Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Mechanical Thrombectomy Global Access For Stroke (MT-GLASS): A Mission Thrombectomy (MT-2020 Plus) Study.

BACKGROUND: Despite the well-established potent benefit of mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke, access to MT has not been studied globally. We conducted a worldwide survey of countries on 6 continents to define MT access (MTA), the disparities in MTA, and its determinants on a global scale. METHODS: Our survey was conducted in 75 countries through the Mission Thrombectomy 2020+ global network between November 22, 2020, and February 28, 2021. The primary end points were the current annual MTA, MT operator availability, and MT center availability. MTA was defined as the estimated proportion of patients with LVO receiving MT in a given region annually. The availability metrics were defined as ([current MT operators×50/current annual number of estimated thrombectomy-eligible LVOs]×100 = MT operator availability) and ([current MT centers×150/current annual number of estimated thrombectomy-eligible LVOs]×100= MT center availability). The metrics used optimal MT volume per operator as 50 and an optimal MT volume per center as 150. Multivariable-adjusted generalized linear models were used to evaluate factors associated with MTA. RESULTS: We received 887 responses from 67 countries. The median global MTA was 2.79% (interquartile range, 0.70-11.74). MTA was <1.0% for 18 (27%) countries and 0 for 7 (10%) countries. There was a 460-fold disparity between the highest and lowest nonzero MTA regions and low-income countries had 88% lower MTA compared with high-income countries. The global MT operator availability was 16.5% of optimal and the MT center availability was 20.8% of optimal. On multivariable regression, country income level (low or lower-middle versus high: odds ratio, 0.08 [95% CI, 0.04-0.12]), MT operator availability (odds ratio, 3.35 [95% CI, 2.07-5.42]), MT center availability (odds ratio, 2.86 [95% CI, 1.84-4.48]), and presence of prehospital acute stroke bypass protocol (odds ratio, 4.00 [95% CI, 1.70-9.42]) were significantly associated with increased odds of MTA. CONCLUSIONS: Access to MT on a global level is extremely low, with enormous disparities between countries by income level. The significant determinants of MT access are the country's per capita gross national income, prehospital LVO triage policy, and MT operator and center availability.

Combining Early Ischemic Change and Collateral Extent for Functional Outcomes After Endovascular Therapy: An Analysis From AcT Trial.

BACKGROUND: Early ischemic change and collateral extent are colinear with ischemic core volume (ICV). We investigated the relationship between a combined score using the Alberta Stroke Program Early Computed Tomography Score and multiphase computed tomography angiography (mCTA) collateral extent, named mCTA-ACE score, on functional outcomes in endovascular therapy-treated patients. METHODS: We performed a post hoc analysis of a subset of endovascular therapy-treated patients from the Alteplase Compared to Tenecteplase trial which was conducted between December 2019 and January 2022 at 22 centers across Canada. Ten-point mCTA collateral corresponding to M2 to M6 regions of the Alberta Stroke Program Early Computed Tomography Score grid was evaluated as 0 (poor), 1 (moderate), or 2 (normal) and additively combined with the 10-point Alberta Stroke Program Early Computed Tomography Score to produce a 20-point mCTA-ACE score. We investigated the association of mCTA-ACE score with modified Rankin Scale score ≤2 and return to prestroke level of function at 90 to 120 days using mixed-effects logistic regression. In the subset of patients who underwent baseline computed tomography perfusion imaging, we compared the mCTA-ACE score and ICV for outcome prediction. RESULTS: Among 1577 intention-to-treat population in the trial, 368 (23%; 179 men; median age, 73 years) were included, with Alberta Stroke Program Early Computed Tomography Score, mCTA collateral, and combination of both (mCTA-ACE score: median [interquartile range], 8 [7-10], 9 [8-10], and 17 [16-19], respectively). The probability of modified Rankin Scale score ≤2 and return to prestroke level of function increased for each 1-point increase in mCTA-ACE score (odds ratio, 1.16 [95% CI, 1.06-1.28] and 1.22 [95% CI, 1.06-1.40], respectively). Among 173 patients in whom computed tomography perfusion data was assessable, the mCTA-ACE score was inversely correlated with ICV (ρ=-0.46; P<0.01). The mCTA-ACE score was comparable to ICV to predict a modified Rankin Scale score ≤2 and return to prestroke level of function (C statistics 0.71 versus 0.69 and 0.68 versus 0.64, respectively). CONCLUSIONS: The mCTA-ACE score had a significant positive association with functional outcomes after endovascular therapy and had a similar predictive performance as ICV.

What Is a Meaningful Difference When Using Infarct Volume as the Primary Outcome?: Results From the HERMES Database.

BACKGROUND: Ischemic stroke lesion volume at follow-up is an important surrogate outcome for acute stroke trials. We aimed to assess which differences in 48-hour lesion volume translate into meaningful clinical differences. METHODS: We used pooled data from 7 trials investigating the efficacy of endovascular treatment for anterior circulation large vessel occlusion in acute ischemic stroke. We assessed 48-hour lesion volume follow-up computed tomography or magnetic resonance imaging. The primary outcome was a good functional outcome, defined as modified Rankin Scale (mRS) scores of 0 to 2. We performed multivariable logistic regression to predict the probability of achieving mRS scores of 0 to 2 and determined the differences in 48-hour lesion volume that correspond to a change of 1%, 5%, and 10% in the adjusted probability of achieving mRS scores of 0 to 2. RESULTS: In total, 1665/1766 (94.2%) patients (median age, 68 [interquartile range, 57-76] years, 781 [46.9%] female) had information on follow-up ischemic lesion volume. Computed tomography was used for follow-up imaging in 83% of patients. The median 48-hour lesion volume was 41 (interquartile range, 14-120) mL. We observed a linear relationship between 48-hour lesion volume and mRS scores of 0 to 2 for adjusted probabilities between 65% and 20%/volumes <80 mL, although the curve sloped off for lower mRS scores of 0-2 probabilities/higher volumes. The median differences in 48-hour lesion volume associated with a 1%, 5%, and 10% increase in the probability of mRS scores of 0 to 2 for volumes <80 mL were 2 (interquartile range, 2-3), 10 (9-11), and 20 (18-23) mL, respectively. We found comparable associations when assessing computed tomography and magnetic resonance imaging separately. CONCLUSIONS: A difference of 2, 10, and 20 mL in 48-hour lesion volume, respectively, is associated with a 1%, 5%, and 10% absolute increase in the probability of achieving good functional outcome. These results can inform the design of future stroke trials that use 48-hour lesion volume as the primary outcome.

Sex-Based Analysis of Workflow and Outcomes in Acute Ischemic Stroke Patients Treated With Alteplase Versus Tenecteplase.

BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Risk of stroke within 3, 7, 14, 21 and 30 days after influenza vaccination in Alberta, Canada: A population-based study.

BACKGROUND AND PURPOSE: Influenza vaccination is associated with a longer-term protective effect against stroke; however, it has a short-term inflammatory response which may increase short-term risk of stroke. The aim was to investigate the association between influenza vaccination and short-term risk of stroke in adults. METHODS: Administrative data were obtained from the Alberta Health Care Insurance Plan for all adults in Alberta, Canada, from September 2009 to December 2018. The hazard of any stroke (acute ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage and transient ischaemic attack) within 3, 7, 14, 21 and 30 days of influenza vaccination compared to unexposed time was analysed using Andersen-Gill Cox models, with adjustment for age, sex, anticoagulant use, atrial fibrillation, chronic obstructive pulmonary disease, diabetes, hypertension, income quintile, and rural or urban home location. RESULTS: In the entire cohort consisting of 4,141,209 adults (29,687,899 person-years), 1,769,565 (42.7%) individuals received at least one vaccination. In total 38,126 stroke events were recorded with 1309 occurring within 30 days of a vaccination event. Influenza vaccination was associated with a significantly reduced hazard of stroke within 3 days (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.73-0.93), 7 days (HR 0.87, 95% CI 0.80-0.95), 14 days (HR 0.87, 95% CI 0.81-0.93), 21 days (HR 0.85, 95% CI 0.80-0.91) and 30 days (HR 0.66, 95% CI 0.65-0.68). CONCLUSIONS: An increased early risk associated with vaccination was not observed. The risk of stroke was reduced at all time points within 30 days after influenza vaccination.

Effect of Needle-To-Puncture Time on Reperfusion Outcome in Acute Ischemic Stroke.

INTRODUCTION: The aim of the study was to investigate the impact of time interval between start of intravenous thrombolysis (IVT) to start of endovascular thrombectomy (EVT) on stroke outcomes. METHODS: Data from the Quality Improvement and Clinical Research (QuICR) provincial stroke registry from Alberta, Canada, were used to identify stroke patients who received IVT and EVT from January 2015 to December 2019. We assessed the impact of the time interval between IVT bolus to EVT puncture (needle-to-puncture times [NPT]) on outcomes. Radiological outcomes included successful initial recanalization (revised Arterial Occlusive Lesion 2b-3), successful initial and final reperfusion (modified thrombolysis in cerebral infarction 2b-3). Clinical outcomes were 90-day modified Rankin Scale (mRS) and mortality. RESULTS: Of the 680 patients, 233 patients (median age: 73, 41% females) received IVT + EVT. Median NPT was 38 min (IQR, 24-60). Arrival during working hours was independently associated with shorter NPT (p < 0.001). Successful initial recanalization and initial and final reperfusion were observed in 12%, 10%, and 83% of patients, respectively. NPT was not associated with initial successful recanalization (OR 0.97 for every 10-min increase of NPT, 95% CI: 0.91-1.04), initial successful reperfusion (OR 1.01, 95% CI: 0.96-1.07), or final successful reperfusion (OR: 1.03, 95% CI: 0.97-1.08). Every 10-min delay in NPT was associated with lower odds of functional independence at 90 days (mRS ≤2; OR: 0.93; 95% CI, 0.88-0.97). Patients with shorter NPT (≤38 min) had lower 90-day mRS scores (median 1 vs. 3; OR: 0.54 [0.31-0.91]) and had lower mortality (6.1% vs. 21.2%; OR, 0.23 [0.10-0.57]) than the longer NPT group. CONCLUSION: Shorter NPT did not impact reperfusion outcomes but was associated with better clinical outcome.

Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial.

BACKGROUND: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 µg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01359202.

Cost-Effectiveness of Endovascular Treatment in Large Vessel Occlusion Stroke With Mild Prestroke Disability: Results From the HERMES Collaboration.

BACKGROUND: The clinical and economic benefit of endovascular treatment (EVT) in addition to best medical management in patients with stroke with mild preexisting symptoms/disability is not well studied. We aimed to investigate cost-effectiveness of EVT in patients with large vessel occlusion and mild prestroke symptoms/disability, defined as a modified Rankin Scale score of 1 or 2. METHODS: Data are from the HERMES collaboration (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials), which pooled patient-level data from 7 large, randomized EVT trials. We used a decision model consisting of a short-run model to analyze costs and functional outcomes within 90 days after the index stroke and a long-run Markov state transition model (cycle length of 12 months) to estimate expected lifetime costs and outcomes from a health care and a societal perspective. Incremental cost-effectiveness ratio and net monetary benefits were calculated, and a probabilistic sensitivity analysis was performed. RESULTS: EVT in addition to best medical management resulted in lifetime cost savings of $2821 (health care perspective) or $5378 (societal perspective) and an increment of 1.27 quality-adjusted life years compared with best medical management alone, indicating dominance of additional EVT as a treatment strategy. The net monetary benefits were higher for EVT in addition to best medical management compared with best medical management alone both at the higher (100 000$/quality-adjusted life years) and lower (50 000$/quality-adjusted life years) willingness to pay thresholds. Probabilistic sensitivity analysis showed decreased costs and an increase in quality-adjusted life years for additional EVT compared with best medical management only. CONCLUSIONS: From a health-economic standpoint, EVT in addition to best medical management should be the preferred strategy in patients with acute ischemic stroke with large vessel occlusion and mild prestroke symptoms/disability.

Infarcts in a New Territory: Insights From the ESCAPE-NA1 Trial.

BACKGROUND: Infarct in a new territory (INT) is a known complication of endovascular stroke therapy. We assessed the incidence of INT, outcomes after INT, and the impact of concurrent treatments with intravenous thrombolysis and nerinetide. METHODS: Data are from ESCAPE-NA1 trial (Safety and Efficacy of Nerinetide [NA-1] in Subjects Undergoing Endovascular Thrombectomy for Stroke), a multicenter, international randomized study that assessed the efficacy of intravenous nerinetide in subjects with acute ischemic stroke who underwent endovascular thrombectomy within 12 hours from onset. Concurrent treatment and outcomes were collected as part of the trial protocol. INTs were identified on core lab imaging review of follow-up brain imaging and defined by the presence of infarct in a new vascular territory, outside the baseline target occlusion(s) on follow-up brain imaging (computed tomography or magnetic resonance imaging). INTs were classified by maximum diameter (<2, 2-20, and >20 mm), number, and location. The association between INT and clinical outcomes (modified Rankin Scale and death) was assessed using standard descriptive techniques and adjusted estimates of effect were derived from Poisson regression models. RESULTS: Among 1092 patients, 103 had INT (9.3%, median age 69.5 years, 49.5% females). There were no differences in baseline characteristics between those with versus without INT. Most INTs (91/103, 88.3%) were not associated with visible occlusions on angiography and 39 out of 103 (37.8%) were >20 mm in maximal diameter. The most common INT territory was the anterior cerebral artery (27.8%). Almost half of the INTs were multiple (46 subjects, 43.5%, range, 2-12). INT was associated with poorer outcomes as compared to no INT on the primary outcome of modified Rankin Scale score of 0 to 2 at 90 days (adjusted risk ratio, 0.71 [95% CI, 0.57-0.89]). Infarct volume in those with INT was greater by a median of 21 cc compared with those without, and there was a greater risk of death as compared to patients with no INT (adjusted risk ratio, 2.15 [95% CI, 1.48-3.13]). CONCLUSIONS: Infarcts in a new territory are common in individuals undergoing endovascular thrombectomy for acute ischemic stroke and are associated with poorer outcomes. Optimal therapeutic approaches, including technical strategies, to reduce INT represent a new target for incremental quality improvement of endovascular thrombectomy. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02930018.

Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis.

BACKGROUND: Emerging data suggest that direct oral anticoagulants may be a suitable choice for anticoagulation for cerebral venous thrombosis (CVT). However, conducting high-quality trials in CVT is challenging as it is a rare disease with low rates of adverse outcomes such as major bleeding and functional dependence. To facilitate the design of future CVT trials, SECRET (Study of Rivaroxaban for Cerebral Venous Thrombosis) assessed (1) the feasibility of recruitment, (2) the safety of rivaroxaban compared with standard-of-care anticoagulation, and (3) patient-centered functional outcomes. METHODS: This was a phase II, prospective, open-label blinded-end point 1:1 randomized trial conducted at 12 Canadian centers. Participants were aged ≥18 years, within 14 days of a new diagnosis of symptomatic CVT, and suitable for oral anticoagulation; they were randomized to receive rivaroxaban 20 mg daily, or standard-of-care anticoagulation (warfarin, target international normalized ratio, 2.0-3.0, or low-molecular-weight heparin) for 180 days, with optional extension up to 365 days. Primary outcomes were annual rate of recruitment (feasibility); and a composite of symptomatic intracranial hemorrhage, major extracranial hemorrhage, or mortality at 180 days (safety). Secondary outcomes included recurrent venous thromboembolism, recanalization, clinically relevant nonmajor bleeding, and functional and patient-reported outcomes (modified Rankin Scale, quality of life, headache, mood, fatigue, and cognition) at days 180 and 365. RESULTS: Fifty-five participants were randomized. The rate of recruitment was 21.3 participants/year; 57% of eligible candidates consented. Median age was 48.0 years (interquartile range, 38.5-73.2); 66% were female. There was 1 primary event (symptomatic intracranial hemorrhage), 2 clinically relevant nonmajor bleeding events, and 1 recurrent CVT by day 180, all in the rivaroxaban group. All participants in both arms had at least partial recanalization by day 180. At enrollment, both groups on average reported reduced quality of life, low mood, fatigue, and headache with impaired cognitive performance. All metrics improved markedly by day 180. CONCLUSIONS: Recruitment targets were reached, but many eligible participants declined randomization. There were numerically more bleeding events in patients taking rivaroxaban compared with control, but rates of bleeding and recurrent venous thromboembolism were low overall and in keeping with previous studies. Participants had symptoms affecting their well-being at enrollment but improved over time. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03178864.

Effect of Time to Thrombolysis on Clinical Outcomes in Patients With Acute Ischemic Stroke Treated With Tenecteplase Compared to Alteplase: Analysis From the AcT Randomized Controlled Trial.

BACKGROUND: The AcT (Alteplase Compared to Tenecteplase) randomized controlled trial showed that tenecteplase is noninferior to alteplase in treating patients with acute ischemic stroke within 4.5 hours of symptom onset. The effect of time to treatment on clinical outcomes with alteplase is well known; however, the nature of this relationship is yet to be described with tenecteplase. We assessed whether the association of time to thrombolysis treatment with clinical outcomes in patients with acute ischemic stroke differs by whether they receive intravenous tenecteplase versus alteplase. METHODS: Patients included were from AcT, a pragmatic, registry-linked, phase 3 randomized controlled trial comparing intravenous tenecteplase to alteplase in patients with acute ischemic stroke. Eligible patients were >18 years old, with disabling neurological deficits, presenting within 4.5 hours of symptom onset, and eligible for thrombolysis. Primary outcome was modified Rankin Scale score 0 to 1 at 90 days. Safety outcomes included 24-hour symptomatic intracerebral hemorrhage and 90-day mortality rates. Mixed-effects logistic regression was used to assess the following: (a) the association of stroke symptom onset to needle time; (b) door (hospital arrival) to needle time with outcomes; and (c) if these associations were modified by type of thrombolytic administered (tenecteplase versus alteplase), after adjusting for age, sex, baseline stroke severity, and site of intracranial occlusion. RESULTS: Of the 1538 patients included in this analysis, 1146 (74.5%; 591 tenecteplase and 555 alteplase) presented within 3 hours versus 392 (25.5%; 196: TNK and 196 alteplase) who presented within 3 to 4.5 hours of symptom onset. Baseline patient characteristics in the 0 to 3 hours versus 3- to 4.5-hour time window were similar, except patients in the 3- to 4.5-hour window had lower median baseline National Institutes of Health Stroke Severity Scale (10 versus 7, respectively) and lower proportion of patients with large vessel occlusion on baseline CT angiography (26.9% versus 18.7%, respectively). Type of thrombolytic agent (tenecteplase versus alteplase) did not modify the association between continuous onset to needle time (Pinteraction=0.161) or door-to-needle time (Pinteraction=0.972) and primary clinical outcome. Irrespective of the thrombolytic agent used, each 30-minute reduction in onset to needle time was associated with a 1.8% increase while every 10 minutes reduction in door-to-needle time was associated with a 0.2% increase in the probability of achieving 90-day modified Rankin Scale score 0 to 1, respectively. CONCLUSIONS: The effect of time to tenecteplase administration on clinical outcomes is like that of alteplase, with faster administration resulting in better clinical outcomes. REGISTRATION: URL: https://classic. CLINICALTRIALS: gov; Unique identifier: NCT03889249.

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.

Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown. METHODS: In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26-52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete. FINDINGS: Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0-4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79-1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93-1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85-1·32]; t statistic -0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91-2·71]). INTERPRETATION: In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke. FUNDING: Bayer AG.

Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial.

BACKGROUND: Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care. METHODS: In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual. FINDINGS: Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis. FUNDING: Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Recanalization and Functional Outcome in Patients with Cervico-cephalic Arterial Dissections.

BACKGROUND: Cervico-cephalic arterial dissections (CeAD) are an important cause of stroke in young patients. This study aimed to determine the frequency and predictors of recanalization in spontaneous CeAD and to study the effect of recanalization on functional outcomes. METHODS: We identified patients presenting with acute ischemic stroke secondary to CeAD from the CT angiography (CTA) database of the Calgary Stroke Program. Dissections were diagnosed based on standard clinical and imaging findings. At the discretion of treating stroke Neurologists, the patients were either treated with single antiplatelet or dual antiplatelet or triple therapy. Follow-up imaging with CTA, magnetic resonance imaging, and DSA was completed, and a Modified Rankin scale (mRS) was performed to determine the outcome. RESULTS: Fifty-six patients with CeAdD were studied. Thirty-four patients (18 VAD; vertebral artery dissection and 16 CAD; carotid artery dissection) were followed up for recanalization. Complete recanalization was observed in 27 subjects; 13 patients with VAD recanalized in comparison to 14 with CAD (p = 0.40). All non-recanalized patients had hypertension. A good clinical outcome (mRS ≤ 2) was observed in 47 patients. Interestingly, the likelihood of a good neurological outcome was not influenced by recanalization status. There was no difference in clinical outcome for different sites in VAD, whereas patients with intracranial CAD had severe strokes (NIHSS > 21). CONCLUSIONS: CeAD has good recanalization rates and neurological outcomes, with recanalization seen even in vessels with initial complete occlusion. The presence of hypertension may influence recanalization. The efficacy of dual antiplatelets and heparin for early recanalization needs to be assessed in future clinical trials.

Vertebral to Basilar Thrombus Migration Post Intravenous Thrombolysis.

Recombinant tissue plasminogen activator improves outcomes in acute ischemic stroke. Alteplase may result in thrombus migration (TM) distally to a critical arterial supply that can worsen perfusion to eloquent brain tissue. Alteplase-related stroke recanalization and clot migration in vertebral artery (VA) occlusion whereby the clot migrates to the basilar artery (BA) may be harmful. We identified seven subjects with isolated symptomatic vertebral occlusion. Two cases suffered early neurologic deterioration due to TM from VA to BA following alteplase. Precautionary transfer to thrombectomy centers may be warranted in alteplase-treated symptomatic VA occlusions in case of migration to basilar occlusion.

Prevalence of high-risk aortic arch atherosclerosis features on computed tomography angiography in embolic stroke of undetermined source.

INTRODUCTION: Embolic stroke of undetermined source (ESUS) comprises a heterogenous group. There is a need to further identify etiologies within this group to guide management strategies. We examined the prevalence of aortic arch atherosclerosis (AAA) on CT angiography (CTA) in patients with embolic stroke of undetermined source (ESUS) to characterize high-risk plaque features. METHODS: All patients from two prospective multicenter acute ischemic stroke studies (INTERRSeCT and PRove-IT) were included if the CTA adequately imaged the proximal aortic arch and the stroke etiology was recorded. Three readers blinded to stroke etiology analyzed the following AAA plaque features on baseline CTA at the time of stroke: 1) thickness in millimetres (mm); 2) morphology (none, smooth, ulcerated, or protruding); 3) location within the aortic arch (proximal, transverse, or distal); and 4) calcification (none, single small, multiple small, single large, or diffuse extensive). RESULTS: We included 1063 patients, of which 293 (27.6%) had ESUS (mean age 67.5 years; 46.4% men; median NIHSS 12; 80.6% large vessel occlusion). Mean AAA thickness was significantly larger in ESUS patients (3.8 mm) compared to non-ESUS patients (3.0 mm; p<0.0001) and to a subgroup of patients with large artery atherosclerosis (2.9 mm; p=0.003). ESUS patients had a significantly higher proportion of ulcerated or protruding plaques (17.4% vs 10.3%; risk ratio 1.7, 95% C.I. 1.2-2.4, p=0.002). The location of AAA in the ESUS group was the ascending aorta in 37.9%, transverse arch in 42.3%, and descending aorta in 84.6%. Although AAA was mostly located in the distal aortic arch, ulcerated or protruding plaques were least common in the distal arch (p=0.002). There was no difference between ESUS and non-ESUS patients in plaque location (p=0.23) or calcification grade (p=0.092). CONCLUSION: ESUS patients in our study had thicker AAA and a higher prevalence of ulcerated or protruding plaques located more proximally within the aortic arch. High-risk plaque features may suggest a causal role of AAA in the ESUS population with visible intracranial occlusions.

Radiographic Characteristics of Mild Ischemic Stroke Patients With Visible Intracranial Occlusion: The INTERRSeCT Study.

BACKGROUND AND PURPOSE: Early neurological deterioration occurs in one-third of mild strokes primarily due to the presence of a relevant intracranial occlusion. We studied vascular occlusive patterns, thrombus characteristics, and recanalization rates in these patients. METHODS: Among patients enrolled in INTERRSeCT (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography), a multicenter prospective study of acute ischemic strokes with a visible intracranial occlusion, we compared characteristics of mild (National Institutes of Health Stroke Scale score, ≤5) to moderate/severe strokes. RESULTS: Among 575 patients, 12.9% had a National Institutes of Health Stroke Scale score ≤5 (median age, 70.5 [63-79]; 58% male; median National Institutes of Health Stroke Scale score, 4 [2-4]). Demographics and vascular risk factors were similar between the two groups. As compared with those with a National Institutes of Health Stroke Scale score >5, mild patients had longer symptom onset to assessment times (onset to computed tomography [240 versus 167 minutes] and computed tomography angiography [246 versus 172 minutes]), more distal occlusions (M3, anterior cerebral artery and posterior cerebral artery; 22% versus 6%), higher clot burden score (median, 9 [6-9] versus 6 [4-9]), similar favorable thrombus permeability (residual flow grades I-II, 21% versus 19%), higher collateral flow (9.1 versus 7.6), and lower intravenous alteplase treatment rates (55% versus 85%). Mild patients were more likely to recanalize (revised arterial occlusion scale score 2b/3, 45%; 49% with alteplase) compared with moderate/severe strokes (26%; 29% with alteplase). In an adjusted model for sex, alteplase, residual flow, and time between the two vessel imagings, intravenous alteplase use (odds ratio, 3.80 [95% CI, 1.11-13.00]) and residual flow grade (odds ratio, 8.70 [95% CI, 1.26-60.13]) were associated with successful recanalization among mild patients. CONCLUSIONS: Mild strokes with visible intracranial occlusions have different vascular occlusive patterns but similar thrombus permeability compared with moderate/severe strokes. Higher thrombus permeability and alteplase use were associated with successful recanalization, although the majority do not recanalize. Randomized controlled trials are needed to assess the efficacy of new thrombolytics and endovascular therapy in this population.