Budget impact of endovascular treatment for acute ischaemic stroke patients in the Netherlands for 2015-2021.

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 €â€¯2.9 million in 2015 to €â€¯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.

Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP): an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial.

BACKGROUND: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset. METHODS: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308. FINDINGS: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17]). INTERPRETATION: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting. FUNDING: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Economic Evaluation of Endovascular Treatment for Acute Ischemic Stroke.

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.

Endovascular Treatment for Acute Ischemic Stroke in Children: Experience From the MR CLEAN Registry.

BACKGROUND AND PURPOSE: Multiple trials have shown the efficacy and safety of endovascular therapy (EVT) of acute ischemic stroke in adults. Trials in children are lacking and only case reports and case series exist. However, the long-term outcome of children with acute ischemic stroke can be devastating with significant mortality and morbidity. In this study, we describe the safety and efficacy of EVT in children with anterior circulation acute ischemic stroke who were included in the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). METHODS: Patients under the age of 18 years who were treated with EVT for acute ischemic stroke between March 2014 and July 2017 were retrospectively reviewed up to 6 months after EVT. Nine children, aged 13 months to 16 years (median 14 years, interquartile range, 3-15 years), underwent EVT. Stroke cause was thromboembolism in children with end-stage heart failure on left ventricular assist device (4 of these 9 cases). Median time from onset to imaging was 133 minutes. Four children received intravenous alteplase before EVT, with median onset to needle time of 165 minutes. In all but one patient, EVT was technically successful. No major periprocedural complications occurred. RESULTS: At 24 hours after EVT, 3 children completely recovered and 4 children showed partial recovery (median National Institutes of Health Stroke Scale, 3.5), whereas 2 patients on left ventricular assist device died within the first week due to the occurrence of multiple strokes. One patient on left ventricular assist device developed a fatal massive intracranial hemorrhage and another child died due to left ventricular assist device-related complications. Among the 5 stroke survivors, all had a favorable outcome (modified Rankin Scale score, 0-2) at 6 months follow-up. CONCLUSIONS: EVT of children with acute ischemic stroke seems safe and feasible. However, these findings should be interpreted with caution as more and larger studies are needed to clarify the trade-off between risks and benefits of this treatment.

Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch (MR ASAP): study protocol for a randomised controlled trial.

BACKGROUND: Some studies have suggested that transdermal administration of glyceryl trinitrate (GTN; nitroglycerin) in the first few hours after symptom onset increases the chance of a favourable outcome after ischaemic stroke or intracerebral haemorrhage, possibly through an increase in intracranial collateral blood flow and a reduction in blood pressure. The Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch (MR ASAP) aims to assess the effect of transdermal GTN, started within 3 h after stroke onset in the prehospital setting, on functional outcome at 90 days in patients with acute ischaemic stroke or intracerebral haemorrhage. METHODS: MR ASAP is a phase III, multicentre, randomised, open-label clinical trial with a blinded outcome assessment. A total of 1400 adult patients with suspected stroke and a systolic blood pressure ≥ 140 mmHg will be randomised to transdermal GTN (5 mg/day), administered as a transdermal patch by paramedics in the prehospital setting within 3 h of stroke onset and continued for 24 h or to standard care. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days, analysed with ordinal logistic regression. Secondary outcomes include blood pressure and collateral circulation at hospital admission, neurological deficit measured with the National Institutes of Health Stroke Scale at 24 h, and mortality and poor outcome (mRS score 3 to 6) at 90 days. This trial will be conducted in the Netherlands and will use a deferred consent procedure. The trial is part of the Collaboration for New Treatments of Acute Stroke (CONTRAST) programme. DISCUSSION: MR ASAP will assess whether very early administration of GTN improves outcome after stroke in a setting where rates of intravenous thrombolysis and endovascular treatment for acute ischaemic stroke are high. The deferred consent procedure facilitates prompt GTN treatment and will prevent delay to revascularisation therapies. If early transdermal GTN treatment proves to be effective, this low-cost treatment can be readily implemented into daily clinical practice. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN99503308 . Registered on 2 January 2018.

Endovascular thrombectomy in patients with acute ischaemic stroke and atrial fibrillation: a MR CLEAN subgroup analysis.

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.

Extracranial Carotid Disease and Effect of Intra-arterial Treatment in Patients With Proximal Anterior Circulation Stroke in MR CLEAN.

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.

Baseline Blood Pressure Effect on the Benefit and Safety of Intra-Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands).

BACKGROUND AND PURPOSE: High blood pressure (BP) is associated with poor outcome and the occurrence of symptomatic intracranial hemorrhage in acute ischemic stroke. Whether BP influences the benefit or safety of intra-arterial treatment (IAT) is not known. We aimed to assess the relation of BP with functional outcome, occurrence of symptomatic intracranial hemorrhage and effect of IAT. METHODS: This is a post hoc analysis of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). BP was measured at baseline, before IAT or stroke unit admission. We estimated the association of baseline BP with the score on the modified Rankin Scale at 90 days and safety parameters with ordinal and logistic regression analysis. Effect of BP on the effect of IAT was tested with multiplicative interaction terms. RESULTS: Systolic BP (SBP) had the best correlation with functional outcome. This correlation was U-shaped; both low and high baseline SBP were associated with poor functional outcome. Higher SBP was associated with symptomatic intracranial hemorrhage (adjusted odds ratio, 1.25 for every 10 mm Hg higher SBP [95% confidence interval, 1.09-1.44]). Between SBP and IAT, there was no interaction for functional outcome, symptomatic intracranial hemorrhage, or other safety parameters; the absolute benefit of IAT was evident for the whole SBP range. The same was found for diastolic BP. CONCLUSIONS: BP does not affect the benefit or safety of IAT in patients with acute ischemic stroke caused by proximal intracranial vessel occlusion. Our data provide no arguments to withhold or delay IAT based on BP. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758.

Two-Year Outcome after Endovascular Treatment for Acute Ischemic Stroke.

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 .).

Admission Glucose and Effect of Intra-Arterial Treatment in Patients With Acute Ischemic Stroke.

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.

Clot Burden Score on Baseline Computerized Tomographic Angiography and Intra-Arterial Treatment Effect in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: A high clot burden score (CBS) is associated with favorable outcome after intravenous treatment for acute ischemic stroke. The added benefit of intra-arterial treatment might be less in these patients. The aim of this exploratory post hoc analysis was to assess the relation of CBS with neurological improvement and endovascular treatment effect. METHODS: For 499 of 500 patients in the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the CBS was determined. Ordinal logistic regression models with and without main baseline prognostic variables were used to assess the association between CBS (continuous or dichotomized at CBS of 6) and a shift toward better outcome on the modified Rankin Scale. The model without main baseline prognostic variables only included treatment allocation and CBS. Models with and without a multiplicative interaction term of CBS and treatment were compared using the χ2 test to assess treatment effect modification by CBS. RESULTS: Higher CBS was associated with a shift toward better outcome on the modified Rankin Scale; adjusted common odds ratio per point CBS was 1.12 (95% confidence interval, 1.04-1.20]. Dichotomized CBS had an adjusted common odds ratio of 1.67 (95% confidence interval, 1.12-2.51). Both effect estimates were slightly attenuated by adding baseline prognostic variables. The addition of the interaction terms did not significantly improve the fit of the models. There was a small and insignificant increase of intra-arterial treatment efficacy in the high CBS group. CONCLUSIONS: A higher CBS is associated with improved outcome and may be used as a prognostic marker. We found no evidence that CBS modifies the effect of intra-arterial treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR1804. URL: http://www.controlled-trials.com. Unique identifier: ISRCTN10888758.

Two-year clinical follow-up of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN): design and statistical analysis plan of the extended follow-up study.

BACKGROUND: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up. METHODS: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up. DISCUSSION: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness. TRIAL REGISTRATION: NTR1804 . Registered on 7 May 2009; ISRCTN10888758 . Registered on 24 July 2012 (main MR CLEAN trial); NTR5073 . Registered on 26 February 2015 (extended follow-up study).

Is Intra-Arterial Treatment for Acute Ischemic Stroke Less Effective in Women than in Men?

INTRODUCTION: Stroke etiology and outcome after ischemic stroke differ between men and women. We examined if sex modifies the effect of intra-arterial treatment (IAT) in a randomized clinical trial of IAT for acute ischemic stroke in the Netherlands (MR CLEAN). PATIENTS AND METHODS: The primary outcome was the score on the modified Rankin scale at 90 days. We tested for interaction between sex and treatment and estimated the treatment effect by sex with multiple ordinal logistic regression with adjustment for prognostic factors. RESULTS: All 500 patients were included in the analysis; 292 (58.4%) were men. The treatment effect (adjusted common odds ratio) was 2.39 [95% confidence interval (CI) 1.55-3.68] in men and 0.99 (95% CI 0.60-1.66) in women (pinteraction = 0.016). In women, mortality was higher in the intervention group than in the control group (24 vs. 15%, p = 0.07). Serious adverse events occurred more often in women than in men undergoing intervention. There were no differences in neuro-imaging outcomes. DISCUSSION AND CONCLUSION: Contrary to other studies, we found a significant interaction between sex and treatment effect in the MR CLEAN trial. Pooled analyses of all published thrombectomy trials did not confirm this finding. In MR CLEAN, women seem to have a slightly more unfavorable profile, causing higher mortality and more serious adverse events, but insufficient to explain the absence of an overall effect. This suggests a play of chance and makes it clear that IAT should not be withheld in women.

The effect of anesthetic management during intra-arterial therapy for acute stroke in MR CLEAN.

BACKGROUND: The aim of the current study was to assess the influence of anesthetic management on the effect of treatment in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). METHODS: MR CLEAN was a multicenter, randomized, open-label trial of intra-arterial therapy (IAT) vs no IAT. The intended anesthetic management at the start of the procedure was used for this post hoc analysis. The primary effect parameter was the adjusted common odds ratio (acOR) for a shift in direction of a better outcome on the modified Rankin Scale (mRS) at 90 days, estimated with multivariable ordinal logistic regression analysis, which included a term for general anesthesia (GA). RESULTS: GA was associated with significant (p = 0.011) effect modification, resulting in estimated decrease of 51% (95% confidence interval [CI] 31%-86%) in treatment effect compared to non-GA. We found a shift in the distribution on the mRS in favor of non-GA compared to control group (acOR 2.18 [95% CI 1.49-3.20]). The shift in distribution between GA and control group was in a similar direction (acOR 1.12 [95% CI 0.71-1.78]) with loss of statistical significance. CONCLUSIONS: In this post hoc analysis, we found that the type of anesthetic management influences outcome following IAT. Only treatment without general anesthesia was associated with a significant treatment benefit in MR CLEAN. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute ischemic stroke undergoing IAT, mRS scores at 90 days improve only in patients treated without GA.

Effect of baseline Alberta Stroke Program Early CT Score on safety and efficacy of intra-arterial treatment: a subgroup analysis of a randomised phase 3 trial (MR CLEAN).

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 intra-arterial 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. FUNDING: Dutch Heart Foundation, AngioCare, Medtronic/Covidien/EV3, Medac/Lamepro, Penumbra, Stryker, and Top Medical.

Early effect of intra-arterial treatment in ischemic stroke on aphasia recovery in MR CLEAN.

OBJECTIVE: To investigate the effect of intra-arterial treatment (IAT) on early recovery from aphasia in acute ischemic stroke. We hypothesized that the early effect of IAT on aphasia is smaller than the effect on motor deficits. METHODS: We included patients with aphasia from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), in which 500 patients with a proximal anterior circulation stroke were randomized to usual care plus IAT (<6 hours after stroke, mainly stent retrievers) or usual care alone. We estimated the effect of IAT on the shift on the NIH Stroke Scale (NIHSS) item language and the NIHSS item motor arm at 24 hours and 1 week after stroke with multivariable ordinal logistic regression as a common odds ratio, adjusted for prognostic variables (acOR). Differences between the effect of IAT on aphasia and on motor deficits were tested in a multilevel model with a multiplicative interaction term. RESULTS: Of the 288 patients with aphasia, 126 were assigned to IAT and 162 to usual care alone. The acOR for improvement of language score at 24 hours was 1.65 (95% confidence interval [CI] 1.05-2.60), and at 1 week 1.86 (95% CI 1.18-2.94). The acOR for improvement of motor deficit at 24 hours was 2.44 (95% CI 1.54-3.88), and at 1 week 2.32 (95% CI 1.43-3.77). The effect of IAT on language deficits was significantly different from the effect on motor deficits at 24 hours and 1 week (p = 0.005 and p = 0.011). CONCLUSIONS: IAT results in better early recovery from aphasia than usual care alone. The early effect of IAT on aphasia is smaller than the effect on motor deficits. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute ischemic stroke IAT increases early recovery from aphasia and that the early effect on aphasia, as measured by the NIHSS, is smaller than the effect on motor deficits.

Collateral Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in Patients With Proximal Anterior Circulation Stroke.

BACKGROUND AND PURPOSE: Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN). METHODS: MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status. RESULTS: We found a significant modification of treatment effect by collaterals (P=0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7-6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0-2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7-2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1-8.7] for patients with absent collaterals (grade 0). CONCLUSIONS: In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl and http://www.controlled-trials.com. Unique identifier: (NTR)1804 and ISRCTN10888758, respectively.

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial.

IMPORTANCE: Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known. OBJECTIVE: To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS: The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015. MAIN OUTCOMES AND MEASURES: Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion. RESULTS: Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours. CONCLUSION AND RELEVANCE: For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1804.

Type of anesthesia and differences in clinical outcome after intra-arterial treatment for ischemic stroke.

BACKGROUND AND PURPOSE: Intra-arterial treatment (IAT) in patients with acute ischemic stroke (AIS) can be performed with or without general anesthesia (GA). Previous studies suggested that IAT without the use of GA (non-GA) is associated with better clinical outcome. Nevertheless, no consensus exists about the anesthetic management during IAT of AIS patients. This study investigates the association between type of anesthesia and clinical outcome in a large cohort of patients with AIS treated with IAT. METHODS: All consecutive patients with AIS of the anterior circulation who received IAT between 2002 and 2013 in 16 Dutch hospitals were included in the study. Primary outcome was functional outcome on the modified Rankin Scale at discharge. Difference in primary outcome between GA and non-GA was estimated using multiple ordinal regression analysis, adjusting for age, stroke severity, occlusion of the internal carotid artery terminus, previous stroke, atrial fibrillation, and diabetes mellitus. RESULTS: Three hundred forty-eight patients were included in the analysis; 70 patients received GA and 278 patients did not receive GA. Non-GA was significantly associated with good clinical outcome (odds ratio 2.1, 95% confidence interval 1.02-4.31). After adjusting for prespecified prognostic factors, the point estimate remained similar; statistical significance, however, was lost (odds ratio 1.9, 95% confidence interval 0.89-4.24). CONCLUSIONS: Our study suggests that patients with AIS of the anterior circulation undergoing IAT without GA have a higher probability of good clinical outcome compared with patients treated with general anesthesia.

A randomized trial of intraarterial treatment for acute ischemic stroke.

BACKGROUND: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking. METHODS: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis). RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage. CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).