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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. 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. 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 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. Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Background In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. Methods Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4–6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. Results Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5–5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. Conclusion In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. Impact Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

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. 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. 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. Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

ObjectiveThe Pragmatic Ischaemic Thrombectomy Evaluation (PISTE) trial was a multicentre, randomised, controlled clinical trial comparing intravenous thrombolysis (IVT) alone with IVT and adjunctive intra-arterial mechanical thrombectomy (MT) in patients who had acute ischaemic stroke with large artery occlusive anterior circulation stroke confirmed on CT angiography (CTA).DesignEligible patients had IVT started within 4.5 hours of stroke symptom onset. Those randomised to additional MT underwent thrombectomy using any Conformité Européene (CE)-marked device, with target interval times for IVT start to arterial puncture of <90 min. The primary outcome was the proportion of patients achieving independence defined by a modified Rankin Scale (mRS) score of 0–2 at day 90.ResultsTen UK centres enrolled 65 patients between April 2013 and April 2015. Median National Institutes of Health Stroke Scale score was 16 (IQR 13–21). Median stroke onset to IVT start was 120 min. In the intention-to-treat analysis, there was no significant difference in disability-free survival at day 90 with MT (absolute difference 11%, adjusted OR 2.12, 95% CI 0.65 to 6.94, p=0.20). Secondary analyses showed significantly greater likelihood of full neurological recovery (mRS 0–1) at day 90 (OR 7.6, 95% CI 1.6 to 37.2, p=0.010). In the per-protocol population (n=58), the primary and most secondary clinical outcomes significantly favoured MT (absolute difference in mRS 0–2 of 22% and adjusted OR 4.9, 95% CI 1.2 to 19.7, p=0.021).ConclusionsThe trial did not find a significant difference between treatment groups for the primary end point. However, the effect size was consistent with published data and across primary and secondary end points. Proceeding as fast as possible to MT after CTA confirmation of large artery occlusion on a background of intravenous alteplase is safe, improves excellent clinical outcomes and, in the per-protocol population, improves disability-free survival.Trial registration numberNCT01745692; Results.

About 13–26% of all acute ischaemic strokes are related to non-valvular atrial fibrillation, the most common cardiac arrhythmia globally. Deciding when to initiate oral anticoagulation in patients with non-valvular atrial fibrillation is a longstanding, common, and unresolved clinical challenge. Although the risk of early recurrent ischaemic stroke is high in this population, early oral anticoagulation is suspected to increase the risk of potentially harmful intracranial haemorrhage, including haemorrhagic transformation of the infarct. This assumption, and current treatment guidelines, are based on historical, mostly observational data from patients with ischaemic stroke and atrial fibrillation treated with heparins, heparinoids, or vitamin K antagonists (VKAs) to prevent recurrent ischaemic stroke. Randomised controlled trials have subsequently shown that direct oral anticoagulants (DOACs; ie, apixaban, dabigatran, edoxaban, and rivaroxaban) are at least as effective as VKAs in primary and secondary prevention of atrial fibrillation-related ischaemic stroke, with around half the risk of intracranial haemorrhage. However, none of these DOAC trials included patients who had experienced ischaemic stroke recently (within the first few weeks). Clinicians therefore remain uncertain regarding when to commence DOAC administration after acute ischaemic stroke in patients with atrial fibrillation. Prospective observational studies and two small randomised trials have investigated the risks and benefits of early DOAC-administration initiation (most with a median delay of 3–5 days) in mild-to-moderate atrial fibrillation-associated ischaemic stroke. These studies reported that early DOAC treatment was associated with a low frequency of clinically symptomatic intracranial haemorrhage or surrogate haemorrhagic lesions on MRI scans, whereas later DOAC-administration initiation (ie, >7 days or >14 days after index stroke) was associated with an increased frequency of recurrent ischaemic stroke. Adequately powered randomised controlled trials comparing early to later oral anticoagulation with DOACs in ischaemic stroke associated with atrial fibrillation are justified to confirm the acceptable safety and efficacy of this strategy. Four such randomised controlled trials (collectively planned to include around 9000 participants) are underway, either using single cutoff timepoints for early versus late DOAC-administration initiation, or selecting DOAC-administration timing according to the severity and imaging features of the ischaemic stroke. The results of these trials should help to establish the optimal timing to initiate DOAC administration after recent ischaemic stroke and whether the timing should differ according to stroke severity. Results of these trials are expected from 2021.

In this multicenter, randomized trial, the administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment at 22 to 36 months of age than placebo and was associated with a higher rate of serious adverse events.

The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only. SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50–85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017. 513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6–60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0–5·8) with CEA plus BMT, 4·4% (2·2–8·6) with CAS plus BMT, and 3·1% (1·0–9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22–3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41–5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group. CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution. German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated. Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6–12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline. We pooled data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0·42, 95% CI 0·32–0·55, p<0·0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0·29, 0·20–0·42, p<0·0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0–2 weeks, two of 6691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5726 in the control group, HR 0·07, 95% CI 0·02–0·31, p=0·0004; at 0–6 weeks, 14 vs 60 participants, 0·19, 0·11–0·34, p<0·0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0·42, 0·26–0·70, p=0·0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6–12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0·97, 0·84–1·12, p=0·67; severity mRS shift OR 1·00, 0·77–1·29, p=0·97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0·90, 95% CI 0·65–1·25, p=0·53; mRS shift OR 0·90, 0·37–1·72, p=0·99), but dipyridamole did reduce risk thereafter (0·76, 0·63–0·92, p=0·005), particularly of disabling or fatal ischaemic stroke (0·64, 0·49–0·84, p=0·0010). We pooled data for 40 531 participants from three trials of aspirin versus control in major acute stroke. The reduction in risk of recurrent ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2–3 day HR 0·37, 95% CI 0·25–0·57, p<0·0001). Our findings confirm that medical treatment substantially reduces the risk of early recurrent stroke after TIA and minor stroke and identify aspirin as the key intervention. The considerable early benefit from aspirin warrants public education about self-administration after possible TIA. The previously unrecognised effect of aspirin on severity of early recurrent stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of dipyridamole have implications for understanding mechanisms of action. Wellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford.

Present mechanical devices are unable to achieve recanalisation in up to 20–40% of large vessel occlusion strokes. We compared efficacy and safety of the Trevo Retriever, a new stent-like device, with its US Food and Drug Administration-cleared predecessor, the Merci Retriever. In this open-label randomised controlled trial, we recruited patients at 26 sites in the USA and one in Spain. We included adults aged 18–85 years with angiographically confirmed large vessel occlusion strokes and US National Institutes of Health Stroke Scale (NIHSS) scores of 8–29 within 8 h of symptom onset. We randomly assigned patients (1:1) with sequentially numbered sealed envelopes to thrombectomy with Trevo or Merci devices. Randomisation was stratified by age (≤68 years vs 69–85 years) and NIHSS scores (≤18 vs 19–29) with alternating blocks of various sizes. The primary efficacy endpoint, assessed by an unmasked core laboratory, was thrombolysis in cerebral infarction (TICI) scores of 2 or greater reperfusion with the assigned device alone. The primary safety endpoint was a composite of procedure-related adverse events. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01270867. Between Feb 3, 2011, and Dec 1, 2011, we randomly assigned 88 patients to the Trevo Retriever group and 90 patients to Merci Retriever group. 76 (86%) patients in the Trevo group and 54 (60%) in the Merci group met the primary endpoint after the assigned device was used (odds ratio 4·22, 95% CI 1·92–9·69; psuperiority<0·0001). Incidence of the primary safety endpoint did not differ between groups (13 [15%] patients in the Trevo group vs 21 [23%] in the Merci group; p=0·1826). Patients who have had large vessel occlusion strokes but are ineligible for (or refractory to) intravenous tissue plasminogen activator should be treated with the Trevo Retriever in preference to the Merci Retriever. Stryker Neurovascular.

Aims This study aimed to evaluate the association between stress hyperglycemia ratio (SHR) and clinical outcomes at 90 days in acute ischemic stroke due to large vessel occlusion receiving endovascular treatment. Methods The RESCUE BT trial was a multicenter, randomized, double‐blind, placebo‐controlled clinical trial, consisting of 948 stroke patients from 55 centers in China. A total of 542 patients with glucose and glycated hemoglobin (HbA1C) values at admission were included in this analysis. SHR, measured by glucose/HbA1C, was evaluated as both a tri‐categorical variable (≤1.07 vs. 1.08–1.29 vs. ≥1.30) and a continuous variable. The primary outcome was a favorable functional outcome (modified Rankin Scale [mRS] score ≤2) at 90 days. The secondary outcome included excellent functional outcome (mRS score ≤1) and safety outcomes, such as 90‐day mortality and intracranial hemorrhage. The study was registered with Chictr.org.cn (ChiCTR‐INR‐17014167). Results Compared with patients in the lowest tertile of SHR, the highest tertile group had significantly lower odds of achieving favorable functional outcome of mRS score of 0–2 (adjusted odds ratio, 0.44; 95% confidence interval, 0.28–0.69; p < 0.001) and excellent clinical outcome of mRS score of 0–1 (adjusted odds ratio, 0.48; 95% confidence interval, 0.29–0.79; p = 0.004) at 90 days after adjusting for potential covariates. Similar results were observed after further adjustment for preexisting diabetes and Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Conclusion Stress hyperglycemia ratio, as measured by the glucose/HbA1C, was associated with a decreased odds of achieving a favorable functional outcome in patients with acute large vessel occlusion stroke at 90 days. Among patients with AIS‐LVO receiving EVT, those in the highest tertiles of SHR have the worst clinical outcomes, suggesting that stress hyperglycemia is associated with poor clinical functional outcome. So early implementation of glucose monitoring may delay stroke progression and improve clinical outcomes after AIS‐LVO.