Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

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.

Concurrent Outbreaks of Hepatitis A, Invasive Meningococcal Disease, and Mpox, Florida, USA, 2021-2022.

In 2022, concurrent outbreaks of hepatitis A, invasive meningococcal disease (IMD), and mpox were identified in Florida, USA, primarily among men who have sex with men. The hepatitis A outbreak (153 cases) was associated with hepatitis A virus genotype IA. The IMD outbreak (44 cases) was associated with Neisseria meningitidis serogroup C, sequence type 11, clonal complex 11. The mpox outbreak in Florida (2,845 cases) was part of a global epidemic. The hepatitis A and IMD outbreaks were concentrated in Central Florida and peaked during March--June, whereas mpox cases were more heavily concentrated in South Florida and had peak incidence in August. HIV infection was more common (52%) among mpox cases than among hepatitis A (21%) or IMD (34%) cases. Where feasible, vaccination against hepatitis A, meningococcal disease, and mpox should be encouraged among at-risk groups and offered along with program services that target those groups.

Tensor-valued diffusion MRI of human acute stroke.

PURPOSE: Tensor-valued diffusion encoding can disentangle orientation dispersion and subvoxel anisotropy, potentially offering insight into microstructural changes after cerebral ischemia. The purpose was to evaluate tensor-valued diffusion MRI in human acute ischemic stroke, assess potential confounders from diffusion time dependencies, and compare to Monte Carlo diffusion simulations of axon beading. METHODS: Linear (LTE) and spherical (STE) b-tensor encoding with inherently different effective diffusion times were acquired in 21 acute ischemic stroke patients between 3 and 57 h post-onset at 3 T in 2.5 min. In an additional 10 patients, STE with 2 LTE yielding different effective diffusion times were acquired for comparison. Diffusional variance decomposition (DIVIDE) was used to estimate microscopic anisotropy (µFA), as well as anisotropic, isotropic, and total diffusional variance (MKA , MKI , MKT ). DIVIDE parameters, and diffusion tensor imaging (DTI)-derived mean diffusivity and fractional anisotropy (FA) were compared in lesion versus contralateral white matter. Monte Carlo diffusion simulations of various cylindrical geometries for all b-tensor protocols were used to interpret parameter measurements. RESULTS: MD was ˜40% lower in lesions for all LTE/STE protocols. The DIVIDE parameters varied with effective diffusion time: higher µFA and MKA in lesion versus contralateral white matter for STE with longer effective diffusion time LTE, whereas the shorter effective diffusion time LTE protocol yielded lower µFA and MKA in lesions. Both protocols, regardless of diffusion time, were consistent with simulations of greater beading amplitude and intracellular volume fraction. CONCLUSION: DIVIDE parameters depend on diffusion time in acute stroke but consistently indicate neurite beading and larger intracellular volume fraction.

Direct to Angiosuite in Acute Stroke with Mobile Stroke Unit.

BACKGROUND: Early reperfusion has the best likelihood for a favorable outcome in acute ischemic stroke (AIS) with large vessel occlusion (LVO). Our experience with mobile stroke unit (MSU) for direct to angiosuite (DTAS) transfer in AIS patients with suspected LVO is presented. METHODS: Retrospective review of prospectively collected data from November 2019 to August 2022, of patients evaluated and transferred by the University of Alberta Hospital MSU and moved to angiosuite for endovascular thrombectomy (EVT). RESULT: A total of 41 cases were included. Nine were chosen for DTAS and 32 were shifted to angiosuite after stopping for computed tomography (CT) angiography of the head and neck (no-DTAS). Stroke severity measured by NIHSS (median with interquartile range (IQR)) was higher in patients of DTAS, 22 (14-24) vs 14.5 (5-25) in no-DTAS (p = 0.001). The non-contrast CT head in MSU showed hyperdense vessels in 8 (88.88%) DTAS vs 11 (34.35%) no-DTAS patients (p = 0.003). The EVT timelines (median with IQR, 90th percentile) including "door to artery puncture time" were 31 (23-50, 49.2) vs 79 (39-264, 112.8) minutes, and "door to recanalization time" was 69 (49-110, 93.2) vs 105.5 (52-178, 159.5) minutes in DTAS vs no-DTAS group, respectively. The workflow times were significantly shorter in the DTAS group (p < 0.001). Eight (88.88%) out of 9 DTAS patients had LVO and underwent thrombectomy. CONCLUSIONS: MSU for DTAS in patients with high NIHSS scores, cortical signs, and CT showing hyperdense vessel is an effective strategy to reduce the EVT workflow time.

Optimizing Triage: Assessing Shock Index, Pediatric Age-Adjusted as an Adjunct to Improve Emergency Severity Index Mistriage.

OBJECTIVE: We investigated the diagnostic value of shock index, pediatric age-adjusted (SIPA) in predicting Emergency Severity Index level 3 patients' outcomes. Secondary objectives included exploring the impact of fever and participant variables on SIPA's predictive ability. METHODS: A retrospective chart review identified children aged 1 to 15 years triaged as a level 3 in the emergency department between January 2018 and December 2021. Shock index, pediatric age-adjusted thresholds based on age, 1 to 6 years (>1.2), 7 to 12 years (>1.0), and 13 to 17 years (>0.9), were used. We assessed elevated SIPA and SIPA corrected for fever to evaluate associations with outcomes and interventions. RESULTS: Our findings, involving 192 patients, revealed that elevated SIPA demonstrated enhanced discrimination relative to nonelevated SIPA. Patients with elevated SIPA had more average interventions: 1.14 versus 0.74, P < 0.016; average interventions using SIPA corrected for fever: 1.14 versus 0.77, P < 0.006; average interventions controlling for race and sex: 1.15 versus 0.71, P < 0.001; hospital admission: 64.4% versus 42.9%, P = 0.004; hospital length of stay (LOS): 3.06 days (SE, 0.42) versus 1.46 days (SE, 0.23); hospital LOS using SIPA corrected for fever: 2.75 days (SE, 0.44) versus 1.72 days (SE, 0.24); ventilatory support: 16.44% versus 3.36%, P < 0.002; fluid bolus: 28.77% versus 14.29%, P < 0.015; intravenous medications (antibiotics, antiepileptics, immune globulin, albumin): 45.21% versus 30.25%, P < 0.036. There was no difference between other interventions, pediatric intensive care admission, and LOS between the 2 groups. Importantly, SIPA was unaffected by fever, race, or sex. CONCLUSIONS: Shock index, pediatric age-adjusted identifies level 3 Emergency Severity Index pediatric patients more likely to require hospital admission, longer LOS, and a lifesaving intervention especially ventilatory support, intravenous fluids, or specific intravenous medications. Shock index, pediatric age-adjusted's predictive ability remained unaffected by fever, race, or sex, making it a valuable tool in preventing mistriage and justifying inclusion in the Emergency Severity Index danger zone vitals criteria for up-triage.

CT Perfusion Map Synthesis from CTP Dynamic Images Using a Learned LSTM Generative Adversarial Network for Acute Ischemic Stroke Assessment.

Computed tomography perfusion (CTP) is a dynamic 4-dimensional imaging technique (3-dimensional volumes captured over approximately 1 min) in which cerebral blood flow is quantified by tracking the passage of a bolus of intravenous contrast with serial imaging of the brain. To diagnose and assess acute ischemic stroke, the standard method relies on summarizing acquired CTPs over the time axis to create maps that show different hemodynamic parameters, such as the timing of the bolus arrival and passage (Tmax and MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV). However, producing accurate CTP maps requires the selection of an arterial input function (AIF), i.e. a time-concentration curve in one of the large feeding arteries of the brain, which is a highly error-prone procedure. Moreover, during approximately one minute of CT scanning, the brain is exposed to ionizing radiation that can alter tissue composition, and create free radicals that increase the risk of cancer. This paper proposes a novel end-to-end deep neural network that synthesizes CTP images to generate CTP maps using a learned LSTM Generative Adversarial Network (LSTM-GAN). Our proposed method can improve the precision and generalizability of CTP map extraction by eliminating the error-prone and expert-dependent AIF selection step. Further, our LSTM-GAN does not require the entire CTP time series and can produce CTP maps with a reduced number of time points. By reducing the scanning sequence from about 40 to 9 time points, the proposed method has the potential to minimize scanning time thereby reducing patient exposure to CT radiation. Our evaluations using the ISLES 2018 challenge dataset consisting of 63 patients showed that our model can generate CTP maps by using only 9 snapshots, without AIF selection, with an accuracy of 84.37 % .

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.

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.

Advances in the management of acute ischemic stroke.

PURPOSE OF REVIEW: This review aims to summarize the therapeutic advances and evidence in the medical management of acute ischemic stroke (AIS). Recent evidence comparing the efficacy and safety of tenecteplase (TNK) with alteplase for intravenous thrombolysis (IVT) in AIS will be highlighted. Recent advances and evidence on improving micro-circulation following endovascular procedures and neuroprotection will be reviewed. RECENT FINDINGS: A significant number of randomized control studies now support the use of tenecteplase for IVT in AIS. TNK 0.25 mg/kg single bolus is as effective and well tolerated as alteplase 0.9 mg/kg infusion for IVT in AIS. Evidence from randomized control trials (RCTs) has shown effective and well tolerated expansion of the therapeutic window of IVT in the wake-up stroke and up to 9 h after last seen well, using advanced neuroimaging with computed tomography perfusion/MRI. Early evidence suggests that intra-arterial alteplase may help improve microcirculation in patients with large vessel occlusion following successful thrombectomy. However, more trials are required to confirm the results. Similarly, early evidence from a recent RCT showed that remote ischemic conditioning confers potential neuroprotection and improves outcomes in AIS. SUMMARY: Converging evidence has demonstrated that for patients with ischemic stroke presenting at under 4.5 h from the onset, TNK is comparable to alteplase. These data along with the practical advantages of TNK have resulted in a shift to replace intravenous TNK as the standard for thrombolysis. Ongoing studies of IVT with TNK are focussed on defining the optimal dose, expanding the time window with multimodal imaging and defining the role of thrombolysis for bridging patients with stroke due to large vessel occlusion.

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.

Timing of Anticoagulation after Acute Ischemic Stroke in Patients with Atrial Fibrillation.

Patients with atrial fibrillation (AF) and ischemic stroke are at high risk for stroke recurrence. Early anticoagulation may reduce the risk of recurrent events but is usually avoided due to the risk of hemorrhagic transformation (HT). Current guidelines are based on empiric expert opinion. The assumed risk of HT is based on historical data from an older generation of anticoagulants. The direct oral anticoagulants (DOACs) have demonstrated lower risk of intracranial hemorrhage compared to older anticoagulants. However, the optimal timing of DOAC initiation after AF-related ischemic stroke has remained an area of clinical equipoise, as the pivotal phase III trials did not include patients in the early period after ischemic stroke. Multiple prospective studies and a few smaller randomized controlled trials evaluating the safety and efficacy of early versus delayed DOAC initiation have been completed. These studies have reported promising results of early DOAC initiation after acute ischemic stroke. However, a standardized documentation of HT rates on follow-up imaging with objective assessment criteria is missing from most of these studies. Larger randomized trials of early versus delayed DOAC are ongoing. A literature review was performed using keywords and Medical Subject Headings in MEDLINE/PubMed and Google Scholar databases. For each relevant paper, the bibliography was scrutinized for other relevant articles and journals. In this article, we review the risk of recurrent ischemic stroke and HT in patients with AF, pathophysiology, classification, predictors, natural history, and outcomes of HT and discuss the studies of early anticoagulation after AF-related ischemic stroke.

Ethical Justification for Deferral of Consent in the AcT Trial for Acute Ischemic Stroke.

The AcT trial (Alteplase Compared to Tenecteplase) compares alteplase or tenecteplase for patients with acute ischemic stroke. All eligible patients are enrolled by deferral of consent. Although the use of deferral of consent in the AcT trial meets the requirements of Canadian policy, we sought to provide a more explicit and rigorous approach to the justification of deferral of consent organized around 3 questions. Ultimately, the approach we outline here could become the foundation for a general justification for deferral of consent.

Outcomes of Cerebral Venous Thrombosis due to Vaccine-Induced Immune Thrombotic Thrombocytopenia After the Acute Phase.

BACKGROUND: Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe condition, with high in-hospital mortality rates. Here, we report clinical outcomes of patients with CVT-VITT after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccination who survived initial hospitalization. METHODS: We used data from an international registry of patients who developed CVT within 28 days of SARS-CoV-2 vaccination, collected until February 10, 2022. VITT diagnosis was classified based on the Pavord criteria. Outcomes were mortality, functional independence (modified Rankin Scale score 0-2), VITT relapse, new thrombosis, and bleeding events (all after discharge from initial hospitalization). RESULTS: Of 107 CVT-VITT cases, 43 (40%) died during initial hospitalization. Of the remaining 64 patients, follow-up data were available for 60 (94%) patients (37 definite VITT, 9 probable VITT, and 14 possible VITT). Median age was 40 years and 45/60 (75%) patients were women. Median follow-up time was 150 days (interquartile range, 94-194). Two patients died during follow-up (3% [95% CI, 1%-11%). Functional independence was achieved by 53/60 (88% [95% CI, 78%-94%]) patients. No new venous or arterial thrombotic events were reported. One patient developed a major bleeding during follow-up (fatal intracerebral bleed). CONCLUSIONS: In contrast to the high mortality of CVT-VITT in the acute phase, mortality among patients who survived the initial hospitalization was low, new thrombotic events did not occur, and bleeding events were rare. Approximately 9 out of 10 CVT-VITT patients who survived the acute phase were functionally independent at follow-up.

Return on Investment in Endovascular Care: The Case of Endovascular Reperfusion Alberta.

OBJECTIVE: We examined the return on investment (ROI) from the Endovascular Reperfusion Alberta (ERA) project, a provincially funded population-wide strategy to improve access to endovascular therapy (EVT), to inform policy regarding sustainability. METHODS: We calculated net benefit (NB) as benefit minus cost and ROI as benefit divided by cost. Patients treated with EVT and their controls were identified from the ESCAPE trial. Using the provincial administrative databases, their health services utilization (HSU), including inpatient, outpatient, physician, long-term care services, and prescription drugs, were compared. This benefit was then extrapolated to the number of patients receiving EVT increased in 2018 and 2019 by the ERA implementation. We used three time horizons, including short (90 days), medium (1 year), and long-term (5 years). RESULTS: EVT was associated with a reduced gross HSU cost for all the three time horizons. Given the total costs of ERA were $2.04 million in 2018 ($11,860/patient) and $3.73 million in 2019 ($17,070/patient), NB per patient in 2018 (2019) was estimated at -$7,313 (-$12,524), $54,592 ($49,381), and $47,070 ($41,859) for short, medium, and long-term time horizons, respectively. Total NB for the province in 2018 (2019) were -$1.26 (-$2.74), $9.40 ($10.78), and $8.11 ($9.14) million; ROI ratios were 0.4 (0.3), 5.6 (3.9) and 5.0 (3.5). Probabilities of ERA being cost saving were 39% (31%), 97% (96%), and 94% (91%), for short, medium, and long-term time horizons, respectively. CONCLUSION: The ERA program was cost saving in the medium and long-term time horizons. Results emphasized the importance of considering a broad range of HSU and long-term impact to capture the full ROI.

Comparing the Prognostic Impact of Age and Baseline National Institutes of Health Stroke Scale in Acute Stroke due to Large Vessel Occlusion.

Background and Purpose: Little is known about the combined effect of age and National Institutes of Health Stroke Scale (NIHSS) in endovascular treatment (EVT) for acute ischemic stroke due to large vessel occlusion, and it is not clear how the effects of baseline age and NIHSS on outcome compare to each other. The previously described Stroke Prognostication Using Age and NIHSS (SPAN) index adds up NIHSS and age to a 1:1 combined prognostic index. We added a weighting factor to the NIHSS/age SPAN index to compare the relative prognostic impact of NIHSS and age and assessed EVT effect based on weighted age and NIHSS. Methods: We performed adjusted logistic regression with good outcome (90-day modified Rankin Scale score 0­2) as primary outcome. From this model, the coefficients for NIHSS and age were obtained. The ratio between the NIHSS and age coefficients was calculated to determine a weighted SPAN index. We obtained adjusted effect size estimates for EVT in patient subgroups defined by weighted SPAN increments of 3, to evaluate potential changes in treatment effect. Results: We included 1750/1766 patients from the HERMES collaboration (Highly Effective Reperfusion Using Multiple Endovascular Devices) with available age and NIHSS data. Median NIHSS was 17 (interquartile range, 13­21), and median age was 68 (interquartile range, 57­76). Good outcome was achieved by 682/1743 (39%) patients. The NIHSS/age effect coefficient ratio was ([−0.0032]/[−0.111])=3.4, which was rounded to 3, resulting in a weighted SPAN index defined as ([3×NIHSS]+age). Cumulative EVT effect size estimates across weighted SPAN subgroups consistently favored EVT, with a number needed to treat ranging from 5.3 to 8.7. Conclusions: The impact on chance of good outcome of a 1-point increase in NIHSS roughly corresponded to a 3-year increase in patient age. EVT was beneficial across all weighted age/NIHSS subgroups.

Health-Related Quality of Life Among Patients With Acute Ischemic Stroke and Large Vessel Occlusion in the ESCAPE Trial.

Background and Purpose: Endovascular thrombectomy (EVT) reduces 90-day disability in patients following acute ischemic stroke due to large vessel occlusion. Patient-reported outcome measures after EVT, such as health-related quality of life and specific functional domains, are less well described. Methods: We report outcomes on the EuroQol-5D (EQ-5D) from the ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) randomized controlled trial at 90 days after stroke. Death was assigned an index value of 0 for EQ-5D. We used quantile regression to evaluate the association between EVT and EQ-5D index scores and logistic regression for the association between EVT and symptom-free status among 90-day survivors for each EQ-5D dimension (self-care, usual activities, mobility, pain/discomfort, and anxiety/depression), assessing for modification by age or sex and adjusting for baseline factors including stroke severity, affected hemisphere, and receipt of alteplase. Lastly, the association between severe disability at 90 days and EQ-5D was evaluated with assessment for modification by EVT, age, and sex. Results: There were 165 patients randomized to EVT and 150 patients randomized to control. Median EQ-5D was significantly higher for those who received EVT compared with best medical management (0.80 versus 0.60; P<0.001). After accounting for the greater number of deaths in the elderly, there was evidence of modification of treatment effect by age, with older age associated with a larger effect size difference in EQ-5D with EVT. Those receiving EVT had higher odds of symptom-free status in self-care, usual activities, mobility for those aged 60 to 79 years, and pain/discomfort for women, but there was no association with anxiety/depression. Severe disability at 90 days was associated with lower EQ-5D in older compared with younger individuals, and the association was not modified by EVT. Conclusions: Patients treated with EVT report substantially improved health-related quality of life, with relatively greater impact in older individuals and observed benefit across multiple dimensions.

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Radiologic Patterns of Intracranial Hemorrhage and Clinical Outcome after Endovascular Treatment in Acute Ischemic Stroke: Results from the ESCAPE-NA1 Trial.

Background Intracranial hemorrhage is a known complication after endovascular treatment in patients with acute ischemic stroke due to large vessel occlusion, but the association between radiologic hemorrhage severity and outcome is controversial. Purpose To investigate the prevalence and impact on outcome of intracranial hemorrhage and hemorrhage severity after endovascular stroke treatment. Materials and Methods The Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke (ESCAPE-NA1) trial enrolled participants with acute large vessel occlusion stroke who underwent endovascular treatment from March 1, 2017, to August 12, 2019. Evidence of any intracranial hemorrhage, hemorrhage multiplicity, and radiologic severity, according to the Heidelberg classification (hemorrhagic infarction type 1 [HI1], hemorrhagic infarction type 2 [HI2], parenchymal hematoma type 1 [PH1], and parenchymal hematoma type 2 [PH2]) was assessed at CT or MRI 24 hours after endovascular treatment. Good functional outcome, defined as a modified Rankin score of 0-2 at 90 days, was compared between participants with intracranial hemorrhage and those without intracranial hemorrhage at follow-up imaging and between hemorrhage subtypes. Poisson regression was performed to obtain adjusted effect size estimates for the presence of any intracranial hemorrhage and hemorrhage subtypes at good functional outcome. Results Of 1097 evaluated participants (mean age, 69 years ± 14 [standard deviation]; 551 men), any degree of intracranial hemorrhage was observed in 372 (34%). Good outcomes were less often achieved among participants with hemorrhage than among those without hemorrhage at follow-up imaging (164 of 372 participants [44%] vs 500 of 720 [69%], respectively; P < .01). After adjusting for baseline variables and infarct volume, intracranial hemorrhage was not associated with decreased chances of good outcome (adjusted risk ratio [RR] = 0.91 [95% CI: 0.82, 1.02], P = .10), but there was a graded relationship of radiologic hemorrhage severity and outcomes, whereby PH1 (RR = 0.77 [95% CI: 0.61, 0.97], P = .03) and PH2 (RR = 0.41 [95% CI: 0.21, 0.81], P = .01) were associated with decreased chances of good outcome. Conclusion Any degree of intracranial hemorrhage after endovascular treatment was seen in one-third of participants. A graded association existed between radiologic hemorrhage severity and outcome. Hemorrhagic infarction was not associated with outcome, whereas parenchymal hematoma was strongly associated with poor outcome, independent of infarct volume. © RSNA, 2021 Clinical trial registration no. NCT01778335 Online supplemental material is available for this article.

Nitroglycerin Is Not Associated with Improved Cerebral Perfusion in Acute Ischemic Stroke.

OBJECTIVE: The study was conducted to test the hypothesis that nitroglycerin (NTG) increases cerebral perfusion focally and globally in acute ischemic stroke patients, using serial perfusion-weighted imaging (PWI) magnetic resonance imaging measurements. PATIENTS AND METHODS: Thirty-five patients underwent PWI immediately before and 72 h after administration of a transdermal NTG patch or no treatment. Patients with baseline mean arterial pressure (MAP) > 100 mmHg (NTG group, n = 20) were treated with transdermal NTG (0.2 mg/h) for 72 h, without a nitrate-free interval. Patients with MAP ≤ 100 mmHg (untreated group, n = 15) were not treated. The primary outcome measure was absolute cerebral blood flow (CBF) in the hypoperfused region at 72 h. RESULTS: The mean baseline absolute CBF in the hypoperfused region was similar in the NTG group (33.3 ± 10.2 ml/100 g/min) and untreated (32.7 ± 8.4 ml/100 g/min, p = 0.4) groups. The median (IQR) baseline infarct volume was 10.4 (2.5-49.3) ml in the NTG group and 32.6 (8.6-96.7) ml in the untreated group (p = 0.09). MAP change in the NTG group was 1.2 ± 12.6 and 8 ± 20.7 mmHg at 2 h and 72 h, respectively. Mean absolute CBF in the hypoperfused region at 72 h was similar in the NTG (29.9 ± 12 ml/100 g/min) and untreated groups (24.1 ± 10 ml/100 g/min, p = 0.8). The median infarct volume increased in untreated (11.8 (5.7-44.2) ml) than the NTG group (3.2 (0.5-16.5) ml; p = 0.033) on univariate analysis, however, there was no difference on regression analysis. CONCLUSION: NTG was not associated with improvement in cerebral perfusion in acute ischemic stroke patients.