Collaterals at angiography guide clinical outcomes after endovascular stroke therapy in HERMES.

BACKGROUND: Robust collateral circulation has been linked with better reperfusion and clinical outcomes. It remains unclear how individual assessments of collateral circulation may be translated into clinical practice. METHODS: The pooled Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) angiography dataset was analyzed by a centralized, independent imaging core blinded to other clinical data. Conventional angiography was acquired immediately prior to endovascular therapy. Collaterals were graded with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN) system and associated with baseline patient characteristics, reperfusion, and day 90 modified Rankin Score (mRS). Both 90-day all-cause mortality and day 90 mRS were modeled via multivariable logistic regression. RESULTS: Angiography was available in 376/605 (62%) patients. Baseline ASPECTS (Alberta Stroke Program Early CT Score) (p=0.043), history of diabetes mellitus (p=0.048), site of occlusion (p<0.001), and degree of subsequent Thrombolysis in Cerebral Infarction (TICI) reperfusion (p<0.001) were associated with collateral grades. ASITN collateral grade was strongly associated with ordinal mRS from baseline to 90 days in an unadjusted analysis (p<0.001). Multivariable regression demonstrated that collateral status is a strong determinant of mRS outcome in the presence of other predictors (OR=1.37 per grade, 95% CI [1.05 to 1.74], p=0.018). By comparing ORs, 1 unit of ASITN was determined to be approximately equivalent to 4.5 points of NIHSS, 11 years of age, 1.5 points of ASPECTS, or 100 min less delay from onset to puncture, in terms of impact on mRS. CONCLUSIONS: Individual collateral physiology may contribute significantly to reperfusion success and clinical outcomes after acute ischemic stroke. Building a consensus for the role of angiographic collateral assessment in the allocation of adjuvant reperfusion therapies may help galvanize a precision medicine approach in stroke.

Lanreotide versus placebo for tumour reduction in patients with a 68Ga-DOTATATE PET-positive, clinically non-functioning pituitary macroadenoma (GALANT study): a randomised, multicentre, phase 3 trial with blinded outcome assessment.

Background: No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. In vivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA. Methods: The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22. Findings: Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo -0·1 mm (95% CI -1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events. Interpretation: Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA. Funding: Ipsen Farmaceutica BV.

Endovascular therapy in acute ischemic stroke with poor reperfusion is associated with worse outcomes compared with best medical management: a HERMES substudy.

BACKGROUND: Functional outcomes in patients with acute ischemic stroke (AIS) with large vessel occlusion (LVO) undergoing endovascular treatment (EVT) with poor reperfusion were compared with patients with AIS-LVO treated with best medical management only. METHODS: Data are from the HERMES collaboration, a patient-level meta-analysis of seven randomized EVT trials. Baseline characteristics and functional outcomes (modified Rankin Scale (mRS) score at 90 days) were compared between patients with poor reperfusion (defined as modified Thrombolysis in Cerebral Infarction Score 0-1 on the final intracranial angiography run as assessed by the central imaging core laboratory) and patients in the control arm with multivariable logistic ordinal logistic regression adjusted for pre-specified baseline variables. RESULTS: 972 of 1764 patients from the HERMES collaboration were included in the analysis: 893 in the control arm and 79 in the EVT arm with final mTICI 0-1. Patients with poor reperfusion who underwent EVT had higher baseline National Institutes of Health Stroke Scale than controls (median 19 (IQR 15.5-21) vs 17 (13-21), P=0.011). They also had worse mRS at 90 days compared with those in the control arm in adjusted analysis (median 4 (IQR 3-6) vs median 4 (IQR 2-5), adjusted common OR 0.59 (95% CI 0.38 to 0.91)). Symptomatic intracranial hemorrhage was not different between the two groups (3.9% vs 3.5%, P=0.75, adjusted OR 0.94 (95% CI 0.23 to 3.88)). CONCLUSION: Poor reperfusion after EVT was associated with worse outcomes than best medical management, although no difference in symptomatic intracranial hemorrhage was seen. These results emphasize the need for additional efforts to further improve technical EVT success rates.

Hemorrhage rates in patients with acute ischemic stroke treated with intravenous alteplase and thrombectomy versus thrombectomy alone.

BACKGROUND: Intravenous alteplase treatment (IVT) for acute ischemic stroke carries a risk of intracranial hemorrhage (ICH). However, reperfusion of an occluded vessel itself may contribute to the risk of ICH. We determined whether IVT and reperfusion are associated with ICH or its volume in the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN)-NO IV trial. METHODS: The MR CLEAN-NO IV trial randomized patients with acute ischemic stroke due to large vessel occlusion to receive either IVT followed by endovascular treatment (EVT) or EVT alone. ICH was classified according to the Heidelberg bleeding classification on follow-up MRI or CT approximately 8 hours-7 days after stroke. Hemorrhage volume was measured with ITK-snap. Successful reperfusion was defined as extended Thrombolysis In Cerebral Infarction (eTICI) score of 2b-3. Multinomial and binary adjusted logistic regression were used to determine the association of IVT and reperfusion with ICH subtypes. RESULTS: Of 539 included patients, 173 (32%) developed ICH and 30 suffered from symptomatic ICH (sICH) (6%). Of the patients with ICH, 102 had hemorrhagic infarction, 47 had parenchymal hematoma, 44 had SAH, and six had other ICH. Reperfusion was associated with a decreased risk of SAH, and IVT was not associated with SAH (eTICI 2b-3: adjusted OR 0.45, 95% CI 0.21 to 0.97; EVT without IVT: OR 1.6, 95% CI 0.91 to 2.8). Reperfusion status and IVT were not associated with overall ICH, hemorrhage volume, and sICH (sICH: EVT without IVT, OR 0.96, 95% CI 0.41 to 2.25; eTICI 2b-3, OR 0.49, 95% CI 0.23 to 1.05). CONCLUSION: Neither IVT administration before EVT nor successful reperfusion after EVT were associated with ICH, hemorrhage volume, and sICH. SAH occurred more often in patients for whom successful reperfusion was not achieved.

Clinical outcome of patients with mild pre-stroke morbidity following endovascular treatment: a HERMES substudy.

BACKGROUND: Analyses of the effect of pre-stroke functional levels on the outcome of endovascular therapy (EVT) have focused on the course of patients with moderate to substantial pre-stroke disability. The effect of complete freedom from pre-existing disability (modified Rankin Scale (mRS) 0) versus predominantly mild pre-existing disability/symptoms (mRS 1-2) has not been well delineated. METHODS: The HERMES meta-analysis pooled data from seven randomized trials that tested the efficacy of EVT. We tested for a multiplicative interaction effect of pre-stroke mRS on the relationship between treatment and outcomes. Ordinal regression was used to assess the association between EVT and 90-day mRS (primary outcome) in the subgroup of patients with pre-stroke mRS 1-2. Multivariable regression modeling was then used to test the effect of mild pre-stroke disability/symptoms on the primary and secondary outcomes (delta-mRS, mRS 0-2/5-6) compared with patients with pre-stroke mRS 0. RESULTS: We included 1764 patients, of whom 199 (11.3%) had pre-stroke mRS 1-2. No interaction effect of pre-stroke mRS on the relationship between treatment and outcome was observed. Patients with pre-stroke mRS 1-2 had worse outcomes than those with pre-stroke mRS 0 (adjusted common OR (acOR) 0.53, 95% CI 0.40 to 0.70). Nonetheless, a significant benefit of EVT was observed within the mRS 1-2 subgroup (cOR 2.08, 95% CI 1.22 to 3.55). CONCLUSIONS: Patients asymptomatic/without disability prior to onset have better outcomes following EVT than patients with mild disability/symptoms. Patients with pre-stroke mRS 1-2, however, more often achieve good outcomes with EVT compared with conservative management. These findings indicate that mild pre-existing disability/symptoms influence patient prognosis after EVT but do not diminish the EVT treatment effect.

Perceived acceptable uncertainty regarding comparability of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment.

BACKGROUND: Most trials comparing endovascular treatment (EVT) alone versus intravenous thrombolysis with alteplase (IVT) + EVT in directly admitted patients with a stroke are non-inferiority trials. However, the margin based on the level of uncertainty regarding non-inferiority of the experimental treatment that clinicians are willing to accept to incorporate EVT alone into clinical practice remains unknown. OBJECTIVE: To characterize what experienced stroke clinicians would consider an acceptable level of uncertainty for hypothetical decisions on whether to administer IVT or not before EVT in patients admitted directly to EVT-capable centers. METHODS: A web-based, structured survey was distributed to a cross-section of 600 academic neurologists/neurointerventionalists. For this purpose, a response framework for a hypothetical trial comparing IVT+EVT (standard of care) with EVT alone (experimental arm) was designed. In this trial, a similar proportion of patients in each arm achieved functional independence at 90 days. Invited physicians were asked at what level of certainty they would feel comfortable skipping IVT in clinical practice, considering these hypothetical trial results. RESULTS: There were 180 respondents (response rate: 30%) and 165 with complete answers. The median chosen acceptable uncertainty suggesting reasonable comparability between both treatments was an absolute difference in the rate of day 90 functional independence of 3% (mode 5%, IQR 1-5%), with higher chosen margins observed in interventionalists (aOR 2.20, 95% CI 1.06 to 4.67). CONCLUSION: Physicians would generally feel comfortable skipping IVT before EVT at different certainty thresholds. Most physicians would treat with EVT alone if randomized trial data suggested that the number of patients achieving functional independence at 90 days was similar between the two groups, and one could be sufficiently sure that no more than 3 out of 100 patients would not achieve functional independence at 90 days due to skipping IVT.

Endovascular treatment for isolated posterior cerebral artery occlusion stroke in the MR CLEAN registry.

BACKGROUND: Endovascular treatment (EVT) is standard of care in anterior circulation large vessel occlusions. In posterior circulation occlusions, data on EVT in isolated posterior cerebral artery (PCA) occlusions are limited, although PCA occlusions can cause severe neurological deficit. OBJECTIVE: To describe in a prospective study the clinical manifestations, outcomes, and safety of EVT in isolated PCA occlusions. METHODS: We used data (2014-2017) from the MR CLEAN Registry, a nationwide, prospective cohort of EVT-treated patients in the Netherlands. We included patients with acute ischemic stroke (AIS) due to an isolated PCA occlusion on CT angiography. Patients with concurrent occlusion of the basilar artery were excluded. Outcomes included change in National Institutes of Health Stroke Scale (ΔNIHSS) score, modified Rankin Scale (mRS) score 0-3 after 90 days, mortality, expanded Thrombolysis in Cerebral Infarction (eTICI), and periprocedural complications. RESULTS: Twenty (12%) of 162 patients with posterior circulation occlusions had an isolated PCA occlusion. Median age was 72 years; 13 (65%) were women. Median baseline NIHSS score was 13 (IQR 5-21). Six (30%) patients were comatose. Twelve patients (60%) received IVT. Median ΔNIHSS was -4 (IQR -11-+1). At follow-up, nine patients (45%) had mRS score 0-3. Seven (35%) died. eTICI 2b-3 was achieved in 13 patients (65%). Nine patients (45%) had periprocedural complications. No symptomatic intracranial hemorrhages (sICH) occurred. CONCLUSIONS: EVT should be considered in selected patients with AIS with an isolated PCA occlusion, presenting with moderate-severe neurological deficits, as EVT was technically feasible in most of our patients and about half had good clinical outcome. In case of lower NIHSS score, a more conservative approach seems warranted, since periprocedural complications are not uncommon. Nonetheless, EVT seems reasonably safe considering the absence of sICH in our study.

Successful reperfusion in relation to the number of passes: comparing outcomes of first pass expanded Treatment In Cerebral Ischemia (eTICI) 2B with multiple-pass eTICI 3.

BACKGROUND: Higher expanded Treatment In Cerebral Ischemia (eTICI) reperfusion scores after endovascular treatment (EVT) are associated with better outcomes. However, the influence of the number of passes on this association is unclear. We aimed to compare outcomes of single-pass good reperfusion (eTICI 2B) with multiple-pass excellent/complete reperfusion (eTICI 2C/3) in daily clinical practice. METHODS: We compared outcomes of patients in the MR CLEAN Registry with good reperfusion (eTICI 2B) in a single pass to those with excellent/complete reperfusion (eTICI 2C/3) in multiple passes. Regression models were used to investigate the association of single-pass eTICI 2B versus multiple-pass eTICI 2C/3 reperfusion with 90-day functional outcome (modified Rankin Scale (mRS)), functional independence (mRS 0-2), per-procedural complications and safety outcomes. RESULTS: We included 699 patients: 178 patients with single-pass eTICI 2B, and 242 and 279 patients with eTICI 2C/3 after 2 and ≥3 passes, respectively. Patients with eTICI 2C/3 after 2 or ≥3 passes did not achieve significantly better functional outcomes compared with patients with single-pass eTICI 2B (adjusted common OR (acOR) 1.06, 95% CI 0.75 to 1.50 and acOR 0.88, 95% CI 0.74 to 1.05 for 90-day mRS, and adjusted OR (aOR) 1.24, 95% CI 0.78 to 1.97 and aOR 0.79, 95% CI 0.52 to 1.22 for functional independence). CONCLUSIONS: Our results did not show better outcomes for patients who achieved eTICI 2C/3 in multiple, that is, two or more, passes when compared with patients with single-pass eTICI 2B. However, this concerns observational data. Further research is necessary to investigate the per-pass effect in relation to reperfusion and functional outcome.

Bifurcation occlusions and endovascular treatment outcome in acute ischemic stroke.

BACKGROUND: A thrombus in the M1 segment of the middle cerebral artery (MCA) can occlude this main stem only or extend into the M1-M2 bifurcation. The occlusion pattern may affect endovascular treatment (EVT) success, as a bifurcated thrombus may be more prone to fragmentation during retrieval. OBJECTIVE: To investigate whether bifurcated thrombus patterns are associated with EVT procedural and clinical outcomes. METHODS: Occlusion patterns of MCA thrombi on CT angiography from MR CLEAN Registry patients were classified into three groups: main stem occlusion, bifurcation occlusion extending into one M2 branch, and bifurcation occlusion extending into both M2 branches. Procedural parameters, procedural outcomes (reperfusion grade and embolization to new territory), and clinical outcomes (24-48 hour National Institutes of Health Stroke Scale [NIHSSFU] score, change in NIHSS scores between 24 and 48 hours and baseline ∆ [NIHSS], and 90-day modified Rankin Scale [mRS] scores) were compared between occlusion patterns. RESULTS: We identified 1023 patients with an MCA occlusion of whom 370 (36%) had a main stem occlusion, 151 (15%) a single branch, and 502 (49%) a double branch bifurcation occlusion. There were no statistically significant differences in retrieval method, procedure time, number of retrieval attempts, reperfusion grade, and embolization to new territory between occlusion patterns. Patients with main stem occlusions had lower NIHSSFU scores than patients with single (7 vs 11, p=0.01) or double branch occlusions (7 vs 9, p=0.04). However, there were no statistically significant differences in ∆ NIHSS or in 90-day mRS scores. CONCLUSIONS: In our population, EVT procedural and long-term clinical outcomes were similar for MCA bifurcation occlusions and MCA main stem occlusions.

Risk factors of unexplained early neurological deterioration after treatment for ischemic stroke due to large vessel occlusion: a post hoc analysis of the HERMES study.

BACKGROUND: Early neurological deterioration (END) after endovascular treatment (EVT) in patients with anterior circulation acute ischemic stroke (AIS) is associated with poor outcome. END may remain unexplained by parenchymal hemorrhage (UnEND). We aim to analyze the risk factors of UnEND in the medical management (MM) and EVT arms of the HERMES study. METHODS: We conducted a post-hoc analysis of anterior AIS patients who underwent EVT for proximal anterior occlusions. Risk factors of UnEND, defined as a worsening of ≥4 points between baseline National Institutes of Health Stroke Scale (NIHSS) and NIHSS at 24 hours without hemorrhage, were compared between both arms using mixed logistic regression models adjusted for baseline characteristics. An interaction analysis between the EVT and MM arms for risk factors of UnEND was conducted. RESULTS: Among 1723 patients assessable for UnEND, 160 patients experienced an UnEND (9.3%), including 9.1% (78/854) in the EVT arm and 9.4% (82/869) in the MM arm. There was no significant difference in the incidence of UnEND between the two study arms. In the EVT population, independent risk factors of UnEND were lower baseline NIHSS, higher baseline glucose, and lower collateral grade. In the MM population, the only independent predictor of UnEND was higher baseline glucose. However, we did not demonstrate an interaction between EVT and MM for baseline factors as risk factors of UnEND. UnEND was, similarly in both treatment groups, a significant predictor of unfavorable outcome in both the EVT (p<0.001) and MM (p<0.001) arms. CONCLUSIONS: UnEND is not an uncommon event, with a similar rate which ever treatment arm is considered. In the clinical scenario of AIS due to large vessel occlusion, no patient-related factor seems to increase the risk for UnEND when treated by EVT compared with MM.

Type of intracranial hemorrhage after endovascular stroke treatment: association with functional outcome.

BACKGROUND: Intracranial hemorrhage (ICH) is a frequent complication after endovascular stroke treatment. OBJECTIVE: To assess the association of the occurrence and type of ICH after endovascular treatment (EVT) with functional outcome. METHODS: We analyzed data from the MR CLEAN-NO IV and MR CLEAN-MED trials. Both trials included adult patients with ischemic stroke with a large vessel occlusion in the anterior circulation, who were eligible for EVT. ICH was classified (1) as asymptomatic or symptomatic (concomitant neurological deterioration of ≥4 points on the NIHSS, or ≥2 points on 1 NIHSS item), and (2) according to the Heidelberg Bleeding Classification. We used multivariable ordinal logistic regression analyses to assess the association of the occurrence and type of ICH with the modified Rankin Scale score at 90 days. RESULTS: Of 1017 included patients, 331 (33%) had an asymptomatic ICH, and 90 (9%) had a symptomatic ICH. Compared with no ICH, both asymptomatic (adjusted common OR (acOR)=0.76; 95% CI 0.58 to 0.98) and symptomatic (acOR=0.07; 95% CI 0.04 to 0.14) ICH were associated with worse functional outcome. In particular, isolated parenchymal hematoma type 2 (acOR=0.37; 95% CI 0.14 to 0.95), combined parenchymal hematoma with hemorrhage outside infarcted brain tissue (acOR=0.17; 95% CI 0.10 to 0.30), and combined hemorrhages outside infarcted brain tissue (acOR=0.14; 95% CI 0.03 to 0.74) were associated with worse functional outcome than no ICH.Strength of the association of ICH with functional outcome depends on the type of ICH. Although the association is stronger for symptomatic ICH, asymptomatic ICH after EVT is also associated with worse functional outcome.

Sex differences in onset to hospital arrival time, prestroke disability, and clinical symptoms in patients with a large vessel occlusion: a MR CLEAN Registry substudy.

BACKGROUND: Women have been reported to have worse outcomes after endovascular treatment (EVT), despite a similar treatment effect in non-clinical trial populations. We aimed to assess sex differences at hospital presentation with respect to workflow metrics, prestroke disability, and presenting clinical symptoms. METHODS: We included consecutive patients from the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in The Netherlands (MR CLEAN) Registry (2014-2018) who received EVT for anterior circulation large vessel occlusion (LVO). We assessed sex differences in workflow metrics, prestroke disability (modified Rankin Scale (mRS) score ≥1), and stroke severity and symptoms according to the National Institutes of Health Stroke Scale (NIHSS) score on hospital admission with logistic and linear regression analyses and calculated the adjusted OR (aOR). RESULTS: We included 4872 patients (47.6% women). Compared with men, women were older (median age 76 vs 70 years) and less often achieved good functional outcome at 90 days (mRS ≤2: 35.2% vs 46.4%, aOR 0.70, 95% CI 0.60 to 0.82). Mean onset-to-door time was longer in women (2 hours 16 min vs 2 hours 7 min, adjusted delay 9 min, 95% CI 4 to 13). This delay contributed to longer onset-to-groin times (3 hours 26 min in women vs 3 hours 13 min in men, adjusted delay 13 min, 95% CI 9 to 17). Women more often had prestroke disability (mRS ≥1: 41.1% vs 29.1%, aOR 1.57, 95% CI 1.36 to 1.82). NIHSS on admission was essentially similar in men and women (mean 15±6 vs 15±6, NIHSS <10 vs ≥10, aOR 0.91, 95% CI 0.78 to 1.06). There were no clear sex differences in the occurrence of specific stroke symptoms. CONCLUSION: Women with LVO had longer onset-to-door times and more often prestroke disability than men. Raising awareness of these differences at hospital presentation and investigating underlying causes may help to improve outcome after EVT in women.

Influence of time metrics on the treatment effect of intravenous alteplase prior to endovascular treatment in MR CLEAN-NO IV.

BACKGROUND: We assessed whether the treatment effect of intravenous alteplase (IVT) prior to endovascular treatment (EVT) on functional outcome is modified by time metrics. METHODS: We used data from all patients included in MR CLEAN-NO IV, a randomized trial of IVT followed by EVT versus EVT alone in patients who presented directly to EVT-capable hospitals. The primary outcome was the modified Rankin Scale score at 90 days. We used ordinal regression with a multiplicative interaction term to assess if the effect of IVT is modified by onset-to-randomization (OTR), onset-to-IV-needle (OTN), door-to-groin (DTG) or needle-to-groin (NTG) times. Secondary outcomes included successful reperfusion (extended Thrombolysis In Cerebral Infarction Scale 2b-3) and symptomatic intracranial hemorrhage (sICH). RESULTS: In 539 included patients (266 allocated to IVT+EVT and 273 to EVT alone), median workflow times were OTR: 93 (IQR 71-145) min; OTN: 98 (IQR 75-156) min; DTG: 64 (IQR 51-78) min; and NTG: 28 (IQR 20-41) min. There was a significant association between worse outcomes and longer time intervals for all metrics except NTG. We found no interaction between any of the time metrics and IVT for the effect on functional outcome (p values for interaction: OTR=0.40, OTN=0.39, DTG=0.61, NTG=0.56). We also did not observe any significant interaction for successful reperfusion or sICH. CONCLUSION: In MR CLEAN-NO IV, the effect of IVT prior to EVT was not modified by OTR, OTN, DTG or NTG times. Our results do not support the use of these metrics to guide IVT treatment decisions prior to EVT in comprehensive stroke centres. TRIAL REGISTRATION NUMBER: ISRCTN80619088.

Benefit of successful reperfusion achieved by endovascular thrombectomy for patients with ischemic stroke and moderate pre-stroke disability (mRS 3): results from the MR CLEAN Registry.

BACKGROUND: Pre-stroke dependent patients (modified Rankin Scale score (mRS) ≥3) were excluded from most trials on endovascular treatment (EVT) for acute ischemic stroke (AIS) in the anterior circulation. Therefore, little evidence exists for EVT in those patients. We aimed to investigate the safety and benefit of EVT in pre-stroke patients with mRS score 3. METHODS: We used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic stroke in the Netherlands (MR CLEAN) Registry. All patients treated with EVT for anterior circulation AIS with pre-stroke mRS 3 were included. We assessed causes for dependence and compared patients with successful reperfusion (defined as expanded Thrombolysis in Cerebral Ischemia scale (eTICI) 2b-3) to patients without successful reperfusion. We used regression analyses with pre-specified adjustments. Our primary outcome was 90-day mRS 0-3 (functional improvement or return to baseline). RESULTS: A total of 192 patients were included, of whom 82 (43%) had eTICI <2b and 108 (56%) eTICI ≥2b. The median age was 80 years (IQR 73-87). Fifty-one of the 192 patients (27%) suffered from previous stroke and 36/192 (19%) had cardiopulmonary disease. Patients with eTICI ≥2b more often returned to their baseline functional state or improved (n=26 (26%) vs n=15 (19%); adjusted odds ratio (aOR) 2.91 (95% CI 1.08 to 7.82)) and had lower mortality rates (n=49 (49%) vs n=50 (64%); aOR 0.42 (95% CI 0.19 to 0.93)) compared with patients with eTICI <2b. CONCLUSIONS: Although patients with AIS with pre-stroke mRS 3 comprise a heterogenous group of disability causes, we observed improved outcomes when patients achieved successful reperfusion after EVT.

Thrombus radiomics in patients with anterior circulation acute ischemic stroke undergoing endovascular treatment.

BACKGROUND: Thrombus radiomics (TR) describe complex shape and textural thrombus imaging features. We aimed to study the relationship of TR extracted from non-contrast CT with procedural and functional outcome in endovascular-treated patients with acute ischemic stroke. METHODS: Thrombi were segmented on thin-slice non-contrast CT (≤1 mm) from 699 patients included in the MR CLEAN Registry. In a pilot study, we selected 51 TR with consistent values across two raters' segmentations (ICC >0.75). Random forest models using TR in addition or as a substitute to baseline clinical variables (CV) and manual thrombus measurements (MTM) were trained with 499 patients and evaluated on 200 patients for predicting successful reperfusion (extended Thrombolysis in Cerebral Ischemia (eTICI) ≥2B), first attempt reperfusion, reperfusion within three attempts, and functional independence (modified Rankin Scale (mRS) ≤2). Three texture and shape features were selected based on feature importance and related to eTICI ≥2B, number of attempts to eTICI ≥2B, and 90-day mRS with ordinal logistic regression. RESULTS: Random forest models using TR, CV or MTM had comparable predictive performance. Thrombus texture (inverse difference moment normalized) was independently associated with reperfusion (adjusted common OR (acOR) 0.85, 95% CI 0.72 to 0.99). Thrombus volume and texture were also independently associated with the number of attempts to successful reperfusion (acOR 1.36, 95% CI 1.03 to 1.88 and acOR 1.24, 95% CI 1.04 to 1.49). CONCLUSIONS: TR describing thrombus volume and texture were associated with more attempts to successful reperfusion. Compared with models using CV and MTM, TR had no added value for predicting procedural and functional outcome.

Clinical Outcome After Endovascular Treatment in Patients With Active Cancer and Ischemic Stroke: A MR CLEAN Registry Substudy.

BACKGROUND AND OBJECTIVES: To explore clinical and safety outcomes of patients with acute ischemic stroke (AIS) and active cancer after endovascular treatment (EVT). METHODS: Using data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry, we compared patients with active cancer (defined as cancer diagnosed within 12 months before stroke, metastatic disease, or current cancer treatment) to patients without cancer. Outcomes were 90-day modified Rankin Scale (mRS) score, mortality, successful reperfusion (expanded Treatment in Cerebral Infarction score ≥2b), symptomatic intracranial hemorrhage (sICH), and recurrent stroke. Subgroup analyses were performed in patients with a prestroke mRS score of 0 or 1 and according to treatment setting (curative or palliative). Analyses were adjusted for prognostic variables. RESULTS: Of 2,583 patients who underwent EVT, 124 (4.8%) had active cancer. They more often had prestroke disability (mRS score ≥2: 34.1% vs 16.6%). The treatment setting was palliative in 25.3% of the patients. There was a shift toward worse functional outcome at 90 days in patients with active cancer (adjusted common odds ratio [acOR] 2.2, 95% confidence interval [CI] 1.5-3.2). At 90 days, patients with active cancer were less often independent (mRS score 0-2: 22.6% vs 42.0%, adjusted OR [aOR] 0.5, 95% CI 0.3-0.8) and more often dead (52.2% vs 26.5%, aOR 3.2, 95% CI 2.1-4.9). Successful reperfusion (67.8% vs 60.5%, aOR 1.4, 95% CI 1.0-2.1) and sICH rates (6.5% vs 5.9%, aOR 1.1, 95% CI 0.5-2.3) did not differ. Recurrent stroke within 90 days was more common in patients with active cancer (4.0% vs 1.3%, aOR 3.1, 95% CI 1.2-8.1). The sensitivity analysis of patients with a prestroke mRS score of 0 or 1 showed that patients with active cancer still had a worse outcome at 90 days (acOR 1.9, 95% CI 1.2-3.0). Patients with active cancer in a palliative treatment setting regained functional independence less often compared to patients in a curative setting (18.2% vs 32.1%), and mortality was higher (81.8% vs 39.3%). DISCUSSION: Despite similar technical success, patients with active cancer had significantly worse outcomes after EVT for AIS. Moreover, they had an increased risk of recurrent stroke. Nevertheless, about a quarter of the patients regained functional independence, and the risk of other complications, most notably sICH, was not increased. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that patients with active cancer undergoing EVT for AIS have worse functional outcomes at 90 days compared to those without active cancer.

Effect of first pass reperfusion on outcome in patients with posterior circulation ischemic stroke.

BACKGROUND: First pass reperfusion (FPR), that is, excellent reperfusion (expanded treatment in cerebral ischemia (eTICI) 2C-3) in one pass, after endovascular treatment (EVT) of an occluded artery in the anterior circulation, is associated with favorable clinical outcome, even when compared with multiple pass excellent reperfusion (MPR). In patients with posterior circulation ischemic stroke (PCS), the same association is expected, but currently unknown. We aimed to assess characteristics associated with FPR and the influence of FPR versus MPR on outcomes in patients with PCS. METHODS: We used data from the MR CLEAN Registry, a prospective observational study. The effect of FPR on 24-hour National Institutes of Health Stroke Scale (NIHSS) score, as percentage reduction, and on modified Rankin Scale (mRS) scores at 3 months, was tested with linear and ordinal logistic regression models. RESULTS: Of 224 patients with PCS, 45 patients had FPR, 47 had MPR, and 90 had no excellent reperfusion (eTICI <2C). We did not find an association between any of the patient, imaging, or treatment characteristics and FPR. FPR was associated with better NIHSS (-45% (95% CI: -65% to -12%)) and better mRS scores (adjusted common odds ratio (acOR): 2.16 (95% CI: 1.23 to 3.79)) compared with no FPR. Outcomes after FPR were also more favorable compared with MPR, but the effect was smaller and not statistically significant (NIHSS: -14% (95% CI: -51% to 49%), mRS acOR: 1.50 (95% CI: 0.75 to 3.00)). CONCLUSIONS: FPR in patients with PCS is associated with favorable clinical outcome in comparison with no FPR. In comparison with MPR, the effect of FPR was no longer statistically significant. Nevertheless, our data support the notion that FPR should be the treatment target to pursue in every patient treated with EVT.

Early recanalization in large-vessel occlusion stroke patients transferred for endovascular treatment.

BACKGROUND: We performed an exploratory analysis to identify patient and thrombus characteristics associated with early recanalization in large-vessel occlusion (LVO) stroke patients transferred for endovascular treatment (EVT) from a primary (PSC) to a comprehensive stroke center (CSC). METHODS: We included patients with an LVO stroke of the anterior circulation who were transferred to our hospital for EVT and underwent repeated imaging between January 2016 and June 2019. We compared patient characteristics, workflow time metrics, functional outcome (modified Rankin Scale at 90 days), and baseline thrombus imaging characteristics, which included: occlusion location, thrombus length, attenuation, perviousness, distance from terminus of intracranial carotid artery to the thrombus (DT), and clot burden score (CBS), between early-recanalized LVO (ER-LVO), and non-early-recanalized LVO (NER-LVO) patients. RESULTS: One hundred and forty-nine patients were included in the analysis. Early recanalization occurred in 32% of patients. ER-LVO patients less often had a medical history of hypertension (31% vs 49%, P=0.04), and more often had clinical improvement between PSC and CSC (ΔNIHSS -5 vs 3, P<0.01), compared with NER-LVO patients. Thrombolysis administration was similar in both groups (88% vs 78%, P=0.18). ER-LVO patients had no ICA occlusions (0% vs 27%, P<0.01), more often an M2 occlusion (35% vs 17%, P=0.01), longer DT (27 mm vs 12 mm, P<0.01), shorter thrombi (17 mm vs 27 mm, P<0.01), and higher CBS (8 vs 6, P<0.01) at baseline imaging. ER-LVO patients had lower mRS scores (1 vs 3, P=0.02). CONCLUSIONS: Early recanalization is associated with clinical improvement between PSC and CSC admission, more distal occlusions and shorter thrombi at baseline imaging, and better functional outcome.

Value of repeated imaging in patients with a stroke who are transferred for endovascular treatment.

BACKGROUND: Patients with a stroke who are transferred to a comprehensive stroke center for endovascular treatment (EVT) often undergo repeated neuroimaging prior to EVT. OBJECTIVE: To evaluate the yield of repeating imaging and its effect on treatment times. METHODS: We included adult patients with a large vessel occlusion (LVO) stroke who were referred to our hospital for EVT by primary stroke centers (2016-2019). We excluded patients who underwent repeated imaging because primary imaging was unavailable, incomplete, or of insufficient quality. Outcomes included treatment times and repeated imaging findings. RESULTS: Of 677 transferred LVO stroke, 551 were included. Imaging was repeated in 165/551 patients (30%), mostly because of clinical improvement (86/165 (52%)) or deterioration (40/165 (24%)). Patients who underwent repeated imaging had higher door-to-groin-times than patients without repeated imaging (median 43 vs 27 min, adjusted time difference: 20 min, 95% CI 15 to 25). Among patients who underwent repeated imaging because of clinical improvement, the LVO had resolved in 50/86 (58%). In patients with clinical deterioration, repeated imaging led to refrainment from EVT in 3/40 (8%). No symptomatic intracranial hemorrhages (sICH) were identified. Ultimately, 75/165 (45%) of patients with repeated imaging underwent EVT compared with 326/386 (84%) of patients without repeated imaging (p<0.01). CONCLUSIONS: Neuroimaging was repeated in 30% of patients with an LVO stroke and resulted in a median treatment delay of 20 minutes. In patients with clinical deterioration, no sICH were detected and repeated imaging rarely changed the indication for EVT. However, in more than half of patients with clinical improvement, the LVO had resolved, resulting in refrainment from EVT.