Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS: In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS: A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS: Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).

Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

OBJECTIVE: We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. METHODS: The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). RESULTS: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. INTERPRETATION: Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024;96:356-364.

Cost-Effectiveness of Endovascular Thrombectomy in Patients with Large Ischemic Stroke.

OBJECTIVES: Whereas highly cost-effective and cost-saving for patients with small infarcts, whether endovascular thrombectomy (EVT) remains cost-effective in patients with extensive ischemic injury is uncertain. METHODS: We conducted a model-based cost-effectiveness analysis from the United States, Australian, and Spanish societal perspectives, using a 7-state Markov model, with each state defined by the modified Rankin Scale (mRS) score. Initial probabilities at 3 months were derived from the SELECT2 trial. All other model inputs, including transition probabilities, health care and non-health care costs, and utility weights, were sourced from published literature and government websites. Our analysis included extensive sensitivity and subgroup analyses. RESULTS: EVT in patients with large ischemic stroke improved health outcomes and was associated with lower costs from a societal viewpoint. EVT was cost-effective with a mean between-group difference of 1.24 quality-adjusted life years (QALYs), and a cost-saving of $23,409 in the United States, $10,691 in Australia, and $30,036 in Spain, in addition to uncosted benefits in productivity for patients and carers. Subgroup analyses were directionally consistent with the overall population, notably with preserved cost-effectiveness in older patients (≥ 70 years) and those with more severe strokes (National Institutes of Health Stroke Scale [NIHSS] ≥ 20). Sensitivity analyses were largely consistent with the base-case results. INTERPRETATION: EVT demonstrated cost-effectiveness in patients with large core across different settings in the United States, Australia, and Spain, including older patients and those with more severe strokes. These results further support adaptation of systems of care to accommodate the expansion of thrombectomy eligibility to patients with large cores and maximize EVT benefits. ANN NEUROL 2024.

Anticoagulation Use and Endovascular Thrombectomy in Patients with Large Core Stroke: A Secondary Analysis of the SELECT2 Trial.

Endovascular thrombectomy (EVT) safety and efficacy in patients with large core infarcts receiving oral anticoagulants (OAC) are unknown. In the SELECT2 trial (NCT03876457), 29 of 180 (16%; vitamin K antagonists 15, direct OACs 14) EVT, and 18 of 172 (10%; vitamin K antagonists 3, direct OACs 15) medical management (MM) patients reported OAC use at baseline. EVT was not associated with better clinical outcomes in the OAC group (EVT 6 [4-6] vs MM 5 [4-6], adjusted generalized odds ratio 0.89 [0.53-1.50]), but demonstrated significantly better outcomes in patients without OAC (EVT 4 [3-6] vs MM 5 [4-6], adjusted generalized odds ratio 1.87 [1.45-2.40], p = 0.02). The OAC group had higher comorbidities, including atrial fibrillation (70% vs 17%), congestive heart failure (28% vs 10%), and hypertension (87% vs 72%), suggesting increased frailty. However, the results were consistent after adjustment for these comorbidities, and was similar regardless of the type of OACs used. Whereas any hemorrhage rates were higher in the OAC group receiving EVT (86% in OAC vs 70% in no OAC), no parenchymal hemorrhage or symptomatic intracranial hemorrhage were observed with OAC use in both the EVT and MM arms. Although we did not find evidence that the effect was due to excess hemorrhage or confounded by underlying cardiac disease or older age, OAC use alone should not exclude patients from receiving EVT. Baseline comorbidities and ischemic injury extent should be considered while making individualized treatment decisions. ANN NEUROL 2024;96:887-894.

PRERISK: A Personalized, Artificial Intelligence-Based and Statistically-Based Stroke Recurrence Predictor for Recurrent Stroke.

BACKGROUND: Predicting stroke recurrence for individual patients is difficult, but individualized prediction may improve stroke survivors' engagement in self-care. We developed PRERISK: a statistical and machine learning classifier to predict individual risk of stroke recurrence. METHODS: We analyzed clinical and socioeconomic data from a prospectively collected public health care-based data set of 41 975 patients admitted with stroke diagnosis in 88 public health centers over 6 years (2014-2020) in Catalonia-Spain. A new stroke diagnosis at least 24 hours after the index event was considered as a recurrent stroke, which was considered as our outcome of interest. We trained several supervised machine learning models to provide individualized risk over time and compared them with a Cox regression model. Models were trained to predict early, late, and long-term recurrence risk, within 90, 91 to 365, and >365 days, respectively. C statistics and area under the receiver operating characteristic curve were used to assess the accuracy of the models. RESULTS: Overall, 16.21% (5932 of 36 114) of patients had stroke recurrence during a median follow-up of 2.69 years. The most powerful predictors of stroke recurrence were time from previous stroke, Barthel Index, atrial fibrillation, dyslipidemia, age, diabetes, and sex, which were used to create a simplified model with similar performance, together with modifiable vascular risk factors (glycemia, body mass index, high blood pressure, cholesterol, tobacco dependence, and alcohol abuse). The areas under the receiver operating characteristic curve were 0.76 (95% CI, 0.74-0.77), 0.60 (95% CI, 0.58-0.61), and 0.71 (95% CI, 0.69-0.72) for early, late, and long-term recurrence risk, respectively. The areas under the receiver operating characteristic curve of the Cox risk class probability were 0.73 (95% CI, 0.72-0.75), 0.59 (95% CI, 0.57-0.61), and 0.67 (95% CI, 0.66-0.70); machine learning approaches (random forest and AdaBoost) showed statistically significant improvement (P<0.05) over the Cox model for the 3 recurrence time periods. Stroke recurrence curves can be simulated for each patient under different degrees of control of modifiable factors. CONCLUSIONS: PRERISK is a novel approach that provides a personalized and fairly accurate risk prediction of stroke recurrence over time. The model has the potential to incorporate dynamic control of risk factors.

Radial Versus Femoral Access for Mechanical Thrombectomy in Patients With Stroke: A Noninferiority Randomized Clinical Trial.

BACKGROUND: Transfemoral access is predominantly used for mechanical thrombectomy in patients with stroke with a large vessel occlusion. Following the interventional cardiology guidelines, routine transradial access has been proposed as an alternative, although its safety and efficacy remain controversial. We aim to explore the noninferiority of radial access in terms of final recanalization. METHODS: The study was an investigator-initiated, single-center, evaluator-blinded, noninferiority randomized clinical trial. Patients with stroke undergoing mechanical thrombectomy, with a patent femoral artery and a radial artery diameter ≥2.5 mm, were randomly assigned (1:1) to either transradial (60 patients) or transfemoral access (60 patients). The primary binary outcome was the successful recanalization (expanded Treatment in Cerebral Ischemia score, 2b-3) assigned by blinded evaluators. We established a noninferiority margin of -13.2%, considering an acceptable reduction of 15% in the expected recanalization rates. RESULTS: From September 2021 to July 2023, 120 patients were randomly assigned and 116 (58 transradial access and 58 transfemoral access) with confirmed intracranial occlusion on the initial angiogram were included in the intention-to-treat analysis. Successful recanalization was achieved in 51 (87.9%) patients assigned to transfemoral access and in 56/58 (96.6%) patients assigned to transradial (adjusted 1 side risk difference [RD], -5.0% [95% CI, -6.61% to +13.1%]) showing noninferiority of transradial access. Median time from angiosuite arrival to first pass (femoral, 30 [interquartile range, 25-37] minutes versus radial: 41 [interquartile range, 33-62] minutes; P<0.001) and from angiosuite arrival to recanalization (femoral: 42 (IQR, 28-74) versus radial: 59.5 (IQR, 44-81) minutes; P<0.050) were longer in the transradial access group. Both groups presented 1 severe access complication and there was no difference in the rate of access conversion: transradial 7 (12.1%) versus transfemoral 5 (8.6%) (P=0.751). CONCLUSIONS: Among patients who underwent mechanical thrombectomy, transradial access was noninferior to transfemoral access in terms of final recanalization. Procedural delays may favor transfemoral access as the default first-line approach. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05225636.

Radial Versus Femoral Access for Mechanical Thrombectomy in Patients With Stroke: A Noninferiority Randomized Clinical Trial.

BACKGROUND: Transfemoral access is predominantly used for mechanical thrombectomy in patients with stroke with a large vessel occlusion. Following the interventional cardiology guidelines, routine transradial access has been proposed as an alternative, although its safety and efficacy remain controversial. We aim to explore the noninferiority of radial access in terms of final recanalization. METHODS: The study was an investigator-initiated, single-center, evaluator-blinded, noninferiority randomized clinical trial. Patients with stroke undergoing mechanical thrombectomy, with a patent femoral artery and a radial artery diameter ≥2.5 mm, were randomly assigned (1:1) to either transradial (60 patients) or transfemoral access (60 patients). The primary binary outcome was the successful recanalization (expanded Treatment in Cerebral Ischemia score, 2b-3) assigned by blinded evaluators. We established a noninferiority margin of -13.2%, considering an acceptable reduction of 15% in the expected recanalization rates. RESULTS: From September 2021 to July 2023, 120 patients were randomly assigned and 116 (58 transradial access and 58 transfemoral access) with confirmed intracranial occlusion on the initial angiogram were included in the intention-to-treat analysis. Successful recanalization was achieved in 51 (87.9%) patients assigned to transfemoral access and in 56/58 (96.6%) patients assigned to transradial (adjusted 1 side risk difference [RD], -5.0% [95% CI, -6.61% to +13.1%]) showing noninferiority of transradial access. Median time from angiosuite arrival to first pass (femoral, 30 [interquartile range, 25-37] minutes versus radial: 41 [interquartile range, 33-62] minutes; P<0.001) and from angiosuite arrival to recanalization (femoral: 42 (IQR, 28-74) versus radial: 59.5 (IQR, 44-81) minutes; P<0.050) were longer in the transradial access group. Both groups presented 1 severe access complication and there was no difference in the rate of access conversion: transradial 7 (12.1%) versus transfemoral 5 (8.6%) (P=0.751). CONCLUSIONS: Among patients who underwent mechanical thrombectomy, transradial access was noninferior to transfemoral access in terms of final recanalization. Procedural delays may favor transfemoral access as the default first-line approach. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05225636.

Cervical Dissection in Patients With Tandem Lesions Is Associated With Distal Embolism and Lower Recanalization Success.

BACKGROUND: Tandem lesions consist of cervical internal carotid artery (ICA) stenosis or occlusion, most commonly of atherosclerosis or dissection etiology, plus a large vessel occlusion. In this study, we compare outcomes in patients with atherosclerosis versus dissection of the cervical ICA. METHODS: This multicenter retrospective cohort study includes data from tandem lesion patients who underwent endovascular treatment from 2015 to 2020. Atherosclerosis was defined as ICA stenosis/occlusion associated with a calcified lesion and dissection by the presence of a tapered or flame-shaped lesion and intramural hematoma. Primary outcome: 90-day functional independence (modified Rankin Scale score, 0-2); secondary outcomes: 90-day favorable shift in the modified Rankin Scale score, modified Thrombolysis in Cerebral Infarction score 2b-3, modified Thrombolysis in Cerebral Infarction score 2c-3, symptomatic intracranial hemorrhage, parenchymal hematoma type 2, petechial hemorrhage, distal embolization, early neurological improvement, and mortality. Analysis was performed with matching by inverse probability of treatment weighting. RESULTS: We included 526 patients (68 [59-76] years; 31% females); 11.2% presented dissection and 88.8%, atherosclerosis. Patients with dissection were younger, had lower rates of hypertension, hyperlipidemia, diabetes, and smoking history. They also exhibited higher rates of ICA occlusion, multiple stents (>1), and lower rates of carotid self-expanding stents. After matching and adjusting for covariates, there were no differences in 90-day functional independence. The rate of successful recanalization was significantly lower in the dissection group (adjusted odds ratio, 0.38 [95% CI, 0.16-0.91]; P=0.031), which also had significantly higher rates of distal emboli (adjusted odds ratio, 2.53 [95% CI, 1.15-5.55]; P=0.021). There were no differences in other outcomes. Acute ICA stenting seemed to increase the effect of atherosclerosis in successful recanalization. CONCLUSIONS: This study reveals that among patients with acute stroke with tandem lesions, cervical ICA dissection is associated with higher rates of distal embolism and lower rates of successful recanalization than atherosclerotic lesions. Using techniques to minimize the risk of distal embolism may mitigate this contrast. Further prospective randomized trials are warranted to fully understand these associations.

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke.

BACKGROUND: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking. METHODS: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data. RESULTS: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P=4.34×10-8). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings. CONCLUSIONS: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

Outcomes of Bridging Intravenous Thrombolysis Versus Endovascular Therapy Alone in Late-Window Acute Ischemic Stroke.

BACKGROUND: Studies comparing bridging intravenous thrombolysis (IVT) with direct endovascular therapy (EVT) in patients with acute ischemic stroke who present late are limited. We aimed to compare the clinical outcomes and safety of bridging IVT in patients with acute ischemic stroke due to anterior circulation large vessel occlusion who underwent EVT 6 to 24 hours after time last known well. METHODS: We enrolled patients with anterior circulation large vessel occlusion stroke and a National Institutes of Health Stroke Scale score of ≥6 from 20 centers across 10 countries in the multicenter retrospective CLEAR study (CT for Late Endovascular Reperfusion) between January 2014 and May 2022. We used inverse probability of treatment weighting modeling adjusted for clinical and imaging confounders to compare functional outcomes, reperfusion success, symptomatic intracranial hemorrhage, and mortality between EVT patients with and without prior IVT. RESULTS: Of 5098 patients screened for eligibility, we included 2749 patients, of whom 549 received bridging IVT before EVT. The timing of IVT was not recorded. Witnessed stroke onset and transfer rates were higher in the bridging IVT group (25% versus 12% and 77% versus 55%, respectively, P value for both <0.0001), and time intervals between stroke onset and treatment were shorter (time last known well-start of EVT median 560 minutes [interquartile range, 432-791] versus 724 minutes [interquartile range, 544-912]; P<0.0001). After adjustment for confounders, there was no difference in functional outcome at 3 months (adjusted common odds ratio for modified Rankin Scale shift, 1.03 [95% CI, 0.89-1.19]; P=0.72) or successful reperfusion (adjusted odds ratio, 1.19 [95% CI, 0.81-1.75]; P=0.39). There were no safety concerns associated with bridging IVT versus direct EVT (symptomatic intracranial hemorrhage: adjusted odds ratio, 0.75 [95% CI, 0.38-1.48]; P=0.40; mortality: adjusted odds ratio, 1.14 [95% CI, 0.89-1.46]; P=0.31). Results were unchanged when the analysis was limited to patients who received IVT >6 hours after last known well. CONCLUSIONS: In patients with an anterior circulation large vessel occlusion stroke who underwent EVT 6 to 24 hours from last known well, bridging IVT was not associated with a difference in outcomes compared with direct EVT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04096248.

Endovascular Versus Medical Therapy in Posterior Cerebral Artery Stroke: Role of Baseline NIHSS Score and Occlusion Site.

BACKGROUND: Acute ischemic stroke with isolated posterior cerebral artery occlusion (iPCAO) lacks management evidence from randomized trials. We aimed to evaluate whether the association between endovascular treatment (EVT) and outcomes in iPCAO acute ischemic stroke is modified by initial stroke severity (baseline National Institutes of Health Stroke Scale [NIHSS]) and arterial occlusion site. METHODS: Based on the multicenter, retrospective, case-control study of consecutive iPCAO acute ischemic stroke patients (PLATO study [Posterior Cerebral Artery Occlusion Stroke]), we assessed the heterogeneity of EVT outcomes compared with medical management (MM) for iPCAO, according to baseline NIHSS score (≤6 versus >6) and occlusion site (P1 versus P2), using multivariable regression modeling with interaction terms. The primary outcome was the favorable shift of 3-month modified Rankin Scale (mRS). Secondary outcomes included excellent outcome (mRS score 0-1), functional independence (mRS score 0-2), symptomatic intracranial hemorrhage, and mortality. RESULTS: From 1344 patients assessed for eligibility, 1059 were included (median age, 74 years; 43.7% women; 41.3% had intravenous thrombolysis): 364 receiving EVT and 695 receiving MM. Baseline stroke severity did not modify the association of EVT with 3-month mRS distribution (Pinteraction=0.312) but did with functional independence (Pinteraction=0.010), with a similar trend on excellent outcome (Pinteraction=0.069). EVT was associated with more favorable outcomes than MM in patients with baseline NIHSS score >6 (mRS score 0-1, 30.6% versus 17.7%; adjusted odds ratio [aOR], 2.01 [95% CI, 1.22-3.31]; mRS score 0 to 2, 46.1% versus 31.9%; aOR, 1.64 [95% CI, 1.08-2.51]) but not in those with NIHSS score ≤6 (mRS score 0-1, 43.8% versus 46.3%; aOR, 0.90 [95% CI, 0.49-1.64]; mRS score 0-2, 65.3% versus 74.3%; aOR, 0.55 [95% CI, 0.30-1.0]). EVT was associated with more symptomatic intracranial hemorrhage regardless of baseline NIHSS score (Pinteraction=0.467), while the mortality increase was more pronounced in patients with NIHSS score ≤6 (Pinteraction=0.044; NIHSS score ≤6: aOR, 7.95 [95% CI, 3.11-20.28]; NIHSS score >6: aOR, 1.98 [95% CI, 1.08-3.65]). Arterial occlusion site did not modify the association of EVT with outcomes compared with MM. CONCLUSIONS: Baseline clinical stroke severity, rather than the occlusion site, may be an important modifier of the association between EVT and outcomes in iPCAO. Only severely affected patients with iPCAO (NIHSS score >6) had more favorable disability outcomes with EVT than MM, despite increased mortality and symptomatic intracranial hemorrhage.

Redefining Disability: Patient-Reported Outcome Measures After Minor Stroke and Transient Ischemic Attack.

BACKGROUND: Long-term outcome assessment patients with stroke is not fully captured by usual clinical scales such as the modified Rankin Scale (mRS). Patient-reported outcome measures (PROMs) are standardized and validated assessments that consider clinical outcomes from the patient perspective. We aim to analyze the added value of PROMs in patients with transient ischemic attack and minor stroke. METHODS: We included consecutive patients with minor stroke or transient ischemic attack (National Institutes of Health Stroke Scale score 0-5) from April 2020 to October 2021 that participated in the PROMs-through-App program (NORA, NoraHealth Barcelona Spain). Clinician and self-evaluated outcomes were assessed at 90 days: clinician-evaluated mRS, self-reported mRS, the 10-item patient-reported outcome measures questionnaire global health survey (v1.2), Hospital Anxiety and Depression Scale, and the Fatigue Assessment Scale. We evaluated the acceptability (response rate), reliability (internal consistency), and construct validity (correlation with mRS and between scales) of each questionnaire. RESULTS: We included 355 patients in the analysis, response rate was patient-reported outcome measures questionnaire 71.3% (253), Hospital Anxiety and Depression Scale 70.7% (251), Fatigue Assessment Scale 71.8% (255), and self-assessed mRS 66.8% (237). PROMS internal consistency was good or excellent, while agreement between clinician and self-reported mRS was fair (k=0.34). Rate of abnormal PROMS scores were as follows (all responders versus clinician-reported mRS score 0-2): patient-reported outcome measures questionnaire mental health (43.1% versus 36.3%), physical health (48.6% versus 43.6%); Hospital Anxiety and Depression Scale-anxiety (21.9% versus 17.7%) and depression (17.1% versus 13.3%); and Fatigue Assessment Scale (40.8% versus 36.4%). PROMs scores correlated with clinician and self-reported mRS at 90 days. CONCLUSIONS: Evaluation of PROMs using a mobile-app-based communication system is a reliable and valid strategy to assess the outcome of patients from their perspective after a mild stroke or transient ischemic attack.

Intracranial Artery Calcifications Profile as a Predictor of Recanalization Failure in Endovascular Stroke Treatment.

BACKGROUND: Acute ischemic stroke with large or medium-vessel occlusion associated with intracranial artery calcification (IAC) is an infrequent phenomenon presumably associated with intracranial atherosclerotic disease. We aimed to characterize IAC and its impact on endovascular treatment outcomes. METHODS: We performed a retrospective cross-sectional study of consecutive patients with stroke treated with thrombectomy from January 2020 to July 2021 in our institution. We described IAC findings (length, density, and location pattern) on baseline noncontrast computed tomography. Patients were divided into 3 groups: IAC related to the occlusion location (symptomatic-IAC group), unrelated to the occlusion (asymptomatic-IAC group), and absence of any IAC (non-IAC group). We analyzed the association between the IAC profile and outcomes using logistic regression models. Intracranial angioplasty and stenting were considered rescue treatments. RESULTS: Of the 393 patients included, 26 (6.6%) patients presented a symptomatic-IAC, 77 (19.6%) patients an asymptomatic-IAC, and in 290 (73.8%) patients no IAC was observed. The rate of failed recanalization (expanded Thrombolysis in Cerebral Infarction 0-2a) before rescue treatment was higher in symptomatic-IAC (65.4%) than in asymptomatic-IAC (15.6%; P<0.001) or non-IAC (13.4%; P<0.001). Rescue procedures were more frequently performed in symptomatic-IAC (26.9%) than in asymptomatic-IAC (1.3%; P<0.001) and non-IAC (4.1%; P<0.001). After adjusting for identifiable clinical and radiological confounders, symptomatic-IAC emerged as an independent predictor of failed recanalization (odds ratio, 11.89 [95% CI, 3.94-35.91]; P<0.001), adoption of rescue procedures (odds ratio, 12.38 [95% CI, 2.22-69.09]; P=0.004), and poor functional outcome (90-day modified Rankin Scale score ≥3; odds ratio, 3.51 [95% CI, 1.02-12.00]; P=0.046). CONCLUSIONS: The presence of IAC related to the occlusion location is associated with worse angiographic and functional outcomes. Therefore, identification of symptomatic-IAC on baseline imaging may guide optimal endovascular treatment strategy, predicting the need for intracranial stenting and angioplasty.

Association of Time of Day With Outcomes Among Patients Triaged for a Suspected Severe Stroke in Nonurban Catalonia.

BACKGROUND: We aim to assess whether time of day modified the treatment effect in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion Trial), a cluster-randomized trial that did not demonstrate the benefit of direct transportation to a thrombectomy-capable center versus nearest local stroke center for patients with a suspected large vessel stroke triaged in nonurban Catalonia between March 2017 and June 2020. METHODS: We performed a post hoc analysis of RACECAT to evaluate if the association between initial transport routing and functional outcome differed according to trial enrollment time: daytime (8:00 am-8:59 pm) and nighttime (9:00 pm-7:59 am). Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with ischemic stroke. Subgroup analyses according to stroke subtype were evaluated. RESULTS: We included 949 patients with an ischemic stroke, of whom 258 patients(27%) were enrolled during nighttime. Among patients enrolled during nighttime, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days (adjusted common odds ratio [acOR], 1.620 [95% CI, 1.020-2.551]); no significant difference between trial groups was present during daytime (acOR, 0.890 [95% CI, 0.680-1.163]; P interaction=0.014). Influence of nighttime on the treatment effect was only evident in patients with large vessel occlusion(daytime, acOR 0.766 [95% CI, 0.548-1.072]; nighttime, acOR, 1.785 [95% CI, 1.024-3.112] ; P interaction<0.01); no heterogeneity was observed for other stroke subtypes (P interaction>0.1 for all comparisons). We observed longer delays in alteplase administration, interhospital transfers, and mechanical thrombectomy initiation during nighttime in patients allocated to local stroke centers. CONCLUSIONS: Among patients evaluated during nighttime for a suspected acute severe stroke in non-urban areas of Catalonia, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days. This association was only evident in patients with confirmed large vessel occlusion on vascular imaging. Time delays in alteplase administration and interhospital transfers might mediate the observed differences in clinical outcome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02795962.

Safety Outcomes of Mechanical Thrombectomy Versus Combined Thrombectomy and Intravenous Thrombolysis in Tandem Lesions.

BACKGROUND: We aimed to describe the safety and efficacy of mechanical thrombectomy (MT) with or without intravenous thrombolysis (IVT) for patients with tandem lesions and whether using intraprocedural antiplatelet therapy influences MT's safety with IVT treatment. METHODS: This is a subanalysis of a pooled, multicenter cohort of patients with acute anterior circulation tandem lesions treated with MT from 16 stroke centers between January 2015 and December 2020. Primary outcomes included symptomatic intracranial hemorrhage (sICH) and parenchymal hematoma type 2. Additional outcomes included hemorrhagic transformation, successful reperfusion (modified Thrombolysis in Cerebral Infarction score 2b-3), complete reperfusion (modified Thrombolysis in Cerebral Infarction score 3), favorable functional outcome (90-day modified Rankin Scale score 0-2), excellent functional outcome (90-day modified Rankin Scale score 0-1), in-hospital mortality, and 90-day mortality. RESULTS: Of 691 patients, 512 were included (218 underwent IVT+MT and 294 MT alone). There was no difference in the risk of sICH (adjusted odds ratio [aOR], 1.22 [95% CI, 0.60-2.51]; P=0.583), parenchymal hematoma type 2 (aOR, 0.99 [95% CI, 0.47-2.08]; P=0.985), and hemorrhagic transformation (aOR, 0.95 [95% CI, 0.62-1.46]; P=0.817) between the IVT+MT and MT alone groups after adjusting for confounders. Administration of IVT was associated with an increased risk of sICH in patients who received intravenous antiplatelet therapy (aOR, 3.04 [95% CI, 0.99-9.37]; P=0.05). The IVT+MT group had higher odds of a 90-day modified Rankin Scale score 0 to 2 (aOR, 1.72 [95% CI, 1.01-2.91]; P=0.04). The odds of successful reperfusion, complete reperfusion, 90-day modified Rankin Scale score 0 to 1, in-hospital mortality, or 90-day mortality did not differ between the IVT+MT versus MT alone groups. CONCLUSIONS: Our study showed that the combination of IVT with MT for tandem lesions did not increase the overall risk of sICH, parenchymal hematoma type 2, or overall hemorrhagic transformation independently of the cervical revascularization technique used. However, intraprocedural intravenous antiplatelet therapy during acute stent implantation might be associated with an increased risk of sICH in patients who received IVT before MT. Importantly, IVT+MT treatment was associated with a higher rate of favorable functional outcomes at 90 days.

Endovascular Versus Medical Management of Posterior Cerebral Artery Occlusion Stroke: The PLATO Study.

BACKGROUND: The optimal management of patients with isolated posterior cerebral artery occlusion is uncertain. We compared clinical outcomes for endovascular therapy (EVT) versus medical management (MM) in patients with isolated posterior cerebral artery occlusion. METHODS: This multinational case-control study conducted at 27 sites in Europe and North America included consecutive patients with isolated posterior cerebral artery occlusion presenting within 24 hours of time last well from January 2015 to August 2022. Patients treated with EVT or MM were compared with multivariable logistic regression and inverse probability of treatment weighting. The coprimary outcomes were the 90-day modified Rankin Scale ordinal shift and ≥2-point decrease in the National Institutes of Health Stroke Scale. RESULTS: Of 1023 patients, 589 (57.6%) were male with median (interquartile range) age of 74 (64-82) years. The median (interquartile range) National Institutes of Health Stroke Scale was 6 (3-10). The occlusion segments were P1 (41.2%), P2 (49.2%), and P3 (7.1%). Overall, intravenous thrombolysis was administered in 43% and EVT in 37%. There was no difference between the EVT and MM groups in the 90-day modified Rankin Scale shift (aOR, 1.13 [95% CI, 0.85-1.50]; P=0.41). There were higher odds of a decrease in the National Institutes of Health Stroke Scale by ≥2 points with EVT (aOR, 1.84 [95% CI, 1.35-2.52]; P=0.0001). Compared with MM, EVT was associated with a higher likelihood of excellent outcome (aOR, 1.50 [95% CI, 1.07-2.09]; P=0.018), complete vision recovery, and similar rates of functional independence (modified Rankin Scale score, 0-2), despite a higher rate of SICH and mortality (symptomatic intracranial hemorrhage, 6.2% versus 1.7%; P=0.0001; mortality, 10.1% versus 5.0%; P=0.002). CONCLUSIONS: In patients with isolated posterior cerebral artery occlusion, EVT was associated with similar odds of disability by ordinal modified Rankin Scale, higher odds of early National Institutes of Health stroke scale improvement, and complete vision recovery compared with MM. There was a higher likelihood of excellent outcome in the EVT group despite a higher rate of symptomatic intracranial hemorrhage and mortality. Continued enrollment into ongoing distal vessel occlusion randomized trials is warranted.

Thrombectomy for anterior circulation stroke beyond 6 h from time last known well (AURORA): a systematic review and individual patient data meta-analysis.

BACKGROUND: Trials examining the benefit of thrombectomy in anterior circulation proximal large vessel occlusion stroke have enrolled patients considered to have salvageable brain tissue, who were randomly assigned beyond 6 h and (depending on study protocol) up to 24 h from time last seen well. We aimed to estimate the benefit of thrombectomy overall and in prespecified subgroups through individual patient data meta-analysis. METHODS: We did a systematic review and individual patient data meta-analysis between Jan 1, 2010, and March 1, 2021, of randomised controlled trials of endovascular stroke therapy. In the Analysis Of Pooled Data From Randomized Studies Of Thrombectomy More Than 6 Hours After Last Known Well (AURORA) collaboration, the primary outcome was disability on the modified Rankin Scale (mRS) at 90 days, analysed by ordinal logistic regression. Key safety outcomes were symptomatic intracerebral haemorrhage and mortality within 90 days. FINDINGS: Patient level data from 505 individuals (n=266 intervention, n=239 control; mean age 68·6 years [SD 13·7], 259 [51·3%] women) were included from six trials that met inclusion criteria of 17 screened published randomised trials. Primary outcome analysis showed a benefit of thrombectomy with an unadjusted common odds ratio (OR) of 2·42 (95% CI 1·76-3·33; p<0·0001) and an adjusted common OR (for age, gender, baseline stroke severity, extent of infarction on baseline head CT, and time from onset to random assignment) of 2·54 (1·83-3·54; p<0·0001). Thrombectomy was associated with higher rates of independence in activities of daily living (mRS 0-2) than best medical therapy alone (122 [45·9%] of 266 vs 46 [19·3%] of 238; p<0·0001). No significant difference between intervention and control groups was found when analysing either 90-day mortality (44 [16·5%] of 266 vs 46 [19·3%] of 238) or symptomatic intracerebral haemorrhage (14 [5·3%] of 266 vs eight [3·3%] of 239). No heterogeneity of treatment effect was noted across subgroups defined by age, gender, baseline stroke severity, vessel occlusion site, baseline Alberta Stroke Program Early CT Score, and mode of presentation; treatment effect was stronger in patients randomly assigned within 12-24 h (common OR 5·86 [95% CI 3·14-10·94]) than those randomly assigned within 6-12 h (1·76 [1·18-2·62]; pinteraction=0·0087). INTERPRETATION: These findings strengthen the evidence for benefit of endovascular thrombectomy in patients with evidence of reversible cerebral ischaemia across the 6-24 h time window and are relevant to clinical practice. Our findings suggest that in these patients, thrombectomy should not be withheld on the basis of mode of presentation or of the point in time of presentation within the 6-24 h time window. FUNDING: Stryker Neurovascular.

Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial.

BACKGROUND: Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. METHODS: In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. FINDINGS: Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [91%] of 201 vs 199 [96%] of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047). INTERPRETATION: Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. FUNDING: Medtronic and University Hospital Bern.

Workflow Times and Outcomes in Patients Triaged for a Suspected Severe Stroke.

INTRODUCTION: Current recommendations for regional stroke destination suggest that patients with severe acute stroke in non-urban areas should be triaged based on the estimated transport time to a referral thrombectomy-capable center. METHODS: We performed a post hoc analysis to evaluate the association of pre-hospital workflow times with neurological outcomes in patients included in the RACECAT trial. Workflow times evaluated were known or could be estimated before transport allocation. Primary outcome was the shift analysis on the modified Rankin score at 90 days. RESULTS: Among the 1,369 patients included, the median time from onset to emergency medical service (EMS) evaluation, the estimated transport time to a thrombectomy-capable center and local stroke center, and the estimated transfer time between centers were 65 minutes (interquartile ratio [IQR] = 43-138), 61 minutes (IQR = 36-80), 17 minutes (IQR = 9-27), and 62 minutes (IQR = 36-73), respectively. Longer time intervals from stroke onset to EMS evaluation were associated with higher odds of disability at 90 days in the local stroke center group (adjusted common odds ratio (acOR) for each 30-minute increment = 1.03, 95% confidence interval [CI] = 1.01-1.06), with no association in the thrombectomy-capable center group (acOR for each 30-minute increment = 1.01, 95% CI = 0.98-1.01, pinteraction  = 0.021). No significant interaction was found for other pre-hospital workflow times. In patients evaluated by EMS later than 120 minutes after stroke onset, direct transport to a thrombectomy-capable center was associated with better disability outcomes (acOR = 1.49, 95% CI = 1.03-2.17). CONCLUSION: We found a significant heterogeneity in the association between initial transport destination and neurological outcomes according to the elapse of time between the stroke onset and the EMS evaluation (ClinicalTrials.gov: NCT02795962). ANN NEUROL 2022;92:931-942.

Thrombectomy versus Medical Management in Mild Strokes due to Large Vessel Occlusion: Exploratory Analysis from the EXTEND-IA Trials and a Pooled International Cohort.

OBJECTIVE: This study was undertaken to evaluate functional and safety outcomes for endovascular thrombectomy (EVT) versus medical management (MM) in patients with large vessel occlusion (LVO) and mild neurological deficits, stratified by perfusion imaging mismatch. METHODS: The pooled cohort consisted of patients with National Institutes of Health Stroke Scale (NIHSS) < 6 and internal carotid artery (ICA), M1, or M2 occlusions from the Extending the Time for Thrombolysis in Emergecy Neurological Deficits - Intra-Arterial (EXTEND-IA) Trial,  Tenecteplase vs Alteplase before Endovascular Thrombectomy in Ischemic Stroke (EXTEND-IA TNK) trials Part I/II and prospective data from 15 EVT centers from October 2010 to April 2020. RAPID software estimated ischemic core and mismatch. Patients receiving primary EVT (EVTpri ) were compared to those who received primary MM (MMpri ), including those who deteriorated and received rescue EVT, in overall and propensity score (PS)-matched cohorts. Patients were stratified by target mismatch (mismatch ratio ≥ 1.8 and mismatch volume ≥ 15ml). Primary outcome was functional independence (90-day modified Rankin Scale = 0-2). Secondary outcomes included safety (symptomatic intracerebral hemorrhage [sICH], neurological worsening, and mortality). RESULTS: Of 540 patients, 286 (53%) received EVTpri and demonstrated larger critically hypoperfused tissue (Tmax > 6 seconds) volumes (median [IQR]: 64 [26-96] ml vs MMpri : 40 [14-76] ml, p < 0.001) and higher presentation NIHSS (median [IQR]: 4 [2-5] vs MMpri : 3 [2-4], p < 0.001). Functional independence was similar (EVTpri : 77.4% vs MMpri : 75.6%, adjusted odds ratio [aOR] = 1.29, 95% confidence interval [CI] = 0.82-2.03, p = 0.27). EVT had worse safety regarding sICH (EVTpri : 16.3% vs MMpri : 1.3%, p < 0.001) and neurological worsening (EVTpri : 19.6% vs MMpri : 6.7%, p < 0.001). In 414 subjects (76.7%) with target mismatch, EVT was associated with improved functional independence (EVTpri : 77.4% vs MMpri : 72.7%, aOR = 1.68, 95% CI = 1.01-2.81, p = 0.048), whereas there was a trend toward less favorable outcomes with primary EVT (EVTpri : 77.4% vs MMpri : 83.3%, aOR = 0.39, 95% CI = 0.12-1.34, p = 0.13) without target mismatch (pinteraction  = 0.06). Similar findings were observed in a propensity score-matched subpopulation. INTERPRETATION: Overall, EVT was not associated with improved clinical outcomes in mild strokes due to LVO, and sICH was increased. However, in patients with target mismatch profile, EVT was associated with increased functional independence. Perfusion imaging may be helpful to select mild stroke patients for EVT. ANN NEUROL 2022;92:364-378.