Impact of time to start of tranexamic acid treatment on rebleed risk and outcome in aneurysmal subarachnoid hemorrhage.

INTRODUCTION: The ULTRA-trial investigated effectiveness of ultra-early administration of tranexamic acid (TXA) in subarachnoid hemorrhage (SAH) and showed that TXA reduces the risk of rebleeding without concurrent improvement in clinical outcome. Previous trials in bleeding conditions, distinct from SAH, have shown that time to start of antifibrinolytic treatment influences outcome. This post-hoc analysis of the ULTRA-trial investigates whether the interval between hemorrhage and start of TXA impacts the effect of TXA on rebleeding and functional outcome following aneurysmal SAH. PATIENTS AND METHODS: A post-hoc comparative analysis was conducted between aneurysmal SAH patients of the ULTRA-trial, receiving TXA and usual care to those receiving usual care only. We assessed confounders, hazard ratio (HR) of rebleeding and odds ratio (OR) of good outcome (modified Rankin Scale 0-3) at 6 months, and investigated the impact of time between hemorrhage and start of TXA on the treatment effect, stratified into time categories (0-3, 3-6 and >6 h). RESULTS: Sixty-four of 394 patients (16.2%) in the TXA group experienced a rebleeding, compared to 83 of 413 patients (19.9%) with usual care only (HR 0.86, 95% confidence interval (CI): 0.62-1.19). Time to start of TXA modifies the effect of TXA on rebleeding rate (p < 0.001), with a clinically non-relevant reduction observed only when TXA was initiated after 6 h (absolute rate reduction 1.4%). Tranexamic acid treatment showed no effect on good outcome (OR 0.96, 95% CI: 0.72-1.27) with no evidence of effect modification on the time to start of TXA (p = 0.53). DISCUSSION AND CONCLUSIONS: This study suggests that the effect of TXA on rebleeding is modified by time to treatment, providing a protective, albeit clinically non-relevant, effect only when started after 6 h. No difference in functional outcome was seen. Routine TXA treatment in the aneurysmal SAH population, even within a specified time frame, is not recommended to improve functional outcome.

Outcome of patients with multivessel occlusion stroke after endovascular treatment.

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

Cost-effectiveness of tenecteplase versus alteplase for acute ischemic stroke.

INTRODUCTION: Alteplase is widely used as an intravenous thrombolytic drug in acute ischemic stroke (AIS). Recently however, tenecteplase, a modified form of tissue plasminogen activator, has been shown to increase early recanalization rate and has proven to be non-inferior with a similar safety profile compared to alteplase. This study aims to evaluate the cost-effectiveness of 0.25 mg/kg tenecteplase versus 0.9 mg/kg alteplase for intravenous thrombolysis in AIS patients from the Dutch healthcare payer perspective. METHODS: A Markov decision-analytic model was constructed to assess total costs, total quality-adjusted life year (QALY), an incremental cost-effectiveness ratio, and incremental net monetary benefit (INMB) of two treatments at willingness-to-pay (WTP) thresholds of €50,000/QALY and €80,000/QALY over a 10-year time horizon. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted to test the robustness of results. Clinical data were obtained from large randomized controlled trials and real-world data. RESULTS: Treatment with tenecteplase saved €21 per patient while gaining 0.05 QALYs, resulting in INMB of €2381, clearly rendering tenecteplase cost-effective compared to alteplase. Importantly, tenecteplase remained the cost-effective alternative in all scenarios, including AIS patients due to large vessel occlusion (LVO). Probabilistic sensitivity analysis proved tenecteplase to be cost-effective with a 71.0% probability at a WTP threshold of €50,000/QALY. CONCLUSIONS: Tenecteplase treatment was cost-effective for all AIS patients (including AIS patients with LVO) compared to alteplase. The finding supports the broader use of tenecteplase in acute stroke care, as health outcomes improve at acceptable costs while having practical advantages, and a similar safety profile.

Admission blood pressure and clinical outcomes in patients with acute ischaemic stroke treated with intravenous alteplase and endovascular treatment versus endovascular treatment alone: A MR CLEAN-NO IV substudy.

INTRODUCTION: High systolic blood pressure (SBP) is associated with poor functional outcome. We analysed whether the association of SBP with outcomes after endovascular treatment (EVT) is modified by prior intravenous thrombolysis (IVT). PATIENTS AND METHODS: This was a post-hoc analysis of MR CLEAN-NO IV, a randomised trial of IVT with alteplase followed by EVT versus EVT alone, within 4.5 h from stroke onset. SBP was recorded on hospital admission. The primary outcome was 90-day modified Rankin Scale (mRS) score and secondary outcomes included symptomatic intracranial haemorrhage (sICH) and successful reperfusion (eTICI 2b-3), analysed with (ordinal) logistic regression. Estimates were calculated per 10 mmHg change in SBP. We assessed whether IVT modified the associations of SBP with these outcomes using multiplicative interaction terms. RESULTS: Of 539 randomised patients, 266 received IVT. The association of SBP with mRS score was J-shaped, with an inflection point at 150 mmHg. Using 150 mmHg as a reference point, SBPs higher than 150 mmHg were associated with poor functional outcome (acOR: 1.23, 95% CI: 1.09-1.38), but lower SBPs were not (acOR: 1.14, 95% CI: 0.99-1.30). Higher SBP was not associated with the risk of sICH (aOR: 1.09, 95% CI: 0.93-1.27) nor with the probability of successful reperfusion (aOR: 1.00, 95% CI: 0.91-1.10). Our main result was that we found no effect modification by IVT (p-values for interaction, mRS = 0.94; sICH = 0.26; successful reperfusion = 0.58). DISCUSSION AND CONCLUSION: There was no effect modification of IVT with SBP for any of the clinical outcomes. Therefore, the level of SBP (if ⩽185/110 mmHg) should not guide IVT decisions in patients otherwise eligible for both IVT and EVT within the 4.5-h time window. TRIAL REGISTRATION: ISRCTN80619088, https://www.isrctn.com/ISRCTN80619088.

Cardiac thrombi detected by CT in patients with acute ischemic stroke: A substudy of Mind the Heart.

Background: Cardiac thrombi are a major risk factor for ischemic stroke, but are rarely diagnosed in the acute phase. We examined characteristics and functional outcome of patients with ischemic stroke and a concomitant cardiac thrombus detected on cardiac CT performed in the acute phase. Patients and Methods: We used data from "Mind the Heart," a prospective cohort study in which consecutive adult patients with acute ischemic stroke underwent prospective ECG-gated cardiac CT during their acute stroke imaging protocol. We compared characteristics, functional outcome (modified Rankin scale) and stroke recurrence rate at 90 days of patients with a cardiac thrombus on CT (defined as filling defect <100 Hounsfield Units) to those without a cardiac thrombus. Results: Among 452 included patients, cardiac CT detected 41 thrombi in 38 (8%) patients. Thrombi were most often located in the left atrial appendage (31/38 [82%]). Patients with a cardiac thrombus more frequently had intracranial occlusions in multiple vascular territories (5% vs 0.5%, p = 0.04) and a higher baseline NIHSS score (17 [IQR 6-22] vs 5 [IQR 2-3], p < 0.001) compared to patients without a cardiac thrombus. In 13/38 (34%) patients with a cardiac thrombus, no atrial fibrillation was detected. A cardiac thrombus was associated with worse functional outcome (adjusted common odds ratio 3.18 95%CI 1.68-6.00). Recurrence rate was not significantly different (8% vs 4%, aOR 1.50 (0.39-5.82). Discussion and Conclusion: Cardiac CT detected a cardiac thrombus in one in every 12 patients with acute ischemic stroke, and these patients had more severe deficits, multivessel occlusions, and a worse functional outcome.

Outcome prediction in large vessel occlusion ischemic stroke with or without endovascular stroke treatment: THRIVE-EVT.

INTRODUCTION: The THRIVE score and the THRIVE-c calculation are validated ischemic stroke outcome prediction tools based on patient variables that are readily available at initial presentation. Randomized controlled trials (RCTs) have demonstrated the benefit of endovascular treatment (EVT) for many patients with large vessel occlusion (LVO), and pooled data from these trials allow for adaptation of the THRIVE-c calculation for use in shared clinical decision making regarding EVT. METHODS: To extend THRIVE-c for use in the context of EVT, we extracted data from the Virtual International Stroke Trials Archive (VISTA) from 7 RCTs of EVT. Models were built in a randomly selected development cohort using logistic regression that included the predictors from THRIVE-c: age, NIH Stroke Scale (NIHSS) score, presence of hypertension, diabetes mellitus, and/or atrial fibrillation, as well as randomization to EVT and, where available, the Alberta Stroke Program Early CT Score (ASPECTS). RESULTS: Good outcome was achieved in 366/787 (46.5%) of subjects randomized to EVT and in 236/795 (29.7%) of subjects randomized to control (P < 0.001), and the improvement in outcome with EVT was seen across age, NIHSS, and THRIVE-c good outcome prediction. Models to predict outcome using THRIVE elements (age, NIHSS, and comorbidities) together with EVT, with or without ASPECTS, had similar performance by ROC analysis in the development and validation cohorts (THRIVE-EVT ROC area under the curve (AUC) = 0.716 in development, 0.727 in validation, P = 0.30; THRIVE-EVT + ASPECTS ROC AUC = 0.718 in development, 0.735 in validation, P = 0.12). CONCLUSION: THRIVE-EVT may be used alongside the original THRIVE-c calculation to improve outcome probability estimation for patients with acute ischemic stroke, including patients with or without LVO, and to model the potential improvement in outcomes with EVT for an individual patient based on variables that are available at initial presentation. Online calculators for THRIVE-c estimation are available at www.thrivescore.org and www.mdcalc.com/thrive-score-for-stroke-outcome.

Cerebrospinal fluid volume improves prediction of malignant edema after endovascular treatment of stroke.

BACKGROUND: The ratio of intracranial cerebrospinal fluid (CSF) volume to intracranial volume (ICV) has been identified as a potential predictor of malignant edema formation in patients with acute ischemic stroke. AIMS: We aimed to evaluate the added value of the CSF/ICV ratio in a model to predict malignant edema formation in patients who underwent endovascular treatment. METHODS: We included patients from the MR CLEAN Registry, a prospective national multicenter registry of patients who were treated with endovascular treatment between 2014 and 2017 because of acute ischemic stroke caused by large vessel occlusion. The CSF/ICV ratio was automatically measured on baseline thin-slice noncontrast CT. The primary outcome was the occurrence of malignant edema based on clinical and imaging features. The basic model included the following predictors: age, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT score, occlusion of the internal carotid artery, collateral score, time between symptom onset and groin puncture, and unsuccessful reperfusion. The extended model included the basic model and the CSF/ICV ratio. The performance of the basic and the extended model was compared with the likelihood ratio test. RESULTS: Malignant edema occurred in 40 (6%) of 683 patients. In the extended model, a lower CSF/ICV ratio was associated with the occurrence of malignant edema (odds ratio (OR) per percentage point, 1.2; 95% confidence interval (CI) 1.1-1.3, p < 0.001). Age lost predictive value for malignant edema in the extended model (OR 1.1; 95% CI 0.9-1.5, p = 0.372). The performance of the extended model was higher than that of the basic model (p < 0.001). CONCLUSIONS: Adding the CSF/ICV ratio improves a multimodal prediction model for the occurrence of malignant edema after endovascular treatment.

Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Rebleeding is an important cause of death and disability in people with aneurysmal subarachnoid haemorrhage. Rebleeding is probably related to the dissolution of the blood clot at the site of the aneurysm rupture by natural fibrinolytic activity. This review is an update of previously published Cochrane Reviews. OBJECTIVES: To assess the effects of antifibrinolytic treatment in people with aneurysmal subarachnoid haemorrhage. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2022), CENTRAL (in the Cochrane Library 2021, Issue 1), MEDLINE (December 2012 to May 2022), and Embase (December 2012 to May 2022). In an effort to identify further published, unpublished, and ongoing studies, we searched reference lists and trial registers, performed forward tracking of relevant references, and contacted drug companies (the latter in previous versions of this review). SELECTION CRITERIA: Randomised trials comparing oral or intravenous antifibrinolytic drugs (tranexamic acid, epsilon amino-caproic acid, or an equivalent) with control in people with subarachnoid haemorrhage of suspected or proven aneurysmal cause. DATA COLLECTION AND ANALYSIS: Two review authors (MRG & WJD) independently selected trials for inclusion, and extracted the data for the current update. In total, three review authors (MIB & MRG in the previous update; MRG & WJD in the current update) assessed risk of bias. For the primary outcome, we dichotomised the outcome scales into good and poor outcome, with poor outcome defined as death, vegetative state, or (moderate) severe disability, assessed with either the Glasgow Outcome Scale or the Modified Rankin Scale. We assessed death from any cause, rates of rebleeding, delayed cerebral ischaemia, and hydrocephalus per treatment group. We expressed effects as risk ratios (RR) with 95% confidence intervals (CI). We used random-effects models for all analyses. We assessed the quality of the evidence with GRADE. MAIN RESULTS: We included one new trial in this update, for a total of 11 included trials involving 2717 participants. The risk of bias was low in six studies. Five studies were open label, and we rated them at high risk of performance bias. We also rated one of these studies at high risk for attrition and reporting bias.  Five trials reported on poor outcome (death, vegetative state, or (moderate) severe disability), with a pooled risk ratio (RR) of 1.03 (95% confidence interval (CI) 0.94 to 1.13; P = 0.53; 5 trials, 2359 participants; high-quality evidence), which showed no difference between groups. All trials reported on death from all causes, which showed no difference between groups, with a pooled RR of 1.02 (95% CI 0.90 to 1.16; P = 0.77; 11 trials, 2717 participants; high-quality evidence). In trials that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for delayed cerebral ischaemia, the RR for poor outcome was 0.98 (95% CI 0.81 to 1.18; P = 0.83; 2 trials, 1318 participants; high-quality evidence).  Antifibrinolytic treatment reduced the risk of rebleeding, reported at the end of follow-up (RR 0.65, 95% CI 0.47 to 0.91; P = 0.01; 11 trials, 2717 participants; absolute risk reduction 7%, 95% CI 3 to 12%; moderate-quality evidence), but there was heterogeneity (I² = 59%) between the trials. The pooled RR for delayed cerebral ischaemia was 1.27 (95% CI 1.00 to 1.62; P = 0.05; 7 trials, 2484 participants; moderate-quality evidence). However, this effect was less extreme after the implementation of ischaemia preventative measures and < 72 hours of treatment (RR 1.10, 95% CI 0.83 to 1.46; P = 0.49; 2 trials, 1318 participants; high-quality evidence). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus (RR 1.09, 95% CI 0.99 to 1.20; P = 0.09; 6 trials, 1992 participants; high-quality evidence). AUTHORS' CONCLUSIONS: The current evidence does not support the routine use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage. More specifically, early administration with concomitant treatment strategies to prevent delayed cerebral ischaemia does not improve clinical outcome. There is sufficient evidence from multiple randomised controlled trials to incorporate this conclusion in treatment guidelines.

Malignant infarction after endovascular treatment: Incidence and prediction.

BACKGROUND: Early prediction of malignant infarction may guide treatment decisions. For patients who received endovascular treatment, the risk of malignant infarction is unknown and risk factors are unrevealed. AIMS: The objective of this study is to estimate the incidence of malignant infarction after endovascular treatment in patients with an occlusion of the anterior circulation, to identify independent risk factors, and to establish a model for prediction. METHODS: We analyzed patients who received endovascular treatment for a large vessel occlusion in the anterior circulation within 6.5 h after symptom onset, included in the Dutch MR CLEAN Registry between March 2014 and June 2016. We compared patients with and without malignant infarction. Candidate predictors were incorporated in a multivariable binary logistic regression model. The final prediction model was established using backward elimination. Discrimination and calibration were evaluated with the area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow test. RESULTS: Of 1445 patients, 82 (6%) developed malignant infarction. Independent predictors were lower age, higher National Institutes of Health Stroke Scale (NIHSS), lower alberta stroke program early CT score (ASPECTS), internal carotid artery occlusion, lower collateral score, longer times from onset to groin puncture, and unsuccessful reperfusion. The AUROC of a prediction model combining these features was 0.83 (95% confidence interval (CI): 0.79-0.88) and the Hosmer-Lemeshow test indicated appropriate calibration (P = 0.937). CONCLUSION: The risk of malignant infarction after endovascular treatment started within 6.5 h of stroke onset is approximately 6%. Successful reperfusion decreases the risk. A prediction model combining easily retrievable measures of age, ASPECTS, collateral status, and reperfusion shows good discrimination between patients who will develop malignant infarction and those who will not.

Brain atrophy and endovascular treatment effect in acute ischemic stroke: a secondary analysis of the MR CLEAN trial.

BACKGROUND: Brain atrophy is suggested to impair the potential for functional recovery after acute ischemic stroke. We assessed whether the effect of endovascular treatment is modified by brain atrophy in patients with acute ischemic stroke due to large vessel occlusion. METHODS: We used data from MR CLEAN, a multicenter trial including patients with acute ischemic stroke due to anterior circulation large vessel occlusion randomized to endovascular treatment plus medical care (intervention) versus medical care alone (control). We segmented total brain volume (TBV) and intracranial volume (ICV) on baseline non-contrast computed tomography (n = 410). Next, we determined the degree of atrophy as the proportion of brain volume in relation to head size (1 - TBV/ICV) × 100%, analyzed as continuous variable and in tertiles. The primary outcome was a shift towards better functional outcome on the modified Rankin Scale expressed as adjusted common odds ratio. Treatment effect modification was tested using an interaction term between brain atrophy (as continuous variable) and treatment allocation. RESULTS: We found that brain atrophy significantly modified the effect of endovascular treatment on functional outcome (P for interaction = 0.04). Endovascular treatment led to larger shifts towards better functional outcome in the higher compared to the lower range of atrophy (adjusted common odds ratio, 1.86 [95% CI: 0.97-3.56] in the lowest tertile vs. 1.97 [95% CI: 1.03-3.74] in the middle tertile vs. 3.15 [95% CI: 1.59-6.24] in the highest tertile). CONCLUSION: Benefit of endovascular treatment is larger in the higher compared to the lower range of atrophy, demonstrating that advanced atrophy should not be used as an argument to withhold endovascular treatment.

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.

The association between computed tomography angiography timing and workflow times in patients with acute ischemic stroke.

BACKGROUND: In most hospitals, computed tomography angiography (CTA) is nowadays routinely performed in patients with acute ischemic stroke. However, it is unclear whether CTA is best performed before or after start of intravenous thrombolysis (IVT), since acquisition of CTA before IVT may prolong door-to-needle times, while acquisition after IVT may prolong door-to-groin times in patients undergoing endovascular treatment. METHODS: We performed a before-versus-after study (CTA following IVT, period I and CTA prior to IVT, period II), consisting of two periods of one year each. This study is based on a prospective registry of consecutive patients treated with IVT in two collaborating high-volume stroke centers; one primary stroke center and one comprehensive stroke center. The primary outcome was door-to-needle times. Secondary outcomes included door-to-groin times. Quantile regression analyses were performed to evaluate the association between timing of CTA and workflow times, adjusted for prognostic factors. RESULTS: A total of 519 patients received IVT during the study period (246 in period I, 273 in period II). In the adjusted analysis, we found a nonsignificant 1.13 min median difference in door-to-needle times (95% confidence interval: 1.03-3.29). Door-to-groin times was significantly shorter in period II in both unadjusted and adjusted analysis with the latter showing a 19.16 min median difference (95% confidence interval: 3.08-35.24). CONCLUSIONS: CTA acquisition prior to start of IVT did not adversely affect door-to-needle times. However, a significantly shorter door-to-groin times was observed in endovascular treatment eligible patients. Performing CTA prior to start of IVT seems the preferred strategy.

Aortic dissection masquerading as a code stroke: A single-centre cohort study.

INTRODUCTION: Data on the incidence of acute aortic dissection in the code stroke population are scarce. We report estimated incidence, clinical manifestations, treatment and outcomes of patients with an acute aortic dissection in a code stroke cohort from a comprehensive stroke centre. PATIENTS AND METHODS: We used data from a single-centre prospective registry of consecutive adult patients who presented to the emergency department between 2015 and 2018 with neurological deficits suggestive of an acute stroke ('code stroke'). All patients routinely underwent non-contrast computed tomography of the brain and computed tomography-angiography of the aortic arch, cervical and intracranial arteries. RESULTS: Of 2874 code stroke patients, 1563 (54.4%) had acute ischaemia (ischaemic stroke or transient ischaemic attack). Fifteen patients (0.5% of code stroke patients and 0.8% of patients with acute ischaemia) had an acute aortic dissection (all Stanford classification type A). Discerning clinical manifestations were decreased consciousness in 11/15 (73%), pain in 8/15 (53%) and low systolic blood pressure (mean 106 mmHg, SD30). Acute aortic dissection was an incidental finding during computed tomography-angiography in 4/15 (27%). Two out of 15 patients (13%) received intravenous thrombolysis, 9/15 (60%) underwent aortic surgery and 10/15 (67%) died. Of those who survived, 3/5 (60%) had a good functional outcome (modified Rankin Scale 0-2). DISCUSSION AND CONCLUSION: In our comprehensive stroke centre, about 1/200 code stroke patients and 1/125 patients with acute ischaemia had an acute aortic dissection. Multicentre studies are necessary to acquire a more reliable estimate of the incidence of acute aortic dissection in the code stroke population. Given the ramifications of missing this diagnosis, imaging of the entire aortic arch is important in these patients.

Mind the Heart: Electrocardiography-gated cardiac computed tomography-angiography in acute ischaemic stroke-rationale and study design.

RATIONALE: About one-third of ischaemic strokes are caused by cardioembolism, and a substantial proportion of cryptogenic strokes likely also originate from the heart or aortic arch. Early determination of aetiology is important to optimise management. Computed Tomography-angiography of the heart is emerging as an alternative to echocardiography to detect cardio-aortic sources of embolism in stroke patients, but its diagnostic yield in acute ischaemic stroke has not been thoroughly assessed.Hypothesis: We hypothesise that electrocardiography-gated computed tomography-angiography of the heart and aortic arch, acquired in the acute phase in patients with ischaemic stroke, has a higher diagnostic yield than transthoracic echocardiography as a first-line screening method for detection of cardio-aortic sources of embolism. METHODS AND DESIGN: Mind the Heart is a single-centre prospective observational cohort study. We will include consecutive adult patients with acute ischaemic stroke who are potentially eligible for reperfusion therapy. Patients undergo non-electrocardiography-gated computed tomography-angiography of the aortic arch, cervical and intracranial arteries, directly followed by prospective sequential electrocardiography-gated cardiac computed tomography-angiography. Routine work-up for cardioembolism including 12-leads electrocardiography, Holter electrocardiography and transthoracic echocardiography is performed as soon as possible. The primary endpoint is the proportion of patients with a predefined high-risk cardio-aortic source of embolism on computed tomography-angiography versus transthoracic echocardiography in patients who underwent both investigations. Based on an expected 5% additional yield of computed tomography-angiography, a sample size of 450 patients is required. CONCLUSIONS: The Mind the Heart study will generate a reliable estimate of the diagnostic yield of echocardiography-gated cardio-aortic computed tomography-angiography performed in the acute phase of ischaemic stroke.

Direct Intra-arterial thrombectomy in order to Revascularize AIS patients with large vessel occlusion Efficiently in Chinese Tertiary hospitals: A Multicenter randomized clinical Trial (DIRECT-MT)-Protocol.

RATIONALE: Intravenous thrombolysis combined with mechanical thrombectomy (MT) has been proven safe and clinical effective in patients with acute ischemic stroke of anterior circulation large vessel occlusion. However, despite reperfusion, a considerable proportion of patients do not recover. Incidence of symptomatic intracerebral hemorrhage was similar between patients treated with the combination of intravenous thrombolysis and MT, as compared to intravenous thrombolysis alone, suggesting that this complication should be attributed to pre-treatment with intravenous thrombolysis. Conversely, intravenous thrombolysis may be beneficial in patients with small clots occluding intracranial arteries with underlying intracranial atherosclerotic disease, not accessible for MT. AIM: To assess whether direct MT is non-inferior compared to combined intravenous thrombolysis plus MT in patients with AIS due to an anterior circulation large vessel occlusion, and to assess treatment effect modification by presence of intracranial atherosclerotic disease. SAMPLE SIZE: Aim to randomize 636 patients 1:1 to receive direct MT (intervention) or combined intravenous thrombolysis plus MT (control). DESIGN: This is a multicenter, prospective, open label parallel group trial with blinded outcome assessment (PROBE design) assessing non-inferiority of direct MT compared to combined intravenous thrombolysis plus MT. OUTCOMES: The primary outcome is the score on the modified Rankin Scale assessed blindly at 90 (±14) days. An common odds ratio, adjusted for the prognostic factors (age, NIHSS, collateral score), representing the shift on the 6-category mRS scale measured at three months, estimated with ordinal logistic regression, will be the primary effect parameter. Non-inferiority is established if the lower boundary of the 95% confidence interval does not cross 0.8. DISCUSSION: DIRECT-MT could result in improved therapeutic efficiency and cost reduction in treatment of anterior circulation large vessel occlusion stroke.

Impact of single phase CT angiography collateral status on functional outcome over time: results from the MR CLEAN Registry.

BACKGROUND: Collateral status modified the effect of endovascular treatment (EVT) for stroke in several randomized trials. We assessed the association between collaterals and functional outcome in EVT treated patients and investigated if this association is time dependent. METHODS: We included consecutive patients from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN) Registry (March 2014-June 2016) with an anterior circulation large vessel occlusion undergoing EVT. Functional outcome was measured on the modified Rankin Scale (mRS) at 90 days. We investigated the association between collaterals and mRS in the MR CLEAN Registry with ordinal logistic regression and if this association was time dependent with an interaction term. Additionally, we determined modification of EVT effect by collaterals compared with MR CLEAN controls, and also investigated if this was time dependent with multiplicative interaction terms. RESULTS: 1412 patients were analyzed. Functional independence (mRS score of 0-2) was achieved in 13% of patients with grade 0 collaterals, in 27% with grade 1, in 46% with grade 2, and in 53% with grade 3. Collaterals were significantly associated with mRS (adjusted common OR 1.5 (95% CI 1.4 to 1.7)) and significantly modified EVT benefit (P=0.04). None of the effects were time dependent. Better collaterals corresponded to lower mortality (P<0.001), but not to lower rates of symptomatic intracranial hemorrhage (P=0.14). CONCLUSION: In routine clinical practice, better collateral status is associated with better functional outcome and greater treatment benefit in EVT treated acute ischemic stroke patients, independent of time to treatment. Within the 6 hour time window, a substantial proportion of patients with absent and poor collaterals can still achieve functional independence.

Clinical prediction of thrombectomy eligibility: A systematic review and 4-item decision tree.

BACKGROUND: A clinical large anterior vessel occlusion (LAVO)-prediction scale could reduce treatment delays by allocating intra-arterial thrombectomy (IAT)-eligible patients directly to a comprehensive stroke center. AIM: To subtract, validate and compare existing LAVO-prediction scales, and develop a straightforward decision support tool to assess IAT-eligibility. METHODS: We performed a systematic literature search to identify LAVO-prediction scales. Performance was compared in a prospective, multicenter validation cohort of the Dutch acute Stroke study (DUST) by calculating area under the receiver operating curves (AUROC). With group lasso regression analysis, we constructed a prediction model, incorporating patient characteristics next to National Institutes of Health Stroke Scale (NIHSS) items. Finally, we developed a decision tree algorithm based on dichotomized NIHSS items. RESULTS: We identified seven LAVO-prediction scales. From DUST, 1316 patients (35.8% LAVO-rate) from 14 centers were available for validation. FAST-ED and RACE had the highest AUROC (both >0.81, p < 0.01 for comparison with other scales). Group lasso analysis revealed a LAVO-prediction model containing seven NIHSS items (AUROC 0.84). With the GACE (Gaze, facial Asymmetry, level of Consciousness, Extinction/inattention) decision tree, LAVO is predicted (AUROC 0.76) for 61% of patients with assessment of only two dichotomized NIHSS items, and for all patients with four items. CONCLUSION: External validation of seven LAVO-prediction scales showed AUROCs between 0.75 and 0.83. Most scales, however, appear too complex for Emergency Medical Services use with prehospital validation generally lacking. GACE is the first LAVO-prediction scale using a simple decision tree as such increasing feasibility, while maintaining high accuracy. Prehospital prospective validation is planned.

Blood pressure-lowering treatment for preventing recurrent stroke, major vascular events, and dementia in patients with a history of stroke or transient ischaemic attack.

BACKGROUND: Stroke is an important cause of death and disability worldwide. Since high blood pressure is an important risk factor for stroke and stroke recurrence, drugs that lower blood pressure might play an important role in secondary stroke prevention. OBJECTIVES: To investigate whether blood pressure-lowering drugs (BPLDs) started at least 48 hours after the index event are effective for the prevention of recurrent stroke, major vascular events, and dementia in people with stroke or transient ischaemic attack (TIA). Secondary objectives were to identify subgroups of people in which BPLDs are effective, and to investigate the optimum systolic blood pressure target after stroke or TIA for preventing recurrent stroke, major vascular events, and dementia. SEARCH METHODS: In August 2017, we searched the Trials Registers of the Cochrane Stroke Group and the Cochrane Hypertension Group, the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), MEDLINE Ovid (1946 to August 2017), Embase Ovid (1974 to August 2017), ClinicalTrials.gov, the ISRCTN Registry, Stroke Trials Registry, Trials Central, and the World Health Organization (WHO) International Clinical Trials Registry Platform Portal. SELECTION CRITERIA: Randomised controlled trials (RCTs) of BPLDs started at least 48 hours after stroke or TIA. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles and abstracts, selected eligible trials, extracted the data, assessed risk of bias, and used GRADE to assess the quality of the evidence. If necessary, we contacted the principal investigators or corresponding authors for additional data. MAIN RESULTS: We included 11 studies involving a total of 38,742 participants: eight studies compared BPLDs versus placebo or no treatment (35,110 participants), and three studies compared different systolic blood pressure targets (3632 participants). The risk of bias varied greatly between included studies. The pooled risk ratios (RRs) of BPLDs were 0.81 (95% confidence interval (CI) 0.70 to 0.93; 8 RCTs; 35,110 participants; moderate-quality evidence), 0.90 (95% CI 0.78 to 1.04; 4 RCTs; 28,630 participants; high-quality evidence) for major vascular event, and 0.88 (95% CI 0.73 to 1.06; 2 RCTs; 6671 participants; high-quality evidence) for dementia. We mainly observed a reduced risk of recurrent stroke in the subgroup of participants using an angiotensin-converting enzyme (ACE) inhibitor or a diuretic (I2 statistic for subgroup differences 72.1%; P = 0.006). The pooled RRs of intensive blood pressure-lowering were 0.80 (95% CI 0.63 to 1.00) for recurrent stroke and 0.58 (95% CI 0.23 to 1.46) for major vascular event. AUTHORS' CONCLUSIONS: Our results support the use of BPLDs in people with stroke or TIA for reducing the risk of recurrent stroke. Current evidence is primarily derived from trials studying an ACE inhibitor or a diuretic. No definite conclusions can be drawn from current evidence regarding an optimal systolic blood pressure target after stroke or TIA.

Quality of life after intra-arterial treatment for acute ischemic stroke in the MR CLEAN trial-Update.

Background Health-related quality of life measured with the EuroQol Group 5-Dimension Self-Report Questionnaire was one of the secondary outcomes in the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN). We reported no statistically significant difference in EuroQol Group 5-Dimension Self-Report Questionnaire score between the intervention and control groups, but deaths were not included. Aims Reanalyze the effect of intra-arterial treatment for large vessel occlusion in acute ischemic stroke patients on health-related quality of life in more detail. We now include patients who died during follow-up. Methods The EuroQol Group 5-Dimension Self-Report Questionnaire questionnaires were obtained 90 days after treatment. We used the Dutch tariff to derive a utility index from the EuroQol Group 5-Dimension Self-Report Questionnaire score. Treatment effect was estimated with the Mann-Whitney U test and linear regression. The effect of treatment on the distribution of EuroQol Group 5-Dimension Self-Report Questionnaire dimension scores was assessed with ordinal logistic regression. Results We obtained EuroQol Group 5-Dimension Self-Report Questionnaire scores from 457 (91.7%) of the 500 patients, including 108 who died before follow-up. Median EuroQol Group 5-Dimension Self-Report Questionnaire score in the intervention group was 0.57, and 0.39 in the control group (p = 0.03). Treatment effect estimated with linear regression was 0.07 (95%CI: -0.001 to 0.143). Treatment specifically affected EuroQol Group 5-Dimension Self-Report Questionnaire dimensions "mobility" (OR: 0.43, 95%CI: 0.29-0.66), "self-care" (OR: 0.60, 95%CI: 0.41-0.89), and "usual activities" (OR: 0.53, 95%CI: 0.36-0.79). Conclusion Treatment had a limited effect on quality of life, as measured with the EuroQol Group 5-Dimension Self-Report Questionnaire. Nevertheless, patients with acute ischemic stroke caused by an intracranial occlusion in the anterior circulation, who had intra-arterial treatment, experience better health-related quality of life than patients without intra-arterial treatment. Trial Registration URL: http://www.isrctn.com/ISRCTN10888758 Unique identifier: ISRCTN10888758.