status at baseline is associated with functional outcome after ischemic stroke and effect of endovascular treatment. We aimed to identify clinical and imaging determinants that are associated with collateral grade on baseline computed tomography angiography in patients with acute ischemic stroke due to an anterior circulation large vessel occlusion. Methods- Patients included in the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; n=500) and MR CLEAN Registry (n=1488) were studied. Collateral status on baseline computed tomography angiography was scored from 0 (absent) to 3 (good). Multivariable ordinal logistic regression analyses were used to test the association of selected determinants with collateral status. Results- In total, 1988 patients were analyzed. Distribution of the collateral status was as follows: absent (7%, n=123), poor (32%, n=596), moderate (39%, n=735), and good (23%, n=422). Associations for a poor collateral status in a multivariable model existed for age (adjusted common odds ratio, 0.92 per 10 years [95% CI, 0.886-0.98]), male (adjusted common odds ratio, 0.64 [95% CI, 0.53-0.76]), blood glucose level (adjusted common odds ratio, 0.97 [95% CI, 0.95-1.00]), and occlusion of the intracranial segment of the internal carotid artery with occlusion of the terminus (adjusted common odds ratio 0.50 [95% CI, 0.41-0.61]). In contrast to previous studies, we did not find an association between cardiovascular risk factors and collateral status. Conclusions- Older age, male sex, high glucose levels, and intracranial internal carotid artery with occlusion of the terminus occlusions are associated with poor computed tomography angiography collateral grades in patients with acute ischemic stroke eligible for endovascular treatment.

Original research: Second IVIg course in Guillain-Barré syndrome with poor prognosis: the non-randomised ISID study.

OBJECTIVE: To compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses. METHODS: From the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression. RESULTS: Of 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an 'early' second IVIg course (1-2 weeks after start of the first IVIg course) and 18 patients a 'late' second IVIg course (2-4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course. CONCLUSIONS: This observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.

Time to Endovascular Treatment and Outcome in Acute Ischemic Stroke: MR CLEAN Registry Results.

BACKGROUND: Randomized, clinical trials in selected acute ischemic stroke patients reported that for every hour delay of endovascular treatment (EVT), chances of functional independence diminish by up to 3.4%. These findings may not be fully generalizable to clinical practice because of strict in- and exclusion criteria in these trials. Therefore, we aim to assess the association of time to EVT with functional outcome in current, everyday clinical practice. METHODS: The MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands) is an ongoing, prospective, observational study in all centers that perform EVT in The Netherlands. Data were analyzed from patients treated between March 2014 and June 2016. In the primary analysis we assessed the association of time from stroke onset to start of EVT and time from stroke onset to successful reperfusion with functional outcome (measured with the modified Rankin Scale), by means of ordinal logistic regression. RESULTS: We analyzed 1488 patients with acute ischemic stroke who underwent EVT. An increased time to start of EVT was associated with worse functional outcome (adjusted common odds ratio, 0.83 per hour; 95% confidence interval, 0.77-0.89) and a 2.2% increase in mortality. Every hour increase from stroke onset to EVT start resulted in a 5.3% decreased probability of functional independence (modified Rankin Scale, 0-2). In the 742 patients with successful reperfusion, every hour increase from stroke onset to reperfusion was associated with a 7.7% decreased probability of functional independence. CONCLUSIONS: Time to EVT for acute ischemic stroke in current clinical practice is strongly associated with functional outcome. Our data suggest that this association might be even stronger than previously suggested in reports on more selected patient populations from randomized, controlled trials. These findings emphasize that functional outcome of EVT patients can be greatly improved by shortening onset to treatment times.

Effect of Workflow Improvements in Endovascular Stroke Treatment.

Background and Purpose- Rapid initiation of endovascular stroke treatment is associated with better clinical outcome. The effect of specific improvements is not well known. We performed a systematic review and meta-analysis on the effectiveness of specific workflow improvements on time to treatment and outcome. Methods- A random-effects meta-analysis was used to evaluate the difference in mean time to treatment between intervention group and control group. Secondary outcomes included good functional outcome at 90 days (modified Rankin Scale score 0-2). Results- Fifty-one studies (3 randomized controlled trials, 13 prepost intervention studies, and 35 observational studies) with in total 8467 patients were included. Most frequently reported workflow intervention types concerned anesthetic management (n=26), in-hospital patient transfer management (n=14), and prehospital management (n=11). Patients in the intervention group had shorter time to treatment intervals (weighted mean difference, 26 minutes; 95% CI, 19-33; P<0.001) compared with controls. Subgroup meta-analysis of intervention types also showed a shorter time to treatment in the intervention group: a mean difference of 12 minutes (95% CI, 6-17; P<0.001) for anesthetic management, 37 minutes (95% CI, 22-52; P<0.001) for prehospital management, 41 minutes (95% CI, 27-54; P<0.001) for in-hospital patient transfer management, 47 minutes (95% CI, 28-67; P<0.001) for teamwork, and 64 minutes (95% CI, 24-104; P=0.002) for feedback. The mean difference in time to treatment of studies with multiple interventions implemented simultaneously was 50 minutes (95% CI, 31-69; P<0.001) in favor of the intervention group. Patients in the intervention group had increased likelihood of favorable outcome (risk ratio [RR], 1.39; 95% CI, 1.15-1.66; P<0.001). Conclusions- Interventions in the workflow of endovascular stroke treatment lead to a significant reduction in time to treatment and results in an increased likelihood of favorable outcome. Acute stroke care should be reorganized by making use of the examples of workflow interventions described in this review to ensure the best medical care for stroke patients.

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.

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.

Development and Validation of a Model to Predict Regression of Large Size Hepatocellular Adenoma.

INTRODUCTION: Surgery is advocated in hepatocellular adenomas (HCA) >5 cm that do not regress to <5 cm after 6-12 months. The aim of this study was to develop a model for these patients, estimating the probability of HCA regression to <5 cm at 1 and 2 years follow-up. METHODS: Data were derived from a multicenter retrospective cohort of female patients diagnosed with HCA >5 cm at first follow-up. Potential predictors included age, body mass index, and HCA diameter at diagnosis (T0), HCA-subtype (hepatocyte nuclear factor 1α inactivated HCA, inflammatory-HCA, unclassified HCA) and "T0-T1 regression-over-time" (percentage of regression between T0 and first follow-up (T1) divided by weeks between T0 and T1). Cox proportional hazards regression was used to develop a multivariable model with time to regression of HCA < 5 cm as outcome. Probabilities at 1 and 2 years follow-up were calculated. RESULTS: In total, 180 female patients were included. Median HCA diameter at T0 was 82.0 mm and at T1 65.0 mm. Eighty-one patients (45%) reached the clinical endpoint of regression to <5 cm after a median of 34 months. No complications occurred during follow-up. In multivariable analysis, the strongest predictors for regression to <5 cm were HCA diameter at T0 (logtransformed, hazard ratio (HR) 0.05), T0-T1 regression-over-time (HR 2.15) and HCA subtype inflammatory-HCA (HR 2.93) and unclassified HCA (HR 2.40), compared to hepatocyte nuclear factor 1α inactivated HCA (reference). The model yielded an internally validated c-index of 0.79. DISCUSSION: In patients diagnosed with HCA > 5 cm that still exceed 5 cm at first follow-up, regression to <5 cm can be predicted at 1 and 2 years follow-up using this model. Although external validation in an independent population is required, this model may aid in decision-making and potentially avoid unnecessary surgery.

Value-based healthcare in ischemic stroke care: case-mix adjustment models for clinical and patient-reported outcomes.

BACKGROUND: Patient-Reported Outcome Measures (PROMs) have been proposed for benchmarking health care quality across hospitals, which requires extensive case-mix adjustment. The current study's aim was to develop and compare case-mix models for mortality, a functional outcome, and a patient-reported outcome measure (PROM) in ischemic stroke care. METHODS: Data from ischemic stroke patients, admitted to four stroke centers in the Netherlands between 2014 and 2016 with available outcome information (N = 1022), was analyzed. Case-mix adjustment models were developed for mortality, modified Rankin Scale (mRS) scores and EQ-5D index scores with respectively binary logistic, proportional odds and linear regression models with stepwise backward selection. Predictive ability of these models was determined with R-squared (R2) and area-under-the-receiver-operating-characteristic-curve (AUC) statistics. RESULTS: Age, NIHSS score on admission, and heart failure were the only common predictors across all three case-mix adjustment models. Specific predictors for the EQ-5D index score were sex (ß = 0.041), socio-economic status (ß = - 0.019) and nationality (ß = - 0.074). R2-values for the regression models for mortality (5 predictors), mRS score (9 predictors) and EQ-5D utility score (12 predictors), were respectively R2 = 0.44, R2 = 0.42 and R2 = 0.37. CONCLUSIONS: The set of case-mix adjustment variables for the EQ-5D at three months differed considerably from the set for clinical outcomes in stroke care. The case-mix adjustment variables that were specific to this PROM were sex, socio-economic status and nationality. These variables should be considered in future attempts to risk-adjust for PROMs during benchmarking of hospitals.

The volume-outcome relationship for hip fractures: a systematic review and meta-analysis of 2,023,469 patients.

Background and purpose - It has been hypothesized that hospitals and surgeons with high caseloads of hip fracture patients have better outcomes, but empirical studies have reported contradictory results. This systematic review and meta-analysis evaluates the volume-outcome relationship among patients with hip fracture patients. Methods - A search of different databases was performed up to February 2018. Selection of relevant studies, data extraction, and critical appraisal of the methodological quality was performed by 2 independent reviewers. A random-effects meta-analysis using studies with comparative cut-offs was performed to estimate the effect of hospital and surgeon volume on outcome, defined as in-hospital mortality and postoperative complications. Results - 24 studies comprising 2,023,469 patients were included. Overall, the quality was reasonable. 11 studies reported better health outcomes in high-volume centers and 2 studies reported better health outcomes in low-volume centers. In the meta-analysis of 11 studies there was a statistically non-significant association between higher hospital volume and both lower in-hospital mortality (adjusted odds ratio (aOR) 0.87, 95% confidence interval (CI) 0.73-1.04) and fewer postoperative complications (aOR 0.87, CI 0.75-1.02). Four studies on surgeon volume were included in the meta-analysis and showed a minor association between higher surgeon volume and in-hospital mortality (aOR 0.92, CI 0.76-1.12). Interpretation - This systematic review and meta-analysis did not find an evident effect of hospital or surgeon volume on health outcomes. Future research without volume cut-offs is needed to examine whether a true volume-outcome relationship exists.

Utility-Weighted Modified Rankin Scale as Primary Outcome in Stroke Trials: A Simulation Study.

BACKGROUND AND PURPOSE: The utility-weighted modified Rankin Scale (UW-mRS) has been proposed as a new patient-centered primary outcome in stroke trials. We aimed to describe utility weights for the mRS health states and to evaluate the statistical efficiency of the UW-mRS to detect treatment effects in stroke intervention trials. METHODS: We used data of the 500 patients enrolled in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Utility values were elicited from the EuroQol Group 5-Dimension Self-Report Questionnaire assessed at 90 days after inclusion, simultaneously with the mRS. Utility weights were determined by averaging the utilities of all patients within each mRS category. We performed simulations to evaluate statistical efficiency. The simulated treatment effect was an odds ratio of 1.65 in favor of the treatment arm, similar for all mRS cutoffs. This treatment effect was analyzed using 3 approaches: linear regression with the UW-mRS as outcome, binary logistic regression with a dichotomized mRS (0-1/2-6, 0-2/3-6, and 0-4/5-6), and proportional odds logistic regression with the ordinal mRS. The statistical power of the 3 approaches was expressed as the proportion of 10 000 simulations that resulted in a statistically significant treatment effect (P≤0.05). RESULTS: The mean utility values (SD) for mRS categories 0 to 6 were: 0.95 (0.08), 0.93 (0.13), 0.83 (0.21), 0.62 (0.27), 0.42 (0.28), 0.11 (0.28), and 0 (0), respectively, but varied substantially between individual patients within each category. The UW-mRS approach was more efficient than the dichotomous approach (power 85% versus 71%) but less efficient than the ordinal approach (power 85% versus 87%). CONCLUSIONS: The UW-mRS as primary outcome does not capture individual variation in utility values and may reduce the statistical power of a randomized trial.