Introduction Endovascular treatment (EVT) has been proven to be both effective and cost-effective for patients with acute ischaemic stroke. We investigated the budget impact of large-scale implementation of EVT for acute ischaemic stroke patients in the Netherlands for 2015–2021. Methods An analysis was performed from a healthcare perspective as a preplanned substudy of the Multicenter Randomized Clinical trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). Estimated yearly costs during follow-up after stroke for patients who had or had not been treated with EVT as add-on to usual care were linked to numbers of new patients retrieved from 2 Dutch registries of EVT that started after the last inclusion in MR CLEAN (2014). Aggregated costs and costs per care sector were calculated based on prevalence using a population dynamic tool. Results From 2015, the yearly number of new acute ischaemic stroke patients receiving EVT increased almost threefold, from 812 in 2015 to 2,370 in 2021. The introduction of EVT plus usual care resulted in estimated net annual savings that increased from € 2.9 million in 2015 to € 58 million in 2021. Conclusion Offering EVT as add-on to usual care for acute ischaemic stroke patients was increasingly cost saving from a national healthcare perspective but affected distinct healthcare sectors differently.

Background The relationship between the interventionist’s experience and outcomes of endovascular thrombectomy (EVT) for acute ischemic stroke of the anterior circulation, is unclear. Objective To assess the effect of the interventionist’s level of experience on clinical, imaging, and workflow outcomes. Secondly, to determine which of the three experience definitions is most strongly associated with these outcome measures. Methods We analysed data from 2700 patients, included in the MR CLEAN Registry. We defined interventionist’s experience as the number of procedures performed in the year preceding the intervention (EXPfreq), total number of procedures performed (EXPno), and years of experience (EXPyears). Our outcomes were the baseline-adjusted National Institutes of Health Stroke Scale (NIHSS) score at 24–48 hours post-EVT, recanalization (extended Thrombolysis in Cerebral Infarction (eTICI) score ≥2B), and procedural duration. We used multilevel regression models with interventionists as random intercept. For EXPfreq and EXPno results were expressed per 10 procedures. Results Increased EXPfreq was associated with lower 24–48 hour NIHSS scores (adjusted (a)β:−0.46, 95% CI −0.70 to −0.21). EXPno and EXPyears were not associated with short-term neurological outcomes. Increased EXPfreq and EXPno were both associated with recanalization (aOR=1.20, 95% CI 1.11 to 1.31 and aOR=1.08, 95% CI 1.04 to 1.12, respectively), and increased EXPfreq, EXPno, and EXPyears were all associated with shorter procedure times (aβ:−3.08, 95% CI−4.32 to −1.84; aβ:−1.34, 95% CI−1.84 to −0.85; and aβ:−0.79, 95% CI−1.45 to −0.13, respectively). Conclusions Higher levels of interventionist’s experience are associated with better outcomes after EVT, in particular when experience is defined as the number of patients treated in the preceding year. Every 20 procedures more per year is associated with approximately one NIHSS score point decrease, an increased probability for recanalization (aOR=1.44), and a 6-minute shorter procedure time.

Background and Purpose: Endovascular treatment for acute ischemic stroke has been proven clinically effective, but evidence of the cost-effectiveness based on real-world data is scarce. The aim of this study was to assess whether endovascular therapy plus usual care is cost-effective in comparison to usual care alone in acute ischemic stroke patients. Methods: An economic evaluation was performed from a societal perspective with a 2-year time horizon. Empirical data on health outcomes and the use of resources following endovascular treatment were gathered parallel to the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) and its 2-year follow-up study. Incremental cost-effectiveness ratios were calculated as the extra costs per additional patient with functional independence (modified Rankin Scale score 0–2) and the extra cost per quality-adjusted life year gained. Results: The mean costs per patient in the intervention group were $126 494 versus $143 331 in the control group (mean difference, −$16 839 [95% CI, −$38 113 to $5456]). Compared with patients in the control group, more patients in the intervention group achieved functional independence, 37.2% versus 23.9% (absolute difference, 13.3% [95% CI, 4.0%–22.0%]) and they generated more quality-adjusted life years, 0.99 versus 0.83 (mean difference of 0.16 [95% CI, 0.04–0.29]). Endovascular treatment dominated standard treatment with $18 233 saved per extra patient with a good outcome and $105 869 saved per additional quality-adjusted life year. Conclusions: Endovascular treatment added to usual care is clinically effective, and cost saving in comparison to usual care alone in patients with acute ischemic stroke. Registration: URL: https://www.trialregister.nl/trial/695 ; Unique identifier: NL695. URL: https://www.isrctn.com ; Unique identifier: ISRCTN10888758.

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.

Background CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. Methods In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1,2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 mu m(2)/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. Findings We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0.47 [95% CI 0.30-0.72], p=0.0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0.77 [0.69-0.86] per 10 mL, p(interaction)=0.29; diffusion MRI OR 0.87 [0.81-0.94] per 10 mL, p(interaction)=0.94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. Interpretation Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imagingto-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

Background and Purpose— Previous studies suggest that intracranial carotid artery calcification (ICAC) volume might influence the clinical outcome of patients after endovascular treatment (EVT) for acute ischemic stroke. Importantly, ICAC can be subtyped into a medial or intimal pattern that may differentially influence the effect of EVT in patients with acute ischemic stroke. Methods— All 500 patients included in the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for acute ischemic stroke in the Netherlands) were evaluated. Volume (mm 3 ) and location pattern (tunica intima or tunica media) of ICAC could be determined on baseline noncontrast computed tomography in 344 patients. Functional outcome at 90 days was assessed with the modified Rankin Scale. Next, we investigated the association of ICAC volume and pattern with functional outcome using adjusted ordinal logistic regression models. Effect modification by EVT was assessed with an interaction term between treatment allocation and ICAC aspect. Results— We found evidence for treatment effect modification by ICAC pattern ( P interaction=0.04). Patients with predominantly medial calcification had better functional outcome with EVT than without this treatment (adjusted common odds ratio, 2.32; 95% CI, 1.23–4.39), but we observed no effect of EVT in patients with predominantly intimal calcifications (adjusted common odds ratio, 0.82; 95% CI, 0.40–1.68). We did not find an association of ICAC volume with functional outcome (adjusted common odds ratio per unit increase ICAC volume 1.01 (95% CI, 0.89–1.13). Moreover, we found no evidence for effect modification by ICAC volume ( P interaction=0.61). Conclusions— The benefit of EVT in acute ischemic stroke patients with a medial calcification pattern is larger than the benefit in patients with an intimal calcification pattern. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR1804. URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

Background and Purpose— Hyperglycemia on admission is common after ischemic stroke. It is associated with unfavorable outcome after treatment with intravenous thrombolysis and after intra-arterial treatment. Whether hyperglycemia influences the effect of reperfusion treatment is unknown. We assessed whether increased admission serum glucose modifies the effect of intra-arterial treatment in patients with acute ischemic stroke. Methods— We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Hyperglycemia was defined as admission serum glucose >7.8 mmol/L. The primary outcome measure was the adjusted common odds ratio for a shift in the direction of a better outcome on the modified Rankin Scale at 90 days, estimated with ordinal logistic regression. Secondary outcome variable was symptomatic intracranial hemorrhage. We assessed treatment effect modification of hyperglycemia and admission serum glucose levels with multiplicative interaction factors and adjusted for prognostic variables. Results— Four hundred eighty-seven patients were included. Mean admission serum glucose was 7.2 mmol/L (SD, 2.2). Fifty-seven of 226 patients (25%) randomized to intra-arterial treatment were hyperglycemic compared with 61 of 261 patients (23%) in the control group. The interaction of either hyperglycemia or admission serum glucose levels and treatment effect on modified Rankin Scale scores was not significant (P=0.67 and P=0.87, respectively). The same applied for occurrence of symptomatic hemorrhage (P=0.39 for hyperglycemia, P=0.39 for admission serum glucose). Conclusions— We found no evidence for effect modification of intra-arterial treatment by admission serum glucose in patients with acute ischemic stroke. Clinical Trial Registration— URL: www.isrctn.com. Unique identifier: ISRCTN10888758.

BACKGROUND:Several trials involving patients with acute ischemic stroke have shown better functional outcomes with endovascular treatment than with conventional treatment at 90 days after initiation of treatment. However, results on long-term clinical outcomes are lacking.METHODS:We assessed clinical outcomes 2 years after patients were randomly assigned to receive either endovascular treatment (intervention group) or conventional treatment (control group) for acute ischemic stroke. The primary outcome was the score on the modified Rankin scale at 2 years; this scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). Secondary outcomes included all-cause mortality and the quality of life at 2 years, as measured by means of a health utility index that is based on the European Quality of Life-5 Dimensions questionnaire (scores range from -0.329 to 1, with higher scores indicating better health).RESULTS:Of the 500 patients who underwent randomization in the original trial, 2-year data for this extended follow-up trial were available for 391 patients (78.2%) and information on death was available for 459 patients (91.8%). The distribution of outcomes on the modified Rankin scale favored endovascular treatment over conventional treatment (adjusted common odds ratio, 1.68; 95% confidence interval [CI], 1.15 to 2.45; P=0.007). There was no significant difference between the treatment groups in the percentage of patients who had an excellent outcome (i.e., a modified Rankin scale score of 0 or 1). The mean quality-of-life score was 0.48 among patients randomly assigned to endovascular treatment as compared with 0.38 among patients randomly assigned to conventional treatment (mean difference, 0.10; 95% CI, 0.03 to 0.16; P=0.006). The cumulative 2-year mortality rate was 26.0% in the intervention group and 31.0% in the control group (adjusted hazard ratio, 0.9; 95% CI, 0.6 to 1.2; P=0.46).CONCLUSIONS:In this extended follow-up trial, the beneficial effect of endovascular treatment on functional outcome at 2 years in patients with acute ischemic stroke was similar to that reported at 90 days in the original trial. (Funded by the Netherlands Organization for Health Research and Development and others; MR CLEAN Current Controlled Trials number, ISRCTN10888758 , and Netherlands Trial Register number, NTR1804 , and MR CLEAN extended follow-up trial Netherlands Trial Register number, NTR5073 .).

Background:The presence of extracranial carotid disease (ECD) is associated with less favorable clinical outcomes in patients with acute ischemic stroke caused by intracranial proximal occlusion. Acute intra-arterial treatment (IAT) in the setting of extracranial and intracranial lesions is considered challenging, and whether it yields improved outcomes remains uncertain.Objective:To examine whether the presence of ECD modified the effect of IAT for intracranial proximal anterior circulation occlusion.Design:Prespecified subgroup analysis of a randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands. (Trial registrations: NTR1804 [Netherlands Trial Register] and ISRCTN10888758).Setting:16 hospitals in the Netherlands.Patients:Acute ischemic stroke caused by proximal intracranial arterial occlusion of the anterior circulation. Extracranial carotid disease was defined as cervical internal carotid artery stenosis (>50%) or occlusion.Intervention:IAT treatment versus no IAT.Measurements:The primary outcome was functional outcome, as measured by the modified Rankin Scale at 90 days and reported as adjusted common odds ratio (acOR) for a shift in direction of a better outcome. Multivariable ordinal logistic regression analysis with an interaction term was used to estimate treatment effect modification by ECD.Results:The overall acOR was 1.67 (95% CI, 1.21 to 2.30) in favor of the intervention. The acOR was 3.1 (CI, 1.7 to 5.8) in the prespecified subgroup of patients with ECD versus 1.3 (CI, 0.9 to 1.9) in patients presenting without ECD. Both acORs are in favor of the intervention (P for interaction = 0.07).Limitation:The study was not powered for subgroup analysis.Conclusion:Intra-arterial treatment may be at least as effective in patients with ECD as in those without ECD, and it should not be withheld in these complex patients with acute ischemic stroke.Primary Funding Source:Dutch Heart Foundation, AngioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO, Penumbra, Stryker, and Top Medical/Concentric.

Background: Intra-arterial treatment in acute ischemic stroke is safe and effective as recently shown in several randomized clinical trials. The level of experience of the interventionist performing the IAT procedure has not been studied. The present study investigates effects of interventionists' experience on technical aspects of the procedure and clinical outcome of the patient.Methods: In this study of 313 patients with a proximal intracranial arterial anterior circulation occlusion, treated in the Netherlands from 2002 until participation in the Multicenter Randomized Clinical trial of Endovascular treatment for acute ischemic stroke (MR CLEAN), data were collected retrospectively. The association of the senior interventionists' experience with duration of the procedure, adverse events, recanalization, neurological outcome, and functional outcome at discharge was analyzed. Multiple regression models adjusted for age, sex, stroke severity, carotid terminus occlusion, use of a retrievable stent and onset to door time were used.Results: No association between interventionists' experience and recanalization, neurological outcome, or functional outcome was observed in a strict selection of patients. This strict selection include a start of intra-arterial treatment within 6 h, no coagulation disturbances, systolic blood pressure <185 mmHg and diastolic blood pressure < 110 mmHg), blood glucose level between 2.7 and 22.2 mmol/L and the existence of a proximal intracranial occlusion. However, significant shorter procedure times were found with more experienced interventionists' [adjusted beta coefficient 0.67, 95% CI: 1.24 to 0.11], when using less strict inclusion criteria.Conclusion: No significant relation between the level of experience and either serious neurologic adverse events or poor outcomes was observed in this study of treatments by interventionists with experience of <50 previous procedures. We need further research to explore the relation of much higher levels of interventionists' and team experience with procedure times, results and patient outcomes. (C) 2017 Elsevier B.V. All rights reserved.

Background Head tremor may be observed in the presence of cervical dystonia and sometimes coexists with headache. We wished to investigate the presence of headache in dystonic head tremor. Methods We studied the files of 19 patients from our outpatient clinic (1997–2017) with dystonic head tremor and assessed the co-occurrence of headache. We also performed a literature search of the topic. Results Cervicogenic headache was present in nearly 37% of patients with dystonic head tremor. More than 85% of our patients presented with a “no-no” head tremor. Discussion Headache is common in dystonic head tremor. Cervicogenic headache seems to be more frequent in patients with dystonic head tremor than in the general population. Future studies should compare the presence of cervicogenic headache in essential head tremor patients with that in patients suffering from dystonic head tremor.

AIMS Endovascular thrombectomy (EVT) improves outcome after acute ischaemic stroke (AIS) caused by an intracranial occlusion. The aim of the present study was to determine whether atrial fibrillation (AF) modifies the effect of EVT. METHODS AND RESULTS MR CLEAN was a randomised clinical trial of EVT plus usual care vs. usual care alone for patients with an intracranial occlusion. The primary outcome was the modified Rankin scale (mRS) score at 90 days. The primary effect parameter was the adjusted common odds ratio (acOR), estimated with ordinal logistic regression and adjusted for age and stroke severity at baseline. Treatment effect modification by AF was assessed using a multiplicative interaction variable. We included all 500 patients. In total, 135 (27%) had AF. These patients were older, had a worse pre-stroke mRS score and were less often treated with IV alteplase. In patients without AF, the estimated treatment effect was similar to the overall treatment effect (acOR 1.9, 95% CI: 1.3 to 2.7). In patients with AF, the treatment effect appeared lower (acOR 1.0, 95% CI: 0.6 to 1.9). The interaction of treatment effect and AF was not significant (p=0.09, after adjustment p=0.12). CONCLUSIONS This study did not show significant difference in the EVT effect between acute stroke patients with and those without AF.

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

We aimed to assess the relation between blood pressure (BP) and functional outcome and intra-arterial treatment (IAT) effect, occurrence of symptomatic intracranial hemorrhage (SICH).

Background and Purpose— Intra-arterial treatment by means of retrievable stents has been proven safe and effective. In MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the choice of the type of thrombectomy device was left to the discretion of the interventionist. The aim of this study was to explore the differences in functional outcome, neurological recovery, reperfusion, extent of infarction, and adverse events according to stent type and make. Methods— The primary outcome was functional outcome at 90 days, assessed with the modified Rankin Scale (mRS). Neuroimaging outcomes included occlusion on computed tomographic angiography at 24 hours, infarct volume at 5 to 7 days, and modified thrombolysis in cerebral infarction scores. Safety outcomes included death within 90 days and any symptomatic intracerebral hemorrhage. We analyzed possible interactions between stent type and treatment with multiple regression models. Treatment effects were adjusted for patient age, stroke severity, and collateral score. Results— Of the 500 patients included in the trial, 233 were allocated to intervention. Of these, 124 (53%) were first treated with Trevo (adjusted common odds ratio for shift on the mRS [acOR, 1.98; 95% confidence interval, 1.30–2.92]), 31 (13%) with Solitaire (acOR, 1.90; 95% confidence interval, 0.97–3.73), 40 (17%) with other retrievable stents or mechanical devices (acOR, 0.96; 95% confidence interval, 0.51–3.93], and 38 (16%) could not be treated. There was no interaction between device and treatment effect on functional outcome and all other secondary and safety outcomes. Conclusions— We found no evidence for a differential effect of thrombectomy for acute ischemic stroke by type of stent. Clinical Trial Registration— URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

BACKGROUND:In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included.METHODS:We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation.FINDINGS:We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2.49, 95% CI 1.76-3.53; p<0.0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2.6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction=0.43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3.68, 95% CI 1.95-6.92), those randomised more than 300 min after symptom onset (1.76, 1.05-2.97), and those not eligible for intravenous alteplase (2.43, 1.30-4.55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations.INTERPRETATION:Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion.FUNDING:Medtronic.

Introduction: MR CLEAN showed benefit of intra-arterial therapy (IAT) with retrievable stents in patients with acute ischemic stroke caused by a proximal intracranial occlusion in the anterior circulation. Uncertainty exists about the effect of IAT in patients who are not eligible for pretreatment with intravenous alteplase (IVT). We tested for treatment effect modification of IAT by IVT. Hypothesis: The effect of IAT is not modified by IVT in patients with acute ischemic stroke. Methods: All 500 patients who were randomized in MR CLEAN were included in this substudy. We distinguished between patients who were and were not pretreated with IVT. Primary outcome was the modified Rankin Scale (mRS) at 90 days. We estimated the effect of IAT on the shift on the mRS and tested for interaction of IVT with IAT by introducing a multiplicative term in a multivariable ordinal logistic regression model. We then combined published unadjusted treatment effect estimates in patients without IVT from MR CLEAN, REVASCAT and ESCAPE trials, of treatment effect in patients without IVT in a fixed effects model after testing for heterogeneity. Results: In MR CLEAN, 55 (11%) patients were not pre-treated with IVT, The effect size in patients not treated with IVT was 2.06 [95% Confidence Interval (CI): 0.69-6.13], and 1.71 [95% CI: 1.22-2.40] in patients pretreated with IVT, without statistical interaction between IAT and IVT (p=0.92). In REVASCAT, the effect of IAT in 56 patients not treated with IVT was 2.6 [95% CI: 1.0-7.1]) and in ESCAPE it was 2.6 [95% CI: 1.1-5.9] in 76 patients. The combined estimate was 2.3 [95% CI: 1.5-3.7], without heterogeneity (p=0.78). Conclusion: The available evidence suggests that patients with acute ischemic stroke and a proximal intracranial anterior circulation occlusion, presenting within 6 hours with contra-indications for intravenous alteplase, benefit from IAT.

The relative frequency of acute intracranial large vessel occlusion (LVO) in patients with acute ischemic stroke (AIS) who could be candidate for intra-arterial treatment (IAT) is not well known. In this study, we determined clinical variables associated with LVO and the proportion of patients with LVO among patients presenting with AIS within 6 h of symptom onset.

Background Whether infarct size modifies intra-arterial treatment effect is not certain, particularly in patients with large infarcts. We examined the effect of the baseline Alberta Stroke Program Early CT Score (ASPECTS) on the safety and efficacy of intra-arterial treatment in a subgroup analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN).Methods MR CLEAN was a randomised, controlled, open-label, phase 3 trial of intra-arterial treatment in patients (aged >= 18 years from the Netherlands) with proximal arterial occlusion of the anterior circulation, given intraarterial treatment within 6 h of stroke onset. The primary outcome was 90 day modified Rankin Scale (mRS) score. We estimated the intra-arterial treatment effect for all patients in MR CLEAN who had ASPECTS graded by using multivariable ordinal logistic regression analysis (a proportional odds model) to calculate the adjusted common odds ratio for a shift towards a better functional outcome according to the mRS for intra-arterial treatment and usual care than for usual care alone. We entered an interaction term into the model to test for interaction with prespecified ASPECTS subgroups: 0-4 (large infarct) versus 5-7 (moderate infarct) versus 8-10 (small infarct). MR CLEAN is registered with the Netherlands Trial Registry, number NTR1804, and the ISRCTN Registry, number ISRCTN10888758.Findings 496 patients-232 (47%) in the intra-arterial treatment and usual care group and 264 (53%) in the usual care alone group were included in the analysis. We noted no significant difference in intra-arterial treatment effect between the ASPECTS subgroups according to 90 day ordinal mRS (adjusted common odds ratio interaction term relative to ASPECTS 8-10: ASPECTS 0-4: 0.79 [95% CI 0.20-3-19], p=0.740; and ASPECTS 5-7: 1.02 [0.44-2.35], p=0.966). Intra-arterial treatment did not cause a significant increase in the proportion of patients with at least one serious adverse event in any of the ASPECTS subgroups (ASPECTS 0-4: eight [73%] of 11 patients in treatment and usual care group vs 11 [58%] of 19 in usual care alone group, p=0.42; ASPECTS 5-7: 32 [59%] of 54 vs 19 [49%] of 39, p=0.31; ASPECTS 8-10: 70 [42%] of 167 vs 82 [40%] of 206; p=0.68). For death within 7 days or within 30 days and hemicraniectomy, the differences between the intra-arterial treatment and usual care versus usual care alone groups were not significant by ASPECTS subgroups. A significantly higher proportion of patients had recurrent ischaemic stroke in the intra-arterial treatment plus usual care group than in the usual care alone group in the ASPECTS 8-10 subgroup (eight [5%] vs one [<1%]; p=0.007).Interpretation Contrary to findings from previous studies suggesting that only patients with non-contrast CT ASPECTS of more than 7 benefit from intra-arterial treatment, data from this study suggest that patients with ASPECTS 5-7 should be treated. Further evidence is needed for patients with ASPECTS 0-4, for whom treatment might yield only marginal absolute benefit.